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Kaim 2014

  1. 1. January 2014 KEY ADVANCES IN MEDICINE © 2014 Macmillan Publishers Limited. All rights reserved
  2. 2. Key Advances in Medicine design:lauramarshall Nature Reviews Cardiology 1 ACUTE CORONARY SYNDROMES | Optimizing revascularization strategies in patients with ACS Gregg W. Stone 3 heart failure | Continue what we are doing to treat HF, but do it better Jay N. Cohn 4 venous thromboembolism | The advent of the novel oral anticoagulants Paolo Prandoni 6 dyslipidaemia | New statin guidelines and promising novel therapeutics Dimitri P. Mikhailidis and Vasilios G. Athyros 8 cardiovascular imaging | New era of evidence-based medicine with noninvasive imaging Puskar Pattanayak and David A. Bluemke Nature Reviews Clinical Oncology 11 lung cancer | Refining standard practice and admitting uncertainty Stephen V. Liu and Giuseppe Giaccone 13 breast cancer | Genomics, drug approval, and optimal treatment duration Adrian V. Lee and Nancy E. Davidson 15 liver cancer | Mutational landscape of HCC—the end of the beginning Augusto Villanueva and Josep M. Llovet 17 melanoma | Melanoma—the run of success continues Dirk Schadendorf and Axel Hauschild 19 cervical cancer | Screening comes of age and treatment progress continues Chris J. L. M. Meijer and Peter J. F. Snijders 21 colorectal cancer | Towards improved drugs, combinations and patient selection Hans-Joachim Schmoll and Alexander Stein The articles included in Nature Reviews Key Advances in Medicine were originally published online and in the February 2014 issues of the eight clinical Nature Reviews journals. The journals’ editors commissioned international experts to write a short essay highlighting up to eight key papers that made the biggest contribution to their field in 2013. Between them, the eight clinical Nature Reviews journals published 45 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 Nature Reviews Key Advances in Medicine. If you would like to find out more about the Nature Reviews series, please visit: http://www.nature.com/reviews/ COPYRIGHT © 2014 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. Don’t miss out on next year’s Key Advances in Medicine Sign up to free e-ALERTS and be notified when next year’s Key Advances in Medicine eBook is published. You won’t miss out on Nature Reviews collections and Focus issues either! http://www.nature.com/register © 2014 Macmillan Publishers Limited. All rights reserved
  3. 3. Nature Reviews Endocrinology 23 puberty | Unravelling the mystery of puberty Sergio R. Ojeda and Alejandro Lomniczi 25 thyroid cancer | Advances in our understanding of differentiated thyroid cancer Christoph Reiners 27 steroid hormones | Glucocorticoids—timing, binding and environment Stafford L. Lightman and Charlotte L. George 29 type 2 diabetes mellitus | A central role of the gut in glucose homeostasis Geltrude Mingrone and Lidia Castagneto-Gissey 30 metabolism | The gut microbiota manages host metabolism Patrice D. Cani 32 adrenal cancer | Time to individualize treatment for adrenocortical cancer? Constantine A. Stratakis Nature Reviews Gastroenterology & Hepatology 35 hepatitis c | HCV causes systemic disorders that can be cured Francesco Negro 37 faecal microbiota transplantation | Developing human gut microbiota as a class of therapeutics Alexander Khoruts 38 coeliac disease | New insights in dietary-gluten‑induced autoimmunity Katri Kaukinen and Markku Mäki 40 barrett oesophagus | Risk stratification and surveillance in Barrett oesophagus Emmanuel C. Gorospe and Kenneth K. Wang 42 ibd | Enriching the therapeutic armamentarium for IBD Silvio Danese and Laurent Peyrin-Biroulet 44 small bowel endoscopy | The reality and the potential Uday C. Ghoshal Nature Reviews Nephrology 46 stem cells | Potential use of stem or progenitor cells for kidney regeneration Luigi Biancone and Giovanni Camussi 48 genetics in kidney disease | Susceptibility genes for renal and urological disorders Jasmin Divers and Barry I. Freedman 50 cardiovascular disease in ckd | Reducing cardiovascular risk —light at the end of the tunnel Jessica Kendrick and Michel Chonchol 51 transplantation immunology | New approaches to diagnosis of rejection Nicholas A. Zwang and Laurence A. Turka 53 acute kidney injury | Breaking barriers for biomarkers in AKI —progress at last Dinna N. Cruz and Ravindra L. Mehta Nature Reviews Neurology 56 epilepsy | Progress across the spectrum of epilepsy research Frances E. Jensen 58 movement disorders | Diagnosing and treating PD—the earlier the better? François Tison and Wassilios G. Meissner 59 stroke | Disappointments and advances in acute stroke intervention Michael Tymianski 61 neuro-oncology | Improving outcome in newly diagnosed malignant glioma Michael Weller and Wolfgang Wick 63 dementia | Frontotemporal lobar degeneration—building on breakthroughs Julie van der Zee and Christine Van Broeckhoven 65 multiple sclerosis | Novel triggers, treatment targets and brain atrophy measures Xavier Montalban and Mar Tintoré Nature Reviews Rheumatology 67 gout | Imaging, genetics and therapy: gout research continues apace Fiona M. McQueen 69 imaging in rheumatology | From images to data to theory Felix Eckstein and C. Kent Kwoh 71 systemic lupus erythematosus | Taking a closer look at biologic therapy for SLE David A. Isenberg and Anisur Rahman 72 epigenetics | DNA methylation and miRNA—key roles in systemic autoimmunity Bruce C. Richardson and Dipak R. Patel 74 rheumatoid arthritis | Translational medicine in RA—time for change Pierre Miossec Nature Reviews Urology 77 testicular cancer | Towards personalized medicine—are we there yet? Jan Oldenburg and Sophie D. Fosså 79 reconstruction | Recapitulating the urinary bladder—where are we heading? Arnulf Stenzl 80 bladder cancer | From genomics to imaging—advances along the care continuum Ahmed Haddad and Yair Lotan 83 female urology | Evaluating progress on longstanding issues Lindsey Cox and J. Quentin Clemens 84 prostate cancer | The changing role of imaging in clinical care Rahul Aggarwal and John Kurhanewicz 86 kidney cancer | From molecular understanding to clinical advances Chung-Han Lee and Robert J. Motzer © 2014 Macmillan Publishers Limited. All rights reserved
  4. 4. KEY ADVANCES IN MEDICINE JANUARY 2014  |  1 CARDIOLOGY ACUTE CORONARY SYNDROMES IN 2013 Optimizing revascularization strategies in patients with ACS Gregg W. Stone Catheter-based revascularization has emerged as the gold-standard therapy for most patients with acute coronary syndromes (ACS). Optimizing outcomes in these patients requires appropriate adjunctive pharmacological therapy and percutaneous coronary intervention. Five studies published in 2013 are expected to have a major effect on treatment and prognosis of patients with ACS. Stone, G. W. Nat. Rev. Cardiol. 11, 67–68 (2014); published online 7 January 2014; doi:10.1038/nrcardio.2013.214 Acute coronary syndromes (ACS), which range from unstable angina to non-ST- segment elevation myocardial infarc- tion to ST-segment elevation myocardial infarction (STEMI), share a common ­pathophysiology—rupture of a lipid-rich, inflamed coronary artery atherosclerotic plaque with superimposed thrombosis. Over the past two decades, numerous ran­ domized trials have demonstrated that the preferred therapy for patients with ACS is urgent or emergent cardiac catheterization followed by revascularization as appro- priate, usually by percutaneous coronary intervention (PCI) with stent implantation. This approach reduces the rate of recurrent ischaemia, r­einfarction, and death, com- pared with more-conservative care. Within this framework, however, intense investi- gation has been ongoing to determine the optimal pharma­cological agents and treat- ment strategies to support PCI. In this Year in Review article, I discuss five important studies published in 2013, all of which will have a major effect on the treatment path- ways, prognosis, and future investigation of patients with ACS. Rapid reperfusion in STEMI using primary PCI, rather than administration of fibrinolytic agents, has been shown to save lives and prevent reinfarction and stroke.1 However, concerns regarding the effect of excessive delays to PCI have been expressed for patients who live >1 h away from a cardiac catheterization facil- ity. For such patients, a pharmacoinvasive approach has been suggested, consisting of early fibrino­lysis followed by transport­ ation to the interventional facility for either emergent PCI (in the case of failed fibrinolysis) or routine PCI, usually within 24 h. In the STREAM trial,2 1,892 patients presenting with STEMI who were unable to undergo primary PCI within 1 h were randomly assigned to a pharmaco­invasive approach (aspirin, clopidogrel, enoxa­ parin, and age-adjusted tenecteplase, fol- lowed by transportation to a PCI hospital and either emergent [36.3% of patients] or routine [63.7% of patients] angio­graphy) or to antiplatelet and antithrombin treat- ment according to local standards and transfer for immediate PCI. The primary end point of the composite of death, shock, congestive heart failure, or reinfarction up to 30 days occurred in 12.4% of patients in the fibrinolysis group and in 14.3% of patients in the primary PCI group (rela- tive risk [RR] for fibrinolysis 0.86, 95% CI 0.68–1.09, P = 0.21). Intracranial haemor- rhage was more common in the fibrinolysis group (1.0% versus 0.2%; P = 0.04).2 This study demonstrates that prehospital fibrino­ lysis with a pharmacoinvasive approach is a reasonable reperfusion strategy for patients with anticipated long delays in transfer for primary PCI. This approach avoids the need for emergent catheterization in two-thirds of patients, although primary PCI is still preferable unless the delays to transfer for PCI are truly excessive. The results of PCI in patients with ACS are improved with effective anti­platelet inhibition, especially with drugs that block the platelet P2Y12 receptor. Four such drugs are available for oral use: clopidog- rel, prasugrel, ticagrelor, and ticlopidine. These agents are most effective when given before PCI. However, all these drugs have delayed gastrointestinal absorption during STEMI, and inhibit platelet func- tion for 3–7 days, which can cause exces- sive bleeding after surgical procedures (for example, CABG surgery). Cangrelor is an investi­gational, potent, direct-acting, intravenously administered P2Y12 -receptor inhibitor with a half-life of 3–6 min. Platelet function is fully restored within 60 min of discontinuing this drug. The safety and effi- cacy of cangrelor compared with clopidog- rel were tested in 10,942 patients with ACS and stable coronary artery disease under- going PCI in the CHAMPION PHOENIX trial.3 Cangrelor, given intravenously at the time of PCI, reduced the primary efficacy end point of death, myocardial infarction, ischaemia-driven revascularization, or stent thrombosis at 48 h (4.7% versus 5.9% with clopidogrel; P = 0.005), without increasing MonkeyBusinessImages|Dreamstime.com © 2014 Macmillan Publishers Limited. All rights reserved
