Drugs - 2008, Vol 68, No.3

DRUGS 2008, Vol 68, No. 3

Drugs Issue Table of Contents 2008, Volume 68, Issue 3 Page # Article/Title

Current Opinion 259

Pharmacological Therapy for Female Sexual Dysfunction: Has Progress Been Made? Susan R Davis; Esme A Nijland

Therapy In Practice 265

Current and Future Therapeutic Options in the Management of Invasive Aspergillosis. Suganthini Krishnan-Natesan; Pranatharthi H Chandrasekar

Review Article 283

Treatment of Acute Severe Hypertension: Current and Newer Agents. Joseph Varon

299

Locally Advanced and Metastatic Gastric Cancer: Current Management and New Treatment Developments.· Kathryn Field; Michael Michael; Trevor Leong

319

Adult-Onset Still's Disease: Pathogenesis, Clinical Manifestations and Therapeutic Advances. Apostolos Kontzias; Petros Efthimiou

339

Drugs for Cardiovascular Disease Prevention in Women: Implications of the AHA Guidelines - 2007 Update. · Nanette K Wenger

Adis Drug Profile 359

Human Papillomavirus Types 16 and 18 Vaccine (Recombinant, AS04 Adjuvanted, Adsorbed) [Cervarix(TM)]. · Susan J Keam; Diane M Harper

373

Amlodipine/Valsartan: Fixed-Dose Combination in Hypertension. Greg L Plosker; Dean M Robinson

Adis Drug Evaluation 383

Sildenafil: A Review of its Use in Pulmonary Arterial Hypertension. Katherine F Croom; Monique P Curran

Drugs 2008; 68 (3): 259-264 0012-6667/08/0003-0259/$53.45/0

CURRENT OPINION

© 2008 Adis Data Information BV. All rights reserved.

Pharmacological Therapy for Female Sexual Dysfunction Has Progress Been Made? Susan R. Davis1 and Esme A. Nijland2 1 2

Women’s Health Program, Department of Medicine, Monash University, Prahran, Victoria, Australia Department of Sexuology and Psychosomatic Obstetrics/Gynaecology, Academic Medical Center, Hanzeplein 1, Groningen, The Netherlands

Abstract

The investigation of female sexual dysfunction (FSD) is an evolving area in which definitions and models for female sexual functioning are being continually reviewed and revised. The lack of consensus amongst experts in the field and regulating authorities regarding appropriate inclusion and exclusion criteria for FSD trials, and main outcome measures appropriate for the evaluation of drug interventions has somewhat hampered progression in this area. Nonetheless, there is evidence from randomized controlled trials that androgen therapy improves the quality of the sexual experience for postmenopausal women with low libido, and preliminary data that this may also apply to premenopausal women.

The study of female sexual dysfunction (FSD) has lagged behind research into male sexual health, resulting in very slow progress in the development of pharmacological therapy for FSD. Historically, the problem was that researchers tried to approach FSD from a male perspective, which has increasingly been acknowledged as inappropriate. The next limitation to emerge was the lack of a definition for ‘normal female sexual function’ and the continuous evolution of the definition of FSD. Furthermore, there is no gold standard self-assessment instrument for the evaluation of female sexual function and thus data of sexual behaviour across the adult female lifespan are lacking.

Available data indicate the most commonly reported sexual problems in women relate to desire, arousal, pleasure and global satisfaction. It has been proposed that each of these present different diagnoses and should be researched and treated differently.[1] However, for most women these problems are part of a continuum of the sexual experience and are inextricably related. Population-based studies indicate that the prevalence of sexual problems among women ranges from 9% to 43%.[2-5] However, the validity and reliability of these data is uncertain as epidemiological studies on female sexual function are constrained by the limited response rate, the limited use of validated instruments, and the lack of information

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about the duration and context of sexual problems.[6] The US FDA’s 2000 draft guidance document for FSD clinical trials recommends the use of the change in the frequency of successful satisfactory sexual events recorded in a daily diary as the primary endpoint and self-administered questionnaires as secondary endpoints.[7] Although this approach remains controversial,[6] it has been the primary approach adopted by the pharmaceutical industry investigating new therapies for FSD in order to meet the requirements set down by the FDA in 2000. Furthermore, inclusion and exclusion criteria for recruitment to the large randomized control trials (RCTs) of pharmacological agents for FSD indicate acknowledgement of the multi-factorial nature of FSD. Thus, in general, women with poor relationships, depression, ill health and other identifiable factors that may underpin their FSD have been excluded. Therefore, the positive findings from the published data are specific to the populations that have been studied and cannot be extrapolated to women with FSD complicated by other conditions. 1. Potential Approaches for Treating Female Sexual Dysfunction (FSD) Early research suggested some benefits of testosterone therapy for women[8,9] and these findings formed the basis of ad hoc administration of testosterone to women by individual practitioners. Subsequently, research approaches to the treatment of FSD have included primarily selective phosphodiesterase (PDE) inhibitors and androgen therapy, specifically testosterone. PDE5 inhibitors are effective in the treatment of male erectile dysfunction. Studies of the PDE5 inhibitor sildenafil in the treatment of symptoms of FSD suggest that this therapy may be useful for some women with genital arousal disorder rather than the larger group of women with low desire and subjective arousal.[10,11] Other subsets of women, such as women with type 1 diabetes mellitus, may also benefit.[12] However, large stud© 2008 Adis Data Information BV. All rights reserved.

ies of PDE5 inhibitors in the general population have been disappointing.[13] Similarly, studies of other agents, such as apomorphine and bupropion, have not as yet provided evidence of significant benefit and have been reviewed elsewhere.[13] 2. Tibolone for FSD Tibolone is a selective tissue estrogenic activity regulator. It is metabolized in the gastrointestinal tract to the 3α and 3β metabolites, which then circulate predominantly in their sulfated inactive forms. These metabolites become estrogenically active when desulfated in target tissues, such that tibolone is effective in the treatment of estrogen deficiency symptoms. Thus, the global effect of tibolone would be expected to be estrogenic. There are some data to suggest that tibolone may improve sexual function, particularly sexual desire and arousal, to a greater extent than traditional estrogenprogestogen therapy in healthy postmenopausal women. These effects have been attributed to (i) the intrinsic capacity of a tissue metabolite of tibolone (the ∆4-isomer) to activate the androgen receptor;[14] and (ii) the reduction in sex hormone binding globulin (SHBG) and hence the increase in bioavailable testosterone. Whether tibolone is more likely to restore sexual well-being than conventional or transdermal estrogen-progestogen therapy in postmenopausal women presenting with FSD was explored in a multicentre RCT. In this study, after exclusion of major study violators, sexual function improved in the tibolone group when compared with transdermal estrogen-progestogen therapy.[15] These data suggest that for postmenopausal women with FSD, a trial of tibolone therapy should precede initiation of testosterone with or without estrogen therapy. Over the last decade, a number of large RCTs have evaluated the use of testosterone therapy for postmenopausal women and, as a result, transdermal testosterone has been approved for the treatment of Drugs 2008; 68 (3)

Pharmacological Therapy for Female Sexual Dysfunction

estrogen-treated surgically menopausal women with hypoactive sexual desire disorder (HSDD) in Europe. Therefore, the remainder of this review focuses on the evidence for the use of testosterone in women. 3. Testosterone for the Treatment of Hypoactive Sexual Desire Disorder A Cochrane review of the earlier studies of the use of testosterone in postmenopausal women for low libido concluded that there are benefits in terms of improved sexual function with the addition of testosterone to standard postmenopausal hormone therapy.[16] Subsequent large RCTs in both surgically menopausal[17-19] and naturally menopausal women[20] for which the frequency of satisfactory sexual events was the primary endpoint, demonstrate that treatment with a transdermal testosterone patch, which delivers 300 µg of testosterone per day (but not a patch delivering 450 µg/day), significantly increased the number of self-reported sexually satisfying events per month when compared with placebo. These studies also demonstrated significant improvements in desire, arousal, responsiveness, orgasm, pleasure and satisfaction. An analysis of data from a number of these studies indicates that women with a SHBG level >160 nmol/L or who are taking concurrent conjugated equine estrogen (CEE) are unlikely to benefit from testosterone therapy.[21] The former is because testosterone binds to SHBG with high affinity; therefore, having an elevated SHBG results in a very low level of free or bioavailable testosterone. The interaction between CEE therapy and exogenous testosterone is unclear, but it may be that a component of CEE interferes with the binding of testosterone to the androgen receptor in addition to increasing SHBG. There is a paucity of data pertaining to the use of testosterone in premenopausal women. Testosterone levels decline in women prior to menopause and do © 2008 Adis Data Information BV. All rights reserved.

261

not appear to change across menopause; hence, women in their late reproductive years are just as likely to have low testosterone levels as women in their early menopausal years.[22,23] A small pilot, randomized, cross-over trial showed that premenopausal women treated with testosterone had significant improvements in sexual functioning and in well-being compared with placebo.[24] Subsequently, a larger RCT compared three different doses of transdermal testosterone with placebo and reported an increase in the frequency of the number of satisfactory sexual events in women treated with the middle dose of testosterone versus placebo.[25] The links between postmenopausal estrogen-progestogen use and both breast cancer and cardiovascular disease, have created a level of concern regarding any form of hormone use in women.[26] Testosterone has been widely used by women as an unapproved therapy for decades. There is no evidence from studies of premenopausal women or postmenopausal women using systemic estrogen treated with testosterone for up to 24 months, or studies of women with chronic androgen excess due to polycystic ovarian syndrome, that elevated testosterone levels, even above what is considered physiologically normal, are associated with altered breast cancer risk.[27,28] Primate and human studies suggest that testosterone may in fact protect the breast from estrogen-induced breast cell proliferation.[29-31] However, this is an area of considerable controversy that needs to be addressed in post-marketing surveillance research. There is also no evidence that in women without insulin resistance, testosterone adversely affects cardiovascular disease risk. We recently demonstrated that endogenous testosterone and the adrenal pre-androgens per se are not significant independent determinants of circulating cardiovascular disease risk markers (C-reactive protein and lipoprotein lipids).[32] However, uncertainty as to the consequences of restoring testosterone levels to those of premenopausal women in those Drugs 2008; 68 (3)

262

who are many years past menopause remains. Now that the testosterone patch has been approved for surgically menopausal women with HSDD despite estrogen therapy (other than CEEs) in Europe, these data will eventually be forthcoming from post-marketing-surveillance studies of women in the community. 4. Who to Treat A pragmatic concern is which women are candidates for pharmacotherapy for FSD? To date, no clinically applicable diagnostic algorithm has achieved acceptance. A low serum testosterone level is not predictive of a diagnosis of low libido nor does it predict likelihood of therapeutic response.[33] The assessment of a woman presenting with low sexual well-being requires a comprehensive clinical evaluation with a full history and physical examination. One must ascertain whether the woman has experienced a decline in sexual function from a previously satisfactory situation. Women who have never experienced satisfactory sexual function need to be assessed differently. Then, relationship issues, partner health, depression, personal social issues (e.g. children and work pressures) and adverse effects of other psychoactive therapies need to be considered. Menstrual and menopausal status must be evaluated and other potentially contributing conditions sought and, if identified, treated. These include estrogen deficiency, vaginismus, dyspareunia, thyroid disease and other systemic illnesses. If no clearly identifiable factor can be found in an otherwise healthy woman, whether she be premenopausal or postmenopausal, a trial of testosterone therapy might be considered. Women who have undergone premature ovarian failure or surgical menopause, or who have adrenal insufficiency or hypopituitarism, are known to have loss of androgen production and also merit consideration for treatment if they exhibit symptoms of sexual dysfunction. © 2008 Adis Data Information BV. All rights reserved.

Davis & Nijland

5. Current Therapeutic Choices As oral estrogen therapy tends to result in an increase in SHBG and hence lower free testosterone,[34] it would be worth while initially changing women from oral estrogen to transdermal therapy and reviewing after at least 3 months to evaluate whether this has resulted in an improvement in sexual interest. This approach seems to be least effective for women who have a low endogenous testosterone level prior to changing formulations. For postmenopausal women, tibolone, where available, should be considered as first-line therapy. As part of the efficacy of tibolone may reside in the reduction of SHBG and hence increase in free testosterone, it may be that women with very low testosterone levels, such as those who have had a surgical menopause, will benefit less. However, there is no clinical data to support this hypothesis. Tibolone should not be used by premenopausal women. Safety issues regarding tibolone and the breast have been raised in a large observational study.[35] However, strong treatment bias in this study make the findings uncertain. Transdermal testosterone patch therapy has only been approved in Europe for women who have undergone surgical menopause. Further large studies of testosterone in naturally menopausal women are currently underway and it is highly likely that the approval will eventually be extended to naturally menopausal women. There has been considerable clinical experience with the administration of testosterone implants in postmenopausal women and these are approved for use in women in the UK. These implants are fused crystalline implants, 4–5 mm in diameter, containing testosterone BP (British Pharmacopoeia) as the active ingredient. A dose of 50 mg is effective[36] and does not cause virilizing adverse effects. This dose can be obtained by bisecting a 100-mg implant under sterile conditions. The implant is inserted subcutaneously (under local anaesthesia), usually Drugs 2008; 68 (3)

Pharmacological Therapy for Female Sexual Dysfunction

into the lower anterior abdominal wall, using a trocar and cannula. This therapy provides a slow release of testosterone with an approximate duration of effect of 3–6 months for a 50-mg implant. There is marked individual variation in this period; therefore, testosterone levels must be carefully monitored, with a testosterone level measured prior to the administration of each subsequent implant. Other modes of delivery of testosterone, including transdermal gel, skin spray and nasal spray, are currently in the research pipeline. 6. Conclusions FSD remains a complex, controversial and under-researched clinical issue. Women experiencing FSD have the right to treatment with effective and safe therapeutic options. Progress in this field has been slow, such that testosterone remains the only treatment specifically approved for the treatment indication of FSD, and this approval is limited oophorectomised women and to European countries. However, there is widespread off-label use by women of testosterone products approved for men and extensive prescription of compounded testosterone products for women in clinical practice. One might conclude that an uncontrolled clinical trial of the safety of testosterone is ongoing in the community. Acknowledgements Dr Davis is a consultant to Acrux Australia Ltd, and an investigator for Procter and Gamble and Acrux Australia. Dr Nijland has no conflicts of interest that are directly relevant to the content of this review. No sources of funding were used in the preparation of this review.

References 1. Basson R, Leiblum S, Brotto L, et al. Revised definitions of women’s sexual dysfunction. J Sex Med 2004; 1 (1): 40-8 2. Laumann E, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999; 281: 531-44

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3. Fugl-Meyer AR, Fugl-Meyer KS. Sexual disabilities, problems and satisfaction in 18 to 74-year-old Swedes. Scan J Sexology 1999; 2 (2): 79-105 4. Fugl-Meyer KS, Arrhult H, Pharmanson H, et al. A Swedish telephone help-line for sexual problems: a 5-year survey. J Sex Med 2004; 1 (3): 278-83 5. Mercer CH, Fenton KA, Johnson AM, et al. Sexual function problems and help seeking behaviour in Britain: national probability sample survey. BMJ 2003; 327 (7412): 426-7 6. Nijland E, Davis S, Laan E, et al. Female sexual satisfaction and pharmaceutical intervention: a critical review of the drug intervention studies in female sexual dysfunction. J Sex Med 2006; 3 (5): 763-77 7. US Food and Drug Administration. FDA guidance document, guidance for industry. Female sexual dysfunction: clinical development of drug products for treatment. Washington, DC: US FDA, 2000 8. Studd JWW. Oestradiol and testosterone implants in the treatment of psychosexual problems in postmenopausal women. Br J Obstet Gynaecol 1977; 84: 314-8 9. Sherwin BB, Gelfand MM. Sex steroids and affect in the surgical menopause: a double blind, cross-over study. Psychoneuroendocrinology 1985; 10 (3): 325-35 10. Berman JR, Berman LA, Toler SM, et al. Safety and efficacy of sildenafil citrate for the treatment of female sexual arousal disorder: a double-blind, placebo controlled study. J Urol 2003; 170 (6 Pt 1): 2333-8 11. Basson R, Brotto LA. Sexual psychophysiology and effects of sildenafil citrate in oestrogenised women with acquired genital arousal disorder and impaired orgasm: a randomised controlled trial. BJOG 2003; 110 (11): 1014-24 12. Caruso S, Rugolo S, Mirabella D, et al. Changes in clitoral blood flow in premenopausal women affected by type 1 diabetes after single 100-mg administration of sildenafil. Urology 2006; 68 (1): 161-5 13. Carey JC. Pharmacological effects on sexual function. Obstet Gynecol Clin North Am 2006; 33 (4): 599-620 14. Kloosterboer H. Tibolone: a steroid with tissue-specific mode of action. J Steroid Biochem Mol Biol 2001; 76: 231-8 15. Nijland E, Weijmar Schultz WCM, Nathorst-Boos J, et al. Tibolone and transdermal E2/NETA for the treatment of female sexual dysfunction in naturally menopausal women: results of a randomized active-controlled trial. J Sex Med. In press 16. Somboonporn W, Davis S, Seif M, et al. Testosterone for periand postmenopausal women. Cochrane Database Syst Rev 2005; (4): CD004509 17. Buster JE, Kingsberg SA, Aguirre O, et al. Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet Gynecol 2005; 105 (5): 944-52 18. Braunstein G, Shifren J, Simon J, et al. Testosterone patches for the treatment of low sexual desire in surgically menopausal women. Proceedings of the 14th Annual Meeting of the North American Menopause Society; 2003 Sep 17; Miami Beach (FL) 19. Davis SR, van der Mooren MJ, van Lunsen RHW, et al. The efficacy and safety of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal

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20.

21.

22.

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26.

27. 28.

