Kaim jan12

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Kaim jan12

  1. 1. January 2012 KEY ADVANCES IN MEDICINE
  2. 2. Access high quality clinical content written by international experts January 2012 volume 9 no. 1 www.nature.com/reviews January 2012 volume 8 no. 1 www.nature.com/reviews ROBOTIC UROLOGIC SURGERY How best to train postgraduates and residents in robotic techniques? January 2012 volume 8 no. 1 www.nature.com/reviews Molecular biomarkers in bladder cancer Stratifying response to targeted therapies nrurol_OFC_JAN12.indd 1 Mucosal pathogenesis and new concepts in the role of mucosal inflammation Clinical applications of MRI in Crohn’s disease January 2012 volume 8 no. 1 www.nature.com/reviews 13/12/2011 10:31 BIOLOGIC THERAPIES Evaluating the extent of intestinal damage nrgastro_OFC_JAN12.indd 1 07/12/2011 16:34 Influence on cardiovascular risk parameters in RA KISSPEPTINS Metabolic regulation of puberty and fertility Cellular and molecular mechanisms of fibrosis nrrheum_OFC_JAN12.indd 1 08/12/2011 11:47 January 2012 volume 8 no. 1 www.nature.com/reviews An official publication of Neuroendocrine neoplasms of the gut and pancreas Knowledge, advances and controversies METABOLOMICS Relevance and potential applications in kidney disease Diagnostic and treatment options nrneph_OFC_JAN12.indd 1 28/11/2011 15:31 January 2012 volume 9 no. 1 www.nature.com/reviews Using breast cancer gene signatures in the clinic NEPHROLOGY Systemic sclerosis CLINICAL ONCOLOGY nrendo_OFC_JAN12.indd 1 nrclinonc_OFC_JAN12.indd 1 RHEUMATOLOGY ENDOCRINOLOGY GERD January 2012 volume 9 no. 1 www.nature.com/reviews UROLOGY GASTROENTEROLOGY & HEPATOLOGY January 2012 volume 9 no. 1 www.nature.com/reviews MULTIPLE SCLEROSIS TRIALS New recommendations for MRI-based monitoring of immunomodulation Time for a rethink to avoid overtreatment of older men and those at low risk 07/12/2011 15:55 nrneurol_OFC_JAN12.indd 1 ATRIAL ARRHYTHMIAS Role of the autonomic nervous system nrcardio_OFC_JAN12.indd 1 Pathogenesis and diagnosis 02/12/2011 12:49 CARDIOLOGY PROSTATE CANCER SCREENING An official publication of NEUROLOGY Acute kidney injury in multiple myeloma Postural tachycardia syndrome Characteristics, neuroepidemiology and pathophysiological mechanisms 13/12/2011 11:42 Transcatheter aortic valve implantation Valves and approaches 24/11/2011 15:32 YOUR DISCIPLINE, YOUR REVIEW JOURNAL • Junior doctors keep up-to-date with Research Highlights • Busy clinicians appreciate “Key point” summaries • Medical Researchers value in-depth Reviews The January issues are freely available on our website: www.nature.com/reviews Follow us. Download the free app for your phone at http://gettag.mobi Get the free mobile app for your phone http:/ / gettag.mobi
  3. 3. design: annette fenner & nicola hawes Cover image: Hippocrates of Cos reflected in the style of the Roman god, Janus. Based on an engraving by Peter Paul Rubens (1638) from ihm.nlm.nih.gov website. Key Advances in Medicine T he articles included in Nature Reviews Key Advances in Medicine were originally published in the February 2012 issues of the eight clinical Nature Reviews journals. The journals’ editors commissioned international experts to write a short essay highlighting up to five key papers that made the biggest contribution to their field in 2011. Between them, the eight clinical Nature Reviews journals published 43 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/ 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 COPYRIGHT © 2012 Nature Publishing Group. 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 the copyright holder. AUTHORIZATION TO PHOTOCOPY material for internal or personal use, or internal or personal use of specific clients, is granted by Nature Publishing Group to libraries and others registered with the Copyright Clearance Center (CCC) Transactional Reporting Service, provided the relevant copyright fee is paid to CCC, 222 Rosewood Drive, Danvers, MA 01923, USA. 