  5. 5. 2  |  JANUARY 2014 www.nature.com/reviews CARDIOLOGY major bleeding.3 This novel agent could, therefore, have numerous applications in patients with ACS u­ndergoing PCI. Safe and effective procedural anti­ coagulation is essential to optimize the results of PCI in ACS. Among 3,602 patients with STEMI undergoing primary PCI in the randomized HORIZONS-AMI trial,4 use of the direct thrombin inhibitor bivali­ rudin reduced the 30‑day and 3‑year rates of major bleeding, thrombocyto­paenia, cardiac death, and all-cause mortality com- pared with unfractionated heparin plus a platelet glycoprotein IIb/IIIa inhib­itor (GPI), which was the previous standard of care. However, the HORIZONS-AMI trial4 was performed before the availabil- ity of the potent P2Y12 inhibitors prasugrel and ticagrelor, and before the widespread use of the radial artery to provide vas- cular access for PCI, which can reduce the risk of bleeding complications. In the EUROMAX trial,5 2,218 patients with STEMI were randomly assigned to heparin initiated in the ambulance, with or without a GPI, or to bivali­rudin alone, followed by transfer for primary PCI. In both groups, ~50% of the patients also received pra­ sugrel or t­icagrelor, and ~50% underwent PCI via radial artery access. The results of the EUROMAX trial5 at 30 days were very similar to those of the HORIZONS-AMI study,4 demonstrating a reduction in the primary end point of death or major bleed- ing with bivalirudin (5.1% versus 8.5% with the heparin strategy; RR 0.60, 95% CI 0.43–0.82, P = 0.005), as well as thrombo- cytopaenia.5 In both trials, however, stent thrombosis occurring within the first 24 h was more frequent with bivalirudin.4,5 In the future, this problem could be addressed with the pre-PCI use of cangrelor rather than prasugrel or ticagrelor. Embolization of thrombus and soft friable plaque down the coronary artery is ubiq­ uitous during primary PCI, and can cause capillary block, increased infarct size, heart failure, and death. Some, but not all, studies have indicated that removing the thrombus by mechanical aspiration before PCI (a fairly low-risk, simple pro­cedure) can prevent distal embolization and improve outcomes.6 These studies, however, were under­powered to be defin­itive. Using a nationwide Swedish registry system, the TASTE trial7 investi­ gators randomly allocated 7,244 patients with STEMI to primary PCI with or without thrombus aspiration. The primary end point of 30‑day mortality occurred in 2.8% of patients in the thrombus aspiration group versus 3.0% in the PCI-only group (HR 0.94, 95% CI 0.72–1.22, P = 0.63).7 Therefore, although thrombus aspiration was safe, no clear benefits were seen with the use of this pro­cedure. The TASTE trial7 is also notable for introducing the format of a randomized trial within a registry, allowing a very large- scale study to be completed fairly quickly and inexpensively. Primary PCI is typically performed on the infarct-causing coronary artery lesion only, because noncontrolled studies have suggested that multivessel PCI in this setting can be harmful.8 However, patients with ACS who have undergone successful PCI are at increased risk of recur­rent events arising from remote lesions in the coro- nary tree, owing to the frequent presence of other ‘vulnerable plaques’.9 The PRAMI study10 investigators, therefore, hypothe- sized that ‘preventative PCI’ of nonruptured coronary lesions might improve outcomes after STEMI. In the PRAMI trial,10 465 patients with STEMI and multivessel disease under­going primary PCI were ran- domly assigned to PCI of the infarct lesion only (control) or to PCI of all stenotic lesions (preventative PCI). During follow- up (mean 23 months), the primary end point of cardiac death, myocardial infarc- tion, or refractory angina was reduced in the preventative PCI group by 65% (HR 0.35, 95% CI 0.21–0.58, P 0.001), as was the rate of unplanned, repeat revascularization procedures (HR 0.30, 95% CI 0.17–0.56, P 0.001).10 Although this trial was too small to promote the preventative PCI approach as routine practice, this strategy might be of benefit in selected patients, and will certainly be examined in future, larger randomized trials. In summary, five important randomized trials were published in 2013 that have identi- fied optimal regimens and pharmaco­therapy usage strategies to support revascularization by PCI in high-risk patients with ruptured plaques and coronary thrombosis.2,3,5,7,10 Investigational drugs and novel treatment strategies are emerging that promise to con- tinue to improve the p­rognosis for patients with ACS. Competing interests The author declares associations with the following companies: Boston Scientific, Eli Lilly, and Daiichi Sankyo. See the article online for full details of the relationships. Columbia University Medical Center, The Cardiovascular Research Foundation, 111 East 59th Street, 11th Floor, New York, NY 10022, USA. gs2184@columbia.edu 1. Keeley, E. C., Boura, J. A. Grines, C. L. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 361, 13–20 (2003). 2. Armstrong, P. W. et al. Fibrinolysis or primary PCI in ST‑segment elevation myocardial infarction. N. Engl. J. Med. 368, 1379–1387 (2013). 3. Bhatt, D. L. et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N. Engl. J. Med. 368, 1303–1313 (2013). 4. Stone, G. W. et al. Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3‑year results from a multicentre, randomised controlled trial. Lancet 377, 2193–2204 (2011). 5. Steg, P. G. et al. Bivalirudin started during emergency transport for primary PCI. N. Engl. J. Med. 369, 2207–2217 (2013). 6. Kumbhani, D. J., Bavry, A. A., Desai, M. Y., Bangalore, S. Bhatt, D. L. Role of aspiration and mechanical thrombectomy in patients with acute myocardial infarction undergoing primary angioplasty: an updated meta-analysis of randomized trials. J.Am. Coll. Cardiol. 62, 1409–1418 (2013). 7. Fröbert, O. et al. Thrombus aspiration during ST‑segment elevation myocardial infarction. N. Engl. J. Med. 369, 1587–1597 (2013). 8. Kornowski, R. et al. Prognostic impact of staged versus “one-time” multivessel percutaneous intervention in acute myocardial infarction: analysis from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial. J.Am. Coll. Cardiol. 58, 704–711 (2011). 9. Stone, G. W. et al. A prospective natural-history study of coronary atherosclerosis. N. Engl. J. Med. 364, 226–235 (2011). 10. Wald, D. S. et al. Randomized trial of preventive angioplasty in myocardial infarction. N. Engl. J. Med. 369, 1115–1123 (2013). Key advances ■■ A pharmacoinvasive strategy (fibrinolysis followed by cardiac catheterization) is a reasonable approach for patients with ST‑segment elevation myocardial infarction (STEMI) when percutaneous coronary intervention (PCI) is anticipated to be delayed2 ■■ The investigational intravenous antiplatelet agent cangrelor is superior to the most-widely used oral antiplatelet agent, clopidogrel, for the prevention of ischaemic complications when given at the time of PCI3 ■■ In patients with STEMI undergoing primary PCI, anticoagulation with bivalirudin has been confirmed to be the optimal antithrombotic regimen5 ■■ Thrombus aspiration was not shown to improve outcomes in patients with STEMI undergoing primary PCI7 ■■ ‘Preventative PCI’ of remote, nonculprit coronary lesions might prevent future ischaemic events in high-risk patients with STEMI10 © 2014 Macmillan Publishers Limited. All rights reserved
  6. 6. KEY ADVANCES IN MEDICINE JANUARY 2014  |  3 CARDIOLOGY HEART FAILURE IN 2013 Continue what we are doing to treat HF, but do it better Jay N. Cohn In 2013, clinical trials in heart failure focused on drugs and devices that might improve treatment of symptomatic patients beyond standard therapy. None achieved this aim. Therefore, future efforts should emphasize increased adherence to current, evidence-based therapy, and trials might better address efforts to prevent, rather than treat, heart failure. Cohn, J. N. Nat. Rev. Cardiol. 11, 69–70 (2014); published online 24 December 2013; doi:10.1038/nrcardio.2013.212 The principles of managing heart failure (HF) became apparent decades ago. When the left ventricle is dilated and under­ going the process of remodelling,1 function can be improved with vasodilatory drugs that reduce impedance to left ventricular ejection. These drugs augment the favour- able effect of diuretics on symptoms and exercise tolerance in patients with HF. Life prolongation, however, is dependent on inhibition of the remodelling, which can be accomplished by neurohormone inhibitors,1 with or without vasodilatory properties, by drugs that enhance nitric oxide activity, and by electrical resynchronization of the ven- tricles.2 However, the therapies used to treat HF with reduced ejection fraction (HFrEF) exhibit little benefit when the ventricle is not dilated—a syndrome now called HF with p­reserved ejection fraction (HFpEF). Trials conducted in the past few years have been devoted to efforts to improve strategies for using effective treatments in HFrEF, and tofindatreatmentforHFpEFthatcanreduce symptomsorimproveoutcomes.Commercial sponsors have sought new drugs or devices, or expanded the use of existing interventions for HFrEF, whereas government sponsors have tried to document the best methods for employing existing treatments. New m­echanistic ­breakthroughs have been scarce. In 2013, this pattern was dramatically apparent. Dissatisfaction with current loop diuretic therapy for acute decompensated HF has generated a number of studies to replace or supplement such drugs. These efforts have generally failed to reveal a more-effective alternative. The Heart Failure Clinical Research Network, funded by the National Heart, Lung, and Blood Institute in the USA, addressed the possibility that low- dose dopamine or low-dose nesiritide could safely augment the diuresis induced by loop diuretics in patients with decompensated HF. The trial, in 360 patients, showed no evidence that diuresis or decongestion was enhanced by such combined therapy or that renal func- tion was better preserved.3 The conclusion is that we should continue what we are doing— maintain an aggressive approach to diuretic therapy, and perhaps concern ourselves less when renal function transiently worsens. Cardiac resynchronization therapy (CRT) has been remarkably effective in improv- ing quality of life and prolonging survival in patients with HFrEF and an electro­ cardiogram(ECG)-measuredprolong­ationof the QRS complex.2 The assumption has been that the ECG abnorm­ality served as a crude surrogate for ventricular dyssynchrony that could be used to distinguish responders from nonresponders. The EchoCRT Study Group,4 funded by Biotronik and GE Healthcare, con- ducted an international trial at 115 centres in 809 patients with HFrEF and demon- strable ventricular dyssynchrony despite a QRS duration 130 ms (the usual cut-off for CRT eligibility). Not only was CRT in such patients ineffective in terms of the primary end point—death or first hospitalization for HF—but a significant increase in mortality occurred in the CRT group.4 Once again, good reasons exist not to change what we are currently doing, even if the QRS criterion seems imprecise. As in all studies of CRT, however, individual variability in the mecha- nisms of HF progression and in the electrical characteristics of ventricular depolarization renders all large-trial data not n­ecessarily applicable to individual patients. Many studies in 2013 focused on patients with HFpEF, both because of the growing recognition of its prevalence and because of the absence of an effective or approved therapy. An attractive potential therapy was phosphodiesterase‑5 (cGMP-specific 3',5'‑cyclic phosphodiesterase) inhibition, which augments cyclic GMP and, therefore, generates nitric oxide. Preliminary studies in this syndrome demonstrated a favourable haemodynamiceffectofp­hosphodiesterase-5 inhibition. Investigators in the RELAX trial,5 funded largely by the NIH, studied the effect of sildenafil in 216 patients with sympto- matic HF and an ejection fraction ≥50%. After 24 weeks of therapy