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women: a randomized, placebo-controlled trial. Menopause 2006; 13 (3): 387-96 Shifren J, Davis SR, Moreau M, et al. Testosterone patch for the treatment of hypoactive sexual desire disorder in naturally menopausal women: results from the INTIMATE NM1 study. Menopause 2006; 13 (5): 770-9 Procter and Gamble Pharmaceuticals I. Intrinsa® (testosterone transdermal system). NDA No. 21-769. In: Drugs ACfRH, ed. Vol. 2006. Washington DC: US Food and Drug Administration, 2006 Davison SL, Bell R, Donath S, et al. Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 2005; 90 (7): 3847-53 Burger HG, Dudley EC, Cui J, et al. A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrinol Metab 2000; 85 (8): 2832-8 Goldstat R, Briganti E, Tran J, et al. Transdermal testosterone improves mood, well being and sexual function in premenopausal women. Menopause 2003; 10 (5): 390-8 Davis SR, Papalia MA, Norman RJ, et al. Effect of transdermal testosterone (T) on sexual function in premenopausal women with low libido: a placebo-controlled, randomised, parallel, dose-ranging study. Proceeding of the 9th Congress of the Australasian Menopause Society; 2005 Sep 22-24; Gold Coast (QLD) Rossouw J, Anderson G, Prentice R, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative Randomised Controlled Trial. JAMA 2002; 288 (3): 321-33 Somboonporn W, Davis S. Testosterone and the breast: therapeutic implications for women. Endocr Rev 2004; 25: 374-88 Wild S, Pierpoint T, Jacobs H, et al. Long-term consequences of polycystic ovary syndrome: results of a 31 year follow-up study. Hum Fertil (Camb) 2000; 3 (2): 101-5

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29. Zhou J, Ng S, Adesanya-Famuiya O, et al. Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression. FASEB J 2000 Sep; 14 (12): 1725-30 30. Dimitrakakis C, Zhou J, Bondy CA. A physiological role for testosterone in limiting primate mammary epithelial proliferation in vivo. Climacteric 2002; 5 (S1): 137 31. Hofling M, Hirschberg AL, Skoog L, et al. Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in postmenopausal women. Menopause 2007; 14 (2): 183-90 32. Bell RJ, Davison SL, Papalia MA, et al. Endogenous androgen levels and cardiovascular risk profile in women across the adult life span. Menopause 2007; 14 (4): 630-8 33. Davis S, Davison S, Donath S, et al. Circulating androgen levels and self-reported sexual function in women. JAMA 2005; 294 (1): 91-6 34. Davison S, Davis SR. Hormone replacement therapies: current controversies. Clin Endocrinol 2003; 58 (3): 249-61 35. Beral V, for the Million Women Study Collaborators. Breast cancer and hormone replacement therapy in the million women study. Lancet 2003 Aug 9; 362 (9382): 419-27 36. Davis SR, McCloud PI, Strauss BJG, et al. Testosterone enhances estradiol’s effects on postmenopausal bone density and sexuality. Maturitas 1995; 21: 227-36

Correspondence: Dr Susan R. Davis, Women’s Health Program, Department of Medicine, Central and Eastern Clinical School, Monash Medical School, Alfred Hospital, Commercial Road, Prahran, VIC 3181, Australia. E-mail: [email protected]

Drugs 2008; 68 (3)

Drugs 2008; 68 (3): 265-282 0012-6667/08/0003-0265/$53.45/0

THERAPY IN PRACTICE

© 2008 Adis Data Information BV. All rights reserved.

Current and Future Therapeutic Options in the Management of Invasive Aspergillosis Suganthini Krishnan-Natesan1,2 and Pranatharthi H. Chandrasekar1 1 2

Department of Internal Medicine, Division of Infectious Diseases, Wayne State University School of Medicine, Detroit, Michigan, USA Department of Medicine, Division of Infectious Diseases, John D. Dingell VA Medical Center, Detroit, Michigan, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 1. Diagnosis of Invasive Pulmonary Aspergillosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266 2. Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268 2.1 Definitive Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268 2.2 Prophylactic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 2.3 Empirical Antifungal Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 2.4 Pre-Emptive Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 2.5 Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 2.6 Salvage Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 2.7 Role of Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 3. Future Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 3.1 Antifungal Agents in the Pipeline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 3.2 Immunomodulatory Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 3.2.1 Recombinant T Helper Cell Type 1 Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 3.2.2 Donor Granulocyte Transfusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 3.2.3 Recombinant Growth Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 3.2.4 Pentraxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 3.2.5 Pathogen-Specific Immune Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 3.3 Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 4. Antifungal Drug Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279

Abstract

The past decade has witnessed significant progress in the management of invasive aspergillosis. Potent, relatively non-toxic antifungal drugs, data on early chest CT scanning and the availability of a non-invasive diagnostic test (serum galactomannan) are the key advances; among these, the contribution of the recently available drugs is the most significant. Safer and earlier intervention resulting in reduced mortality and improved outcome is being demonstrated. Newer strategies enable clinicians to provide drug therapy in a highly targeted manner, such that empirical use of antifungal drugs may decline. Voriconazole has become the drug of choice for primary therapy, while posaconazole shows

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promise as a prophylactic drug. Echinocandins are effective for salvage therapy and are under evaluation for primary therapy. Preliminary data for efficacy of combination therapy with a mould-active azole plus an echinocandin are of promise and clinical trials are under way. Reports of emergence of less-susceptible Aspergillus spp. during azole therapy are of concern and close monitoring is needed. Remarkably, the era of polyenes appears to be nearing the end in the therapy of invasive aspergillosis. The promise of newer classes of drugs, immunemodulating therapies and vaccines are exciting future additions to the arsenal against invasive aspergillosis.

Aspergillosis comprises a wide variety of manifestations, the principal entities being acute invasive forms, notably pulmonary disease with or without dissemination, and chronic forms, namely chronic necrotizing aspergillosis, pulmonary/sinus aspergilloma (fungal balls) and allergic bronchopulmonary aspergillosis. Although several species of Aspergillus have been reported as human pathogens, A. fumigatus is the most common aetiological agent of aspergillosis followed by A. flavus (table I);[1] the organs primarily affected being the lungs and the sinuses. The most devastating infection in immunocompromised (cancer/transplant) patients is the invasive form with a 357% increase in mortality rates reported in the US between 1980 and 1997.[2] This trend is probably related to the increased number of Table I. Characteristics of various pathogenic Aspergillus spp. Species

Frequency in clinical infection (%)

Clinical significance

A. fumigatus

65

Most common cause of IPA. Resistance to triazoles reported

A. flavus

14

Frequent cause of sinusitis and skin infections. Resistance to triazoles reported

A. niger

5

Role in invasive infections less well established. Less pathogenic probably because larger conidia do not reach the alveoli

A. terreus

5

Usually susceptible to triazoles. Increasing reports of resistance to amphotericin B. Blood cultures may be positive

A. ustus

1

Intrinsically higher MIC values (resistance) to triazoles and polyenes IPA = invasive pulmonary aspergillosis; MIC = minimum inhibitory concentration.

© 2008 Adis Data Information BV. All rights reserved.

individuals at risk of the infection as a result of advances in modern medicine, such as bone marrow and solid organ transplantation, and prolonged survival of critically ill and susceptible patients. In addition, the aging of the population has increased the number of susceptible individuals. The number of patients undergoing transplantation has vastly increased in recent years. Transplant recipients are among the most significant subgroups of immunosuppressed hosts at risk for invasive aspergillosis.[2-4] Transplantation practices, immunosuppressive regimens and the characteristics of patients undergoing transplantation have continued to evolve. Current data show that invasive aspergillosis in stem cell recipients now predominantly occurs late after engraftment in non-neutropenic patients in whom graft-versus-host disease (GVHD) and its management with increasingly intense immunosuppression have emerged as major risk factors.[5] Despite the heightened awareness of the profiles of patients at risk for invasive aspergillosis and a number of therapeutic options today (table II),[6] the mortality rate remains high. High mortality from invasive aspergillosis has been due to compromised host immunity, delayed diagnosis and the limited availability of safe and effective antifungal drugs.[7] 1. Diagnosis of Invasive Pulmonary Aspergillosis This section is a brief overview of the recent advances in the diagnostic techniques of invasive aspergillosis. For a detailed discussion, the reader is referred to a review by Hope et al.[8] Drugs 2008; 68 (3)

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Table II. An overview of antifungal drugs approved for invasive aspergillosis[6] Drug

Absorption/protein binding

Metabolism

Mechanism of action

Triazoles Voriconazole

Bioavailability 96%; food ↓ absorption; not pH dependent; CYP3A4, CYP2C9/19 ≈60% protein binding Excreted in bile and stools Good CNS concentrations

Posaconazole

No IV formulation; food with fat ↑ absorption; not pH dependent; bioavailability 96%; ≈98% protein binding Good CNS concentrations

CYP3A4 only Excreted in bile and stools

Itraconazole

IV not pH dependent Oral pH dependent; food ↑ absorption; bioavailability 55%; ≈99.8% protein binding Minimal CNS concentrations

CYP3A4 only Excreted in bile and stools

Significant protein binding Minimal to undetectable CNS concentrations Tissue concentrations are unknown

No CYP metabolism N-acetylation in liver Eliminated in bile and stools (35%), urine (41%)

Inhibit lanosterol demethylase

Echinocandins Caspofungin

Micafungin

Hepatic-aryl sulfatase, COMT and hydroxylation Eliminated in stools

Anidulafungin

Chemical degradation to a ringopened peptide that lacks antifungal activity

Inhibit 1,3-β-Dglucan

Polyenes AMB deoxycholate AMB colloidal dispersion Liposomal AMB AMB lipid complex

AMB deoxycholate and liposomal AMB have significant No CYP metabolism Bind to ergosterol protein binding Metabolism pathway unclear resulting in CNS concentrations of liposomal AMB are more than membrane pores deoxycholate, lipid complex and colloidal dispersion AMB Peak concentrations in liver, spleen and lung Excreted in urine and stools AMB = amphotericin B; COMT = catechol-O-methyl transferase; CYP = cytochrome P450 enzyme; IV = intravenous; ↑ indicates increase; ↓ indicates decrease.

The lack of reliable and non-invasive diagnostic procedures remains a major obstacle in the successful early intervention of invasive pulmonary aspergillosis. Clinical signs and symptoms are non-specific, culture and microscopy of lower respiratory tract specimens have a low sensitivity, and tissue for histopathological examination is not easy to obtain because of the frequent presence of thrombocytopenia and coagulation abnormalities. Thus, most clinical cases of invasive pulmonary aspergillosis are classified as possible or probable infections in view of the diagnostic difficulty. In recent years, efforts have been directed towards identifying noninvasive markers for rapid and reliable diagnosis of invasive aspergillosis. In particular, tests based on identifying fungal antigens or metabolites released into the circulation have become available. © 2008 Adis Data Information BV. All rights reserved.

Galactomannan is a polysaccharide cell wall component of Aspergillus spp. that is released into the circulation during fungal growth in the tissues.[9] The double-sandwich, enzyme-linked immunosorbent assay, which can detect galactomannan, is a useful tool for the early diagnosis of Aspergillus infection. Studies evaluating the role of galactomannan assay in the diagnosis of invasive aspergillosis have largely been conducted with patients undergoing cancer chemotherapy or haematopoietic stem cell transplantation (HSCT) recipients. In these patients, a sensitivity of 67–100% and a specificity of 86–98.8% has been documented. When serially monitored, the galactomannan test preceded the diagnosis of invasive aspergillosis by an average of 6–14 days. False positives with this assay are not Drugs 2008; 68 (3)

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uncommon; cross-reactivity of Platelia™ 1 Aspergillus galactomannan enzyme immunoassay (EIA) with Penicillium spp. and bacteria, such as Bifidobacterium spp., has been noted but is deemed to be of little clinical relevance as these are rarely pathogens in humans.[5,10] The use of antifungal agents may lower the sensitivity of the galactomannan assay by decreasing the fungal load. Use of piperacillin/tazobactam and amoxicillin/clavulanic acid may result in a false-positive test for galactomannan.[11] The timing of collection of the sample may influence the test results, with false-positive results being less likely in samples collected at trough concentrations or prior to the administration of the dose. Despite the shortcomings of the test, galactomannan antigen testing is under active scrutiny for the diagnosis of invasive aspergillosis, especially in the transplant population. 1,3-β-D-Glucan is an integral component of the cell walls of a number of pathogenic yeasts and filamentous fungi. In addition to aspergillosis and candidiasis, it may be detected in infections caused by less common fungi (e.g. Fusarium, Trichosporon, Acremonium and Saccharomyces spp.). The sensitivity and specificity of the test has ranged from 67% to 100% and 84% to 100%, respectively.[10] Polymerase chain reaction (PCR)-based molecular diagnostic tests for Aspergillus are not commercially available and remain largely nonstandardized. Such assays, when performed on blood or bronchoalveolar lavage samples, have shown a negative predictive value for invasive aspergillosis ranging from 92% to 99%. PCR results are usually positive when the galactomannan assay is highly positive; 12 of 20 PCR assays that yielded a positive result were observed in association with high galactomannan values.[12] A prospective comparison of real-time PCR, galactomannan and 1,3-β-D-glucan assays as weekly screening for invasive aspergillosis in patients with haematological disorders showed that the galactomannan test was relatively more sensitive in predicting the diagnosis.[12] 1

Chest radiographic findings are not sensitive and a high-resolution chest CT scan is the preferred method to detect early changes of invasive pulmonary aspergillosis; radiographic contrast is not required. However, the radiological signs (halo sign and air crescent sign) are not specific and other entities may mimic invasive pulmonary aspergillosis.[13] 2. Management 2.1 Definitive Therapy

The drugs currently approved for the primary management of invasive aspergillosis include amphotericin B deoxycholate (conventional formulation) and voriconazole;[14-16] echinocandins are also under investigation[17] (table II). Amphotericin B has been the gold standard for the treatment of invasive aspergillosis for many decades; however, its toxicities, particularly renal toxicity, are well known. The therapeutic advantages of amphotericin B include excellent fungicidal activity, rapid clearance of organisms from tissue and the paucity of emergence of resistant organisms.[6] The landmark study that led to the approval of voriconazole for the primary treatment of invasive aspergillosis was published in 2002 by Herbrecht et al.[18] The study was performed in patients with haematological malignancy, including those who underwent HSCT. This randomized, open-label trial evaluated 144 patients in the voriconazole group and 133 patients in the amphotericin B deoxycholate group. Patients were followed for a period of 12 weeks; at the end of the study period, the clinical response rate was 52.8% among voriconazole recipients (complete response in 20.8% and partial response in 31.9%) and 31.6% among amphotericin B recipients (complete response in 16.5% and partial response in 15%). There was a significant difference in drug adherence between the two groups; 62 of 144 patients in the voriconazole arm continued to take the drug, compared with only 2 of 133 patients in the amphotericin B arm, reflecting poor tolerance

The use of trade names is for identification purposes only and does not imply endorsement.

© 2008 Adis Data Information BV. All rights reserved.

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Management of Invasive Aspergillosis

to the latter drug. The difference in survival rate at the end of 12 weeks was statistically significantly between the two groups, with 71% and 58% surviving in the voriconazole and amphotericin B arms, respectively. Similar results were observed in the intent-to-treat population that included all randomized patients. Since the publication of this study, voriconazole is widely accepted as the drug of first choice for the treatment of invasive aspergillosis. Whether initial therapy with higher than standard doses (3–5 mg/kg) of a lipid form of amphotericin B would have a better outcome has been debated. A recent, randomized, double-blind, prospective trial (AmBiLoad Trial) compared the safety and efficacy of a high-dose regimen of liposomal amphotericin B versus the standard dose as initial therapy for invasive aspergillosis. The standard-dose group received 3 mg/kg/day and the high-dose group received 10 mg/kg/day of liposomal amphotericin B for 14 days, followed by 3 mg/kg/day in both groups. The favourable response to treatment at 12 weeks was similar in both study groups: 50% with the standard dose and 46% with the high dose. Survival rate at 12 weeks was similar as well, with 72% and 59% with the standard-dose and high dose-regimens, respectively. Nephrotoxicity occurred in 14% of the standard-dose group versus 31% of the highdose group (p < 0.02). The authors concluded that there was no beneficial effect with administration of a high loading dose of liposomal amphotericin B and, in fact, the high dose was associated with an increased risk of nephrotoxicity.[19] In an analysis of 85 allogeneic HSCT recipients (78% with invasive aspergillosis) treated with amphotericin B lipid complex, the overall response rate was 41%, with a 44% response in patients with GVHD.[20] These results are comparable to those achieved with other available drugs. With its better tolerability, voriconazole is preferred to amphotericin B or its lipid formulations.[21] It is to be noted that the efficacy of voriconazole has not been compared with that of a lipid formulation of amphotericin B and such a study is unlikely to be performed. Amphotericin B, either conventional or a lipid formulation, may be preferred to vori© 2008 Adis Data Information BV. All rights reserved.

269

conazole in certain situations as follows: (i) previous use of a mould-active drug for prophylaxis or empiric therapy; (ii) concomitant use of drugs with major interactions with voriconazole, such as sirolimus, rifampin or warfarin; (iii) presence of significant hepatic impairment; (iv) high suspicion for zygomycosis; or (v) the presence of cardiac risk factors such as prolonged QT interval and cardiomyopathy. Echinocandins have undergone very limited evaluation as first-line therapy for invasive aspergillosis. The study by Candoni et al.[17] reported 32 patients with haematological malignancies who received caspofungin as primary or first-line therapy for probable or proven aspergillosis. Most patients (97%) were neutropenic and had pulmonary localization. All patients with neutropenia (97%) received granulocyte colony-stimulating factor (GCSF) in addition to caspofungin. The overall response rate was 56%, with neutrophil recovery and stable haematological disease (remission) associated with a favourable response rate. A small proportion of patients who had partial response were rescued with voriconazole. The second study by Denning et al.[14] evaluated the efficacy of micafungin alone or in combination with other antifungal agents. Although there were 331 patients enrolled in the study, the group that received micafungin alone was small (23 patients) and the response rate was 50% in that group. Although echinocandins appear promising, monotherapy with echinocandins for invasive aspergillosis is not recommended pending data from definitive studies. With the established diagnosis of invasive aspergillosis, primary therapy must be initiated with voriconazole. With clinical and radiological improvement, therapy is continued for a period of at least 3 months. Lack of response or progression of infection could be secondary to host factors or drug failure. If drug failure is suspected, switching to a different class of antifungal agents or addition of a second agent (i.e. echinocandin) has become a common clinical practice. In situations where there is a concern with the pharmacokinetics (specifically, drug absorption), the drug concentration should be Drugs 2008; 68 (3)

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Invasive aspergillosis

Start voriconazole (second choice is a lipid formulation of amphotericin B)

Improvement - clinical - radiological - immunological

Yes

No improvement or progression of infection

Continue therapy (duration: 3 months or longer)

Host factors

1. Decrease immunosuppression 2. Surgical debridement 3. Immunomodulation

+/–

Drug failure

1. Check voriconazole concentrations 2. Change drug therapy to an echinocandin or a lipid amphotericin 3. Add an echinocandin

Fig. 1. An algorithm for the clinical management of invasive aspergillosis.

obtained and the dose of voriconazole adjusted accordingly (figure 1). 2.2 Prophylactic Therapy

Institution of therapy for aspergillosis in a highrisk patient without any clinical and/or radiological evidence or history of aspergillosis is considered primary prophylaxis. Several factors should be considered prior to initiating prophylactic therapy, including the frequency and outcome of infection, difficulty with early diagnosis, drug efficacy, drug interactions, safety and cost. The antifungal drugs that may be effective as prophylaxis against invasive aspergillosis include itraconazole, voriconazole, posaconazole, conventional or lipid formulations of amphotericin B, caspofungin, micafungin and anidulafungin (table II).[6] Mattiuzzi et al.[22] performed a randomized, open-label trial to compare the efficacy and safety of liposomal amphotericin B versus an unusual com© 2008 Adis Data Information BV. All rights reserved.

bination (fluconazole plus itraconazole) as prophylaxis against invasive fungal infections in patients undergoing induction chemotherapy for newly diagnosed acute myelogenous leukaemia or myelodysplastic syndrome. A total of 49% of the liposomal amphotericin B group and 48% of the fluconazole plus itraconazole group completed prophylactic therapy and the azole combination, as expected, had a better tolerability profile. There was no difference observed in the incidence of infection or the mortality rates between the two groups. The concept of using two azoles simultaneously for prophylaxis may not be appealing to most clinicians. A meta-analysis of 13 randomized controlled trials compared the efficacy of itraconazole versus fluconazole for the primary prophylaxis of invasive fungal infections in neutropenic patients with haematological malignancies. The study assessed 3597 patients and concluded that itraconazole significantly decreased the incidence of and mortality from invasive fungal infections. A statistically sigDrugs 2008; 68 (3)

Management of Invasive Aspergillosis

nificant reduction (48 ± 21%) in the incidence of invasive aspergillosis was observed in the itraconazole (solution) group. Importantly, the authors noted that the effect of prophylaxis was dependent on the pharmacokinetics and oral bioavailability of itraconazole.[23] The solution is preferred to the capsule formulation and the frequent drug-drug interactions with itraconazole make it a not-so-desirable drug.[6] Two clinical trials have compared the prophylactic efficacy of fluconazole versus itraconazole against invasive fungal infections in patients undergoing allogeneic HSCT. The earlier study by Winston and colleagues[24] involved 138 patients who received either itraconazole or fluconazole prophylaxis and were followed for a period of 180 days post-HSCT. In this relatively small study, itraconazole prevented more invasive fungal infections than fluconazole, probably because of the efficacy of the former drug against invasive moulds. The second trial by Marr et al.[25] found no difference between the efficacies of fluconazole and itraconazole during the study period; however, in a subset of patients who tolerated itraconazole, fewer patients developed invasive mould infection while receiving prophylaxis. The trial had to be terminated because of the high incidence of adverse effects (renal and hepatic toxicities) reported in the itraconazole group, which were perhaps due to a larger than standard dose of itraconazole (200 mg three times daily) that was administered. Recently, Cornely and colleagues[26] compared the prophylactic efficacy of posaconazole and either fluconazole or itraconazole in patients with prolonged neutropenia in the setting of acute myelogenous leukaemia or myelodysplastic syndrome. In this randomized multicentre study, a total of 304 patients received posaconazole and 298 patients received fluconazole (240 patients) or itraconazole (58 patients). Proven or probable invasive fungal infections were reported in 7 patients (2%) in the posaconazole group and in 25 patients (8%) in the fluconazole or itraconazole group; the difference was statistically significant. Posaconazole reduced the number of invasive fungal infections and improved survival, with an all-cause mortality rate of © 2008 Adis Data Information BV. All rights reserved.