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. Nature Reviews Cardiology S1 acute coronary syndromes | Walking the tightrope between efficacy and bleeding Payal Kohli and Christopher P. Cannon S3 atrial fibrillation | Stroke prevention in AF Gregory Y. H. Lip S5 heart failure | Heart failure therapy—technology to the fore John J. V. McMurray S7 hypertension | New insights—from risk factors to treatment implications George L. Bakris S9 valvular disease | Breakthrough for intervention? Volkmar Falk Nature Reviews Clinical Oncology S11 ovarian cancer | Mutations and non-inferiority analyses show a way forward Maurie Markman S12 prostate cancer | Hitting old targets better and identifying new targets Yu Chen and Howard I. Scher S14 hematological cancer | New therapeutic targets and treatment strategies Paula Cramer and Michael Hallek S16 melanoma | A new paradigm tumor for drug development Alexander M. M. Eggermont and Caroline Robert S18 bone cancer | Prevention and treatment of bone metastases Robert E. Coleman
  4. 4. Nature Reviews Endocrinology Nature Reviews Neurology S21 thyroid disease in pregnancy | Thyroid function—effects on mother and baby unraveled Anthony P. Weetman S55 stroke | Major advances across the spectrum of stroke care Lee H. Schwamm S22 primary aldosteronism | Towards a better understanding of causation and consequences Michael Stowasser S24 polycystic ovary syndrome | Genes, aging and sleep apnea in polycystic ovary syndrome Andrea Dunaif S26 epigenetics and metabolism | Epigenetics, the life-course and metabolic disease Peter D. Gluckman S28 osteoporosis | Osteoporosis therapy—dawn of the postbisphosphonate era Roland Baron S57 movement disorders | Translating new research findings into clinical practice Christine Klein and Dimitri Krainc S58 multiple sclerosis | Advances in therapy, imaging and risk factors in MS Bianca Weinstock-Guttman and Murali Ramanathan S60 dementia | Microbleeds in dementia—singing a different ARIA Philip Scheltens and Jeroen D. C. Goos S62 epilepsy | Insights into epilepsy treatments and biomarkers Fernando Cendes S30 type 1 diabetes mellitus | Heterogeneity of T1DM raises questions for therapy Paolo Pozzilli Nature Reviews Gastroenterology & Hepatology Nature Reviews Rheumatology S33 hepatitis c | A new standard of care and the race towards IFN-free therapy Wolf Peter Hofmann and Stefan Zeuzem S65 rheumatoid arthritis | Advances in diagnosis, treatment and definition of remission Gerd R. Burmester S35 hepatocellular carcinoma | Genomics in hepatocellular carcinoma—a big step forward Ryosuke Tateishi and Masao Omata S67 juvenile idiopathic arthritis | New takes on categorization and treatment Alberto Martini S36 ibd | Advances in IBD management—towards a tailored approach Guillame P. Pineton de Chambrun and William J. Sandborn S68 systemic lupus erythematosus | Deciphering the role of NETs and networks in SLE Thomas Dörner S38 the gut microbiota | Translating the microbiota to medicine Fergus Shanahan S40 neurogastroenterology | Emerging concepts in neurogastroenterology and motility Keith A. Sharkey and Gary M. Mawe S70 osteoarthritis | Age-related OA—a concept emerging from infancy? Thomas Aigner and Wiltrud Richter S72 systemic sclerosis | From mechanisms to medicines Luc Mouthon S74 vasculitis | The renaissance of granulomatous inflammation in AAV Stephan D. Gadola and Wolfgang L. Gross Nature Reviews Nephrology Nature Reviews Urology S43 glomerular disease | New clues to environmental influences in glomerular disease Peter J. Nelson and Charles E. Alpers S77 prostate cancer | Redefining the therapeutic landscape for CRPC Carmel Pezaro and Gerhardt Attard S44 polycystic kidney disease | Connecting the dots toward a polycystic kidney disease therapy Vicente E. Torres and Peter C. Harris S79 bladder cancer | The dawn of personalized medicine Thomas W. Flaig and Dan Theodorescu S46 acute kidney injury | Biomarkers are transforming our understanding of AKI Lakhmir S. Chawla and John A. Kellum S48 nondialysis chronic kidney disease | Progression, prediction, populations and possibilities Adeera Levin S50 dialysis | Can cardiovascular risk in dialysis patients be decreased? Peter Stenvinkel and Peter Bárány S52 transplantation | New agents, new ideas and new hope Titte R. Srinivas and Bruce Kaplan S80 sexual dysfunction | Advances in epidemiology, pathophysiology and treatment Eric Chung and Gerald B. Brock S82 male factor infertility | Semen quality, sperm selection and hematospermia Amichai Kilchevsky and Stanton Honig S84 kidney cancer | Objectifying risk for localized renal masses Marc C. Smaldone and Robert G. Uzzo
