A DECADE IN MEDICINE
November 2015
UROLOGY ENDOCRINOLOGY CLINICAL ONCOLOGY
NEPHROLOGY CARDIOLOGY NEUROLOGY GASTROENTEROLOGY & HE
PATOLOGY
RHEUMATOLOGY
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A Decade in Medicine The articles included in A Decade in Medicine were originally published online and in the November 2014 or November 2015 issues of the eight clinical Nature Reviews journals. To celebrate the 10th anniversary of the launch of these journals, the editors commissioned international experts to write short essays highlighting the key papers that made the biggest contribution to their field in the past decade. Between them, the clinical Nature Reviews journals published 47 articles, which are collated in this eBook; if you choose to cite an article, please use the original journal citation rather than citing the eBook. We hope you enjoy reading A Decade in Medicine. If you would like to find out more about the Nature Reviews series, please visit: http://www.nature.com/reviews/
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Nature Reviews Cardiology COPYRIGHT © 2015 Macmillan Publishers Limited. All rights reserved. Printed in the United Kingdom. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form (electronic or otherwise) without prior permission from permissions@ nature.com. DISCLAIMER: Although every effort is made by the publishers to see that no inaccurate or misleading data, opinions or statements appear in this collection, they wish to make it clear that the data and opinions appearing in articles and advertisements herein are the responsibility of the contributor or advertiser concerned. The journal does include the personal opinions of the authors; therefore, it is not intended to be relied on solely as a guide to good practice or safe treatment. Accordingly, the publishers, employees, offices and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. Although every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that the new methods and techniques involving drug usage and described within this journal should only be followed in conjunction with the drug manufacturer’s own published literature.
1
acute coronary syndromes | Successes and future objectives in acute
coronary syndrome Frans Van de Werf 3 5
arrhythmias | Cardiac fibrillation—challenges and evolving solutions Stanley Nattel cardiomyopathies | Cardiomyopathy on the move
Magdi H. Yacoub 6 8
dyslipidaemia | Resurgence of targets and compounds to treat dyslipidaemia John J. P. Kastelein heart failure | 10 Years of progress in HF research—what have we learned?
Henry Krum 10 hypertension | The past decade in hypertension—facts, hopes, and hypes Thomas Unger 12 peripheral vascular disease | 10 Years of breakthroughs in peripheral vascular disease Mark A. Creager 14 valvular disease | Current perspectives on treatment of valvular heart disease Friedrich W. Mohr
© 2015 Macmillan Publishers Limited. All rights reserved
Nature Reviews Clinical Oncology 16 clinical trials | Shifting paradigms in cancer clinical trial design Daniel J. Sargent and Edward L. Korn 18 targeted therapy | Successes, toxicities and challenges in solid tumours Joel W. Neal and George W. Sledge 19 haematological cancer | Advances in biology and therapy S. Vincent Rajkumar and Philippe Moreau 21 cancer immunotherapy | Entering the mainstream of cancer treatment Steven A. Rosenberg 23 genomics | A decade of discovery in cancer genomics Kenneth Offit 25 funding in cancer research | National Cancer Institute awards —a work in progress Tito Fojo and Paraskevi Giannakakou
Nature Reviews Endocrinology 28 bone | Great strides made but still further to go Ian R. Reid 29 thyroid disease | The endocrinology of thyroid disease from 2005 to 2015 P. Reed Larsen 31 type 2 diabetes mellitus | At the centre of things Guang Ning 33 paediatric endocrinology | New genes, new therapies Mehul T. Dattani 35 reproductive endocrinology | Understanding reproductive endocrine disorders Ursula B. Kaiser
53 polycystic kidney disease | Slowing progression of autosomal dominant polycystic kidney disease Robert W. Schrier 54 renal transplantation | A spectrum of advances in renal transplantation Bruce Kaplan