271

16% in the posaconazole group versus 22% in the standard azole group (p = 0.048). Posaconazole was superior to fluconazole and itraconazole as prophylaxis treatment against invasive aspergillosis and was as well tolerated as the other two drugs. As GVHD is a significant risk factor for invasive aspergillosis in HSCT recipients, Ullmann et al.,[27] in an randomized, double-blind international trial, compared the prophylactic efficacy of posaconazole (301 patients) versus fluconazole (299 patients) in this population. At the end of the fixed 112-day treatment period, posaconazole was found to be as effective as fluconazole in preventing all invasive fungal infections (5.3% vs 9%; p = 0.07) but was superior to fluconazole in the prevention of invasive aspergillosis (2.3% vs 7%; p = 0.006) and was associated with a lower incidence of breakthrough fungal infections (2.4% vs 7.6%; p = 0.004), particularly invasive aspergillosis (1% vs 5.9%; p = 0.001). In summary, while itraconazole has lost its appeal in view of its unfavourable adverse effect profile, posaconazole appears to be an effective prophylactic drug in high-risk patients and data for voriconazole are awaited. Lack of an intravenous formulation of posaconazole at the present time is a drawback, particularly in cancer and transplant patients with gastrointestinal abnormalities. Additionally, drug interactions involving azoles remain a significant concern. Echinocandins are attractive agents for prophylaxis, as they have good anti-Aspergillus activity and have an excellent adverse effect profile with minimal drug interactions. Caspofungin has been evaluated as a prophylactic agent in comparison with intravenous itraconazole in patients undergoing induction chemotherapy for high-grade myelodysplastic syndrome or acute myelogenous leukaemia. There was no significant difference in the incidence of invasive fungal infections in the two groups (5 of 86 in the itraconazole group and 7 of 106 in the caspofungin group).[28] Van Burik et al.[29] compared the prophylactic efficacy of micafungin with fluconazole against invasive fungal infections during preengraftment neutropenia in patients undergoing Drugs 2008; 68 (3)

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HSCT. Both drugs had comparable efficacy in the prevention of candida infection. However, there were few patients with invasive aspergillosis because the study was conducted during the relatively short pre-engraftment neutropenic period. The disadvantages of echinocandins include the lack of an oral formulation and their relatively narrow spectrum of activity. There are no data addressing the issue of how long the prophylaxis should continue and so clinicians frequently opt to provide chemoprophylaxis during long periods of intense immunosuppression (e.g. neutropenia or GVHD treated with high-dose corticosteroids). The term ‘secondary prophylaxis’ is used when the drug is administered to patients previously treated for invasive aspergillosis but who are still at risk because of continued immunosuppression. A common example is a patient who has a history of aspergillosis and is receiving reinduction chemotherapy for relapsed leukaemia. Voriconazole has largely replaced the use of itraconazole or a polyene for secondary prophylaxis. A retrospective review by Martino et al.[30] analysed the outcome of 129 patients with a history of invasive aspergillosis who underwent allogeneic HSCT, of whom 57 (44%) received a reduced-intensity conditioning. Overall, 27 patients with invasive aspergillosis relapsed or recurred after the allogeneic HSCT (cumulative incidence at 2 years of 22%). Antifungal drugs used for prior therapy included liposomal amphotericin B, amphotericin B lipid complex, caspofungin and voriconazole. Since several different strategies of drug therapy were used for secondary antifungal prophylaxis during conditioning and post-transplantation follow-up, it was difficult to identify differences among specific strategies. However, a subset analysis showed that the use of voriconazole for secondary prophylaxis reduced the risk of progression of invasive aspergillosis (12% in 31 voriconazole recipients compared with 22% in the remaining 98 patients; p < 0.15). © 2008 Adis Data Information BV. All rights reserved.

Krishnan-Natesan & Chandrasekar

2.3 Empirical Antifungal Therapy

Empirical treatment is antifungal therapy provided to high-risk patients with signs and symptoms suggestive of invasive fungal infection, such as patients with neutropenia and fever unresponsive to broad-spectrum antibacterials. The difficulties associated with the early diagnosis of invasive fungal infections led to the introduction of empirical antifungal therapy in the early 1980s. The scientific rationale for such treatment was based on two prospective randomized trials. The first trial, with a modest number of patients, concluded that empirical antifungal therapy resulted in a lower incidence of invasive fungal infections, particularly invasive candidiasis.[31] The second larger EORTC (European Organisation for Research and Treatment of Cancer) trial assessed the role of adding empirical antifungal therapy to antibacterial therapy after 4 days of persistent febrile neutropenia in 132 patients. The clinical response rate in the amphotericin B arm was 69% versus 53% in the control group. There were six (9%) documented fungal infections in the control group and one (1%) in the amphotericin B group. No fungal-related deaths occurred in the amphotericin B group compared with four (6%) in the control group (p = 0.05).[32] Although the emphasis in these trials was on invasive candidiasis, they paved the way for further studies in empirical therapy for invasive aspergillosis.[33] Subsequently, there have been several trials that have evaluated empirical therapy with different antifungal drugs. Either liposomal or conventional amphotericin B was compared with different antifungal drugs: fluconazole,[34-37] itraconazole,[38] voriconazole[39-41] or caspofungin.[42,43] Most trials have used composite endpoints. Excluding the toxicities associated with the conventional amphotericin B preparation, similar outcomes were observed with liposomal or conventional amphotericin B with respect to clinical response, survival and the number of cases of breakthrough aspergillosis. Itraconazole was found to be as effective as amphotericin B when used for empirical therapy in patients with cancer and persistent febrile neutropenia, although significant nephrotoxicity was seen in the Drugs 2008; 68 (3)

Management of Invasive Aspergillosis

latter group.[38] More recently, voriconazole failed to meet the pre-specified non-inferiority criteria in a prospective, randomized, open-label, multicentre, international trial, when compared with liposomal amphotericin B. When defervescence, a less sensitive endpoint, was removed from the composite endpoint, results with voriconazole were improved.[39] Walsh et al.[42] have showed caspofungin to be as effective and better tolerated than liposomal amphotericin B for empirical therapy of patients with persistent febrile neutropenia. Importantly, a meta-analysis of 24 randomized trials published in 1997 has questioned the role of empirical antifungal therapy in the management of patients with persistent febrile neutropenia.[44] It is clear that antifungal drugs, when given empirically, are frequently administered to a large number of patients with no fungal infection. With the availability of non-invasive diagnostic markers (e.g. chest CT scan and serum galactomannan antigen test), it is anticipated that the high-risk patients can be better identified and hence empirical therapy may decline in clinical practice. 2.4 Pre-Emptive Therapy

Pre-emptive therapy for invasive aspergillosis is gaining momentum with the availability of the galactomannan antigen test for invasive aspergillosis. This strategy is a risk-based intervention for high-risk patients with persistent febrile neutropenia plus the presence of other evidence of invasive fungal infection, such as positive surveillance cultures, radiological features or a positive galactomannan antigen test.[45] The concept of preemptive therapy for invasive aspergillosis is akin to the utilization of antigen/PCR measurement for cytomegalovirus (CMV) infection in transplant patients. On the basis of the currently available diagnostic tests, pre-emptive therapy is considered appropriate in the setting of compatible radiological findings and antigen tests in high-risk patients. However, the false positives/negatives associated with the galactomannan antigen test and the nonstandardized PCR techniques make it difficult for a reliably uniform pre-emptive approach.[8] © 2008 Adis Data Information BV. All rights reserved.

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A recent study by Maertens and colleagues[46] assessed the value of pre-emptive therapy in patients with acute leukaemia or allogeneic HSCT and persistent febrile neutropenia, based on serum galactomannan antigen test results. A total of 88 patients received prophylactic therapy with fluconazole and were followed with daily serum galactomannan testing and thorax CT scans if needed. Liposomal amphotericin B was instituted as pre-emptive therapy in patients with positive galactomannan tests or compatible radiological findings with culture or histopathological confirmation. A total of 19 patients had proven or probable invasive aspergillosis. Overall, 35% of patients met criteria for empirical therapy (i.e. persistent febrile neutropenia), whereas only 7% of patients received therapy based on the preemptive strategy; there was a 78% reduction in the use of antifungal agents between the two strategies. It is noteworthy that the galactomannan antigen test could be falsely negative in the presence of circulating Aspergillus antibodies or in patients receiving anti-Aspergillus drugs for prophylactic or empirical therapy; the test could be falsely positive in patients receiving β-lactam drugs (e.g. piperacillin/tazobactam).[11] Lin et al.[47] used a PCR screening assay with panfungal primers for the early detection of invasive fungal infections and therapy with amphotericin B was instituted only in patients with two positive PCR results. The authors showed that a PCR-based therapeutic approach reduced mortality in cancer patients with febrile neutropenia and fungal infections. Although employing PCR tests for pre-emptive strategies appears promising, the tests are not standardized and are not yet commercially available. Chest CT scans play a critical role in the early diagnosis of invasive pulmonary aspergillosis. Greene et al.[48] evaluated baseline chest CT scan findings in 235 patients with invasive pulmonary aspergillosis. The authors compared the response to treatment and survival after 12 weeks of treatment in 143 patients with a halo sign (a feature of early infection) to 79 patients with other CT findings. The former group had a significantly better response to treatment (52% vs 29%; p < 0.001) and improved Drugs 2008; 68 (3)

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survival (71% vs 53%; p = 0.01). Thus, early initiation of antifungal treatment on the basis of identification of a halo sign on the chest CT scan was associated with a better outcome. Also, a prospective review of the baseline imaging and treatment response of 343 immunocompromised patients reported that patients at risk for developing invasive pulmonary aspergillosis and presenting with compatible radiological findings benefit from early antifungal therapy.[49] One study noted that detection of serum galactomannan antigen by EIA did not precede detection of compatible lesions on a thoracic CT scan.[50] Since daily galactomannan testing may not be a practical approach, Stephanie et al.[45] have proposed determining serum galactomannan levels at the time of onset of fever, repeated after 72 hours with a chest CT scan if fever persists and then twice weekly thereafter. On the basis of data from these studies, chest CT scans and serum galactomannan antigen tests are being increasingly utilized in pre-emptive strategies for the management of invasive aspergillosis. There is considerable overlap between the empirical and pre-emptive strategies. As non-invasive diagnostic tools become refined and more reliable for early diagnosis, the empirical approach may be replaced by pre-emptive therapy. 2.5 Combination Therapy

In recent years, compared with amphotericin B, voriconazole has contributed to improved outcomes in invasive aspergillosis. Nevertheless, therapeutic success rates continue to be suboptimal, particularly in stem cell recipients. In a further attempt to improve outcome, based on data from in vitro and animal studies, several antifungal drug combinations have been tried with variable success.[51,52] In the past, the concurrent use of amphotericin B and an azole elicited controversy, given the potential antifungal antagonism. The introduction of the echinocandin class of drugs with a different target site has invigorated the prospects of combination therapy. There are in vitro and animal data to show that © 2008 Adis Data Information BV. All rights reserved.

echinocandins may provide additive or synergistic activity in combination with triazoles.[53,54] The combination of voriconazole and caspofungin (n = 40) as primary therapy for invasive aspergillosis in solid organ transplant recipients was investigated by Singh et al.[52] in a prospective multicentre study. The authors reported that combination therapy was independently associated with an improved 90-day survival, particularly in patients with renal failure or A. fumigatus infection. Marr et al.[55] conducted a retrospective study of 47 patients with invasive pulmonary aspergillosis after HSCT and chemotherapy. Most patients in this study received amphotericin B as primary therapy and were switched to either voriconazole alone or a combination of voriconazole plus caspofungin as salvage therapy. The mortality rate in patients who received the combination was lower than that in the monotherapy group. At present, the sequential addition of an echinocandin is being increasingly used as a salvage strategy. The pilot Combistrat trial (n = 30 patients) studied the efficacy of the combination of caspofungin plus liposomal amphotericin B (3 mg/kg/day) versus monotherapy with high-dose liposomal amphotericin B (10 mg/kg/day) as primary therapy for invasive aspergillosis. At the end of treatment period, the favourable overall response rate was 67% for the combination versus a relatively low 27% for the high-dose liposomal amphotericin B group (p = 0.028). The study concluded that the combination of caspofungin and liposomal amphotericin B could be more efficacious in high-risk patients with haematological malignancies. As this was a phase IV clinical trial, carefully controlled and well designed randomized clinical trials are needed before any firm recommendations are made.[56] Another echinocandin, micafungin, was evaluated in two- and three-drug combinations with amphotericin B and azoles as salvage therapy. The combination was found to be well tolerated and effective for refractory aspergillosis in bone marrow transplant patients.[57] At present, for patients with refractory/progressive aspergillosis, the addition of a second agent (an Drugs 2008; 68 (3)

Management of Invasive Aspergillosis

echinocandin) may be reasonable (figure 1). In practice, an azole plus an echinocandin as initial therapy in seriously ill patients is becoming common place in the absence of evidence based data. As the two drug classes target entirely different sites, potential synergism is a reasonable expectation. However, as drug-related toxicities and cost may negate the potential clinical benefits, a randomized trial for primary therapy comparing a single drug (triazole) to a combination (triazole plus echinocandin) of drugs needs to be performed. 2.6 Salvage Therapy

Lipid amphotericin B formulations and caspofungin have been approved by the US FDA for salvage therapy of invasive aspergillosis. The lipid amphotericin formulations maintain a broad spectrum of antifungal activity with fewer infusion related toxicities. However, the EORTC group[16] demonstrated that the initial choice of antifungal therapy is critical to a successful outcome. In their study of 139 patients, patients received initial therapy with either voriconazole or amphotericin B deoxycholate and were switched to other licensed therapies as needed. The overall response rate was 30% in the amphotericin B group and 55% in the voriconazole group, independent of the salvage therapy that was administered. The efficacy of caspofungin as salvage therapy was evaluated in an open-label, non-comparative, multicentre trial that demonstrated a 45% favourable response to caspofungin therapy.[58] This led to the use of caspofungin as salvage therapy for invasive aspergillosis in North America and Europe. Echinocandin as initial monotherapy for invasive aspergillosis is under evaluation. In addition, it is unclear whether higher than ‘standard doses’ of echinocandin may have improved efficacy against invasive aspergillosis. In an open-label, multicentre study, Walsh et al.[59] investigated the efficacy and safety of posaconazole in patients with invasive aspergillosis and other mycoses who were refractory to or intolerant of conventional antifungal therapy. The study included 107 posaconazole recipients and 86 control © 2008 Adis Data Information BV. All rights reserved.

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subjects. The overall success rate was 42% for the posaconazole group and 26% for the control subjects (p = 0.006). This benefit was observed as early as 30 days into salvage therapy and continued to the end of the study; survival advantage was also noted with posaconazole. Perfect et al.[60,61] studied the use of voriconazole as salvage therapy for refractory fungal infections, including invasive aspergillosis. The efficacy rate of voriconazole for invasive aspergillosis was 43.7%; the drug was well tolerated and treatment-related discontinuation occurred in 3)-{beta}-D-glucan test in weekly screening for invasive aspergillosis in patients with hematological disorders. J Clin Microbiol 2004; 42: 2733-41 13. Caillot D, Couaillier JF, Bernard A, et al. Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol 2001; 19: 253-9 14. Denning DW, Marr KA, Lau WM, et al. Micafungin (FK463), alone or in combination with other systemic antifungal agents for the treatment of acute invasive aspergillosis. J Infect 2006; 53: 337-49 15. Sheehan DJ, Hitchcock CA, Sibley CM. Current and emerging azole antifungal agents. Clin Microbiol Rev 1999; 12: 40-79 16. Patterson TF, Boucher HW, Herbrecht R, et al. European Organization for Research and Treatment of Cancer (EORTC), Invasive Fungal Infections Group (IFIG) and the Pfizer Global Aspergillus Study Group. Strategy of following voriconazole versus amphotericin B therapy with other licensed antifungal

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17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

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therapy for primary treatment of invasive aspergillosis: impact of other therapies on outcome. Clin Infect Dis 2005; 41: 1448-52 Candoni A, Mestroni R, Damiani D, et al. Caspofungin as first line therapy of pulmonary invasive fungal infections in 32 immunocompromised patients with hematological malignancies. Eur J Hematology 2005; 75: 227-33 Herbrecht R, Denning DW, Patterson, et al. Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group. Voriconazole versus Amphotericin B for Primary therapy of invasive aspergillosis. N Engl J Med 2002; 347: 408-15 Cornely OA, Maertens J, Bresnik M. Liposomal amphotericin B (L-AMB) as initial therapy for invasive filamentous fungal infections (IFFI): a randomized prospective trial of a high loading dose regimen versus standard dosing (Ambiload trial) [abstract]. Blood 2005; 106: 3222 Ito JI, Chandrasekar PH, Hooshmand-R Rad R. Effectiveness of amphotericin B lipid complex (ABLC) treatment in allogeneic hematopoietic stem cell transplant (HSCT) recipients with invasive aspergillosis (IA). Bone Marrow Transplant 2005; 36: 873-7 Segal BH, Walsh TJ. Current approaches to diagnosis and treatment of invasive aspergillosis. Am J Respir Crit Care Med 2006; 173: 707-17 Mattiuzzi GN, Estey E. Raad I, et al. Liposomal amphotericin B versus the combination of fluconazole and itraconazole as prophylaxis for invasive fungal infections during induction chemotherapy for patients with acute myelogenous leukemia and myelodysplastic syndrome. Cancer 2003; 97: 450-6 Glasmacher A, Prentice A, Gorschluter M, et al. Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematological malignancies: evidence from a meta analysis of 3,597 patients. J Clin Oncol 2003; 21: 4615-26 Winston DJ, Maziarz RT, Chandrasekar PH, et al. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogenic hematopoietic stem cell transplant recipients: a multicenter randomized trial. Ann Intern Med 2003; 138: 705-13 Marr KA, Crippa F, Leisenring W, et al. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood 2004; 103: 1527-33 Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356: 348-59 Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007; 356: 335-47 Mattiuzzi GN, Alvarado G, Giles FJ, et al. Open-label randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematological malignancies. Antimicrob Agents Chemother 2006; 50: 143-7 Van Burik J, Ratanatharathorn V, Stefan DE, et al. Randomized, double-blind trial of micafungin (MI) versus fluconazole (FL) for prophylaxis of invasive fungal infections in patients (pts) undergoing hematopoietic stem cell transplant (HSCT). Clin Infect Dis 2004; 39: 1407-16 Martino R, Parody R, Fukuda T, et al. Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: a retrospective survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Blood 2006; 108: 2928-36