  5. 5. CARDIOLOGY ACUTE CORONARY SYNDROMES IN 2011 Walking the tightrope between efficacy and bleeding Payal Kohli and Christopher P . Cannon Major advances in the diagnosis of acute coronary syndromes (ACS) have occurred in 2011, but physicians treating ACS still walk the tightrope between efficacy and bleeding. Key publications have shed light on this delicate balance and heralded a new era of novel oral anticoagulants for the treatment of ACS. Kohli, P & Cannon, C. P Nat. Rev. Cardiol. 9, 69–71 (2012); published online 20 December 2011; doi:10.1038/nrcardio.2011.206 . . The year 2011 has witnessed an evolution in all aspects of the management of acute coronary syndromes (ACS). The intro­ uction of d new-generation troponin assays has compli­ cated the diagnostic dilemma in ACS by increasing the number false positive diagnoses. One of the most-interesting studies of 2011 addressed whether the reduced threshold for detection of myocardial injury translated into improved clinical outcomes. Mills et al. undertook a prospective study of >1,000 patients who presented with possible ACS before and after the introduction of a lower diagnostic threshold (from 0.20 ng/ml to 0.05 ng/ml) for myocardial infarction (MI) using a high-sensitivity troponin assay with a low coefficient of variability (<10%).1 The study demonstrated that the lower threshold resulted in a 29% increase in detection of MI. Among patients with small increases in troponin (0.05–0.19 ng/ml), this diagnostic reclassification was also associated with improved risk stratification and better use of evidence-based therapies. Most importantly, the rate of death or recurrent MI was 52% lower (P = 0.01) during the period in which the lower troponin thres­ old was used.1 h Therefore, we can surmise that changing the diagnostic threshold for myocardial injury has identified a new, previously misclassified high-risk patient population that was and has led to improvements in clinical outcomes. Individualized medicine and tailored treatments have continued to be a dominant theme of this decade. The ELEVATETIMI 562 and GRAVITAS3 studies tested the effects of high-dose clopidogrel on platelet reactivity and clinical outcomes, respectively. In ELEVATE-TIMI 56,2 hetero­zygote carriers of the CYP2C19*2 allele needed 225 mg of clopidogrel to achieve the same KEY ADVANCES IN MEDICINE degree of platelet inhibition as noncarriers receiving 75 mg, suggesting that genotype could be important for choosing not only the type of antiplatelet agent, but also the dose. Homozygote carriers of CYP2C19*2 in ELEVATE-TIMI 56 were highly resistant to clopidogrel and maintained high degrees of platelet reactivity, even with 300 mg of the drug. Whereas ELEVATE-TIMI 56 confirmed the importance of pharmaco­ enomic interg actions in platelet reactivity, the GRAVITAS trial3 bridged the gap between laboratory findings and clinical outcomes and answered the question of whether increasing doses of clopidogrel would improve clinical outcomes. The investi­ ators randomly assigned g 2,214 patients with high on-­ reatment platet let reactivity to high-dose (600 mg loading, 150 mg maintenance) or standard-dose (75 mg maintenance alone) clopidogrel. Key advances ■■ Use of a sensitive troponin assay with a lower threshold for diagnosis of MI reduced death and recurrent MI in high-risk patients1 ■■ Increased doses of clopidogrel are necessary to achieve platelet inhibition in CYP2C19*2 heterozygotes 2 ■■ Apixaban 5 mg twice daily increases bleeding without decreasing the risk