with sildenafil or placebo, no difference was observed between groups in either peak exercise capacity or clinical status. Consistently with other trials in patients with HFpEF, therefore, no thera- peutic benefit of the e­xperimental treatment could be demonstrated. Ivabradine has exhibited a dramatic ben­­efit inoutcomesinpatientswith HFrEF.6 Whether heart-rate slowing with this If ‑channel inhibitor could favourably affect the course of HFpEF was the subject of a small trial in 61 patients from Poland and Australia.7 This short, 7‑day, placebo-controlled­trial showed a significant increase in peak exer- cise capacity between baseline and follow- up (4.2 ± 1.8 metabolic equivalents versus 5.7 ± 1.9 metabolic equivalents; P = 0.001), pres­umably mediated by the haemodynamic effects of heart-rate slowing. To determine whether this pharmacological effect results in a significant improvement in quality of life in patients HFpEF requires a far larger trial of longer duration. However, nothing in the data or the known mechan­ism of drug action would generate optimism about a ­long-termfavourableeffectonmorbidevents. A more-attractive therapeutic approach to HFpEF is the use of spironolactone, Key advances ■■ Infusion of low-dose dopamine or nesiritide did not increase urinary output, further relieve congestion, or protect renal function in patients with acute decompensated heart failure already treated with conventional therapy3 ■■ Resynchronization therapy in patients with ventricular dyssynchrony, but normal QRS duration, was ineffective in improving symptoms of heart failure4 ■■ Phosphodiesterase‑5 inhibition did not improve symptoms in patients with heart failure with preserved ejection fraction (HFpEF) in a 24‑week study5 ■■ Ivabradine to slow heart rate in patients with HFpEF improved diastolic function and increased maximal exercise capacity in a 7‑day trial7 ■■ Outcome data with spironolactone have been disappointing, despite the beneficial effect of this drug on diastolic function and exercise capacity in a 1‑year study of patients with HFpEF9 © 2014 Macmillan Publishers Limited. All rights reserved
  7. 7. 4  |  JANUARY 2014 www.nature.com/reviews CARDIOLOGY which has demonstrated favourable long- term effects in patients with HFrEF and is thought to inhibit collagen synthesis, which is involved in stiffening of the left ventricle and inducing the diastolic dysfunction that might be a critical aetiological factor in HFpEF.8 The Aldo‑DHF trial,9 supported by a German government agency, was con- ducted in 422 patients from Germany and Austria with HFpEF and diastolic dysfunc- tion. After 12 months of follow-up, the investigators noted that the spironolactone- treated group exhibited a reduction in left ventricular mass (adjusted mean differ- ence −6 g/m2 ; 95% CI −10 g/m2 to −1 g/m2 , P = 0.009) and an improvement in diastolic left ventricular function (adjusted mean dif- ference in E/e' −1.5; 95% CI −2.0 to −0.9, P 0.001).9 Exercise performance and HF symptoms, however, were not improved.9 A more-definitive evaluation of spirono- lactone in HFpEF was carried out in the TOPCAT trial,10 sponsored by the US National Heart, Lung, and Blood Institute. The long-awaited results of this multi­ national trial involving 3,445 patients was reported at the AHA Scientific Sessions in November 2013, but have not yet been published in a peer-reviewed journal. After follow-up (mean 3.3 years), the difference in morbid events between the spirono­ lactone and placebo groups was about 10% and did not reach statistical significance.10 Therefore, despite the attractiveness of the concept, spironolactone, as with all other drugs known to inhibit left ventricular struc- tural remodelling through neuro­hormonal m­echanisms, has failed to alter the course of HFpEF. Two messages emerge from all these trials that have not further reduced morbidity and mortality in HF beyond that achieved with existing treatments. First, our current, evidence-based therapy, properly employed, produces as much benefit as we can reason­ ably expect in both HFrEF and HFpEF. The gap between routine clinical practice and knowledgeable care, however, remains tr­oubling, and efforts to close that gap could yield dramatic population benefits. The second and more-subtle message is that treatment instituted late in the disease process has, at most, modest benefits. Efforts to prevent HF should yield far greater long- term benefits. HF, as with all cardiovascular morbid events, is a progressive process that can be detected long before symptoms occur. Early detection of the HF phenotype should identify individuals who might be particu- larly responsive to therapeutic interventions to slow its progression (Figure 1). We might hope that 2014 and subsequent years will bring a growing interest in trials aimed at preventing disease. In HFrEF, early detection should allow interventions with inhibitors of left ventricular remodel- ling that could substantially prolong life. In HFpEF, the dysfunction of the left ventricle is probably an ageing effect on the vasculature and myocardium that is largely unrespon- sive to therapy, but might be substantially delayed by early intervention. Trials to docu- ment such therapeutic efficacy are urgently needed. Such trials in years to come will hopefully demonstrate more t­herapeutic potential than the trials of 2013. Age (years) Leftventricularremodelling Natural history Treatment Prevention Symptoms Death Figure 1 | The natural history of heart failure exhibits age-dependent progression of left ventricular remodelling, with the development of symptoms and premature death. Treatment after symptoms develop is aimed at reversing or slowing progression of these symptoms and delaying death. Clinical trials in 2013 were largely unsuccessful in accomplishing benefit beyond that of background therapy. Preventive therapy instituted before symptom development should be more effective in preventing symptoms and prolonging life. Cardiovascular Division, University of Minnesota Medical School, Mayo Mail Code 508, 420 Delaware Street Southeast, Minneapolis, MN 55455, USA. cohnx001@umn.edu Competing interests The author declares no competing interests. 1. Cohn, J. N. Structural basis for heart failure: ventricular remodeling and its pharmacological inhibition. Circulation 91, 2504–2507 (1995). 2. Bristow, M. R. et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N. Engl. J. Med. 350, 2140–2150 (2004). 3. Chen, H. H. et al. Low-dose dopamine or low- dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA http://dx.doi.org/ 10.1001/jama.2013.282190. 4. Ruschitzka, F. et al. Cardiac-resynchronization therapy in heart failure with a narrow QRS complex. N. Engl. J. Med. 369, 1395–1405 (2013). 5. Redfield, M. M. et al. Effect of phosphodiesterase‑5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 309, 1268–1277 (2013). 6. Swedberg, K. et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 376, 875–885 (2010). 7. Kosmala, W. et al. Effect of If ‑channel inhibition on hemodynamic status and exercise tolerance in heart failure with preserved ejection fraction: a randomized trial. J. Am. Coll. Cardiol. 62, 1330–1338 (2013). 8. Pitt, B. et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N. Engl. J. Med. 341, 709–717 (1999). 9. Edelmann, F. et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo‑DHF randomized controlled trial. JAMA 309, 781–791 (2013). 10. Pfeffer, M. A. Treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT). Presented at the American Heart Association Scientific Sessions 2013. VENOUS THROMBOEMBOLISM IN 2013 The advent of the novel oral anticoagulants Paolo Prandoni New findings published in 2013 strongly support the use of novel oral anticoagulants in the treatment of thromboembolic disorders. These drugs have been shown to have a more-favourable benefit-to-risk profile than older compounds, enabling their use from the start of treatment and in the whole spectrum of clinical presentations. Prandoni, P. Nat. Rev. Cardiol. 11, 70–72 (2014); published online 14 January 2014; doi:10.1038/nrcardio.2013.210 The availability of antithrombotic com- pounds that can be administered orally in fixed doses without the need for laboratory control, owing to their predict- able pharmaco­kinetics and pharmaco­ dynamics and low potential for drug and © 2014 Macmillan Publishers Limited. All rights reserved
  8. 8. KEY ADVANCES IN MEDICINE JANUARY 2014  |  5 CARDIOLOGY food interactions, has opened new horizons for the treatment of patients with venous thrombo­embolism (VTE). These drugs include three factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban) and a direct thrombin inhibitor (dabigatran etexilate). For three of these four compounds (apixa- ban, dabigatran, and edoxaban) the results of l­andmark trials have been p­ublished in 2013. The efficacy of apixaban for the initial treatment of VTE was investigated in the AMPLIFY study,1 a randomized, double- blind trial in which apixaban (10 mg twice daily for 7 days followed by 5 mg twice daily for 6 months) was compared with enoxa- parin followed by warfarin (conventional therapy) for the treatment of 5,400 patients with acute VTE, of whom one-third had pulmonary embolism. Recurrent VTE or VTE-associated death occurred in 59 patients in the apixaban group (2.3%) and 71 (2.7%) in the conventional therapy group (relative risk [RR] 0.84, 95% CI 0.60–1.18, P 0.001 for noninferiority). Major bleed- ing occurred in 15 (0.6%) and 49 patients (1.8%) in these two groups, respectively (RR 0.31, 95% CI 0.17–0.55, P 0.001 for superiority). Major and clinically relevant nonmajor bleeding occurred in 4.3% and 9.7% of these groups, respectively (RR 0.44, 95% CI 0.36–0.55, P 0.001). The results of this study suggest that the advent of novel anticoagulants has enabled antithrombotic benefits to be dissociated from haemor- rhagic potential to a much greater extent than with the older drugs. In addition, analogous with the strategy adopted for rivaroxaban,2,3 apixaban was administered from the beginning of treatment in the AMPLIFY trial,1 without the need for initial parenteral heparin treatment. The suitabil- ity of a few emerging compounds that are effective and safe for patients with VTE from the start of treatment opens new and interesting scenarios for the management of these disorders. Firstly, a greater propor- tion of patients will be able to be treated directly at home than is currently possible. Secondly, treatment of these disorders will become immediately feasible with oral com- pounds, whenever the clinical suspicion of VTE arises, without the need for inconven- ient parenteral drugs, the use of which can require l­aboratory s­urveillance and medical expertise. In the AMPLIFY-EXT trial,4 2,500 patients who had completed 6–12 months of treatment for deep-vein thrombosis or pulmonary embolism were randomly assigned to receive apixaban 2.5 mg twice daily, apixaban 5.0 mg twice daily, or placebo for 12 months. Both doses of apixaban demonstrated superiority compared with placebo in the reduction of the composite end point of symptomatic, recurrent VTE and death from any cause (3.8% and 4.2% in the 2.5 mg and 5.0 mg apixaban groups, respectively, versus 11.6% in the placebo group; P 0.001). Apixaban was also super­ ior to placebo for the predefined second- ary efficacy outcome of recurrent VTE and VTE-associated death (1.7% in both the apixaban groups versus 8.8% in the placebo group; P 0.001). The rate of major bleed- ing was comparable for the 2.5 mg (0.2%) and 5.0 mg (0.1%) doses of apixaban and for placebo (0.5%). The rate