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31. Pizzo PA, Robichaud KJ, Gill FA, et al. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. Am J Med 1982; 72: 101-11 32. EORTC International Antimicrobial Therapy Cooperative Group. Empiric antifungal therapy in febrile granulocytopenic patients. Am J Med 1989; 86: 668-72 33. Klastersky J. Antifungal therapy in patients with fever and neutropenia: more rational and less empirical? N Engl J Med 2004; 351: 1445-7 34. Malik IA, Moid I, Aziz Z. A randomized comparison of fluconazole with amphotericin B as empiric anti-fungal agents in cancer patients with prolonged fever and neutropenia. Am J Med 1998; 105: 478-83 35. Viscoli C, Castagnola E, Van Lint MT, et al. Fluconazole versus amphotericin B as empirical antifungal therapy of unexplained fever in granulocytopenic cancer patients: a pragmatic, multicentre, prospective and randomised clinical trial. Eur J Cancer 1996; 32: 814-20 36. Walsh TJ, Finberg RW, Arndt C, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 1999; 340: 764-71 37. Winston DJ, Hathorn JW, Schuster MG, et al. A multicenter, randomized trial of fluconazole versus amphotericin B for empiric antifungal therapy of febrile neutropenic patients with cancer. Am J Med 2000; 108: 282-9 38. Boogaerts M, Winston DJ, Bow EJ, et al. Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy: a randomized, controlled trial. Ann Intern Med 2001; 135: 412-22 39. Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002; 346: 225-34 40. Johnson JR, Ullmann AJ, Heussel CP, et al. Voriconazole versus liposomal amphotericin B for empirical antifungal therapy. N Engl J Med 2002; 346: 1745-7 41. Walsh TJ, Lee J, Dismukes WE, et al. Decisions about voriconazole versus liposomal amphotericin B. N Engl J Med 2002; 346: 1499 42. Walsh TJ, Teppler H, Donowitz GR, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 2004; 351: 1391-402 43. Kontoyiannis DP, Lewis RE, Tattevin P, et al. Caspofungin versus liposomal amphotericin B for empirical therapy. N Engl J Med 2005; 352: 410-4 44. Gotzsche PPC, Johansen HK. Meta-analysis of prophylactic or empirical antifungal treatment versus placebo or no treatment in patients with cancer complicated by neutropenia. BMJ 1997; 314: 1238-44 45. Stephanie PM, Gottardi M, Zanetti F, et al. Pre-emptive antifungal therapy among neutropenic patients. Clin Infect Dis 2006; 42: 1507-8 46. Maertens J, Theunissen K, Verhoef G, et al. Galactomannan and computed tomography-based pre-emptive antifungal therapy in neutropenic patients at high risk for invasive fungal infections; a prospective feasibility study. Clin Infect Dis 2005; 41: 1242-50 47. Lin MT, Lu HC, Chen WL. Improving efficacy of antifungal therapy by polymerase chain reaction based strategy among febrile patients with neutropenia and cancer. Clin Infect Dis 2001; 33: 1621-7

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Management of Invasive Aspergillosis

48. Greene RE, Schlamm HT, Oestmann JW, et al. Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis 2007; 44: 373-9 49. Greene R. Radiology of fungal infections in the immunocompromised patient. In: Wingard JR, Anaisse EJ, editors. Fungal infections in the immunocompromised patient. Boca Raton (FL): Taylor & Francis Group LLC, 2005: 407-8(B) 50. Weisser M, Rausch C, Droll A, et al. Galactomannan does not precede major signs on a pulmonary computerized tomographic scan suggestive of invasive aspergillosis in patients with hematological malignancies. Clin Infect Dis 2005; 41: 1143-9 51. Viscoli C. Combination therapy for invasive aspergillosis. Clin Infect Dis 2004; 39: 803-5 52. Singh N, Limaye AP, Forrest G, et al. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Transplantation 2006; 81: 320-6 53. Kirkpatrick WR, Perea S, Coco BJ. Efficacy of caspofungin alone and in combination with voriconazole in a guinea pig model of invasive aspergillosis. Antimicrob Agents Chemother 2002; 46: 2564-8 54. Petraitis V, Petraitiene R, Sarafandi AA, et al. Combination therapy in treatment of experimental pulmonary aspergillosis: synergistic interaction between an antifungal triazole and an echinocandin. J Infect Dis 2003; 187: 1834-43 55. Marr KA, Boeckh M, Carter RA, et al. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis 2004; 39: 797-802 56. Caillot D, Thiebaut A, Herbrecht R, et al. Liposomal amphotericin B in combination with caspofungin versus liposomal amphotericin B high dose regimen for the treatment of invasive aspergillosis in immunocompromised patients: randomized pilot study (Combistrat trial) [abstract no. P-004]. Focus on Fungal Infections 16; 2006 Mar 8-10; Las Vegas (NV) 57. Ratnatharathorn V, Flynn P, Van Burik JA, et al. Micafungin in combination with systemic antifungal agents in the treatment of refractory aspergillosis (RA) in bone marrow transplant (BMT) patients [abstract no. 2472]. 44th Annual Meeting of the American Society of Hematology; 2002 Dec 6-10; Philadelphia (PA) 58. Maertens J, Raad I, Petrikkos G, et al. For the Caspofungin Salvage Aspergillosis Study Group. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis 2004; 39: 1563-71 59. Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis 2007 Jan 1; 44: 2-12 60. Perfect J, Gonz´alez-Ruiz A, Lutsar I, et al. Voriconazole (VORI) for the treatment of resistant and rare fungal pathogens [abstract no. 303]. 38th Annual Meeting of the Infectious Diseases Society of America; 2000 Sep 7-10; New Orleans (LA) 61. Perfect JR, Marr KA, Walsh TJ, et al. Voriconazole treatment for less-common, emerging or refractory fungal infections. Clin Infect Dis 2003; 36: 1122-31 62. Denning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: review of 2121 published cases. Rev Infect Dis 1990; 12: 1147-201 63. Reichenberger F, Habicht J, Kaim A, et al. Lung resection for invasive pulmonary aspergillosis in neutropenic patients with

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hematologic diseases. Am J Resp Crit Care Med 1998; 158: 885-90 Habicht JM, Matt P, Passweg JR, et al. Invasive pulmonary fungal infection in hematological patients: is resection effective? Hematology J 2001; 2: 250-6 Safdar A. Strategies to enhance immune function in hematopoietic transplantation patients with invasive fungal infections. Bone Marrow Transplant 2006; 38: 327-37 Chiou CC, Groll AH, Walsh TJ. New drugs and novel targets for the treatment of invasive fungal infections in patients with cancer. Oncologist 2000; 5: 120-35 Steinbach WJ, Stevens DA. Review of newer antifungal and immunomodulatory strategies for invasive aspergillosis. Clin Infect Dis 2003; 37 Suppl. 3: S157-87 Hata K, Kimura J, Miki H, et al. Efficiency of ER-30346, a novel oral triazole antifungal agent, in experimental models of aspergillosis, candidiasis and cryptococcosis. Antimicrob Agents Chemother 1996; 40: 2243-7 Offner F, Krcmery V, Boogaerts M, et al. Liposomal nystatin in patients with invasive aspergillosis refractory to or intolerant of amphotericin B. Antimicrob Agents Chemother 2004; 48: 4808-12 Walsh TJ, Giri N. Pradimicins: a novel class of broad-spectrum antifungal compounds. Eur J Clin Microbiol Infect Dis 1997; 16: 93-7 Ganesan LT, Manavathu EK, Cutright JL, et al. In-vitro activity of nikkomycin Z alone and in combination with polyenes, triazoles or echinocandins against Aspergillus fumigatus. Clin Microbiol Infect 2004; 10: 961-6 Herreros E, Martinez CM, Almela MJ, et al. Sordarins: in vitro activities of new antifungal derivatives against pathogenic yeasts, Pneumocystis carini and filamentous fungi. Antimicrob Agents Chemother 1998; 42 (11): 2863-9 Cenci E, Mencacci A, Fe d’Ostiani C, et al. Cytokine and Thelper-dependent lung mucosal immunity in mice with invasive pulmonary aspergillosis. J Infect Dis 1998; 178: 1750-60 Cenci E, Mencacci A, Del Sero G, et al. Interleukin-4 causes susceptibility to invasive pulmonary aspergillosis through suppression of protective type I response. J Infect Dis 1999; 180: 1957-68 Hamilton JA, Whitty GA, Royston AKM, et al. Interleukin-4 suppresses granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor levels in stimulated monocytes. Immunology 1992; 76: 566-71 Safdar A, Rodriguez G, Ohmagari N, et al. The safety of interferon-gamma-1b therapy for invasive fungal infections after hematopoietic stem cell transplantation. Cancer 2005; 103: 731-9 Casadevall A, Pirofski L. Adjunctive immune therapy for invasive fungal infections. Clin Infect Dis 2001; 33: 1048-56 Nemunaitis J, Buckner CD, Dorsey KS, et al. Retrospective analysis of infectious diseases in patients who received recombinant human granulocyte-macrophage colony-stimulating factor versus patients not receiving a cytokine who underwent autologous bone marrow transplantation for treatment of lymphoid cancer. Am J Clin Oncol 1998; 21: 341-6 Brummer E, Maqbool A, Stevens DA. In vivo GM-CSF prevents dexamethasone suppression of killing of Aspergillus fumigatus conidia by bronchoalveolar macrophages. J Leukoc Biol 2001; 70: 868-72 Rowe JM, Andersen JW, Maza J, et al. A randomized, placebocontrolled phase III study of granulocyte-macrophage colonystimulating factor in adult patients (>55 to 70 years of age)

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with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 1995; 86: 45762

93. Marr KA, Carter RA, Crippa F, et al. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002; 34: 909-17

81. Ito JI, Lyons JM, Hong TB, et al. Vaccinations with recombinant variants of Aspergillus fumigatus allergen Asp f 3 protect mice against invasive aspergillosis. Infect Immun. 2006; 74: 5075-84

94. Marty FM, Cosimi LA, Baden LR. Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants. N Engl J Med 2004; 350: 950-2

82. Feldmesser M. Prospects of vaccines for invasive aspergillosis. Med Mycol 2005; 43: 571-87

95. Verweij PE, Mellado E, Melchers WGJ. Multiple triazole resistant aspergillosis. N Engl J Med 2007; 356: 1481-3

83. Denikus N, Orfaniotou F, Wulf G, et al. Fungal antigens expressed during invasive aspergillosis. Infect Immun 2005; 73 (8): 4704-13 84. Sheppard DC, Edwards Jr JE. Development of a vaccine for invasive aspergillosis. Clin Infect Dis 2004; 38: 1137-8 85. Stevens DA. Vaccinate against aspergillosis! A call to arms of the immune system. Clin Infect Dis 2004; 38: 1131-6 86. Hebart H, Bollinger C, Fisch P, et al. Analysis of T-cell responses to Aspergillus fumigatus antigens in healthy individuals and patients with hematologic malignancies. Blood 2002; 100: 4521-8 87. Ito JI, Lyons JM. Vaccination of corticosteroid immunosuppressed mice against invasive pulmonary aspergillosis. J Infect Dis 2002; 186: 869-71 88. Bozza S, Gaziano R, Lipford GB, et al. Vaccination of mice against invasive aspergillosis with recombinant Aspergillus proteins and CpG oligodeoxynucleotides as adjuvants. Microbes Infect 2002; 4: 1281-90 89. Bozza S, Perruccio K, Montagnoli C, et al. A dendritic cell vaccine against invasive aspergillosis in allogeneic hematopoietic transplantation. Blood 2003; 102: 380714 90. Cenci E, Mencacci A, Bacci A, et al. T cell vaccination in mice with invasive pulmonary aspergillosis. J Immunol 2000; 165: 381-8 91. Cenci E, Mencacci A, Spreca A, et al. Protection of killer antiidiotypic antibodies against early invasive aspergillosis in a murine model of allogeneic T-cell-depleted bone marrow transplantation. Infect Immun 2002; 70: 2375-82 92. Baddley JW, Stroud TP, Salzman D, et al. Invasive mold infections in allogeneic bone marrow transplant recipients. Clin Infect Dis 2001; 232: 1319-24

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96. Slaven JW, Anderson MJ, Sanglard D, et al. Increased expression of a novel Aspergillus fumigatus ABC transporter gene, atrF, in the presence of itraconazole in itraconazole resistant clinical isolate. Fungal Genet Biol 2002; 36: 199-206 97. Mann PA, Parmegiani RM, Wei SO, et al. Mutations in Aspergillus fumigatus resulting in reduced susceptibility to posaconazole appear to be restricted to a single amino acid in the cytochrome P450 14α-demethylase. Antimicrob Agents Chemother 2003; 47: 577-81 98. Diaz-Guerra TM, Mellado E, Cuenca-Estrella M, et al. A point mutation in the 14α-sterol demethylase gene cyp51A contributes to itraconazole resistance in Aspergillus fumigatus. Antimicrob Agents Chemother 2003; 47: 1120-4 99. Nascimento AM, Goldman GH, Park S, et al. Multiple resistance mechanisms among Aspergillus fumigatus mutants with high-level resistance to itraconazole. Antimicrob Agents Chemother 2003; 47: 1719-26 100. Warris A, Weemaes CM, Verwaij PE. Multidrug resistance in A. fumigatus. N Engl J Med 2002; 347: 2173-4

Correspondence: Dr Suganthini Krishnan-Natesan, Department of Medicine, Division of Infectious Diseases, John. D. Dingell VA Medical Center, 427 Lande Building, 550 E. Canfield Ave, Detroit, MI 48201, USA. E-mail: [email protected]

Drugs 2008; 68 (3)

Drugs 2008; 68 (3): 283-297 0012-6667/08/0003-0283/$53.45/0

REVIEW ARTICLE

© 2008 Adis Data Information BV. All rights reserved.

Treatment of Acute Severe Hypertension Current and Newer Agents Joseph Varon1,2,3 1 2 3

The University of Texas Health Science Center at Houston, Houston, Texas, USA The University of Texas Medical Branch at Galveston, Galveston, Texas, USA St Luke’s Episcopal Hospital/Texas Heart Institute, Houston, Texas, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 1. Classification of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 2. Hypertensive Crises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 2.1 Hypertensive Urgencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 2.2 Hypertensive Emergencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 2.2.1 Operative and Postoperative Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 2.2.2 Hypertension in Acute Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 2.3 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 3. Initial Management of Severe Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 3.1 Pharmacological Agents Used in the Treatment of Hypertensive Crises . . . . . . . . . . . . . . . . . . . . 287 3.1.1 Enalaprilat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 3.1.2 Labetalol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 3.1.3 Esmolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 3.1.4 Clevidipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 3.1.5 Nicardipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 3.1.6 Nifedipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 3.1.7 Fenoldopam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 3.1.8 Hydralazine and Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 3.1.9 Nitroglycerin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 3.1.10 Sodium Nitroprusside . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293

Abstract

Approximately 72 million people in the US experience hypertension. Worldwide, hypertension may affect as many as 1 billion people and be responsible for ≈7.1 million deaths per year. It is estimated that ≈1% of patients with hypertension will, at some point, develop a hypertensive crisis. Hypertensive crises are further defined as either hypertensive emergencies or urgencies, depending on the degree of blood pressure elevation and presence of end-organ damage. Immediate reduction in blood pressure is required only in patients with acute end-organ damage (i.e. hypertensive emergency) and requires treatment with a titratable, shortacting, intravenous antihypertensive agent, while severe hypertension without acute end-organ damage (i.e. hypertensive urgency) is usually treated with oral antihypertensive agents.

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The primary goal of intervention in a hypertensive crisis is to safely reduce blood pressure. The appropriate therapeutic approach of each patient will depend on their clinical presentation. Patients with hypertensive emergencies are best treated in an intensive care unit with titratable, intravenous, hypotensive agents. Rapid-acting intravenous antihypertensive agents are available, including labetalol, esmolol, fenoldopam, nicardipine and sodium nitroprusside. Newer agents, such as clevidipine and fenoldopam, may hold considerable advantages to other available agents in the management of hypertensive crises. Sodium nitroprusside is an extremely toxic drug and its use in the treatment of hypertensive emergencies should be avoided. Similarly, nifedipine, nitroglycerin and hydralazine should not to be considered first-line therapies in the management of hypertensive crises because these agents are associated with significant toxicities and/or adverse effects.

In the US, it is estimated that approximately 72 million people experience hypertension (defined as systolic blood pressure [SBP] >140 mmHg and/or diastolic [DBP] >90 mmHg; taking antihypertensive medication; or being told at least twice by a physician, or other health professional, that one has high blood pressure [BP]).[1] Affecting ≈30% of the US population aged >20 years old, hypertension is one of the most common chronic medical conditions,[2,3] and occurs almost twice as often in African-Americans than in Caucasians.[4-6] Moreover, the incidence of hypertension increases with age[7] and affects men at a slightly higher rate than women. Worldwide, hypertension may affect as many as 1 billion people and be responsible for ≈7.1 million deaths per year.[8] 1. Classification of Hypertension The classification and approach to hypertension undergoes periodic review by the Joint National Committee (JNC) on Detection, Evaluation, and Treatment of High Blood Pressure.[9-15] The most recent report, JNC 7, classifies high BP in the following four stages: (i) normal; (ii) prehypertension; (iii) stage I; and (iv) stage II (table I). The JNC 7 complete report[16,17] identifies patients with a SBP of >180 mmHg or a DBP >120 mmHg as having a ‘hypertensive crisis’. This report goes on to define the operational classification of hypertensive crisis as either ‘hypertensive emergencies’ (i.e. severe elevations in BP [>180/ © 2008 Adis Data Information BV. All rights reserved.