Nature Reviews Neurology 57 dementia | A decade of discovery and disappointment in dementia research John R. Hodges 58 multiple sclerosis | New drugs and personalized medicine for multiple sclerosis Paul M. Matthews 60 epilepsy | Edging toward breakthroughs in epilepsy diagnostics and care Daniel H. Lowenstein 62 movement disorders | Tracking the pathogenesis of movement disorders Oksana Suchowersky 63 stroke | Progress in acute ischaemic stroke treatment and prevention Jose G. Romano and Ralph L. Sacco 65 migraine | Incredible progress for an era of better migraine care Peter J. Goadsby 67 cns infections | Major advances against a moving target of CNS infections Lisa F. P. Ng and Tom Solomon
Nature Reviews Rheumatology
Nature Reviews Gastroenterology & Hepatology
69 translational rheumatology | Ten years after: rheumatology research from bench to bedside Nunzio Bottini and Gary S. Firestein
37 hcv | Hepatitis C therapy—a fast and competitive race Stefan Zeuzem
71 paediatric rheumatology | A field on the move Seza Ozen
38 hepatocellular carcinoma | HCC—subtypes, stratification and sorafenib Gregory J. Gores
72 technology | Technological advances transforming rheumatology William H. Robinson and Rong Mao
40 gut microbiota | The gut microbiota era marches on Francisco Guarner 42 fgids | ‘Functional’ gastrointestinal disorders—a paradigm shift Nicholas J. Talley 43 pancreatic diseases | Advances in understanding and care of pancreatic diseases Randall E. Brand 45 ibd | IBD—genes, bacteria and new therapeutic strategies Jean-Frederic Colombel
74 clinical rheumatology | 10 years of therapeutic advances in the rheumatic diseases John D. Isaacs
Nature Reviews Urology 77 bladder cancer | International progress: from cytology to genomics James C. Costello and Dan Theodorescu 79 imaging | A decade in image-guided prostate biopsy Baris Turkbey and Peter L. Choyke
Nature Reviews Nephrology
81 urinary incontinence | Advances in female urology and voiding dysfunction Marisa M. Clifton and Howard B. Goldman
48 glomerular disease | The glomerulus reveals some secrets Agnes B. Fogo
82 kidney cancer | Discoveries, therapies and opportunities W. Marston Linehan and Christopher J. Ricketts
50 genetics of kidney diseases | Genetic dissection of kidney disorders Friedhelm Hildebrandt
84 sexual dysfunction | Post-RP erectile dysfunction—therapies for the next decade Emmanuel Weyne and Maarten Albersen
51 acute kidney injury | Acute kidney injury—a decade of progress Rinaldo Bellomo
86 prostate cancer | A decade of progress in detection and treatment Behfar Ehdaie and Peter T. Scardino
© 2015 Macmillan Publishers Limited. All rights reserved
CARDIOLOGY DECADE IN REVIEW—ACUTE CORONARY SYNDROMES
Successes and future objectives in acute coronary syndrome Frans Van de Werf
The past decade has seen considerable advances in the treatment of acute coronary syndromes (ACS), particularly in the search for improved antithrombotic therapies. Despite these successes, however, renewed efforts are needed to improve long-term outcomes after ACS by reducing recurrent ischaemic events and lowering the risk of bleeding complications. Van de Werf, F. Nat. Rev. Cardiol. 11, 624–625 (2014); published online 2 September 2014; doi:10.1038/nrcardio.2014.129
By 10 years ago, aspirin and clopidogrel therapy for 1 year was already the standard treatment for all patients with acute coronary syndrome (ACS), despite the benefit of this dual antiplatelet therapy never having been formally studied in patients with ST-segment elevation myocardial infarction (STEMI). Without a doubt, the majority of clinical studies in ACS performed in the past decade have focused on attempts to find more efficacious and safer antithrombotic treatments than aspirin and clopidogrel dual antiplatelet therapy. The most successful trial in this regard was PLATO,1 which showed significantly improved outcomes (including recurrent myocardial infarction, stent thrombosis, death from vascular causes, and even allcause mortality) with ticagrelor, a new oral, reversible, direct-actingP2Y purinoreceptor 12 (P2Y12) antagonist, when compared with clopidogrel; the study included patients with either STEMI or non-STEMI (NSTEMI). Pleiotropic actions, such as increased adenosine plasma concentrations, were suggested to have contributed to the beneficial effect of ticagrelor. The overall excess spontaneous bleeding rate with this new, more powerful agent was small, but the trend towards an increased risk of intra cranial haemorrhage observed in this study was a concern. One of the possible reasons why newer P2Y12 antagonists, such as cangrelor, pra sugrel, and ticagrelor, are superior to clopid ogrel in large clinical trials is the existence of genetic variants of hepatic cytochrome P450 (CYP) enzymes responsible for converting clopidogrel to its active metabolite. Several studies have shown that