of the compo­ site of major bleeding and clinically rel- evant nonmajor bleeding for the 5.0 mg apixa­ban group (4.3%) was higher than in the placebo group (2.7%), whereas the rate in the 2.5 mg apixaban group (3.2%) was similar to that with placebo.4 The RE‑SONATE5 and the RE‑MEDY5 clinical trials were designed to assess the value of dabigatran for the extended treat- ment of VTE. The efficacy and safety of this antithrombin compound for the treatment of acute VTE had already been demonstrated 4 years previously in the RE‑COVER trial.6 In the RE‑SONATE study,5 1,343 patients with VTE who had completed 6–18 months of anticoagulant therapy were randomly assigned to receive dabigatran (150 mg twice daily) or placebo for an additional period of 6 months. A 92% reduction in the relative risk of recurrent VTE was shown with dabigatran, with a low risk of major bleeding (0.3%). In the RE‑MEDY study,5 2,856 patients treated for 6 months with vitamin K antagonists for a first VTE were randomly assigned to receive dabigatran (150 mg twice daily) or warfarin (treated to a target international normal- ized ratio of 2–3) and followed up for up to 3 years. Dabigatran was shown to be noninferior to warfarin in terms of the primary outcome of recurrent or fatal VTE (1.8% versus 1.3%; HR 1.44, 95% CI 0.78–2.64, P = 0.01 for noninferiority). Major bleeding complications occurred in 0.9% and 1.8% of patients in the dabigatran and warfarin groups, respectively (48% ­reduction in r­elative risk with dabigatran). The results of the RE‑SONATE and RE‑MEDY studies5 consolidate and expand those obtained in the AMPLIFY-EXT study4 by providing the first head-to-head comparison between a novel anticoagulant drug and warfarin in the extended treat- ment of patients with VTE. The findings are consistent with those already obtained with rivaroxaban 2 years previously,2 and open new avenues for the long-term treatment of patients with unprovoked VTE. Indeed, the availability of drugs with better safety profiles than vitamin K antagonists raises the possibility of extended periods of anti- coagulation for patients whose natural clini- cal course in the absence of anti­­coagulation is characterized by a VTE recurrence rate ~50%.7 The results of the AMPLIFY-EXT study4 suggest that halving the initial dose of apixaban after the first 6 months in patients with unprovoked VTE is likely to preserve protection against recurrent VTE, while reducing the haemorrhagic potential.4 Novel oral anticoagulant shop NPG Key advances ■■ The availability of compounds that can be used from the beginning of treatment for venous thromboembolism (VTE) has the potential to streamline therapy, making outpatient management feasible1 ■■ The improved safety profile of novel anticoagulants compared with older compounds makes prolonged anticoagulation therapy for patients with unprovoked VTE a realistic possibility4,5 ■■ Favourable outcomes among patients with severe pulmonary embolism treated with novel anticoagulants challenges the view that aggressive thrombolytic treatment should be considered for all patients with right ventricular dysfunction8 © 2014 Macmillan Publishers Limited. All rights reserved
  9. 9. 6  |  JANUARY 2014 www.nature.com/reviews CARDIOLOGY DYSLIPIDAEMIA IN 2013 New statin guidelines and promising novel therapeutics Dimitri P. Mikhailidis and Vasilios G.Athyros The new ACC/AHA guidelines on treatment of blood cholesterol focus on intensity of statin therapy rather than target levels of lipids. Early studies show substantial reductions in LDL-cholesterol level with antibodies against PCSK9. MicroRNA silencing and gene-repair techniques to treat dyslipidaemia are promising strategies under development. Mikhailidis, D. P. Athyros, V. G. Nat. Rev. Cardiol. 11, 72–74 (2014); published online 24 December 2013; doi:10.1038/nrcardio.2013.209 In this Year in Review article, we discuss the main advances in the prevention and treat- ment of dyslipidaemia during 2013. The new ACC/AHA practice guidelines for the treat- ment of blood cholesterol, the aim of which is to reduce the risk of atherosclerotic cardio- vasculardisease(ASCVD),includenewequa- tions to estimate this risk.1 These equations are based on the pooled results of five large cohort studies and consider age, sex, ethnic- ity, total-cholesterol and HDL-cholesterol (HDL‑C) levels, systolic blood pressure, presence of diabetes mellitus, smoking status, and treatment for hypertension.1 As in the Framingham equation, a family history of premature ASCVD is missing, but the risk of stroke is included, which is useful. These guidelines do not set treatment targets for LDL cholesterol (LDL‑C) or non-HDL‑C.1 Instead, they focus on the intensity of statin therapy to reduce ASCVD risk in combin­ ation with a healthy lifestyle.1 High-intensity statin therapy, which lowers the LDL‑C level by≥50%,isrecommendedmainlyforthesec- ondary prevention of ASCVD. Moderate-to- highintensitystatintherapy,whichlowersthe LDL‑C level by 30–50%, is recommended for primary prevention in patients at high risk of ASCVD. Low-intensity statin therapy, which lowers the LDL‑C level by 30%, is recom- mended for primary prevention in patients at m­oderate-to-low risk of ASCVD.1 These recommend­ations are conceptually different from those in previous guidelines, which set The results from the randomized, double- blind Hokusai‑VTE trial,8 addressing the efficacy of edoxaban, were also published in 2013. After initial treatment with parenteral drugs, 4,921 patients with deep-vein throm- bosis and 3,319 individuals with pulmonary embolism (associated with right ventricular dysfunction in approximately one-third of trial participants) were allocated to receive edoxaban 60 mg once daily (30 mg in patients with moderate renal failure, body weight 60 kg, or both), or warfarin for 3–12 months at the discretion of attending physicians. At 1 year, edoxaban was non­ inferior to warfarin with respect to the inci- dence of recurrent VTE, which occurred in 130 patients in the edoxaban group and 146 in the warfarin group (3.2% versus 3.5%; HR 0.89, 95% CI 0.70–1.13, P 0.001 for noninferiority). Major or clinically relevant bleeding complications occurred in 349 and 423 of patients in these groups, respectively (8.5% versus 10.3%; HR 0.81, 95% CI 0.71– 0.94, P = 0.004 for superiority). Interestingly, when the analysis was confined to the 938 patients with pulmonary embolism and right ventricular dysfunction, VTE com- plications were significantly less frequent in patients allocated to edoxaban than in those who received warfarin (3.3% versus 6.2%; HR 0.52, 95% CI 0.28–0.98). These find- ings are consistent with those obtained in the EINSTEIN‑PE study,3 and challenge the growing view that an aggressive thrombo­ lytic treatment should be considered for all patients with pulmonary embolism who exhibit biochemical character­istics (assessed using laboratory tests) or find- ings on ultrasonography compatible with right ventricular dysfunction despite appar- ent clinical and haemodynamic stability.9 Additional interesting findings are that halving the dose in selected patients does not impair the overall efficacy of edoxaban, and that efficacy is preserved after discon- tinuation of the drug, which was achieved after 3–6 months in approximately 60% of patients.8 After 50 years without any substantial progress, antithrombotic treatment of patients with VTE has finally evolved. On the basis of results from studies published in 2013, novel anticoagulants such as apixaban, dabigatran, and edoxaban could conceiv­ ably become standard therapy for VTE in the next few years. However, clinical data are still absent for the long-term safety and efficacy of these drugs. The optimal management of bleeding complications in patients receiving these novel anti­coagulants remains unclear, and their use in patients with severe renal failure requires caution. Studies addressing the benefits and the risks of these drugs in patients with cancer and VTE, and in pregnant women, are needed. Although the current absence of specific antidotes to the novel anticoagulants is a major concern, several potential antidotes are being investigated with a good chance of successful development.10 Department of Medicine,Vascular Medicine Unit, University of Padua,Via Giustiniani 2, 35028 Padua, Italy. paoloprandoni@tin.it Competing interests The author declares associations with the following companies: Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer. See the article online for full details of the relationships. 1. Agnelli, G. et al. Oral apixaban for the treatment of acute venous thromboembolism. N. Engl. J. Med. 369, 799–808 (2013). 2. Bauersachs, R. et al. Oral rivaroxaban for symptomatic venous thromboembolism. N. Engl. J. Med. 363, 2499–2510 (2010). 3. Büller, H. R. et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N. Engl. J. Med. 366, 1287–1297 (2012). 4. Agnelli, G. et al. Apixaban for extended treatment of venous thromboembolism. N. Engl. J. Med. 368, 699–708 (2013). 5. Schulman, S. et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N. Engl. J. Med. 368, 709–718 (2013). 6. Schulman, S. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N. Engl. J. Med. 361, 2342–2352 (2009). 7. Prandoni, P. et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism: a prospective cohort study in 1,626 patients. Haematologica 92, 199–205 (2007). 8. Büller, H. R. et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N. Engl. J. Med. 369, 1406–1415 (2013). 9. Konstantinides, S. Goldhaber, S. Z. Pulmonary embolism: risk assessment and management. Eur. Heart J. 33, 3014–3022 (2012). 10. Prandoni, P., Barbar, S., Milan, M., Vedovetto, V. Pesavento, R. The risk of recurrent thromboembolic disorders in patients with unprovoked venous thromboembolism: new scenarios and opportunities. Eur. J. Intern. Med. http://dx.doi.org/10.1016/j.ejim.2013.09.005. © 2014 Macmillan Publishers Limited. All rights reserved