120 mmHg] complicated by evidence of impending or progressive target organ dysfunction) that require immediate BP reduction (not necessarily to normal) to prevent or limit target-organ damage, or ‘hypertensive urgencies’ (i.e. situations associated with severe elevations in BP without progressive targetorgan dysfunction). Although not specifically addressed in the JNC 7 report, patients with a SBP >179 mmHg or a DBP >109 mmHg are usually defined as having ‘severe’ or ‘accelerated’ hypertension, and should be addressed as hypertensive crises. Accelerated hypertension is defined as a recent significant increase over baseline BP that is associated with target-organ damage. The term ‘malignant hypertension’, a syndrome characterized by elevated BP accompanied by encephalopathy or nephropathy,[11,14] has been used in the past; however, this term is a misnomer. Hence, it has been removed from National and International Blood Pressure Control guidelines and is Table I. Joint National Committee (JNC)-7 classification of blood pressure for adults (reproduced from Chobanian et al.,[16] with permission) BP classifications

Systolic BP (mmHg) Diastolic BP (mmHg)

Normal

120

Stage II

Drugs 2008; 68 (3)

Acute Severe Hypertension

best referred to as a hypertensive emergency or acute severe hypertension.[14,15]

285

Table II. Examples of acute severe hypertension related conditions Condition Acute coronary syndrome Acute left ventricular failure with pulmonary oedema

2. Hypertensive Crises

Acute myocardial infarction/unstable angina pectoris Acute renal failure

The epidemiology of hypertensive crises are similar to that of hypertension (i.e. higher among African-Americans and the elderly); however, men are affected approximately two times more frequently than women.[18-21] It is estimated that ≈1% of patients with hypertension will, at some point, develop a hypertensive crisis.[22,23]

Dissecting aortic aneurysm Eclampsia HELLP syndrome Hypertensive encephalopathy Intracerebral haemorrhage Microangiopathic haemolytic anaemia Pulmonary oedema with respiratory failure Severe pre-eclampsia HELLP = haemolysis, elevated liver enzymes, low platelets.

2.1 Hypertensive Urgencies 2.2 Hypertensive Emergencies

Hypertensive urgencies are hypertensive crises associated with severe elevations in BP without progressive target-organ dysfunction.[16,17,20,24-28] Examples include upper levels of stage II hypertension associated with severe headache, shortness of breath, epistaxis or severe anxiety. The majority of these patients present as noncompliant or inadequately treated hypertensive individuals, often with little or no evidence of target-organ damage. In patients with hypertensive urgencies, BP control can be achieved within a few hours to prevent organ damage.[25,29] Unfortunately, the term hypertensive ‘urgency’ has led to overly aggressive management of many patients with severe, uncomplicated hypertension. Aggressive administration of intravenous drugs or even oral agents to rapidly lower BP may be associated with significant morbidity.[30-32] Oral loading doses of antihypertensive agents can lead to cumulative effects causing hypotension. The BP of patients with hypertensive urgencies should be gradually lowered over a period of 24–48 hours, usually with oral medication.[33] Such patients may benefit from treatment with a short-acting agent, such as oral captopril, intravenous labetalol or oral clonidine,[34,35] followed by several hours of observation.[16,17] Examples of hypertensive urgencies include upper levels of stage II hypertension associated with, but not necessarily caused by, severe headache, shortness of breath, epistaxis or severe anxiety. © 2008 Adis Data Information BV. All rights reserved.

Hypertensive emergencies (i.e. acute severe hypertension) are hypertension crises characterized by severe elevations in BP (>180/120 mmHg) complicated by evidence of impending or progressive target-organ dysfunction. Organ dysfunction is uncommon with a DBP 169 mmHg or a DBP >109 mmHg in a pregnant woman is considered a hypertensive emergency requiring immediate pharmacological management.[37] 2.2.1 Operative and Postoperative Hypertension

In the surgical setting, a hypertensive crisis may be encountered during cardiac surgery, major vascular surgery (e.g. carotid endarterectomy, aortic surgery), neurosurgery, head and neck surgery, renal transplantation or major trauma (e.g. burns or head injury). In addition, hypertension, and hypertensive crises, are very common in the early postoperative period and are related to increased sympathetic tone and vascular resistance.[38] Postoperative hypertension (arbitrarily defined as SBP ≥190 mmHg and/or DBP ≥100 mmHg on two consecutive readings following surgery)[15,39] may have significant adverse sequelae in both cardiac and noncardiac patients. The incidence of postoperative hypertensive crises Drugs 2008; 68 (3)

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varies depending on the population examined, being reported in 4–35% of patients shortly after the surgical procedure.[40-42] The transient nature of postoperative hypertension and the unique clinical factors present in the postoperative period require that this clinical syndrome be given individual consideration. Like other forms of accelerated hypertension, a history of hypertension is commonly seen in patients with perioperative hypertension. 2.2.2 Hypertension in Acute Stroke

Control of hypertension in patients with acute stroke is directed at maintaining adequate cerebral blood flow to minimize ischaemic damage and control of intracerebral pressure. There is currently controversy about whether or not to treat elevated BP caused by stroke as it is theorized that elevation of BP is likely to be neuroprotective. With adequate blood flow around the central area of the stroke or penumbra, cells may be salvaged.[43-46] Hence, the inappropriate lowering of the BP in acute stroke may increase neurological damage. As a result of the complexities associated with the management of hypertension in acute stroke, this subject warrants a review that is beyond the scope and size limitations of this article, and thus will not be addressed further. The reader is encouraged to consult other published literature on the subject.[47] 2.3 Pathophysiology

The pathophysiology of hypertensive crises is not fully understood, but it is thought to be due to abrupt increases in systemic vascular resistance that are likely to be related to humoral vasoconstrictors.[48,49] A hypertensive crisis can develop de novo, or can complicate underlying essential or secondary hypertension. The acute nature of onset suggests a triggering factor superimposed on pre-existing hypertension.[36] With severe elevations of BP, endothelial injury occurs and fibrinoid necrosis of the arterioles ensues.[48,49] This vascular injury leads to deposition of platelets and fibrin, and a breakdown of the normal autoregulatory function. The resulting ischaemia prompts further release of vasoactive substances, completing a vicious cycle.[49] © 2008 Adis Data Information BV. All rights reserved.

Many patients with severe hypertension (DBP >110 mmHg) have no acute end-organ damage. Why some patients with severe hypertension develop end-organ damage (hypertensive emergency) while others do not (hypertensive urgency) remains unclear. Rapid antihypertensive therapy in the hypertensive urgency setting may be associated with significant morbidity.[30,31,50] However, there are true hypertensive emergencies in which the rapid (controlled) lowering of BP is indicated.[22,51,52] 3. Initial Management of Severe Hypertension On initial evaluation, most patients with severe hypertension will have no evidence of end-organ damage, and thus present as hypertensive urgency. Since there is no preliminary indication of acute end-organ damage, these patients may present for evaluation of another complaint, and the elevated BP may represent an acute recognition of chronic hypertension. Utilizing oral medications, such as captopril, labetalol or clonidine, to lower the BP gradually over 24–48 hours is one approach to the management of these patients.[16,17] The use of sublingual nifedipine capsules in hypertensive emergencies should be abandoned[53] as the US FDA concluded the practice of administering sublingual/ oral nifedipine was neither safe nor efficacious.[54] Rapid correction of severely elevated BP below the autoregulatory range of critical arterial beds (cerebral, coronary and renal) can result in a marked reduction in perfusion, causing ischaemia and infarction, and may be associated with significant morbidity in hypertensive urgencies or emergencies due to a shift to the right in the pressure/flow autoregulatory curve in these vascular beds.[32] BP must be reduced in these patients; however, it must be lowered in a slow and controlled fashion to prevent organ hypoperfusion. Hypertensive urgencies do not mandate admission to a hospital. On the other hand, patients with a hypertensive emergency should be admitted to an intensive care unit (ICU) for continuous cardiac monitoring, and frequent assessment of neurological status and urine output. Altered autoregulation also occurs in paDrugs 2008; 68 (3)

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tients in a hypertensive crisis, and since end-organ damage is already present, rapid and excessive correction of the BP can further reduce perfusion and propagate further injury. Therefore, patients with a hypertensive crisis are best managed with a continuous infusion of a short-acting, titratable antihypertensive agent. As a result of unpredictable pharmacodynamics, the sublingual and intramuscular route should be avoided. According to the JNC 7 report, “The initial goal of therapy in hypertensive emergencies is to reduce mean arterial BP by no more than 25% (within minutes to 1 hour) then, if stable, to 160/ 100–110 mmHg within the next 2–6 hours”. Advancing these guidelines, this author believes the physician would be wise to consider the immediate goal of therapy in hypertensive emergencies to reduce DBP by 10–15%, or to approximately 110 mmHg, over a period of 30–60 minutes. Sodium and volume depletion can be significant, and gentle volume expansion with an intravenous saline solution will serve to restore organ perfusion and prevent an abrupt decline in BP when antihypertensive regimens are initiated. For those patients with the most severe clinical manifestations or with the most labile BP, intraarterial BP monitoring may be prudent. There are a variety of rapid-acting intravenous agents that are available for use in patients with a hypertensive crisis, and the agent of choice depends on which manifestation of end-organ damage is present. Rapid-acting intravenous agents should not be used outside of the monitored setting of an ICU to prevent steep declines of BP that may have significant morbidity or mortality. In patients with aortic dissection, the BP should be reduced rapidly (within 5–10 minutes), targeting a SBP of 220 mmHg.[101-103] Familiar adverse effects of intravenous nicardipine are chiefly related to its antihypertensive effects; however, hypotension, as a treatment adverse effect, may be less frequent with nicardipine than with sodium nitroprusside because nicardipine does not cause venodilation. 3.1.6 Nifedipine

Nifedipine has been widely used via oral or sublingual administration in the management of hypertensive emergencies, severe hypertension associated with chronic renal failure, postoperative hypertension and pregnancy-induced hypertension. Nonetheless, the routine use of short-acting nifedipine capsules in hypertensive emergencies should be abandoned.[53] Although nifedipine has been administered via the sublingual route, the drug is poorly soluble and is not absorbed through the buccal mucosa, but is rapidly absorbed from the gastrointestinal tract after the capsule has dissolved.[104] This mode of administration has not been approved by the US FDA. The half-life of nifedipine in plasma is ≈2 hours.[105] A significant decrease in BP is usually observed 5–10 minutes after nifedipine administration, with a peak effect from 30 to 60 minutes, and a duration of action of approximately 6–8 hours.[106] Sudden, uncontrolled and severe reductions in BP accompanying the administration of nifedipine may precipitate cerebral, renal and myocardial ischaemic events that have been associated with fatal outcomes.[53] Elderly hypertensive patients with underlying organ impairment and structural vascular disease are more vulnerable to the rapid and uncontrolled reduction in arterial pressure. Given the seriousness of the reported adverse events and the lack of any clinical documentation attesting to a Drugs 2008; 68 (3)

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benefit, the use of nifedipine capsules for hypertensive emergencies and ‘pseudo emergencies’ should be abandoned.[53] Over 20 years ago, the Cardiorenal Advisory Committee of the FDA concluded that the practice of administering sublingual/oral nifedipine needed to be abandoned because this agent was neither safe nor efficacious.[54] Nifedipine is not to be considered an acceptable therapy in the management of either hypertensive emergencies or urgencies.[29] 3.1.7 Fenoldopam

Fenoldopam is unique among the parenteral BP agents because it mediates peripheral vasodilation by acting on peripheral dopamine type 1 receptors. Fenoldopam is rapidly and extensively metabolized by conjugation in the liver, without participation of cytochrome P450 enzymes. The onset of action is within 5 minutes, with the maximal response being achieved by 15 minutes.[107-110] The elimination half-life of fenoldopam is ≈5 minutes,[111] with a duration of action from 30 to 60 minutes, and BP gradually returning to pretreatment values without rebound once the infusion is stopped.[107-109] No adverse effects have been reported.[107] An initial starting dose of 0.1 µg/kg/min is recommended, titrated by increments of 0.05–0.1 µg/kg/min to a maximum of 1.6 µg/kg/min. Fenoldopam improves creatinine clearance, urine flow rates and sodium excretion in severely hypertensive patients with both normal and impaired renal function.[112-114] The use of fenoldopam as a prophylactic agent to prevent contrast-induced nephropathy has been disappointing.[115,116] Moreover, clinical studies with fenoldopam have failed to demonstrate a clinically significant reduction in death or renal replacement therapy in patients at risk for acute renal failure.[117,118] Fenoldopam causes dose-dependent increases in intraocular pressure, and its use should be avoided in patients at risk for with intraocular hypertension and intracranial hypertension. In addition, fenoldopam is in a solution that contains a sodium metabisulfate, and patients with potential sulfite sensitivity may develop acute allergic reactions. © 2008 Adis Data Information BV. All rights reserved.

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3.1.8 Hydralazine and Diuretics

Hydralazine is a direct-acting arteriolar vasodilator, often chosen as a first-line agent for critically ill patients with pregnancy-induced hypertension. Following intramuscular or intravenous administration, there is an initial latent period of 5–15 minutes, followed by a progressive and often precipitous fall in BP that can last up to 12 hours;[119,120] however, its maximum effect is usually noted between 10 and 80 minutes. Although the circulating half-life of hydralazine is only approximately 3 hours, the half-time of its effect on BP is approximately 10 hours.[121,122] Because of the prolonged and unpredictable antihypertensive effects of hydralazine, and the inability to effectively titrate its hypotensive effect, it is best avoided in the management of hypertensive crises. Volume depletion is common in patients with hypertensive emergencies and the administration of a diuretic together with a hypertensive agent can lead to a precipitous drop in BP. Diuretics should be avoided unless specifically indicated for volume overload, as occurs in renal parenchymal disease or coexisting pulmonary oedema. Familiar adverse effects of intravenous hydralazine include prolonged duration of action in patients with renal dysfunction, hypotension, salt retention, fluid retention, tachyphylaxis and drug-induced lupus syndrome.[123,124] Hydralazine is not to be considered an acceptable primary therapy in the management of either hypertensive emergencies or urgencies,[29] but may be a suitable adjunct therapy. 3.1.9 Nitroglycerin

Nitroglycerin is a potent venodilator and only at high doses affects arterial tone.[125] It has pharmacokinetic properties similar to sodium nitroprusside, and causes hypotension and reflex tachycardia, which are exacerbated by the volume depletion characteristic of hypertensive emergencies. Nitroglycerin reduces BP by reducing preload and cardiac output, which are undesirable effects in patients with compromised cerebral and renal perfusion. Intravenous nitroglycerin has an onset time of 2–5 minutes, duration of action of ≈10–20 minutes and is eliminated by hepatic metabolism in Drugs 2008; 68 (3)

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≈1–4 minutes.[123,124,126] Intravenous nitroglycerin is generally not considered as a first-line therapy for hypertension as it is not as efficacious as sodium nitroprusside, may have little or no efficacy when used alone and its antihypertensive action is caused by venodilation. Low-dose administration (approximately 60 mg/min) may, however, be used as an adjunct to intravenous antihypertensive therapy in patients with hypertensive emergencies associated with acute coronary syndromes or acute pulmonary oedema. Familiar adverse effects of intravenous nitroglycerin include hypotension, hypoxaemia from ventilation perfusion mismatching, methemoglobinaemia, reflex tachycardia and tachyphylaxis.[123,124] Nitroglycerin is not to be considered an acceptable primary therapy in the management of either hypertensive emergencies or urgencies,[29] but may be a suitable adjunct therapy. 3.1.10 Sodium Nitroprusside

Sodium nitroprusside is an arterial and venous vasodilator that decreases both afterload and preload.[127,128] Sodium nitroprusside decreases cerebral blood flow while increasing intracranial pressure, effects that are particularly detrimental in patients with hypertensive encephalopathy or following a cerebrovascular accident.[129-132] In patients with coronary artery disease, a significant reduction in regional blood flow (coronary steal) can occur.[133] In a large, randomized, placebo-controlled trial,[134] sodium nitroprusside was shown to increase mortality when infused in the early hours after acute myocardial infarction (mortality at 13 weeks, 24.2% vs 12.7%). Sodium nitroprusside is a very potent agent, with an onset of action of seconds, a duration of action of 1–2 minutes and a plasma half-life of 3–4 minutes.[127] As a result of the potency, rapidity of action of this agent and the development of tachyphylaxis, we recommend intra-arterial BP monitoring. In addition, sodium nitroprusside requires special handling to prevent its degradation by light. These factors limit the use of this drug.[135] The molecule of sodium nitroprusside contains 44% cyanide by weight.[136] Cyanide is released non-enzymatically from nitroprusside, the amount generated being dependent on the dose of sodium © 2008 Adis Data Information BV. All rights reserved.

nitroprusside administered. Cyanide is metabolized in the liver to thiocyanate, which is 100-fold less toxic than cyanide.[136,137] The thiocyanate generated is excreted largely through the kidneys. Therefore, cyanide removal requires adequate liver function, renal function and bioavailability of thiosulfate. Thus, the use of sodium nitroprusside may cause cytotoxicity due to the release of cyanide, with interference of cellular respiration.[138,139] In the author’s experience, patients can develop cyanide toxicity as early as 6–8 hours after initiation of the infusion of sodium nitroprusside. Cyanide toxicity has been documented to result in ‘unexplained cardiac arrest’, coma, encephalopathy, convulsions and irreversible focal neurological abnormalities.[128,138] The current methods of monitoring for cyanide toxicity are insensitive. Metabolic acidosis is usually a preterminal event. In addition, a rise in serum thiocyanate levels is a late event and not directly related to cyanide toxicity. RBC cyanide level (although not widely available) may be a more reliable method of monitoring for cyanide toxicity.[136] An RBC cyanide level >40 nmol/mL results in detectable metabolic changes. Levels >200 nmol/mL are associated with severe clinical symptoms and levels >400 nmol/mL are considered lethal.[136] Data suggest that sodium nitroprusside infusion rates >4 µg/ kg/min, for as little as 2–3 hours may lead to cyanide levels in the toxic range.[136] The recommended doses of sodium nitroprusside of up to 10 µg/kg/min results in cyanide formation at a far greater rate than humans can detoxify. Sodium nitroprusside has also been demonstrated to cause cytotoxicity through the release of nitric oxide, with hydroxyl radical and peroxynitrite generation leading to lipid peroxidation.[139-142] Considering the potential for severe toxicity with nitroprusside, this drug should only be used when other intravenous antihypertensive agents are not available and then, only in specific clinical circumstances in patients with normal renal and hepatic function.[128] An initial starting dose should be 0.5 µg/kg/min and then titrated as tolerated. The duration of treatment should be as short as possible and the infusion rate should not be >2 µg/kg/min. Drugs 2008; 68 (3)

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An infusion of thiosulfate should be used in patients receiving higher dosages (4–10 µg/kg/min) of sodium nitroprusside.[137]

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with significant toxicities and/or adverse effects. Newer agents, such as clevidipine and fenoldopam, may hold considerable advantages to other available agents in the management of hypertensive crises.

4. Conclusion Acknowledgements The primary goal of intervention in a hypertensive crisis is to safely reduce BP. The appropriate therapeutic approach of each patient will depend on their clinical presentation. Safe and efficacious management of the patient experiencing hypertensive crises requires the physician to discriminate the crisis as either a hypertensive urgency or hypertensive emergency. Rapid antihypertensive therapy is not warranted in patients with hypertensive urgencies (i.e. a hypertension crisis associated with severe elevations in BP without progressive end-organ dysfunction). Conversely, immediate BP reduction is indicated in patients experiencing hypertensive emergencies (i.e. a hypertension crisis characterized by severe elevations in BP [>180/120 mmHg] complicated by evidence of impending or progressive target-organ dysfunction) to prevent progressive end-organ damage. Hypertension associated with cerebral infarction or intracerebral haemorrhage requires treatment under special circumstances and the use of pharmacological agents must be tailored to each patient’s condition. It should be noted that currently there are no widely accepted guidelines for the treatment of hypertension associated with cerebral infarction or intracerebral haemorrhage. Patients with hypertensive emergencies are best treated in an ICU with titratable intravenous hypotensive agents. Several rapid-acting intravenous antihypertensive agents are available, including labetalol, esmolol, fenoldopam, nicardipine and sodium nitroprusside. While sodium nitroprusside is commonly used to treat severe hypertension, it is an extremely toxic drug that should be used only in rare circumstances. If the use of sodium nitroprusside cannot be avoided, it should not be used at a dose that exceeds 2 µg/kg/min. Similarly, nifedipine, nitroglycerin and hydralazine should not to be considered acceptable therapies in the management of hypertensive crises because these agents are associated © 2008 Adis Data Information BV. All rights reserved.