carriers of an allele that resulted in reduced CYP function had lower levels of the active metabolite and higher rates of major cardio vascular events. As such, carriers of CYP loss-of-function variants who are receiving clopidogrel are likely to be especially at risk of stent thrombosis. The concerns about interindividual variability in the antiplatelet effect of clopidogrel have led to a number of studies aimed at monitoring platelet function and adjusting treatment accordingly. Surprisingly, in one of the largest randomized studies, which included 2,440 patients scheduled for coronary stenting (of whom 657 had NSTEMI), no improvement in clinical outcomes at 1 year was observed with platelet-function monitoring and treatment adjustments as compared with standard treatment without monitoring.2 Genetic testing and platelet-function monitoring have not become routine tests in patients taking clopidogrel.
‘‘
…recurrent ischaemic events and long-term mortality remain high
’’
Bivalirudin has replaced heparin in many hospitals, especially for patients undergoing primary percutaneous coronary intervention (PCI), owing mainly to the results of the HORIZONS‑AMI study.3 This trial showed significantly reduced bleeding rates and decreased 30‑day mortality with bivalirudin alone when compared with heparin plus a glycoprotein (GP) IIb/IIIa (integrin αIIbβ3) antagonist.3 However, the benefit of bivalirudin for primary PCI was challenged by the results of a single-centre
trial (HEAT‑PPCI4),in which GP IIb/IIIa antagonists were used only for bailout (bivalirudin versus heparin): fewer ischaemic events occurred with heparin than with bivalirudin and, surprisingly (in contrast to all previous trials), no reduction in bleeding complications was found with bivalirudin. Whether these data should change practice and whether a new, large multicentre trial is needed is currently a matter of hot debate. Despite the progress made with anti thrombotic therapy and revascularization in the early phase of an ACS, recurrent ischaemic events and long-term mortality remain high. One explanation could be that dual antiplatelet therapy consisting of aspirin and clopidogrel does not provide sufficient long-term protection against recurrent thrombotic events. In two large studies, 5,6 an additional antithrombotic agent was tested in combination with aspirin and c lopidogrel: vorapaxar, an antagonist of the thrombin receptor PAR‑1 (protease-activated receptor 1), was used in the TRA 2P trial, 5 and rivaroxaban, a direct oral inhibitor of factor Xa, was used in ATLAS‑2.6 Although increased bleeding rates were observed in both studies (and the TRA 2P study even had to be stopped prematurely in the subgroup of patients with a history of stroke, owing to an excess rate of intracranial haemorrhage), selected populations did benefit from adding a third antithrombotic drug. In the group of >17,000 patients with a previous myocardial infarction, addition of vorapaxar reduced the risk of cardiovascular death, myoc ardial infarction, or stroke—at the cost of an increased risk of moderate or severe bleeding, but without a significant NOVEMBER 2015 | 1
A DECADE IN MEDICINE © 2015 Macmillan Publishers Limited. All rights reserved
CARDIOLOGY PLATO1 and subgroups of TRA 2P5 or ATLAS-26
Haemorrhagic risk
No option
Standard antithrombotic treatment
Range of possible results of a simplified antithrombotic regimen Risk of thrombosis
Figure 1 | The balance of risks in treatment of acute coronary syndrome. Patients with acute coronary syndrome receive therapies aimed at reducing the risk of thrombosis, but antithrombotic treatments carry an increased risk of bleeding complications. New therapeutic approaches should minimize the possibility of thrombotic events while keeping haemorrhagic risk at acceptable levels, or even reduce the risk when compared with current treatment.