  10. 10. KEY ADVANCES IN MEDICINE JANUARY 2014  |  7 CARDIOLOGY [ASO]thattargetsapolipoprotein BmRNAto reduceLDLsynthesis)andlomitapide(which inhibits the microsomal trigly­ceride transfer protein, necessary for VLDL-cholesterol pro- duction), which have already been approved. These novel drugs will be available to lower the LDL‑C level in patients with all forms of acquired or hereditary dyslipidaemia, and will increase the percentage of patients at high risk of ASCVD who attain target lipid levelsbeyondthatwhichcanbeachievedwith statin treatment alone.2,4–7 Other therapeutic strategies have been in development during 2013. A specific Key advances ■■ The new ACC/AHA guidelines on the treatment of blood cholesterol specify the intensity of statin therapy rather than defining target LDL-cholesterol levels1 ■■ Antibodies against proprotein convertase subtilisin/kexin type 9 are a promising novel therapy for dyslipidaemia and atherosclerosis2,6 ■■ The development of efficacious adjunct therapies to statins will increase the numbers of patients who reach their target LDL-cholesterol level2,6 ■■ MicroRNA‑33 is involved in cell cholesterol efflux; silencing this microRNA (or others) might prove to be clinically beneficial8 ■■ Genetic engineering, currently being used to investigate gene-repair techniques in mice, is a potentially substantial advance in future treatments for dyslipidaemia and atherosclerosis9 target LDL‑C levels. Nonalcoholic fatty liver disease and rheumatoid arthritis—high-risk equivalents in some previous guidelines— are not mentioned. The new guidelines focus on the benefits of statin treatment as estab- lished by prospective, randomized, placebo- controlle­d studies with cardiovascular end points. However, some patients will not achieve a target LDL‑C level (as is still rec- ommended by the ESC and the European Atherosclerosis Society) with statins. This category of patients includes those intoler- ant to statins, and many with familial hyper- cholesterolaemia (FH), for whom other ­treatment options are needed. An LDL receptor binds a single LDL par- ticle and is internalized; the receptor then leaves the LDL particle inside the cell before recycling to the cell surface. Proprotein convertase subtilisin/kexin type 9 (PCSK9) enhances the degradation of LDL receptors.2 Therefore, monoclonal antibodies against PCSK9 prolong LDL-receptor activity, result- ing in a reduced circulating LDL‑C level.2 The effect of decreased PCSK9 activity was shown in the 15‑year follow-up of the ARIC study3 (n = 12,887).ParticipantswithaPCSK9 nonsense mutation had a substantially lower LDL‑C level and rate of ASCVD events (reduced by up to 88%) than i­ndividuals with optimal PCSK9 function.3 In the phase II LAPLACE‑TIMI 57 trial,2 the fully human, monoclonal, IgG2, antibody AMG 145 (Amgen, USA; drug now known as evolocumab) was administered sub­cutan­ e­ously at various doses and was compared with placebo in 631 individuals with hyper- cholesterolaemia (LDL‑C level 85 mg/dl; 45% at high risk of ASCVD). Participants also received a stable dose of a statin, with or without ezetimibe. Up to 90% and 97% of individualsreceivingAMG 145every2 weeks or 4 weeks, respectively, attained the LDL‑C target level of 70 mg/dl (P 0.001 versus placebo).2 Additionally,upto90%and97%of high-risk individuals treated with AMG 145 at the same time intervals achieved the triple target of LDL‑C level 70 mg/dl, apolipo- protein B level 80 mg/dl, and non-HDL‑C level 100 mg/dl (P 0.001 versus placebo, for all targets and all doses of AMG 145).2 Therefore, adding AMG 145 to background statin therapy, with or without ezetimibe, sig- nificantly increases the likelihood of patients at high risk of ASCVD achieving the target levels of LDL‑C and other lipids.2 Another analysis from the LAPLACE- TIMI 57study,4 showedthatAMG 145signif- icantly reduces the leveloflipoprotein(a)—an emerging vascular risk factor—by ≤32%. A two-part, phase II–III study to assess the safety, tolerability, and efficacy of AMG 145 in individuals (n = 8) with homozygous FH has also been published.5 This study included subcutaneous injection of AMG 145 at a dose of 420 mg every 4 weeks for 12 weeks, and then every 2 weeks for an additional 12 weeks.5 In the two LDL-receptor-negative patients, no reduction in the LDL‑C level occurred. Over the two treatment periods, the mean reductions in LDL‑C level in the sixpatientswithdefectiveLDLreceptorswere 19.3%and26.3%withthe4‑weekand2‑week dosing regimens, respectively (P = 0.03 for each).5 Data from the OSLER study,6 in which 1,104 patients with hypercholesterol­ aemia were followed up for ≥1 year and given evolocumab every 4 weeks, supported the long-term efficacy, safety, and tolerability of the drug.6 A phase III study involving 25,000 patients with hypercholesterolaemia has been initiated to evaluate the incremental clinical benefit of evolocumab in patients at high risk of ASCVD, whose LDL‑C level is not adequately controlled with maximum-dose statin treatment plus ezetimibe therapy. As with AMG 145, the PCSK9 inhibitor alirocumab (Sanofi, France and Regeneron, UK) has been shown to reduce the LDL‑C level by 40–72% when administered in addi- tion to atorvastatin in 183 patients with an LDL‑C level ≥100 mg/dl.7 Therefore, data from phase II–III trials indicate that PCSK9 inhibitors will hopefully be added to the list of novel lipid-lowering drugs—together with mipomersen (an antisense oligonucleotide Cytoplasm MicroRNA gene or intron Transcription Pri-microRNA Cleavage Pre-microRNA 5' 3' Exportin-5 GTP Ran Nuclear export 5' 3' Pre-microRNA Cleavage Dicer TRBP MicroRNA duplex Mature microRNA RISC formation Degradation mRNA target cleavage Translational repression mRNA deadenylation RNA Pol II/III Drosha DGCR8 5' 3' 5' 3' 3' 5' Ago2 5' 3' 5' 3' Nucleus Figure 1 | microRNA maturation and gene repression. Pre‑microRNA is exported from the nucleus and cleaved in the cytoplasm to its mature length. The functional (red) strand of the mature microRNA, together with ago2 proteins, guides the RISC to silence target mRNAs via mRNA cleavage, translational repression, or deadenylation. Abbreviations: Ago2, protein argonaute‑2; Dicer, endoribonuclease Dicer; Drosha, ribonuclease 3; DGCR8, microprocessor complex subunit DGCR8; Pol II/III, polymerase II or III; Ran, GTP-binding nuclear protein Ran; RISC, RNA-induced silencing complex; TRBP, RISC-loading complex subunit TARBP2. Permission obtained from Nature Publishing Group © Winter, J. et al. Nat. Cell Biol. 11, 228–234 (2009). © 2014 Macmillan Publishers Limited. All rights reserved
  11. 11. 8  |  JANUARY 2014 www.nature.com/reviews CARDIOLOGY microRNA, miR‑33, has been shown to repress several genes involved in cellular cholesterol trafficking (Figure 1).8 In chow- fed Lldr–/– mice injected with anti-miR‑33 ASO,theHDL‑Clevelandcellularcholesterol efflux increased, whereas plaque size and macrophage content significantly decreased, compared with mice injected with a placebo or nontargeting ASO.8 By contrast, anti- miR‑33 ASO did not increase the HDL‑C level when mice were fed a Western diet, but a significant reduction in athero­sclerotic plaque size was observed.8 These effects might be useful in reducing residual ASCVD risk, even after effective LDL‑C control. An animal gene-repair study might herald a new era in the treatment of dyslipid­­­aemia and atherosclerosis.9 Apoe gene repair was performed in chow-fed hypomorphic apolipo­protein E mice that are deficient in LDL-receptor expression and which develop hyperlipidaemia and atherosclerosis.9 Gene repair was associated with a twofold reduc- tion in plasma LDL‑C and triglyceride levels and a decrease in the ratio of non- HDL‑C to HDL‑C.9 This intervention also halted ather­oma lesion growth, and pro- moted both macro­phage loss and accumu­ lation of collagen, without changes in other genes i­mplicated in cholesterol efflux or in inflammation.9 In 2013, statins remain the cornerstone of lipid-lowering treatment. However, mono- clonal antibodies that delay LDL-receptor degradation, anti-microRNA ASO, and the repair of genes implicated in hyperlipidaemia are on the horizon. Cost-effectiveness might be a substantial limiting factor to introducing these novel therapies into clinical practice. Department of Clinical Biochemistry (Vascular Prevention Clinic), Royal Free Hospital Campus, University College School of Medicine, Pond Street, London NW3 2QG, UK (D. P. Mikhailidis). Atherosclerosis and Metabolic Syndrome Outpatient Units, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, 15 Marmara Street, 55132 Thessaloniki, Greece (V. G. Athyros). Correspondence to: D. P. Mikhailidis mikhailidis@aol.com Competing interests D. P. Mikhailidis declares associations with the following companies: Genzyme and MSD. See the article online for full details of the relationships. V. G. Athyros declares no competing interests. 1. Stone, N. J. et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation http://dx.doi.org/10.1161/ 01.cir.0000437738.63853.7a. 2. Desai, N. R. et al. AMG 145, a monoclonal antibody against PCSK9, facilitates achievement of NCEP‑ATP III LDL‑C goals among high risk patients: an analysis from the LAPLACE‑TIMI 57 trial. J.Am. Coll. Cardiol. http://dx.doi.org/ 10.1016/j.jacc.2013.09.048. 3. Cohen, J. C., Boerwinkle, E., Mosley, T. H. Jr  Hobbs, H. H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N.Engl.J.Med. 354,1264–1272 (2006). 4. Desai, N. R. et al. AMG 145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9, significantly reduces lipoprotein(a) in hypercholesterolemic patients receiving statin therapy. Circulation 128, 962–969 (2013). 5. Stein, E. A. et al. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation 128, 2113–2120 (2013). 6. Koren, M. J. et al. Efficacy and safety of longer- term administration of evolocumab (AMG 145) in patients with hypercholesterolemia. Circulation http://dx.doi.org/10.1161/ CIRCULATIONAHA.113.007012. 7. McKenney, J. M. et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J.Am. Coll. Cardiol. 59, 2344–2353 (2012). 8. Rotllan, N., Ramírez, C. M., Aryal, B., Esau, C. C. Fernández-Hernando, C. Therapeutic silencing of microRNA‑33 inhibits the progression of atherosclerosis in Ldlr–/– mice—brief report. Arterioscler.Thromb.Vasc. Biol. 33, 1973–1977 (2013). 9. Eberlé, D. et al. Inducible Apoe gene repair in hypomorphic ApoE mice deficient in the low‑density lipoprotein receptor promotes atheroma stabilization with a human-like lipoprotein profile. Arterioscler.Thromb.Vasc. Biol. 33, 1759–1767 (2013). CARDIOVASCULAR IMAGING IN 2013 New era of evidence-based medicine with noninvasive imaging Puskar Pattanayak and David A. Bluemke In 2013, advances in noninvasive imaging methods pushed traditional boundaries in the detection, diagnosis, and functional assessment of coronary artery disease, atherosclerotic plaque, and myocardial function. We highlight five important studies that demonstrate how these developments are allowing medicine to become increasingly evidence‑based and personalized. Pattanayak, P. Bluemke, D. A. Nat. Rev. Cardiol. 11, 74–76 (2014); published online 14 January 2014; doi:10.1038/nrcardio.2013.215 Diagnostic and interventional imaging meth­ods have frequently laid the foun- dation for advances in the diagnosis and treatment of cardiovascular diseases. Are engineering advancements in imaging scan- ners pushing evidence-based medicine into a new era? Dozens of high-impact cardiac imaging articles were published in 2013. In this Year in Review article, we discuss five of the most‑important studies on noninvasive imaging. Cardiac magnetic resonance (CMR) technology has added substantially to the assessment of myocardial scarring. After injection of the routinely used contrast agent gado­linium, bright areas of late enhance- ment indicate regions of myocardial scar tissue. The current dogma is that severe left ventricular wall thinning is indicative of a transmural myocardial infarction with no residual viable tissue. An end-diastolic wall thickness 5–6 mm has been presumed to be trans­mural myocardial scarring.1 How­ ever, a few case reports have suggested that areas of thinning might not be entirely com- posed of scar tissue. Therefore, Shah and colleagues used CMR to investigate 201 patients with coronary artery disease (CAD) and regional wall thinning.2 Overall, 18% of myocardial segments (5.5 mm regions) were found to have limited (≤50% extent) or no scarring evident on late gadolinium enhancement. For patients with limited scar- ring, resolution of thinning occurred after revascularization, with a substantial increase in end-diastolic wall thickness. Contrary to current assumptions, this report suggests that patients with regional wall thinning might have viable tissue remaining. Therefore, viability testing should be considered to assess whether patients would benefit from revascular­ization.Furtherprospectivestudies are required to determine whether patient outcomes can be improved using CMR g­uidance for co­ronary revascularization. Coronary computed tomography angio­ graphy (CCTA) shows high sensitivity for the detection of coronary stenosis (Figure 1). © 2014 Macmillan Publishers Limited. All rights reserved