The author would like to thank Dr Richard Pistolese for his assistance in the preparation and review of this article. The author did not receive support of any kind in the form of equipment, drugs or grants related to this article. The author has received honoraria for lectures from PDL Pharmaceuticals, Eli Lilly & Company and The Medicines Company, and has served as a consultant for The Medicines Company.

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110. Weber RR, McCoy CE, Ziemniak JA, et al. Pharmacokinetic and pharmacodynamic properties of intravenous fenoldopam, a dopamine1-receptor agonist, in hypertensive patients. Br J Clin Pharmacol 1988 Jan; 25 (1): 17-21 111. Bedford Laboratories. Fenoldopam mesylate injection USP prescribing information [online]. Available from URL: http:// www.bedfordlabs.com/products/inserts/fenoldopam_pi.pdf [Accessed 2007 Jul 16] 112. Shusterman NH, Elliott WJ, White WB. Fenoldopam, but not nitroprusside, improves renal function in severely hypertensive patients with impaired renal function. Am J Med 1993 Aug; 95 (2): 161-8 113. Elliott WJ, Weber RR, Nelson KS, et al. Renal and hemodynamic effects of intravenous fenoldopam versus nitroprusside in severe hypertension. Circulation 1990 Mar; 81 (3): 970-7 114. White WB, Halley SE. Comparative renal effects of intravenous administration of fenoldopam mesylate and sodium nitroprusside in patients with severe hypertension. Arch Intern Med 1989 Apr; 149 (4): 870-4 115. Ng TM, Shurmur SW, Silver M, et al. Comparison of Nacetylcysteine and fenoldopam for preventing contrast-induced nephropathy (CAFCIN). Int J Cardiol 2006 May 24; 109 (3): 322-8 116. Pannu N, Wiebe N, Tonelli M. Prophylaxis strategies for contrast-induced nephropathy. JAMA 2006 Jun 21; 295 (23): 2765-79 117. Tumlin JA, Finkel KW, Murray PT, et al. Fenoldopam mesylate in early acute tubular necrosis: a randomized, double-blind, placebo-controlled clinical trial. Am J Kidney Dis 2005 Jul; 46 (1): 26-34 118. Landoni G, Biondi-Zoccai GG, Tumlin JA, et al. Beneficial impact of fenoldopam in critically ill patients with or at risk for acute renal failure: a meta-analysis of randomized clinical trials. Am J Kidney Dis 2007 Jan; 49 (1): 56-68 119. Schroeder HA. Effects on hypertension of sulfhydryl and hydrazine compounds. J Clin Invest 1951 Nov; 30 (5): 672-3 120. Shepherd AM, Ludden TM, McNay JL, et al. Hydralazine kinetics after single and repeated oral doses. Clin Pharmacol Ther 1980 Dec; 28 (6): 804-11 121. Ludden TM, Shepherd AM, McNay JL, et al. Hydralazine kinetics in hypertensive patients after intravenous administration. Clin Pharmacol Ther 1980 Dec; 28 (6): 736-42 122. O’Malley K, Segal JL, Israili ZH, et al. Duration of hydralazine action in hypertension. Clin Pharmacol Ther 1975 Nov; 18 (5 Pt 1): 581-6 123. Gerber JG, Nies AS. Antihypertensive agents and the drug therapy of hypertension. In: Goodman LS, Gilman A, Gilman AG, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 8th ed. New York (NY): Pergamon Press, 1990: 784-813 124. Straka RJ, Lohr B, Borchardt-Phelps P, et al. Antihypertensive agents. In: Irwin RS, Cerra FB, Rippe JM, editors. Intensive care medicine. 3rd ed. Boston (MA): Little Brown, 1996: 2286-317 125. Bussmann WD, Kenedi P, von Mengden HJ, et al. Comparison of nitroglycerin with nifedipine in patients with hypertensive crisis or severe hypertension. Clin Investig 1992 Dec; 70 (12): 1085-8 126. Parke Davis Pharmaceuticals Ltd. Nitrostat® (nitroglycerin tablets, USP) prescribing information [online]. Available from URL: http://www.pfizer.com/pfizer/download/uspi_nitrostat.pdf [Accessed 2007 Jul 16]

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Acute Severe Hypertension

127. Friederich JA, Butterworth JFT. Sodium nitroprusside: twenty years and counting. Anesth Analg 1995 Jul; 81 (1): 152-62 128. Robin ED, McCauley R. Nitroprusside-related cyanide poisoning: time (long past due) for urgent, effective interventions. Chest 1992 Dec; 102 (6): 1842-5 129. Hartmann A, Buttinger C, Rommel T, et al. Alteration of intracranial pressure, cerebral blood flow, autoregulation and carbondioxide-reactivity by hypotensive agents in baboons with intracranial hypertension. Neurochirurgia (Stuttg) 1989 Mar; 32 (2): 37-43 130. Kondo T, Brock M, Bach H. Effect of intra-arterial sodium nitroprusside on intracranial pressure and cerebral autoregulation. Jpn Heart J 1984 Mar; 25 (2): 231-7 131. Griswold WR, Reznik V, Mendoza SA. Nitroprusside-induced intracranial hypertension. JAMA 1981 Dec 11; 246 (23): 2679-80 132. Anile C, Zanghi F, Bracali A, et al. Sodium nitroprusside and intracranial pressure. Acta Neurochir (Wien) 1981; 58 (3-4): 203-11 133. Mann T, Cohn PF, Holman LB, et al. Effect of nitroprusside on regional myocardial blood flow in coronary artery disease: results in 25 patients and comparison with nitroglycerin. Circulation 1978 Apr; 57 (4): 732-8 134. Cohn JN, Franciosa JA, Francis GS, et al. Effect of short-term infusion of sodium nitroprusside on mortality rate in acute myocardial infarction complicated by left ventricular failure: results of a Veterans Administration cooperative study. N Engl J Med 1982 May 13; 306 (19): 1129-35 135. Tumlin JA, Dunbar LM, Oparil S, et al. Fenoldopam, a dopamine agonist, for hypertensive emergency: a multicenter randomized trial. Fenoldopam Study Group. Acad Emerg Med 2000 Jun; 7 (6): 653-62

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136. Pasch T, Schulz V, Hoppelshauser G. Nitroprusside-induced formation of cyanide and its detoxication with thiosulfate during deliberate hypotension. J Cardiovasc Pharmacol 1983 Jan-Feb; 5 (1): 77-85 137. Hall VA, Guest JM. Sodium nitroprusside-induced cyanide intoxication and prevention with sodium thiosulfate prophylaxis. Am J Crit Care 1992 Sep; 1 (2): 19-25; quiz 6-7 138. Izumi Y, Benz AM, Clifford DB, et al. Neurotoxic effects of sodium nitroprusside in rat hippocampal slices. Exp Neurol 1993 May; 121 (1): 14-23 139. Niknahad H, O’Brien PJ. Involvement of nitric oxide in nitroprusside-induced hepatocyte cytotoxicity. Biochem Pharmacol 1996 Apr 26; 51 (8): 1031-9 140. Gobbel GT, Chan TY, Chan PH. Nitric oxide- and superoxidemediated toxicity in cerebral endothelial cells. J Pharmacol Exp Ther 1997 Sep; 282 (3): 1600-7 141. Nakamura Y, Yasuda M, Fujimori H, et al. Cytotoxic effect of sodium nitroprusside on PC12 cells. Chemosphere 1997 Feb; 34 (2): 317-24 142. Rauhala P, Khaldi A, Mohanakumar KP, et al. Apparent role of hydroxyl radicals in oxidative brain injury induced by sodium nitroprusside. Free Radic Biol Med 1998 May; 24 (7-8): 106573

Correspondence: Professor Joseph Varon, 2219 Dorrington St, Houston, TX 77030-3209, USA. E-mail: [email protected]

Drugs 2008; 68 (3)

Drugs 2008; 68 (3): 299-317 0012-6667/08/0003-0299/$53.45/0

REVIEW ARTICLE

© 2008 Adis Data Information BV. All rights reserved.

Locally Advanced and Metastatic Gastric Cancer Current Management and New Treatment Developments Kathryn Field,1 Michael Michael1 and Trevor Leong1,2 1 2

Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia University of Melbourne, Melbourne, Victoria, Australia

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 1. Commonly Used Chemotherapy Regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 1.1 Epirubicin, Cisplatin plus Fluorouracil (ECF) and Other Combinations . . . . . . . . . . . . . . . . . . . . . . 301 1.2 Taxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 1.3 Oxaliplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 1.4 Irinotecan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 1.5 Oral Fluoropyrimidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 1.5.1 Capecitabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 1.5.2 S-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 1.5.3 Tegafur/Uracil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 1.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 2. Targeted Therapies and Novel Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 2.1 Bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 2.2 Cetuximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 2.3 Gefitinib and Erlotinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 2.4 Trastuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 2.5 Bortezomib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 2.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 3. New Developments in Locally Advanced Gastric Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 4. On the Horizon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 4.1 Pharmacogenomic Profiling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 4.2 Vaccine Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 4.3 Intraperitoneal Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 4.4 Novel Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312

Abstract

The management of gastric cancer remains a challenge. In recent years, the most important advances have been achieved in the adjuvant setting for patients with locally advanced disease, where significant survival benefits have been demonstrated for both perioperative chemotherapy and adjuvant chemoradiotherapy. These findings have changed the standard of care for patients with resectable disease. In the setting of metastatic gastric cancer, the development of new cytotoxic regimens must consider the balance between efficacy and toxicity in patients

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whose overall prognosis is poor. Major advances in recent years include the development of orally administered fluoropyrimidine analogues, which can be used in place of intravenous fluorouracil, and the addition of newer agents such as oxaliplatin and docetaxel, which have demonstrated efficacy in patients with advanced disease. Targeted therapies have had a major impact on the management of certain malignancies, and while their evaluation in the treatment of advanced gastric cancer remains early, it is likely that these agents will continue to be developed and studied in combination with chemotherapy. This article reviews recent advances in the use of chemotherapy for advanced gastric cancer. Targeted therapies, their mechanisms of action and emerging data supporting their use in gastric cancer are also discussed. The two randomized phase III trials supporting adjuvant therapy for locally advanced, resectable gastric cancer are discussed in detail, together with strategies for future trials in this area. Overall, there remains optimism that further incremental gains will be achieved with future studies combining chemotherapy, radiotherapy and targeted therapies, both in the adjuvant and metastatic disease settings.

Gastric cancer is a common malignancy that, despite considerable research effort, remains difficult to treat and carries a poor prognosis. The National Cancer Institute SEER (Surveillance Epidemiology and End Results) database projected over 11 000 deaths from gastric cancer in the US for 2007 alone, despite having one of the lowest incidence rates in the world.[1] There is a large geographical variation in incidence rates. In Eastern Asia, 46 per 100 000 males and 21 per 100 000 females develop gastric cancer, compared with world figures of 22 (male) and 10 (female) per 100 000. Gastric cancer is the second most common cause of cancer-related death in the world (after lung cancer), and globally 700 000 deaths annually are attributed to the disease.[2] Even those initially treated with curative intent have a 60% chance of developing loco-regional or distant metastatic disease,[3] and the median survival with metastatic disease is generally 39°C) and spiking, usually daily and occasionally twice daily.[39] The spike is usually observed late in the afternoon or early evening and resolves spontaneously.[40] Fever is considered to be a prerequisite for the diagnosis, as its overall incidence in five of the largest retrospective studies was estimated to be 95.7%.[1] Symptoms that occasionally precede the fever or rash and that should raise suspicion about the underlying cause include sore throat, seen in more than 70% of patients, as well as constitutional symptoms such as anorexia, myalgia or arthralgia, fatigue, nausea and weight loss. Wasting, evidenced by metabolic markers, such as low albumin levels, tends to follow the inflammatory activity of the disease.[41] 1.2.2 Still’s Rash

The rash, which is often named ‘Still’s rash’, after the disease, is characterized by evanescence, salmon-pink colour and morbilliform maculopapular eruptions. It commonly involves the proximal limbs and the trunk, while rarely affecting the face and distal limbs. It presents typically during the febrile attacks, can be mildly pruritic, and is frequently mistaken for a pharmacogenic rash.[39,40] The appearance of new skin lesions in areas previously traumatized, known in the literature as ‘Koebner’s phenomenon’, has been reported. Skin Drugs 2008; 68 (3)

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Diagnostic approach in AOSD • • • •

• Viral syndromes • Reactive arthritis • Other systemic rheumatic diseases (dermatomyositis, etc.) • Kikuchi's lymphadenitis • Haemophagocytic syndrome (primary, infection, or malignancyassociated) • Haematological malignancies

Clinical suspicion in the presence of symptoms

Exclusion of other systemic conditions

Laboratory evidence indicative of the disease

Radiographic evaluation of the disease

Fever Rash Arthritis Septicaemia-like presentation • At least three negative blood cultures • Failure of antibacterials • Response to corticosteroids

• −ve RF and ANA • ↑ CRP and ESR • Serum ferritin >1000 ng/mL • Glycosylated fraction of ferritin 10.0 x 109/L • Mild normocytic anaemia • Reactive thrombocytosis

Fig. 1. Diagnostic approach to adult-onset Still’s disease (AOSD). ANA = antinuclear antibodies; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; RF = rheumatoid factor; WBC = white blood cell; ↑ indicates increased; ↓ indicates decreased; –ve = negative.

biopsy of the affected areas reveals a picture of chronic inflammation with a perivascular mononuclear preponderance, vascular dilation and dermal oedema.[14] The mean incidence of Still’s rash has been estimated to be as high as 72.7% in a retrospective analysis of large series of AOSD patients.[1] 1.2.3 Arthritis

Clinically, AOSD closely resembles its paediatric sibling, sudden-onset JIA. Arthritis is a prominent feature of the disease with an overall estimated prevalence ranging from 64% to 100%.[1] Arthritis may initially present as oligoarthritis (i.e. involving fewer than four joints, and then develop into polyarthritis, affecting both large and small joints).[41] Although joint involvement does not follow a specific pattern, it seems that knees, wrists and ankles are the © 2008 Adis Data Information BV. All rights reserved.

most commonly affected. Other sites involved include elbows, shoulders, proximal and distal interphalangeal joints, metacarpophalangeal (and metatarsophalangeal) joints, temporomandibular joints and hip joints. Ankylosing carpal arthritis seems to be a consistent feature of late (1–3 years after onset) AOSD, preceded by gradual, selective, carpometacarpal and intercarpal non-erosive joint space narrowing.[42] Notably, this pericapitate pattern of arthritic involvement has been suggested to be a differential diagnostic characteristic between AOSD and rheumatoid arthritis (RA).[43] Severe involvement of the hip joint, leading to bilateral hip destruction in nine patients in less than 4 years has been reported from a French group, although the finding has not been supported by other series.[44] Drugs 2008; 68 (3)

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Table II. The most commonly used diagnostic criteria for adult-onset Still’s disease (AOSD) Reference

Minor criteria

Diagnosis

Yamaguchi et al.[35] 1. Fever ≥39°C, lasting ≥1 week (sensitivity 96.2%; 2. Arthralgia lasting ≥2 weeks specificity 92.1%) 3. Typical rash 4. Leukocytosis (≥10 000/mm3) including ≥80% of granulocytes

Major criteria

1. Sore throat 2. Lymphadenopathy and/or splenomegaly 3. Liver dysfunction 4. Negative RF and negative ANA

Exclusions: 1. Infections (especially sepsis and infectious mononucleosis) 2. Malignancies (especially malignant lymphoma) 3. Rheumatic diseases (especially polyarteritis nodosa and rheumatoid vasculitis with extraarticular features) Classification of AOSD requires: 5 or more criteria including 2 or more major criteria

Cush et al.[36] (sensitivity 84%)

(1 point) 1. Onset 39°C 2. Still’s (evanescent) rash 3. WBC count >12 000/mm3 + ESR >40 mm/h 4. Negative RF and ANA 5. Carpal ankylosis

1. Spiking fever ≥39°C 1. Maculopapular rash Classification of AOSD requires: 4 or more 2. Arthralgia 2. Leukocytes ≥10 000/mm3 major criteria or 3 major criteria + 2 minor 3. Transient erythema criteria 4. Pharyngitis 5. PMN ≥80% 6. Glycosylated ferritin ≥20% ANA = antinuclear antibodies; ESR = erythrocyte sedimentation rate; LFT = liver function test; PMN = polymorphonuclear leukocytes; RES = reticuloendothelial system; RF = rheumatoid factor; WBC = white blood cell. Fautrel et al.[37] (sensitivity 80.6%; specificity 98.5%)

1.2.4 Liver Abnormalities

Liver pathology, as indicated by hepatomegaly on physical examination, and elevated aminotransferases in laboratory tests, is seen in approximately 50–75% of patients.[6,8,14] Abnormal liver function is thought to be part of the inflammatory process of the disease itself, yet concomitant use of potentially hepatotoxic treatments often complicates the causative mechanisms of the biochemical picture.[15,39] Fulminant hepatic failure requiring liver transplantation is extremely rare.[45,46] 1.2.5 Other Less Common Manifestations

AOSD can affect all organ systems with great variability. Serositis, in the form of pleuritis and pericarditis, can be encountered in the clinical picture of AOSD, although this is rare. Splenomegaly has been reported in 43.9% of cases.[1] Pulmonary manifestations extend from fibrosis and pleural effusions to adult respiratory distress syndrome in very rare cases.[47-49] Cardiac tamponade and myocarditis leading to fibrinoid necrosis have also been infrequently reported.[50] Renal involvement can © 2008 Adis Data Information BV. All rights reserved.

take place in the form of interstitial nephritis, subacute glomerulitis, renal amyloidosis or collapsing glomerulopathy.[51-54] Reactive haemophagocytic syndrome (RHS), characterized by unrestrained Tcell and macrophage proliferation with cytokine overproduction, although rare, may be life-threatening and may have a higher incidence in AOSD than in those with other inflammatory diseases.[55] Thrombocytopenia or absence of hyperleukocytosis, lymphopenia, coagulopathy and high triglyceride levels are prominent features of this complication.[55] Finally, AOSD can be complicated by thrombotic thrombocytopenic purpura, pure red aplasia or can present with neurological complications such as cranial neural palsies, seizures or aseptic meningoencephalitis.[6,8,56,57] 1.3 Laboratory and Radiographic Abnormalities

Although the diagnosis of AOSD remains clinical, certain laboratory abnormalities may play a role in helping clinicians establish a diagnosis. Drugs 2008; 68 (3)

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Immune dysregulation of AOSD is generally not reflected by positive titres of rheumatoid factor or antinuclear antibodies as in other rheumatic diseases, and the absence of positive titres of these markers has been used as a classification criterion.[1,35] 1.3.1 Acute Phase Reactants