increase in intracranial haemorrhage.5 In ATLAS‑2,6 low-dose rivaroxaban (2.5 mg twice daily) also significantly reduced the risk of the composite end point of cardio vascular death, myocardial infarction, and stroke and, surprisingly, also reduced rates of stent thrombosis and death from any cause. Whether these agents are also beneficial and safe when, for instance, ticagrelor or prasugrel is used in combination with aspirin, is unknown. Similarly, whether aspirin can be dropped if a new P2Y12 antagonist is given in combination with vorapaxar or low-dose rivaroxaban remains to be determined. New studies of simplified antithrombotic regimens that are underway or in the planning phase should take into account the possible benefits and risks of new antithrombotic combinations (Figure 1).
‘‘
…use of increasingly powerful antithrombotic agents has raised concern about bleeding
’’
A number of trials to study the optimal timing of angiography and revascularization in patients with NSTEMI yielded discordant results. In the TIMACS trial,7 >3,000 patients with ACS were randomly assigned to either routine early intervention or delayed intervention (either 36 h after treatment assignment, respectively). In the total population, a nonsignificant 2 | NOVEMBER 2015
15% reduction in the composite end point of death, myocardial infarction, or stroke was observed when comparing early versus delayed treatment. However, in line with other studies, early intervention in highrisk patients led to a significant 35% reduction in the risk of death, new myocardial infarction, or stroke when compared with delayed intervention.7 The use of increasingly powerful anti thrombotic agents has raised concern about bleeding. Major bleeding complications are indeed common, and most occur at the vascular access site. In the RIVAL trial,8 >7,000 patients with ACS, including almost 2,000 patients with STEMI, were randomly allocated to either radial or femoral access. Overall, a lower rate of local vascular complications was observed with the radial approach than with femoral access. Remarkably, patients with STEMI had better clinical outcomes (including reduced mortality) when treated via radial access, suggesting that this approach might be particularly preferable in patients with STEMI.8 Data from all registries show that, in patients with STEMI, door-to-balloon times have declined significantly over the past 10 years. The implementation of emergency medical systems based on a network of hospitals with various levels of technology connected by an efficient ambulance system has reduced pre-PCI delays in many places. 9 Howe ver, in a large US study of almost 100,000 patients with STEMI, inhospital mortality remained unchanged despite significant improvement in doorto-balloon times, indicating that other components of the total ischaemic time need to be targeted.9 Administration of a fibrinolytic agent to patients who cannot undergo timely PCI is a strategy that might be incorporated into prehospital care. In the STREAM trial 10 of ~2,000 patients presenting with early STEMI, prehospital administration of tenecteplase (half the normal dose in elderly individuals) to patients who could not undergo PCI within 1 h resulted in rates of the composite end point of death, shock, congestive heart failure, or recurrent infarction at 30 days that were similar to those in patients receiving standard primary PCI. Emergency coronary angiography on arrival in the PCI hospital could be avoided in almost two-thirds of patients treated with tenecte plase.10 This strategy needs to be further explored in patients with long transport times, especially elderly patients.
In summary, 30‑day mortality after ACS has decreased remarkably in all age categories in the past decade, thanks to improved antithrombotic treatment and early revascularization. As a consequence, profound changes in the epidemiology of ACS have also taken place: more patients with ACS survive the initial event and go on to develop recurrent ischaemic events, heart failure, atrial fibrillation, or noncardiac diseases (such as cancer), and are dying at an older age. In the future, more attention will have to be paid to the longterm care of patients after ACS, of which antithrombotic agents will remain an important component. Department of Cardiovascular Sciences, University of Leuven, Herestraat 49, B‑3000 Leuven, Belgium.