  12. 12. KEY ADVANCES IN MEDICINE JANUARY 2014  |  9 CARDIOLOGY mean age was 14.6 years. The cumulative anthracycline dose was 224 mg/m2 for girls and 184 mg/m2 for boys. Abnormal left or right ventricular function (ejection fraction 45%) was detected in 18% and 27% of the participants, respectively. Subnormal left or right ventricular function (ejection frac- tion 45–55%) was seen in 61% and 53% of individuals, respectively. Left and right ven- tricular end-systolic and left ventricular end- diastolic volumes were increased, compared with reference values. None of the patients had CMR-detected focal myocardial fibrosis. This study was the first to show a high preva- lenceofbiventricularmyocardialdysfunction after fairly low anthracycline doses, in the absence of focal myocardial scarring, in sur- vivors of childhood cancer. The lifelong con- sequences of myocardial dysfunction from anthracycline therapy will require long-term follow-up to understand the i­mplications for these patients. Identification of ruptured or high-risk atherosclerotic plaque is not currently pos- sible using noninvasive imaging. In 2012, 18 F‑NaF was shown to be a marker of vas- cular calcification.9 A report from Joshi and colleagues now suggests that the radio­active tracer 18 F‑NaF might localize in unstable or ruptured plaque during PET–CT.10 This study included 40 patients with a myo- cardial infarction, 40 patients with stable angina, and 12 patients who had undergone carotid endarterectomy. Patients with myo- cardial infarction and stable angina under- went 18 F‑NaF and 18 F‑fluorodeoxyglucose (18 F‑FDG, which localizes in areas of inflam- mation) PET–CT, and ICA. In patients with stable angina, 18 F‑NaF uptake was com- pared with the results from intravascular ultrasonography. Furthermore, compari- sons were made between carotid specimen a b Figure 1 | Coronary CT angiogram of the heart. a | 3D representation. b | A heavily calcified right coronary artery showing moderate lumen narrowing. However, the technique tends to over­estimate stenosis severity. In some patients, only half of lesions identified using CCTA are actually confirmed as being physiologically relevant using invasive coronary angio­graphy (ICA).3 Fractional flow reserve measured using CT (FFRCT ) has emerged as a non­invasive method to determine whether stenoses observed using CCTA are haemodynamic­ ally relevant and actually causing ischaemia. FFRCT is calculated using computational fluid dynamic modelling. In 2013, Nakazato and colleaguesassessedtheperformanceofFFRCT to diagnose lesions of intermediate severity (30–69% stenosis as determined using CT).4 Patients underwent ICA and CCTA, and a total of 150 vessels of intermediate stenosis wereevaluated.FFRwasmeasuredusingICA with a pressure-monitoring guidewire placed distally to the stenosis. FFR and FFRCT ≤80% was considered ischaemic, and CT stenosis ≥50% was considered obstructive. FFRCT was found to have a high diagnostic perfor- mance compared with CT for the diagnosis of ischaemia—a twofold increase in sensitiv- ity (74% versus 34% per vessel) and a higher negative predictive value (90% versus 78% per vessel) was reported. FFRCT is one of several new applications of CCTA, with the aim of substantially improving noninvasive assessment of coronary anatomy. CCTA is likely to have an important future role in the noninvasive diagnosis of CAD. Although single-photon emission com- puted tomography (SPECT) is widely used in the detection of ischaemia, perfusion CMR has also been increasingly used for this purpose in clinical practice. CMR has been used on the basis of studies showing a strong diagnostic performance of CMR compared with ICA.5 Therefore, in the MR‑IMPACT II trial,6 Schwitter and col- leagues compared the diagnostic perform­ ance of CMR and SPECT for the detection of CAD. This prospective trial involved 425 patients at 33 centres. ICA was used as the reference standard. To define patients with CAD (that is, to define per­fusion defects), the presence of a ≥50% stenosis in more than one coronary artery 2 mm in diameter was used. A high perform­ance of perfusion CMR to detect CAD was demonstrated. The sensi- tivity of perfusion CMR (0.67) was superior to that of perfusion SPECT (0.59). However, the specificity of perfusion CMR (0.61) was inferior to that of perfusion SPECT (0.72). This study shows that perfusion CMR is a safe alternative to SPECT for detecting per- fusion abnormalities in patients with CAD, because CMR has the advantage over SPECT of not using i­onizing radiation. With increased survival from child­hood cancer, the need to assess the cardiotoxic effects of chemotherapeutic agents has grown, particularly given that increased myocardial fibrosis has been detected in endo­myocardial biopsies of survivors. Further­­more, a cumulative incidence of congestive heart failure 7.5% at 30 years in patients with a dose of anthracycline ≥250 mg/m2 has been reported.7 Therefore, Ylanen and colleagues used CMR to evalu- ate the prevalence of left and right ventricu- lar dysfunction and signs of focal fibrosis among long-term survivors of childhood cancer who had been exposed to anthra- cycline.8 The cohort comprised 62 patients who were in remission from cancer, and the Key advances ■■ Patients with thin myocardial walls, previously defined as scar tissue, might have myocardium that is viable and recovers some function and wall thickness after therapy2 ■■ CT fractional flow reserve (FFRCT ) is one of several new applications of coronary CT angiography (CCTA) that aim to substantially improve the noninvasive assessment of coronary stenosis4 ■■ Perfusion cardiac magnetic resonance (CMR) is a safe and sometimes superior alternative to single-photon emission computed tomography for detecting perfusion abnormalities in coronary artery disease6 ■■ CMR imaging detects a high prevalence of myocardial dysfunction after a fairly low dose of anthracycline chemotherapy in survivors of childhood cancer8 ■■ 18 F‑NaF uptake identifies ruptured and high-risk atherosclerotic plaques in symptomatic patients with coronary or carotid artery disease10 © 2014 Macmillan Publishers Limited. All rights reserved
  13. 13. 10  |  JANUARY 2014 www.nature.com/reviews CARDIOLOGY histology and 18 F‑NaF uptake. The highest coronary 18 F‑NaF uptake was seen in the culprit plaque in 93% of patients with myo- cardial infarction. By contrast, conventional 18 F‑FDG PET–CT did not accurately identify high-risk plaques. A total of 45% of patients with stable angina had plaques with focal 18 F‑NaF uptake. These plaques were asso­ ciated with more high-risk features on intra- vascular ultrasonography than those without 18 F‑NaF uptake. In the carotid artery, the site of plaque rupture showed marked 18 F‑NaF uptake. These preliminary findings suggest a new, high-sensitivity imaging technique that might help to distinguish between high- risk plaques and stable calcium deposits in mature plaques. Prospective studies will be required to investigate whether 18 F‑NaF PET can be used to predict cardiovascular events. In summary, developments in non­invasive imaging methods have been rapid and p­rom­ ise to change the future of diagnostic cardio­ logy. In 2013, imaging methods pushed traditional boundaries in the understanding of CAD, atherosclerotic plaque development and diagnosis, as well as myocardial function. Given the attractiveness of noninvasive tech- niquestoanincreasingnumberofresearchers in the field, 2014 promises to be yet another exciting year in cardiovascular imaging. National Institutes of Health Clinical Center, National Institute of Biomedical Imaging and Engineering, 10 Center Drive, Bethesda, MD 20892, USA (P. Pattanayak, D. A. Bluemke). Correspondence to: D. A. Bluemke bluemked@nih.gov Acknowledgements The views and opinions of the authors do not necessarily state or reflect those of the US Government, and they may not be used for advertising or product endorsement purposes. Competing interests The authors declare no competing interests. 1. Schmidt, M. et al. F‑18‑FDG uptake is a reliable predictor of functional recovery of akinetic but viable infarct regions as defined by magnetic resonance imaging before and after revascularisation. Magn. Reson. Imaging 22, 229–236 (2004). 2. Shah, D. J. et al. Prevalence of regional myocardial thinning and relationship with myocardial scarring in patients with coronary artery disease. JAMA 309, 909–918 (2013). 3. Meijboom, W. B., Van Mieghem, C. A.  van Pelt, N. Comprehensive assessment of coronary artery stenoses: computed tomography coronary angiography versus conventional coronary angiography and correlation with fractional flow reserve in patients with stable angina. J.Am. Coll. Cardiol. 52, 636–643 (2008). 4. Nakazato, R. et al. Noninvasive fractional flow reserve derived from computed tomography angiography for lesions of intermediate stenosis severity: results from the DeFACTO study. Circ. Cadiovasc. Imaging 6, 881–889 (2013). 5. Plein, S. et al. High spatial resolution myocardial perfusion cardiac magnetic resonance for the detection of coronary artery disease. Eur. Heart J. 29, 2148–2155 (2008). 6. Schwitter, J. et al. MR‑IMPACT II: magnetic resonance imaging for myocardial perfusion assessment in coronary artery disease trial: perfusion cardiac magnetic resonance vs single photon emission compute tomography for the detection of coronary artery disease: a comparative multicentre, multivendor trial. Eur. Heart J. 34, 775–781 (2013). 7. Mulrooney, D. A. et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the childhood cancer survivor study cohort. BMJ 339, b4606 (2009). 8. Ylanen, K. et al. Cardiac magnetic resonance imaging in the evaluation of the late effects of anthracyclines among long term survivors of childhood cancer. J.Am. Coll. Cardiol. 61, 1539–1547 (2013). 9. Dweck, M. R. et al. Coronary arterial 18 F‑fluoride uptake: a novel marker of plaque biology. J.Am. Coll. Cardiol. 59, 1539–1548 (2012). 10. Joshi, N. V. et al. 18 F‑fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial. Lancet http:// dx.doi.org/10.1016/S0140-6736(13)61754-7. © 2014 Macmillan Publishers Limited. All rights reserved