The erythrocyte sedimentation rate (ESR) is invariably elevated in AOSD patients,[8,39] as is generally the case with CRP,[21] serum amyloid A,[19] haptoglobin and serum complement.[6] A characteristic laboratory abnormality, although not necessarily diagnostic, is the often extreme, elevated serum level of ferritin, a known acute phase protein. The underlying mechanism of high ferritin levels seems to be irrelevant to its role in iron metabolism. It is probably the by-product of the uninhibited action of cytokines, such as IL-1β, IL-18, TNFα and IL-6, which ‘whip’ the reticuloendothelial system into producing and releasing massive amounts of ferritin.[26] Elevated serum ferritin levels (approximately 1000 ng/mL), higher than five times the upper limits of normal (40–200 ng/mL) may suggest the presence of the disease with an 80% sensitivity and 46% specificity.[58,59] Much higher ferritin levels, ranging up to 30 000 ng/mL, are not infrequent.[41] Ferritin has been proposed to be a very useful marker of disease activity, as its levels correlate with clinical scores and tend to predict clinical response to treatment.[60-62] Its low specificity reflects the fact that high ferritin levels can also be found in several other conditions such as liver disease (e.g. haemochromatosis, Gaucher’s disease), infections (e.g. sepsis, HIV), malignancies (e.g. leukaemia, lymphoma) and RHS.[41,55,59] The glycosylated fraction of ferritin, which tends to drop in inflammatory diseases, is consistently found below 20% in AOSD,

making it a more specific marker of the disease.[37,58,59] Fautrel et al.[58] combined the 5-fold increase of serum ferritin with its characteristically low glycosylated fraction increasing the specificity (93%) but lowering the sensitivity (43%) of this diagnostic tool. Unfortunately, except from a few designated centres, it is not a widely available biochemical test, so its use is not meaningful in everyday clinical practice. Another novel candidate acute phase marker of AOSD, which can also be useful in the differential diagnosis of diseases characterized by high ferritin levels, is haem oxygenase 1 (HO-1). HO-1 has antiinflammatory properties that are mediated by haem’s degradation products. HO-1 levels were significantly higher in patients with active haemophagocytic syndrome and AOSD than in other rheumatic diseases and its levels correlated well with serum ferritin. Additionally, serum levels of both ferritin and HO-1 returned to normal after treatment. Of interest, hyperferritinaemia caused by liver diseases or frequent transfusions due to haematological diseases is not associated with increased HO-1 levels.[63] 1.3.2 Haematological Abnormalities

The most commonly associated laboratory finding in AOSD is, without doubt, the leukocytosis (predominantly neutrophilic) resulting from bone marrow granulocyte hyperplasia.[64] Peripheral blood leukocyte counts >15 × 109/L were found in 50% of 62 patients, while counts >20 × 109/L were encountered in 37% of cases in the same series.[8] Anaemia of chronic disease is frequently seen during flares, in contrast to periods of remission when haemoglobin values tend to normalize. Reactive thrombocytosis is common. Importantly, if the opposite (i.e. thrombocytopenia) is present, then

Table III. Patterns of adult-onset Still’s disease and prognostic features Patterns

Features

Prognosis

Self limiting/monocyclic

Systemic symptoms such as fever, rash, serositis, organomegaly

Majority of patients achieve remission within 1 year of initial episode. Favourable prognosis

Intermittent/polycyclic systemic

Recurrent flares with or without articular symptoms

Complete remission between episodes that tend to be far apart and milder than initial episode

Chronic articular

Predominance of articular symptoms

Joint destruction may occur, necessitating surgical intervention. Unfavourable prognosis

© 2008 Adis Data Information BV. All rights reserved.

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RHS, a life-threatening complication of AOSD requiring immediate immunosuppressive treatment, should be strongly suspected.[55,64] Coagulation abnormalities are infrequent and reflected by prolonged times of prothrombin and partial thromboplastin. Rarely, disseminated intravascular coagulation has been reported.[8] 1.3.3 Radiographic Imaging Techniques

Initially, as expected, radiographs do not provide any specific diagnostic information except for possible tissue swelling, joint effusion, mild periarticular demineralization or even normal anatomy.[8] Years later, if the disease follows the chronic articular form, a distinctive radiographic pattern of intercarpal, pericapitate ankylosis may become apparent. Additionally, intertarsal and cervical zygapophyseal ankylosis has been noted to occur in 19% and 12% of patients with AOSD, respectively.[41] Also, in the chronic articular form, Fujii et al.[65] have proposed the ‘carpo-metacarpal ratio’ as a radiographic quantitative index of carpal joint involvement. 2. Conventional Treatment of AOSD Until very recently, AOSD was treated with NSAIDs, systemic corticosteroids and traditional immunosupressants, with methotrexate being the most common immunosupressants. 2.1 NSAIDs

Since the initial description of AOSD in 1971, our understanding of its underlying inflammatory mechanisms has evolved alongside the development of anti-inflammatory drugs. At the time of the initial description of the disease, the most widely used antiinflammatory drugs were NSAIDs and corticosteroids. Therefore, it is understandable why NSAIDs were initially investigated as treatment for the disease, in an effort to oppose the overt inflammatory response. NSAIDs work through inhibition of the cyclo-oxygenase enzyme, thus impairing the transformation of arachidonic acid to prostaglandins, prostacyclin and thromboxanes.[66] Early studies were disappointing, as they demonstrated minimal efficacy of NSAIDs as monotherapy in only 7–15% © 2008 Adis Data Information BV. All rights reserved.

of patients.[6,8] A subsequent larger, multicentre, randomized French study confirmed the previous results, providing a comparative description of the most prevalent treatment options at that time (i.e. aspirin, NSAIDs and corticosteroids).[67] This study made it clear that aspirin was ineffective, suggested a modest, adjunct role for NSAIDs, such as naproxen or indomethacin, and clearly showed that 88% of the patients studied eventually required corticosteroids for symptomatic control.[39] 2.2 Corticosteroids

When NSAIDs were proven ineffective, the use of corticosteroids came to the therapeutic forefront owing to their potent anti-inflammatory actions. These actions include inhibition of the production of proinflammatory cytokines such as TNFα and IL-1 by macrophages and lymphocytes,[68] modulation of the signalling pathway of IFNγ,[69] induction of lymphocyte apoptosis,[70] inhibition of lymphocyte proliferation[71] and inhibition of phospholipase A2, thereby blocking the production of prostaglandin and leukotrienes.[72] Most studies support the need for corticosteroids in the majority of patients at some point in the course of the disease.[26] Prednisone proved to be a reliable anti-inflammatory agent in a study of 45 patients where 76% of them experienced improvement of their symptoms.[9] The initial dose of prednisone is usually 0.5–1.0 mg/kg/day administered orally. In refractory cases, intravenous pulse methylprednisolone and dexamethasone have been used successfully.[73,74] Despite their success in suppressing both systemic and articular symptoms, they appear to be ineffective in modifying the progressive anatomical, and radiographically evident, joint destruction in the chronic articular form of the disease.[16] Long-term corticosteroid use is marred by clinically significant adverse events. Thinning of the skin, cataracts, hypertension, hyperlipidaemia and osteoporosis are among the common ones. Management of cardiovascular risk factors and preventive administration of calcium, vitamin D and bisphosphonates are all indicated for patients taking corticosteroids for long periods of time. Other adverse Drugs 2008; 68 (3)

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effects include gastritis, infection, diabetes mellitus and mood changes.[75] 2.3 Disease-Modifying Antirheumatic Drugs

The use of a disease-modifying antirheumatic drug (DMARD) during the course of AOSD treatment often becomes a necessity in refractory cases where corticosteroids have been given at therapeutic doses without signs of remission, or as corticosteroid-sparing agents.[1] Additionally, given the fact that a portion of symptom-free patients develop destructive arthritis despite treatment with corticosteroids,[4,9,67] it has become common practice to add a DMARD early in the course of the disease, especially in patients with the prolonged febrile, polycyclic, or chronic articular disease patterns.[19] Apart from methotrexate, other DMARDs used to treat AOSD with variable efficacy are ciclosporin,[76] hydroxychloroquine, gold, penicillamine, azathioprine, leflunomide,[39,77] cyclophosphamide[78] and tacrolimus.[79] 2.3.1 Methotrexate

The efficacy of methotrexate in AOSD can probably be attributed to its pharmacological mechanism, which is characterized by increased adenosine release and activity. This results from inhibition of the enzyme aminoimidazolecarboxamidoadenosineribonucleotide transformylase, which, in turn, leads to inhibition of adenosine-degrading enzymes such as adenosine deaminase and adenosine monophosphate deaminase.[80] Adenosine interferes with neutrophil function and the synthesis of proinflammatory cytokines, such as TNFα and IL-6, that seem to play an important role in AOSD pathogenesis.[81,82] Similar to its use in RA, methotrexate is administered orally, once a week, in doses up to 30 mg/week.[1] Bearing in mind the recurrent nature of the disease, its low prevalence and the different clinical courses it may manifest, the execution of doubleblind, randomized trials using different therapeutic protocols is difficult. As a result, treatment of refractory cases of AOSD with methotrexate was initially empirical, based on extrapolated data from its effective use in treating RA and systemic-onset JIA. © 2008 Adis Data Information BV. All rights reserved.

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In a study of 26 patients who did not respond to corticosteroids or who developed potentially serious adverse effects, 18 (69%) achieved complete remission and 11 (42%) were able to remain symptom free without taking corticosteroids when a low dose (7.5–17.5 mg) of methotrexate was administered.[83] Another retrospective study of 13 Japanese patients not only confirms methotrexate’s efficacy in controlling disease activity but also suggests methotrexate be used in patients who have not previously been treated with conventional agents such as corticosteroids.[84] In another smaller corroborating study, a weekly 10-mg dose of methotrexate proved to be useful in reducing acute symptoms in four of six patients, although the risk of flare recurrence was not reduced. In addition, it was suggested that a 6month treatment should be considered to allow the methotrexate treatment to take effect.[85] An 85% reduction in corticosteroid dosage in a French study of 13 patients adds to the undoubted value of methotrexate in treating patients not tolerating corticosteroid adverse effects.[67] Methotrexate has been used both alone and in combination with biological agents, which are starting to gain popularity in AOSD treatment because of their promising results.[86-99] Because the treatment regimen in AOSD patients is established in a stepwise manner depending on its efficacy and tolerability, comparative prospective trials investigating methotrexate monotherapy and methotrexate in combination with a biological agent are rare. Methotrexate was first indicated for RA in the early 1980s and, therefore, it has a long-studied safety profile. In general, long-term experience shows that methotrexate is relatively safe provided that monthly full blood counts and liver function tests are performed. Most of its adverse reactions are caused by its antifolate activity. While in RA folate coadministration has proved to be beneficial, especially regarding its oral and gastrointestinal adverse effects,[100] in AOSD, randomized, controlled trials are yet to be carried out. Additionally, there is much scepticism about the fact that folate supplementation undermines methotrexate efficacy via a competitive affinity of folinic acid and methotrexate for the same Drugs 2008; 68 (3)

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cellular transport molecules.[101,102] This explains the lack of consensus concerning folate supplementation in the treatment scheme of either RA or AOSD patients. Adverse reactions in AOSD patients treated with methotrexate include gastrointestinal symptoms such as vomiting and nausea, mouth ulcers, headache, acute interstitial pneumonia, liver toxicity, blood test abnormalities, such as neutropenia[83,84] or pancytopenia,[103] and opportunistic infections.[104] Although most of these adverse effects have a relatively strong causal relationship with methotrexate, the cause of the liver toxicity remains to be elucidated. AOSD is well known to cause a large spectrum of liver abnormalities, from abnormal laboratory tests, such as elevated transaminases, to a rare form of cytolytic hepatitis and liver failure,[14,15,105,106] although most of the time patients remain asymptomatic. In a European single-centre study of 17 patients, 76% demonstrated abnormal biochemical liver indices and 47% had hepatomegaly at clinical examination.[15] Thus, it is hard for clinicians to interpret liver abnormalities in that many available treatment modalities, even the more ‘innocent’ ones such as NSAIDs, have the potential to cause liver toxicity. However, recommended NSAID doses for AOSD, far from being able to induce drug-related hepatitis, usually lead to a complete clinical and biological recovery in 3 weeks, even in cases of severe hepatitis.[15,67] Liver toxicity, in the form of elevated liver function tests, even due to low-dose methotrexate has been reported in patients with RA, especially in the initial treatment stages, [107,108] as well as in AOSD patients.[84] Nevertheless, in cases of life-threatening hepatitis, treatment options should be chosen cautiously, as fulminant hepatic failure has been reported in AOSD patients.[45,109] Methotrexate, used to treat other rheumatological disorders, has been known to cause opportunistic infections, particularly of the upper respiratory tract,[110] such as histoplasmosis in a child with JIA.[111] In addition, patients with RA or JIA treated with methotrexate seem to be prone to haematological malignancies such as lymphoma, especially Epstein-Barr virus-associated lymphoma.[112,113] © 2008 Adis Data Information BV. All rights reserved.

Kontzias & Efthimiou

2.3.2 Intravenous Immunoglobulins

Intravenous immunoglobulin (IVIG) constitutes a mixture of pooled polyspecific IgG derived from the blood of healthy human donors.[114] They have long been used as immunomodulating agents in the treatment of several autoimmune and inflammatory diseases such as Kawasaki’s disease[115] and JIA.[116] Bearing in mind that IVIG possesses potent antiinflammatory activity, as evidenced by its beneficial effects on inflammatory diseases, it seemed logical that it would act similarly in AOSD. The body of evidence pointing to the efficacy of IVIG in NSAID-refractory cases of AOSD is not vast and data collected mostly originate from small, uncontrolled, nonblinded studies and case reports.[117-120] In such a study, four of seven patients treated early with IVIG achieved remission, suggesting that use of IVIG prior to corticosteroids can lead to early control of the disease.[118] IVIG in combination with mycophenolate mofetil in an African man with refractory AOSD proved to be beneficial at a dose of 0.4 g/kg daily for 5 days.[51] The favourable effect of IVIG in AOSD could be explained by its multifactorial mechanisms of action. Among them, modulation of the distorted cytokine network,[114] which in AOSD is skewed in favour of Th1 cytokines, can be inferred to be the prevalent mechanism.[29] Of interest, published data suggest that IVIG plays a significant role in restoring the existing imbalance of Th1 and Th2 in various autoimmune diseases.[114] In view of the plausible efficacious IVIG treatment of patients with AOSD, clinical trials to document its results are imperative. Most of the adverse effects of IVIG are mild and transient, and include headache, flushing, fever, chills, nausea, fatigue, myalgia, arthralgia, back pain and, especially in patients at risk for hypertension, elevated blood pressure.[114] Elderly patients who are not well hydrated are prone to develop oliguric acute renal failure, which is transient and preventable with sufficient hydration and a slow infusion rate. Thromboembolic complications are an additional issue particularly in high-risk patients such as in those who are immobilized for prolonged periods or those with diabetes.[114,121] Aseptic meningitis is a rare adverse effect, which resolves spontaneously Drugs 2008; 68 (3)

Adult-Onset Still’s Disease

and can be prevented with administration of NSAIDs.[122] Rarely, anaphylactic reactions have been reported in patients who were IgA deficient, but careful screening and administration of IgAdepleted immunoglobulin to these patients is the proper course of action.[114,123] Anaphylaxis in patients with IgA deficiency treated with IVIG is correlated with the presence of anti-IgA antibodies of the IgG and IgE isotypes in the patients’ serum.[124] 2.3.3 Ciclosporin, Chloroquine, Gold, Penicillamine, Azathioprine, Cyclophosphamide and Tacrolimus

The use of combinations of DMARDs became prevalent in non-remissive AOSD patients in an effort to explore other potential therapeutic strategies or to minimize adverse effects of the existing regimens. Considering the diverse immunogenetic background, which might play a role in the therapeutic response in AOSD patients, investigators attempted to override mechanisms of resistance by administering a series of immunosuppressive agents. Nevertheless, their efficacy remains equivocal. Wouters and van de Putte[39] demonstrated a mere 44% (8 of 18 trials) clinical improvement with one or several of the following: chloroquine (0 of 3 responded), gold (6 of 8), penicillamine (4 of 6) and azathioprine (0 of 1). In a more recent study of 65 patients who received corticosteroids in combination with either methotrexate or chloroquine as first-line treatment, it was demonstrated that 21 of 28 (75%) responded to a corticosteroid/chloroquine regimen and 30 of 36 (83%) responded to the corticosteroid/ methotrexate scheme.[17] In the same study, two patients treated initially with corticosteroids and azathioprine clinically improved, whereas a patient treated with a combination of corticosteroids and sulfasalazine failed to achieve remission.[17] Several case reports with diverse success have emerged in the literature, using agents such as ciclosporin,[76] tacrolimus,[79] combined leflunomide and azathioprine,[77] and cyclophosphamide.[47,125] © 2008 Adis Data Information BV. All rights reserved.

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3. New Treatments for AOSD: Biological Response Modifiers In light of the growing body of evidence on pathogenetic concepts of the disease and given the fact that many AOSD patients do not respond to the broadly accepted first-line treatment (methotrexate, prednisone ± NSAIDs), novel treatment modalities were sought (figure 2; table IV). These agents, well known for their efficacy in other inflammatory diseases, such as RA, target biological molecules, which seem to play a pivotal role in the mechanism of the disease. Consequently, inhibiting the action of proinflammatory cytokines, such as TNFα, IL-1 and IL-6, was a decisive step forward in the treatment of refractory AOSD patients. One of the first TNFα inhibitors put to the test in AOSD was etanercept. Etanercept is a fully humanized fusion protein constructed of two recombinant p75 soluble TNFα receptors (CD120b) linked to the Fc portion of human IgG1.[140] Additionally, etanercept binds TNFβ and, as opposed to infliximab, it does not lyse cells expressing transmembrane TNFα in the presence or absence of complement.[141] Of note, both etanercept and infliximab, apart from their TNFα-inhibiting effect, have proved to AOSD therapeutic approach

Low-dose prednisone +/– methotrexate Response

Yes • Regular clinical evaluation until complete remission • Periodic lab testing for disease markers (ferritin) and drug adverse effects (CBC, LFTs) as long as treatment is needed

No Addition of biological agent: First-line agents: IL-1 receptor antagonist (anakinra) Second-line agents: TNF inhibitors (infliximab > etanercept) or anti-IL-6 (tocilizumab)

Yes No Second-line agents: leflunomide, ciclosporin, IVIG, azathioprine, cyclophasphamide, tacrolimus, gold

Fig. 2. Therapeutic algorithm for adult-onset Still’s disease (AOSD). CBC = complete blood count; IL = interleukin; IVIG = intravenous immunoglobulin; lab = laboratory; LFT = liver function test; TNF = tumour necrosis factor; > indicates greater efficacy.