[email protected] Acknowledgements I thank all my colleagues on both sides of the Atlantic with whom I was able to collaborate in performing important clinical trials that have improved the treatment of patients with acute coronary syndrome. Competing interests F.V.d.W. declares that he has received research grants and fees for participating in advisory boards, data and safety monitoring boards, and speaking activities from AstraZeneca, Boehringer Ingelheim, Merck, and The Medicines Company. 1.
Wallentin, L. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 361, 1045–1057 (2009). 2. Collet, J. P. et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N. Engl. J. Med. 367, 2100–2109 (2012). 3. Stone, G. W. et al. Bivalirudin during primary PCI in acute myocardial infarction. N. Engl. J. Med. 358, 2218–2230 (2008). 4. Shahzad, A. et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an openlabel, single centre, randomised controlled trial. Lancet http://dx.doi.org/10.1016/S01406736(14)60924-7. 5. Morrow, D. A. et al. Vorapaxar in the secondary prevention of atherothrombotic events. N. Engl. J. Med. 366, 1404–1413 (2012). 6. Mega, J. L. et al. Rivaroxaban in patients with a recent acute coronary syndrome. N. Engl. J. Med. 366, 9–19 (2012). 7. Mehta, S. R. et al. Early versus delayed invasive intervention in acute coronary syndromes. N. Engl. J. Med. 360, 2165–2175 (2009). 8. Jolly, S. S. et al. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial. Lancet 377, 1409–1420 (2011). 9. Menees, D. S. et al. Door‑to‑balloon time and mortality among patients undergoing primary PCI. N. Engl. J. Med. 369, 901–909 (2013). 10. Armstrong, P. W. et al. Fibrinolysis or primary PCI in ST‑segment elevation myocardial infarction. N. Engl. J. Med. 368, 1379–1387 (2013).
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CARDIOLOGY DECADE IN REVIEW—ARRHYTHMIAS
Cardiac fibrillation—challenges and evolving solutions Stanley Nattel
Cardiac rhythm disorders, or ‘arrhythmias’, are major sources of morbidity and mortality, and have been challenging to treat because classic pharmacological therapies are often ineffective and sometimes dangerous. In the past decade, groundbreaking developments have revolutionized the management of arrhythmias and prepared the groundwork for new advances in the future. Nattel, S. Nat. Rev. Cardiol. 11, 626–627 (2014); published online 9 September 2014; doi:10.1038/nrcardio.2014.133
At the onset of the 2000s, effective and definitive therapies were available for most types of cardiac arrhythmia. However, two common and important rhythm disorders remained major therapeutic challenges —sudden cardiac death (SCD) and atrial fibrillation (AF). SCD typically occurs owing to a chaotic, disorganized rhythm, ‘ventricular fibrillation’, which renders effective heart pumping impossible and causes death if not effectively managed within minutes of onset (Figure 1). AF resembles ventricular fibrillation in being a totally disorganized rhythm, but AF affects the atria, which are not essential for cardiac pumping (Figure 1). AF causes problems by firing the heart at an inappropriately rapid rate, leading to a range of symptoms and, in extreme cases, heart muscle weakening that leads to heart failure. In addition, the ineffect ive pumpi ng action of the atria allows blood clots to form in the stagnant atrial blood pool. These clots can propagate to the brain and cause strokes. Consequently, AF is a major cause of strokes, particularly in the elderly. Work during the past decade has greatly improved our ability to prevent and manage both SCD and AF, and enabled further progress in the future. Towards the end of the 20th century, the use of implantable devices to detect and rapidly terminate ventricular tachyarrhythmias that might otherwise lead to SCD had become widespread. However, their effectiveness in reducing mortality was unclear. Despite preventing SCD, such devices might not actually reduce mortality, particularly if SCD constitutes a small portion of the overall mortality, and if device-related complications can themselves increase the likelihood of death. An important milestone was a study by Bardy and colleagues, who