  14. 14. Editors’ picks of the year Myofibroblast-mediated mechanisms of pathological remodelling of the heart Karl T. Weber, Yao Sun, Syamal K. Bhattacharya, Robert A. Ahokas and Ivan C. Gerling In the diseased heart, cardiomyocytes undergo necrotic cell death. A healing response results in myofibroblast production of collagen and other matrix molecules, which initially serve to preserve the structural integrity of the myocardium. However, myofibroblast dispersion fails to occur in many cardiac diseases, and perpetual matrix formation leads to adverse remodelling of the heart. doi:10.1038/nrcardio.2012.158 Assessment and management of blood-pressure variability Gianfranco Parati, Juan E. Ochoa, Carolina Lombardi and Grzegorz Bilo Blood pressure is characterized by short-term and long-term fluctuations, which are the result of complex interactions between environmental and behavioural factors and, additionally, cardiovascular regulatory mechanisms. Increased blood pressure variability leads to cardiac, vascular, and renal damage, and is associated with an increased risk of cardiovascular morbidity and mortality. doi:10.1038/nrcardio.2013.1 Targeting the renin–angiotensin–aldosterone system in heart failure Chim C. Lang and Allan D. Struthers The renin–angiotensin–aldosterone system is well established as a therapeutic target in patients with heart failure. Professors Lang and Struthers discuss new indications for existing drugs in patients who have heart failure with or without reduced ejection fraction. They also review novel ways of targeting the renin– angiotensin–aldosterone system in these patients. doi:10.1038/nrcardio.2012.196 The biology behind the atherothrombotic effects of cigarette smoke Adam Csordas and David Bernhard Cigarette smoke is an aerosol that exerts multiple atherothrombotic effects on smokers and the individuals around them. In this Review, Csordas and Bernhard describe the current knowledge of the mechanisms through which cigarette smoke affects all stages of plaque formation and development, as well as pathological thrombus formation. doi:10.1038/nrcardio.2013.8 The roles of senescence and telomere shortening in cardiovascular disease Frej Fyhrquist, Outi Saijonmaa and Timo Strandberg Telomere shortening, and various other endogenous and environmental factors, can drive cells into senescence, which is involved in the complex process of biological ageing. Fyhrquist and colleagues discuss the associations between cardiovascular risk factors and telomere shortening, and whether cellular senescence has a causal role in conditions such as atherosclerosis, heart failure, and hypertension. doi:10.1038/nrcardio.2013.30 Renal sympathetic denervation: applications in hypertension and beyond Michael Böhm, Dominik Linz, Daniel Urban, Felix Mahfoud and Christian Ukena Increased sympathetic activity is associated with a number of diseases, including resistant hypertension. Renal denervation is increasingly being used as a treatment for patients with resistant hypertension in some parts of the world. The pathophysiology of this technique, its use in treating patients with hypertension, and its potential in the treatment of patients with other conditions are discussed in this Review. doi:10.1038/nrcardio.2013.89 Update on atrial fibrillation catheter ablation technologies and techniques Jane Dewire and Hugh Calkins Atrial fibrillation is one of the most common heart arrhythmias. Dewire and Calkins discuss the development and role of catheter ablation to electrically isolate the pulmonary veins in patients with paroxysmal, persistent, or longstanding persistent atrial fibrillation. They go on to highlight novel tools that improve the safety, efficacy, and precision of ablation techniques. doi:10.1038/nrcardio.2013.121 Optimal revascularization for complex coronary artery disease Javaid Iqbal, Patrick W. Serruys and David P. Taggart Patients with coronary artery disease who do not respond to optimal medical therapy are candidates for revascularization. The choice of revascularization technique is dependent on a patient’s overall medical state. Iqbal and colleagues review the evidence for coronary artery bypass graft surgery versus percutaneous coronary intervention as the optimal revascularization method in various groups of patients with complex coronary artery disease. doi:10.1038/nrcardio.2013.138 Mechanisms and management of TAVR-related complications Amir-Ali Fassa, Dominique Himbert and Alec Vahanian Transcatheter aortic valve replacement is an effective treatment for patients with severe aortic stenosis who are not suitable candidates for surgery. However, serious complications can occur. In this Review, Alec Vahanian and colleagues describe TAVR-related complications, the mechanisms that cause these events, and methods of preventing them. doi:10.1038/nrcardio.2013.156 Silent cerebral infarcts associated with cardiac disease and procedures Mariëlla E. C. Hassell, Robin Nijveldt, Yvo B. W. Roos, Charles B. L. Majoie, Martial Hamon, Jan J. Piek and Ronak Delewi Silent cerebral infarcts frequently occur in association with cardiovascular disease and cardiac interventional procedures, but their prognostic importance is unknown. In this Review, Hassell and colleagues assess the incidence and detection of silent cerebral infarcts, and their possible association with adverse neurological outcomes, such as stroke, depression, cognitive decline, and dementia. doi:10.1038/nrcardio.2013.162 February 2014 volume 11 no. 2 www.nature.com/reviews REFRACTORY ANGINA Treatment options for patients not suitable for revascularization Endovascular repair of AAAs Current and future strategies CARDIOLOGY An official publication of nrcardio_OFC_FEB14.indd 1 09/01/2014 14:36 * * * * * * * * * * A selection of articles published during 2013 in Nature Reviews Cardiology: Don’t miss out! Sign up to free e-ALERTS and be notified when new articles are published in Nature Reviews Cardiology. Research Highlights, News Views, Reviews, and Perspectives—you won’t miss a thing! http://www.nature.com/register © 2014 Macmillan Publishers Limited. All rights reserved
  15. 15. KEY ADVANCES IN MEDICINE JANUARY 2014  |  11 CLINICAL ONCOLOGY LUNG CANCER IN 2013 Refining standard practice and admitting uncertainty Stephen V. Liu and Giuseppe Giaccone In 2013, the treatment of several NSCLC subtypes was refined. PROFILE‑1007 and LUX-Lung 3 confirmed that targeted therapy was superior to chemotherapy, whereas NCIC BR19 and PointBreak failed to show superiority of adjuvant gefitinib and combined maintenance therapy, respectively. These studies reinforced some practices and discouraged others, underscoring the need for new prospective studies. Liu, S. V. Giaccone, G. Nat. Rev. Clin. Oncol. 11, 69–70 (2014); published online 21 January 2014; doi:10.1038/nrclinonc.2013.251 The extensive molecular characterization of non-small-cell lung cancer (NSCLC) over the past decade has led to the identification of unique subsets of NSCLC that benefit from targeted therapies. NSCLC tumours that harbour activating mutations in EGFR or rearrange­ments in the anaplastic lym- phoma kinase (ALK) gene are routinely and effectively treated with tyrosine kinase inhibitors (TKI) such as erlotinib and crizo- tinib, respectively. Several important studies reported in 2013 have provided valuable insight into the evolving treatment para- digms of NSCLC, p­articularly with regard to targeted therapies (Table 1). Rearrangements in ALK are present in approximately 5% of adenocarcinoma of the lung and the small molecule TKI crizo- tinib has emerged as a standard treatment in this setting.1 Crizotinib was granted accelerated approval by the FDA in 2011 for patients with ALK-positive NSCLC with no restrictions on line of therapy.1 Crizotinib also received conditional approval in 2012 from the European Medicines Agency. These approvals were based on two, single- arm studies that demonstrated impressive response rates in patients with ALK-positive NSCLC.1,2 Approval was contingent on a formal comparison between crizotinib and chemotherapy in these patients; the phase III PROFILE‑1007 trial, published in 2013, pro- vides that comparison. This open-label trial randomly assigned 347 patients with ALK‑ positive NSCLC previously treated with one platinum-based chemotherapy regimen to receive crizotinib or standard pemetrex­ed or docetaxel-based chemotherapy.3 Inthis study, crizotinib was more effective than chemo- therapy. Patients treated with crizotinib had a median progression-free survival (PFS) of 7.7 months compared with 3.0 months with chemotherapy (HR 0.49; 95% CI 0.37–0.64, P 0.001). There was no significant differ- ence in overall survival in the interim analy- sis, likely due to crossover, as 64% of patients who were assigned to receive chemotherapy subsequently received crizotinib. Patients in the crizotinib arm also had a higher response rate (65% versus 20%) and a greater improve- ment in quality of life. Although crizotinib had already received conditional approval in this setting, the random­ized, prospective PROFILE‑1007 trial provides important information c­onfirming what has become common practice.3 A similar trial conducted in patients with EGFR-mutant NSCLC reinforced this theme. The phase III LUX-Lung 3 trial explored the activity of afatinib, an inhibitor of the EGFR family that targets EGFR, HER2 and HER4.4 LUX-Lung 3 was the largest random- ized trial for patients with advanced-stage EGFR-mutant NSCLC; this study randomly assigned 345 patients with advanced-stage adenocarcinoma in a 2:1 ratio to receive either afatinib or chemotherapy with cispla- tin plus pemetrexed. As seen in similar trials featuring erlotinib and gefitinib, the targeted agent was superior to chemotherapy. Median PFS, the primary end point, with afatinib was 11.1 months compared with 6.9 months with chemotherapy (HR 0.58; 95% CI 0.43–0.78, P = 0.001).Therewasnosignificantdifference in overall survival between these arms (HR 1.12; 95% CI 0.73–1.73, P = 0.60) and again, crossover might be responsible for this lack of superiority in survival, as 65% of patients in the chemotherapy arm received EGFR tar- geted therapy at disease progression. Afatinib was associated with greater improvement in dyspnoea and cough, as well as better global healthstatususingtheEORTCQualityofLife questionnaire C30.5 In addition, this study also provided prospective data on the activity ofafatinibinpatientsharbouringuncommon EGFR alterations, including L861Q, G719X andS768I.6 Despitethesefindings,theoptimal use of afatinib is not readily apparent: will it Table 1 | Trials in non-small-cell lung cancer in 2013 Trial Patients Treatment Outcome Comments PROFILE‑10073 Pretreated ALK‑positive Crizotinib Cis + Pem PFS HR 0.49 (95% CI 0.37–0.64) P 0.001 No OS benefit possibly due to 64% crossover from Cis + Pem to crizotinib LUX-Lung 34 Untreated EGFR-mutant Afatinib Cis + Pem PFS HR 0.58 (95% CI 0.43–0.78) P = 0.001 No OS benefit possibly due to 65% crossover from Cis + Pem to EGFR targeted therapy NCIC CTG BR197 Resected stage IB–IIIA, unselected Gefitinib Placebo DFS HR 1.84 (95% CI 0.44–7.73) P = 0.395 Analysis of EGFR-mutant subset (n = 15) failed to show benefit PointBreak10 Untreated stage IIIB/IV PemCBev PacCBev OS HR 1.00 (95% CI 0.86–1.16) P = 0.949 PFS benefit with PemCBev did not translate to OS benefit Abbreviations: Cis, cisplatin; DFS, disease-free survival; OS, overall survival; PacCBev, paclitaxel plus carboplatin plus bevacizumab with bevacizumab maintenance; Pem, pemetrexed; PemCBev, pemetrexed plus carboplatin plus bevacizumab with pemetrexed plus bevacizumab maintenance; PFS, progression-free survival. © 2014 Macmillan Publishers Limited. All rights reserved