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Table IV. Retrospective overall outcome analysis of studies utilizing biological response modifiers in adult-onset Still’s disease Studies

No. of patients/cases

Total patients

Usual treatment scheme

44

Infliximab + DMARDs +

Remission

Infliximab Kraetsch et al.[126]

6

Dechant et al.[127]

8

Fautrel et al.[94]

91% (40/44)

corticosteroid

15

Kokkinos et al.[89]

4

Cavagna et al.[88]

3

Huffstutter and Sienknecht[90]

2

Caramaschi et al.[92]

1

Bonilla Hernan et al.[91]

2

Dilhuydy et al.[93]

1

Michel et al.[128]

1

Olivieri et al.[129]

1

Etanercept Husni et al.[87]

12

Fautrel et al.[94]

10

Serratrice et al.[130]

1

Kumari and Uppal[131]

1

Asherson and Pascoe[132]

1

25

Etanercept + methotrexate +

72% (18/25)

corticosteroid

Adalimumab Benucci et al.[95]

1

1

23

Adalimumab + methotrexate + corticosteroid

100% (1/1)

Anakinra Haraoui et al.[133]

4

Fitzgerald et al.[99]

4

Kotter et al.[134]

4

Kalliolias et al.[135]

4

Vasques Godinho et al.[136]

1

Rudinskaya and Trock[137]

1

Quartuccio and De Vita[138]

1

Chu et al.[139]

4

Anakinra + methotrexate +

91% (21/23)

corticosteroid

Tocilizumab Iwamoto et al.[96]

1

1

Tocilizumab + methotrexate + corticosteroid

100% (1/1)

DMARDs = disease-modifying antirheumatic drugs.

downregulate the T-cell production of IFNγ and granulocyte-macrophage colony-stimulating factor,[142] which are inferred to participate in the inflammatory process of the disease.[12,29,31] Etanercept is administered subcutaneously twice weekly at a dose of 25 mg. As with RA, etanercept is frequently coadministered with methotrexate, even if it is approved as monotherapy,[141] and has been similarly used in AOSD. In a 6-month, open-label pilot study in which 12 patients participated, 66.7% experienced amelio© 2008 Adis Data Information BV. All rights reserved.

ration of their symptoms after etanercept treatment. Nine of the patients received prednisone concomitantly and methotrexate was added to the treatment scheme of five patients during the study.[87] Several other case reports contribute to the usefulness of etanercept in refractory AOSD patients,[120,130,131] though larger double-blind cohort studies are required in order to validate its potential beneficial effects. Larger-scale etanercept studies may be executed taking into consideration several safety issues deDrugs 2008; 68 (3)

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rived from the long-term experience of its use in RA and JIA. A common adverse effect is injection site reaction, such as redness, pain, swelling and itching, particularly in the first month of treatment. Other frequent adverse effects that need to be addressed are mild upper respiratory tract infections, pharyngitis, respiratory disorders, dyspepsia, abdominal discomfort and rashes.[143] In a 4-year study of 34 patients with JIA who received etanercept, the rate of serious adverse effects was 0.13 per patient-year and the rate of serious infections was 0.04 per patientyear in a total etanercept exposure of 225 patientyears.[144] Nevertheless, blocking the activity of TNFα leads to a limited and defective protection against pathogenic organisms, especially opportunistic ones such as Mycobacterium tuberculosis, atypical species of Mycobacterium, Candida, Histoplasma, Cryptococcus and Listeria spp.[141,145,146] Infliximab is a genetically engineered chimeric monoclonal antibody, 75% human and 25% mouse in origin, which binds to soluble and transmembrane TNFα but not to TNFβ. The human portion accounts for its activity, whereas the mouse portion contains a variable region binding site. Infliximab has been shown in vitro to lyse cells expressing TNFα on their surface via complement and antibody-dependent cell-mediated cytotoxicity.[141] Infliximab is administered intravenously and after an initial infusion, it is administered at 2, 6 and then every 8 weeks thereafter.[147] This treatment scheme applies to RA, although AOSD patients have been treated similarly. Infliximab has been used successfully in refractory cases of AOSD. One of the first reports to demonstrate its efficacy was that of Cavagna et al.,[88] who administered infliximab (together with methotrexate and prednisone) in three patients at a dose of 3 mg/kg at weeks 0, 2, 6 and once every 8 weeks for 50 weeks. The overall scheme yielded very favourable results in terms of both clinical response (fever control) and inflammatory activity reflected by biochemical markers (ESR, CRP and serum ferritin).[88] A consequent corroborating small cohort study of six patients demonstrated very promising results as all patients achieved clinical © 2008 Adis Data Information BV. All rights reserved.

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remission early in the course of the disease, suggesting that early administration of TNFα inhibitors might have more beneficial results.[126] The latter is inferred in a case of early (1 month) AOSD where methotrexate was thought to be contraindicated because of hepatitis B virus (HBV) infection with persistent low titres of HBV DNA.[129] Ten AOSD patients unresponsive to methotrexate and corticosteroids achieved remission only after infliximab infusion in several open-label studies.[89-93] Although it is difficult to ascribe the clinical improvement of each patient to appropriate treatment because of the recurrent nature of the disease, it is postulated that anti-TNFα therapy may have a lasting beneficial effect, as five of eight patients treated with infliximab remained in remission in a 5-year follow-up period even after termination of treatment.[127] Infliximab and etanercept were investigated in a European, multicentre, observational study of 20 patients who were previously treated with high doses of methotrexate and corticosteroids without success. Clinical response was noted in patients with a systemic form of the disease as well as in patients with the polyarticular form. Most patients (16 of 25) responded partially to the treatment with either one of the agents (7 of 10 on etanercept and 9 of 15 on infliximab), while 5 of 20 achieved complete remission (four on infliximab and one on etanercept). Of interest, switching between TNFα antagonists does not seem to be as effective as it is in RA.[94] Adalimumab is a fully humanized monoclonal antibody, which binds both soluble and membrane TNFα, blocking the interaction with the p55 and p75 receptors. It has been shown to lyse cells expressing TNFα on their surface in the presence of complement.[141] Currently, it is indicated for clinical use in RA, psoriatic arthritis, ankylosing spondylitis and Crohn’s disease.[148] It is administered subcutaneously every week or every other week at a dose of 40 mg.[147] In AOSD, there is a single case report referring to clinical improvement in disease refractory to methotrexate and corticosteroids.[95] Overall, the experience with this agent is limited in AOSD, as it was the most recently approved by the US FDA anti-TNFα agent, and probably also beDrugs 2008; 68 (3)

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cause of the recent shift in attention to IL-1 inhibition, discussed in more detail in the next paragraph. The most common adverse effects associated with adalimumab, derived from experience with its use in RA, include injection site reactions, upper respiratory tract infections, headache, rash, urinary tract infections and hypertension.[147] Bearing in mind the shared pathogenetic components of JIA and AOSD, and the fact that proinflammatory cytokines play a significant role in AOSD, some investigators have used IL-1-receptor antagonists in cases refractory to conventional agents and TNFα inhibitors.[149] The purified recombinant human IL-1-receptor antagonist exerts its effects via the competitive inhibition of binding of IL-1α and IL-1β to the IL-1 receptor, thereby blunting the activity of this proinflammatory cytokine.[150] In one of the first case reports showing the favourable response to the IL-1 receptor antagonist anakinra, a patient with a 4-year history of AOSD had frequent flares despite being treated with high doses of corticosteroids (up to 1 mg/day), several DMARDs and, later on, infliximab. As soon as anakinra was administered at a dose of 100 mg/day subcutaneously in addition to methotrexate, prednisolone and naproxen, the patient experienced a rapid amelioration of her systemic and joint symptoms.[97] A consequent paper corroborating the therapeutic benefits of anakinra demonstrated rapid haematological, biochemical and cytokine defervescence in four non-remitting AOSD patients. Of note, when anakinra was withheld on two occasions, patients relapsed, only to improve after reintroduction of the agent. Additionally, it was postulated that the beneficial effects of TNFα inhibition are exerted through reduced production of IL-1 given that TNFα is known to induce IL-1.[99] Although well established prospective studies comparing anakinra with other biological agents are still needed to solidify any potential therapeutic advantage, emerging evidence supports its use in terms of efficacy, rapidity of action, corticosteroid-sparing effects and tolerability. © 2008 Adis Data Information BV. All rights reserved.

Kontzias & Efthimiou

Anakinra was very well tolerated in all of the patients in the aforementioned study.[99] Data extrapolated from large series of patients with RA treated with anakinra for an extended period of time (up to 36 months)[151,152] demonstrate that it is well tolerated and worth considering for resistant cases of AOSD. The most frequent adverse effects reported include injection site reactions, upper respiratory tract infections, headaches, arthralgia, sinusitis, nausea and diarrhoea. Concomitant corticosteroid use (which is common in AOSD) is thought to increase the risk of serious adverse effects such as pneumonia and cellulitis.[152] Thus, careful monitoring of patients with additional risk factors for infections is mandatory and justifies the fact that anakinra is contraindicated in patients with active infections.[152] The recent death of an AOSD patient treated with anakinra due to cardiac complications[153] and another case of reversible thrombocytopenia associated with the use of anakinra in AOSD[138] pose questions for possible causal relationships but, as yet, any inferred association remains speculative. IL-6, a proinflammatory cytokine, is considered to play a reinforcing role in the development of the inflammatory process in AOSD. Studies have shown that serum IL-6 levels are higher in AOSD patients (with both systemic and articular disease) than in patients with inactive disease or healthy controls. Furthermore, its levels correlate with clinical activity and biochemical markers of the disease, making IL-6 a candidate biomarker.[30,31] These data, in addition to the clinical benefit of IL-6 blockade demonstrated in one particularly refractory AOSD case in Japan[96] and in related sudden-onset JIA,[154,155] support the rationale of administering IL-6 receptor antagonists in AOSD. Tocilizumab, formerly known as MRA, is a humanized anti-IL-6 receptor monoclonal antibody of κIgG1 subclass that has been shown to compete for both the membrane-bound and soluble forms of the human IL-6 receptor, thus diminishing the proinflammatory activity of IL-6.[156] In patients with sudden-onset JIA, safety signals associated with intravenous infusions of tocilizumab Drugs 2008; 68 (3)

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at doses of up to 8 mg/kg were infections, such as herpes simplex mouth ulcers, and a mild elevation of total cholesterol levels.[154,155] In a European study where tocilizumab was used to treat RA patients unresponsive to methotrexate, there was a doserelated increase in the mean serum transaminase level (accentuated by concomitant use of methotrexate), with no evidence of clinical hepatitis. Moreover, abnormal serum lipid levels, as evidenced by elevated total cholesterol levels, triglycerides and high density lipoproteins, occurred during tocilizumab treatment.[157] Tocilizumab is in the late stages of development for the treatment of RA.

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need to be validated in larger studies, and while convincing the pharmaceutical industry to design new drugs for rare diseases may be extremely difficult, asking them to provide currently available drugs for new indications may be a more pragmatic approach. Acknowledgements No sources of funding were used to assist in the preparation of this article. The authors have no conflicts of interest that are directly relevant to the content of this review article.

References 4. Conclusion AOSD is a rare, multi-system, inflammatory disease of unknown aetiology and with considerable phenotypic variability. Since all available evidence comes from case reports and case series, the quality of the available evidence is limited. The rarity of the disease, combined with the lack of a funded, international collaborative research initiative, makes the execution of rigorous clinical trials wishful thinking. The only encouraging news comes from the relatively newly formed National Institutes of Health Rare Diseases Clinical Research Network, which could be instrumental in coordinating such an effort for AOSD and other rare diseases. Until such an effect occurs, a rational therapeutic approach could be to capitalize on the findings of basic science, such as cytokine biology, and the identification of specific therapeutic targets. Although firstline agents such as methotrexate and prednisone have proved to be effective in a majority of patients with the disease, there are still groups of patients with refractory disease who can benefit from the use of the biological agents more recently incorporated into clinical practice. For example, the discovery of the significance of IL-1 led to use of the currently available IL-1 receptor antagonist (anakinra), with far better success in AOSD than in RA, the indication for which it was originally approved. Currently existing agents (e.g. anti-TNFα) or those in the late stages of development (e.g. anti-IL-6) may offer therapeutic alternatives. These results obviously © 2008 Adis Data Information BV. All rights reserved.

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biologic agents in rheumatoid arthritis. Drugs 2005; 65 (5): 661-94 148. Kuek A, Hazleman BL, Ostor AJ. Immune-mediated inflammatory diseases (IMIDs) and biologic therapy: a medical revolution. Postgrad Med J 2007 Apr; 83 (978): 251-60 149. Efthimiou P, Georgy S. Pathogenesis and management of adultonset Still’s disease. Semin Arthritis Rheum 2006 Dec; 36 (3): 144-52 150. Arend WP, Welgus HG, Thompson RC, et al. Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest 1990 May; 85 (5): 1694-7 151. den Broeder AA, de Jong E, Franssen MJ, et al. Observational study on efficacy, safety, and drug survival of anakinra in rheumatoid arthritis patients in clinical practice. Ann Rheum Dis 2006 Jun; 65 (6): 760-2 152. Fleischmann RM, Tesser J, Schiff MH, et al. Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis 2006 Aug; 65 (8): 1006-12 153. Ruiz PJ, Masliah E, Doherty TA, et al. Cardiac death in a patient with adult-onset Still’s disease treated with the interleukin 1 receptor inhibitor anakinra. Ann Rheum Dis 2007 Mar; 66 (3): 422-3 154. Yokota S, Miyamae T, Imagawa T, et al. Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 2005 Mar; 52 (3): 818-25 155. Woo P, Wilkinson N, Prieur AM, et al. Open label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement. Arthritis Res Ther 2005; 7 (6): R1281-8 156. Nishimoto N, Kishimoto T. Inhibition of IL-6 for the treatment of inflammatory diseases. Curr Opin Pharmacol 2004 Aug; 4 (4): 386-91 157. Maini RN, Taylor PC, Szechinski J, et al. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 2006 Sep; 54 (9): 2817-29

Correspondence: Dr Petros Efthimiou, Rheumatology Division, Lincoln Medical and Mental Health Center, 234 E. 149th Street, New York, NY 10451, USA. E-mail: [email protected]

Drugs 2008; 68 (3)

Drugs 2008; 68 (3): 339-358 0012-6667/08/0003-0339/$53.45/0

REVIEW ARTICLE

© 2008 Adis Data Information BV. All rights reserved.

Drugs for Cardiovascular Disease Prevention in Women Implications of the AHA Guidelines – 2007 Update Nanette K. Wenger1,2,3 1 2 3

Emory University School of Medicine, Atlanta, Georgia, USA Grady Memorial Hospital, Atlanta, Georgia, USA Emory Heart and Vascular Center, Atlanta, Georgia, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339 1. Lifestyle Category (Dietary Intake) Omega-3 Fatty Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341 1.1 Primary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341 1.2 Secondary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344 2. Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344 2.1 Secondary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344 3. Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 3.1 Primary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 3.2 Secondary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347 4. Lipids: Primary and Secondary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347 5. Aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349 5.1 Primary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349 5.2 Secondary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350 6. ACE Inhibitors/Angiotensin II Receptor Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350 6.1 Primary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350 6.2 Secondary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350 7. β-Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351 7.1 Secondary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351 8. Aldosterone Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352 8.1 Secondary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352 9. Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352 9.1 Primary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352 10. Folic Acid, and Vitamins B6 and B12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353 10.1 Primary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353 10.2 Secondary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353 11. Menopausal Hormone Therapy (MHT)/Selective Estrogen Receptor Modulators (SERMs) . . . . . . . . 354 11.1 Primary Prevention: MHT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354 11.2 Secondary Prevention: MHT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355 11.3 Secondary Prevention: SERMs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355 12. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355

Abstract

Lifestyle interventions constitute the initial strategy for the primary and secondary prevention of cardiovascular disease in women. However, pharmacotherapy is often indicated for control of major cardiovascular risk factors, and

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Wenger

abundant clinical trial data support the morbidity and mortality benefit of a number of categories of drug therapy following a coronary event. Although women have increasingly been enrolled in clinical trials of pharmacotherapy, under representation of women in most research studies limits the gender-specific assessment of outcomes. Equally importantly, recent randomized clinical trial data have highlighted inappropriate preventive therapies for women (i.e. those lacking effectiveness and potentially imparting harm). Decision-making data for drug therapy for women also derive from a number of clinical trials conducted solely in women. The drug classes reviewed in this article include omega-3 fatty acids, aspirin, ACE inhibitors and angiotensin II receptor antagonists or blockers, β-adrenoceptor antagonists (β-blockers), aldosterone antagonists, antioxidants, folic acid and vitamins B6 and B12, and menopausal hormone therapy and selective estrogen-receptor modulators. Information is sparse regarding specific cardiovascular pharmacotherapies for elderly women, and women of racial and ethnic minorities. Owing to the under representation of the subset of women in many trials, analysis by age, race and ethnicity is not appropriate. This information gap presents a major challenge for future studies, as these subgroups constitute populations of women at high cardiovascular risk.

Coronary heart disease (CHD) remains the leading cause of mortality among women in the US and among women in many countries worldwide. A pivotal issue is that many risk factors for cardiovascular disease (CVD) and CHD are modifiable or preventable, hence, the widespread emphasis on coronary risk reduction as a means to favourably affect both coronary risk factors and clinical manifestations of CHD. As with the initial 2004 Prevention Guidelines for women,[1] the emphasis focuses on a partnership between women and their healthcare providers, but the 2007 Guideline Update[2] displays a simpler algorithm for ascertaining cardiovascular risk status, defining women as at high risk, at risk or at optimal risk (table I). Furthermore, given the 10-year average delay in onset of clinical manifestations of CHD in women compared with men, the emphasis of the 2007 Guideline Update is on reduction of lifetime risk, rather than the limited viewpoint of 10-year risk. This simplification of the classification of cardiovascular risk status derives from the overview that most studies providing the evidence base for the © 2008 Adis Data Information BV. All rights reserved.

guidelines were conducted either in apparently healthy women or in women with established CVD. Given the high lifetime risk of CHD for women, and the documentation that most US women have at least one coronary risk factor,[3] most women are candidates for preventive therapies. The guideline citations are categorized as follows: (i) lifestyle interventions, which are recommended for all women, with virtually all having a class I level of recommendation; (ii) major risk-factor interventions; and (iii) preventive drug interventions (table II). Highly relevant are the class III interventions that have not proved useful or effective and may impart harm (table III). The classifications and levels of evidence are those used in most clinical practice guidelines (table IV). The studies included in the systematic search for this article were randomized clinical trials or large prospective cohort studies (>1000 subjects) of cardiovascular risk-reducing interventions, metaanalyses that used a quantitative systematic review process or surrogate endpoint studies with at least ten cases of major clinical CVD endpoints reported. A total of 5774 articles were initially identified: 828 Drugs 2008; 68 (3)

Drugs for Cardiovascular Disease Prevention in Women

were included for full-text screening, and 246 met the inclusion criteria and were included in the evidence tables. This article addresses solely those recommendations that involve pharmacotherapy, such that the bibliography encompassing the evidence base for the guideline recommendations for lifestyle interventions (e.g. smoking cessation, physical activity, cardiovascular or stroke rehabilitation, dietary intake, weight maintenance/reduction or depression screening/referral) is not provided. The pharmacotherapy bibliography cited includes those references that provided the basis and levels of evidence for the clinical recommendations discussed, and includes a review of trial results and gender-specific outcomes, when available, published up to June 2006. Table I. Classification of cardiovascular disease (CVD) risk status in women (reproduced from Mosca et al.,[2] with permission, © 2007, American Heart Association, Inc.) Criteria High risk Established coronary heart disease Cerebrovascular disease Peripheral arterial disease Abdominal aortic aneurysm End-stage or chronic renal disease Diabetes mellitus 10-Year Framingham global risk >20%a At risk ≥1 major risk factors for CVD, including: cigarette smoking poor diet physical inactivity obesity, especially central adiposity family history of premature CVD (CVD at