compared the effects of amiodarone (the most effective antiarrhythmic drug) with an implantable cardioverter–defibrillator (ICD), or placebo in patients with systolic heart failure, who are known to be at high risk of SCD.1 Amiodarone did not reduce all-cause mortality during a median 45.5‑month follow-up period compared with placebo; however, ICD-therapy significantly reduced all-cause mortality (by 23%; P = 0.007).1 These findings established ICDs as a potentially life-saving intervention in patients at increased risk of SCD. Whereas some patients at increased risk of SCD are easily identified, the majority of these arrhythmias occur in individuals without known high-risk factors. More work is, therefore, needed to understand the factors leading to SCD and thereby effectively identify at-risk individuals. An important contribution was provided by Haïssaguerre et al. who showed that
a specif ic electrocardiographic variant (known as early repolarization) is much more common in individuals resuscitated after SCD than in a matched control population.2 This study led to extensive clinical and basic science investigations into the underlying mechanisms and clinical importance of early repolarization. The early repolarization pattern is a common electrocardiographic variant in otherwise normal individuals, particularly young, physicallyactive men, so distinguishing between the common benign early-repolarization pat tern and early repolarization associated with increased SCD risk is an important challenge. The combination of electro cardiographic ‘J‑waves’ (an elevated junction between the end of the QRS and the onset of the ST-segment) and a horizontal or descending ST-segment is associated with increased risk of SCD. Howe ver, no early repolarization pattern alone (in the absence of malignant arrhythmias) is presently sufficient to warrant prophylactic therapy (such as an ICD) to prevent SCD. A further major advance in understanding the pathophysiology of SCD was the demonstration by Itzhaki and colleagues that skin fibroblasts from patients with an inherited SCD syndrome can be transformed into induced pluripotent stem cells, and then differentiated into cardiomyocytes that reproduce the cardiac electrical dysfunction underlying SCD risk. 3 This work establishes a novel technique to aid the understanding of SCD pathophysio logy in individual patients and might ultimately lead to patient-specific medical and biological therapies.
Ventricular fibrillation Implanted defibrillator prevents death1
Atrial fibrillation
Early repolarization: a novel cause2
Rate control as good as rhythm control in heart failure4
Lenient versus strict rate control5
Prevention by risk-factor reduction10
Drug therapy complications in high-risk patients6
Novel anticoagulants prevent stroke9
Ablation as initial therapy7
LA AVN
RA
RV
LV
IPSCs for pathophysiology and therapy3
Mechanism-directed ablation8
Figure 1 | Major advances in arrhythmia research during the past decade. The rate of impulse transmission through the AVN determines the ventricular response rate during atrial fibrillation, and is the target of rate-control therapy. Abbreviations: AVN, atrioventricular node; IPSC, induced pluripotent stem cell; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
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A DECADE IN MEDICINE © 2015 Macmillan Publishers Limited. All rights reserved
CARDIOLOGY Two potential approaches to managing AF exist: leaving the patient in AF, but controlling the ventricular response rate (known as rate control); and keeping the patient out of AF, generally with the use of antiarrhythmic drugs (known as rhythm control). AF is a particularly important risk factor for death and complications in patients with heart failure, so rhythm control would be expected to be of maximal value in these individuals. This hypothesis was tested in a prospective, randomized trial by Roy et al. who found that an effective rhythm-control strategy had no bene ficial effects on cardiac function, survival, or physical function in patients with heart failure and AF.4
‘‘
In the past decade, the management and understanding of cardiac arrhythmias have been greatly advanced
’’
Despite the value of rate control in controlling adverse consequences of AF, the parameters characterizing optimum rate control are largely unknown. Van Gelder and colleag ues compared a ‘lenient’ rate-control strate gy (resting heart rate