  16. 16. 12  |  JANUARY 2014 www.nature.com/reviews CLINICAL ONCOLOGY displace erlotinib and gefitinib in the front- line setting or will it be reserved for patients withacquiredresistancetotheseexisting,and potentially better tolerated, agents? Now that several well-designed studies have shown EGFR targeted agents are more effective than chemo­therapy in the first-line setting, hopefully LUX-Lung 3 marks the end of this study design and the use of approved EGFR targeted agents in the comparator arm should now become stand­ard. It is also worth reinfor­cingtheneedfortheseinitialstudies,as although treatment of ALK-positive NSCLC is very similar to EGFR-mutant NSCLC, the optimal treatment strategy may be different for other putative driver mutations. We will await results from ongoing studies interrogat- ing different subtypes, including those with a­berrations in ROS1, RET, BRAF and others. Targeted therapy in early-stage NSCLC remains highly controversial, in large part owing to the results of the NCIC CTG BR19 study of gefitinib versus placebo in resected NSCLC.7 This trial was designed to ran- domly assign 1,242 unselected patients with completely resected stage IB–IIIA NSCLC to receive either gefitinib or placebo for 2 years. Thistrialwasclosedprematurelyin2005after 503patientswereenrolled,basedontwoother negative studies with gefitinib.8,9 This left the NCIC CTG BR19 study under­powered for its final analysis. In addition, standard use of adjuvant chemotherapy emerged after this trial had launched and only 17% of patients received this proven treatment. With these shortcomings in mind, use of gefitinib did not improve disease-free survival (DFS) or overall survival in the unselected popula- tion. Somewhat surprisingly, gefitinib also did not improve either DFS (HR 1.84, 95% CI 0.44–7.73, P = 0.395) or overall survival (HR 3.16, 95% CI 0.61–16.45, P = 0.15) in the EGFR-mutant subset (n = 15). It is difficult to make meaningful conclusions on the basis of this study and targeted therapy may still prove effective in early-stage NSCLC. Given these results, however, use of EGFR targeted agents in the adjuvant setting should be in the context of a clinical trial, such as the recently completed RADIANT study. Another major advance over the past few years has been the emergence of main- tenance therapy in NSCLC. The standard chemotherapy strategy for NSCLC had been 4–6 cycles of platinum-doublet therapy fol- lowed by observation. With the development of better tolerated agents and improved sup- portive care,dataemerged supporting the use of several agents in the maintenance setting, buttheoptimalmaintenancestrategyremains unclear. In 2013, the randomized, phase III PointBreak trial10 compared two popular maintenance strategies in patients with advanced-stage, nonsquamous NSCLC. In this study, 939 patients were randomly assigned to receive carboplatin, paclitaxel and bevacizumab followed by bevacizumab maintenance, as used in the ECOG 4599 study,orcarboplatin,pemetrexedand bevaci­ zumab followed by bevacizumab and pem­ etrexed maintenance. This trial showed no survival advantage with the additional maintenance agent; median overall survival in the group assigned to receive paclitaxel was 13.4 months compared to 12.6 months with the pemetrexed strategy (P = 0.949). There was a superior PFS with pemetrexed (6.0 monthsversus5.6 months,P = 0.012)and this was more pronounced in the subset of patients who completed initial therapy and successfully reached the main­tenance phase (8.6 months versus 6.9 months), but this did not translate into a benefit in overall sur- vival. The toxic effects were different in the two arms, with more anaemia, thrombocyto­ penia and fatigue seen in the pemetrexed arm and more neutro­penia, febrile neutropenia, neuro­pathy and alopecia in the paclitaxel arm. The PointBreak study did not establish a clear standard in the maintenance setting and that is still an unanswered question. The ongoing three-armed ECOG 5508 trial—in which patients receiving induction with carbo­platin, paclitaxel and bevacizumab will be randomly assigned to receive maintenance withbevacizumab,pem­etrexedorboth—may offer further insight. The underlying theme, however, is that the benefit of cytotoxic therapy is not necessarily exhausted after 4–6 cycles, p­rovided toxicity can be managed. Genomic-based targeted therapy repre- sents the most important paradigm in the treatment of advanced-stage lung cancer. Although the use of crizotinib and afatinib in molecularly defined populations was supported by the PROFILE‑1007 and LUX- Lung 3 studies, the adjuvant NCIC CTG BR19 study warns against early adoption and reminds us of the need for prospec- tive studies. Similarly, the PointBreak study serves as a reminder that more is not neces­ sarily better. Given the developments over the past year, we expect the coming years to further optimize induction, maintenance and adjuvant therapy for these and other subtypes of NSCLC. Importantly, strategies designed to delay or overcome acquired resistance to therapy will emerge in the near future. Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road NW,Washington, DC 20007, USA (S. V. Liu, G. Giaccone). Correspondence to: G. Giaccone giacconeg@mail.nih.gov Competing interests The authors declare no competing interests. 1. Camidge, D. R. et al. Activity and safety of crizotinib in patients with ALK-positive non‑small‑ cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 13, 1011–1019 (2012). 2. Kim, D. W. et al. Results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC) [abstract]. J. Clin. Oncol. 30 (Suppl. 15), a7533 (2012). 3. Shaw, A. T. et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 368, 2385–2394 (2013). 4. Sequist, L. V. et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 31, 3327–3334 (2013). 5. Yang, J. C. et al. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 31, 3342–3350 (2013). 6. Yang, J. C. et al. Activity of afatinib in uncommon epidermal growth factor receptor (EGFR) mutations: findings from three prospective trials of afatinib in EGFR mutation-positive lung cancer [abstract]. World Conference on Lung Cancer, 1114, 003.05 (Sidney, Australia, 2013). 7. Goss, G. D. et al. Gefitinib versus placebo in completely resected non‑small‑cell lung cancer: results of the NCIC CTG BR19 study. J. Clin. Oncol. 31, 3320–3326 (2013). 8. Kelly, K. et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non‑small‑cell lung cancer: SWOG S0023. J. Clin. Oncol. 26, 2450–2456 (2008). 9. Thatcher, N. et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non‑small‑cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366, 1527–1537 (2005). 10. Patel, J. D. et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIb or IV nonsquamous non‑small‑cell lung cancer. J. Clin. Oncol. 31, 4349–4357 (2013). Key advances ■■ In advanced-stage lung cancer, targeted therapy continues to be a more effective option than chemotherapy, specifically, crizotinib in ALK-positive lung cancer3 and afatinib in EGFR-mutant lung cancer4 ■■ In the adjuvant setting, the role of targeted therapy remains unclear7 ■■ Combination maintenance therapy with pemetrexed plus bevacizumab after induction with pemetrexed-based chemotherapy was not superior to bevacizumab maintenance alone after induction with a paclitaxel-based regimen10 © 2014 Macmillan Publishers Limited. All rights reserved
  17. 17. KEY ADVANCES IN MEDICINE JANUARY 2014  |  13 CLINICAL ONCOLOGY BREAST CANCER IN 2013 Genomics, drug approval, and optimal treatment duration Adrian V. Lee and Nancy E. Davidson 2013 saw much progress in breast cancer research. Advances in high- throughput technologies continue to refine our knowledge of the molecular biology of breast cancer, and are beginning to give insight into cancer evolution, drug resistance, and how to deploy precision therapeutics. Lee, A. V. Davidson, N. E. Nat. Rev. Clin. Oncol. 11, 71–72 (2014); published online 14 January 2014; doi:10.1038/nrclinonc.2013.250 The tremendous molecular diversity in cancers, both between patients and within a single patient, challenges standard basic research techniques and traditional drug design and testing. Breast cancer is con- sidered the most common cause of cancer deaths among women worldwide. It is a clinically and biologically heterogeneous disease that will require new approaches for the translation of precision medicine into new treatments tailored to the biology of the specific tumour. In one comprehensive genomic report, TheCancerGenomeAtlas(TCGA)research- ers performed an analysis to identify somatic point mutations and small insertions or del­ etions in 12 cancer types. This study showed that breast cancer has one of the lowest muta- tion rates in solid tumours, with an average of ~3,000 somatic mutations per tumour (range ~90–60,000).1 Breast cancers were enriched with mutations in TP53, PIK3CA, GATA3, MAP3K1, CDH1, and MLL3. In a separate study, Alexandrov and col- leagues analysed somatic mutations from 7,000 tumours (representing 30 different classes) and found that the mutation rate in breast cancer samples was strikingly similar to that observed in the TCGA pan-cancer analysis.2 Breast cancers showed foci of h­ypermutation—termed kataegis—that were associated with large structural rearrange- ments. Specific mutation signatures were strongly associated with tumours harbouring loss of BRCA1 or BRCA2. The researchers also identified a unique type of base pair mutation (CT and CG at TCN trinucleo- tides) that is consistent with aberrant activity of endogenous APOBECs proteins, cytidine deaminases that normally convert cytidine to uracil. Several other studies in 2013 revealed a role for the overexpression of APOBEC family members in breast and other cancers, suggest­ing that the APOBEC-mediated cyti- dine deami­nation might represent a general mechanism to generate mutations during tumorigenesis. Overall, published reports in the past 2–3 years have comprehensively identified several somatic point mutations and small insertions or d­eletions in primary breast tumours. Breast cancer genomics remains an evolv- ing story, as most large sequencing studies have so far focused on primary breast cancer. Furthermore, recent reports of sequencing in metastases have described mutations that are absent or present at very low frequencies in primary tumours (such as in rare subclones), supporting the need for further mutational analysis of metastases. Indeed, one of the greatest surprises in breast cancer genetics in 2013 was the identification of mutations in the gene encoding the oestrogen recep- tor (ER, ESR1) in breast cancer metastases. As ER is a central driver and a primary target in breast cancer, most researchers had sur- mised that it must be mutated at least in some endocrine-resistant tumours. However, very few mutations have been identified des­ pite intensive efforts. For example, TCGA identified somatic mutations in ESR1 in only two of 825 primary breast cancers (0.2%). The genomic landscape changed dramati- cally when the analysis was shifted from primary tumours to advanced-stage and hormone-resistant disease. In a Herculean effort designed to sequence and character- ize patient-derived xenografts, Ellis and col- leagues identified ESR1 somatic mutations in advanced-stage breast cancer samples from patients refractory to antihormonal therapy.3 These findings were substantiated in two subsequent studies that reported the identification of ESR1 somatic mutations in six out of 11 (55%) and 14 of 80 (17.5%) patients with ER‑positive metastatic breast cancer, respectively.4,5 Importantly, these mutations were found almost exclusively in advanced-stage ER‑positive breast cancers, and they emerged after patients were treated with an aromatase inhibitor rather than an antioestrogen. The somatic mutations clus- tered in the ligand binding domain of the ER; structure–function studies showed that these mutations resulted in conformational changes to the ER, leading to its constitutive activation. This ligand-independent activ- ity caused complete resistance to aromatase inhibitors and partial resistance to selective oestrogen-receptor modulators and degrad- ers. Together, these findings open up a new avenue in the development of therapies for ER‑positive advanced-stage breast cancer by investigating the mechanism of hormone action and suggest the use of inhibitors that specifically target the mutated ER. Sequencing of distinct tumour regions, and single cancer cells, has revealed tremen­ dous intratumour heterogeneity. TCGA and other large genomic projects have struggled to address the degree of intra­ tumour hetero­geneity. Moreover, deter- mining the extent and clinical significance of such hetero­geneity is hampered by the difficulty in obtaining repeated tissue biop­sies. An attractive alternative is the NPG © 2014 Macmillan Publishers Limited. All rights reserved

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