of cardiovascular death, MI, and stroke in patients with ACS5 ■■ Adding very low dose rivaroxaban to dual antiplatelet therapy reduces cardiovascular death, MI, and stroke with no increase in fatal hemorrhage, despite a dosedependent increase in major bleeding6 ■■ A bleeding risk score derived and validated on the basis of baseline characteristics demonstrated effective risk stratification for major bleeding in patients with ACS8 Despite a 22% absolute reduction in high on-treatment platelet reactivity at 30 days and 6 months with the high-dose strategy (P <0.001), no difference was observed between the two groups in the incidence of cardiovascular death, MI, and stent thrombo­ sis or in the rate of severe or moderate bleeding at 6 months (although the overall number of events in the trial was small).3 These results emphasize that, despite variation in drug metabolism and activity, no clinical impact of altering the dosing regimen of clopidogrel has yet been demon­strated. Furthermore, the reduction in platelet reactivity with second generation thienopyridines appears marginal as the dose is increased, and the effects in homozygote carriers of CYP2C19*2 are severely limited. With the introduction of more-potent agents, including prasugrel and ticagrelor, many of these pitfalls can potentially be avoided. With the emergence of novel oral anti­ coagulants that require minimal monitoring, a new paradigm for treating ACS was ushered in—combining a low dose anticoagulant with dual antiplatelet therapy. With novel direct factor Xa inhibitors, such as apixaban, rivaroxaban, and darexaban, straightforward outpatient anticoagulation finally became a realistic option for patients with ACS. However, the road was not without its stumbling blocks. In a phase II trial of darexa­ an, increases in bleeding b were demon­strated without an improvement in efficacy.4 The phase III APPRAISE‑2 trial5 of 7,392 patients with ACS was stopped early after an increase in major bleeding (HR 2.59, P = 0.001) emerged for apixaban (5 mg twice daily) without an improvement in efficacy.5 Against these headwinds, the results of the ATLAS ACS 2‑TIMI 51 trial6 were JANUARY 2012  |  S1
  6. 6. CARDIOLOGY 15 – APPRAISE–2 Events* per 1,000 patients Safety Safety P = 0.001 10 – 5– ATLAS ACS 2-TIMI 56 P = NS TRACER Safety P <0.001 P <0.001 P <0.001 P = 0.03 P = 0.04 P = NS 0– –5 – P = NS Efficacy P = 0.002 –10 – P = 0.02 Efficacy –15 – CVD, MI, stroke CVD, MI, stroke, RI, UR Death P = NS Efficacy TIMI major bleeding ICH Figure 1 | Comparison of the results of the APPRAISE‑2,5 ATLAS ACS 2‑TIMI 56,6 and TRACER7 trials. The data are for the study drug versus placebo. Bleeding was increased in all studies; only the ATLAS ACS 2‑TIMI 56 trial demonstrated efficacy and decreased mortality (data for rivaroxaban 2.5 mg shown with modified intention-to-treat analysis). Follow-up times are as follows: APPRAISE‑2 median 8 months; ATLAS ACS 2‑TIMI 56 mean 13 months; TRACER median 16.5 months. *Events are reported on the basis of individual end points. Abbreviations: CVD, cardiovascular death; ICH, intracranial hemorrhage; MI, myocardial infarction; RI, recurrent ischemia with rehospitalization; UR, urgent coronary revascularization. particu­larly favorably received. The investi­ gators randomly assigned 15,526 patients with ACS to rivaroxaban 2.5 mg or 5.0 mg twice daily, or placebo on a background of aspirin alone (stratum 1) or aspirin plus a thienopyridine (stratum 2; 93% of patients). Notably, the doses of rivaroxaban used were much lower than that used for full anticoagulation, such as in atrial fibrillation (20 mg once daily). In the pooled cohort, a highly significant 16% relative risk reduction (8.9% vs 10.7%, P = 0.008) in cardiovascular death, MI, and stroke was observed for rivaroxaban, with a similar reduction in all-cause mortality, MI, and stroke (9.2% vs 11.0%, P = 0.006) and a 31% (2.3% vs 2.9%, P = 0.02) reduction in stent thrombosis over a 2‑year period. A dose-dependent increase in TIMI major bleeding occurred (placebo: 0.6% vs rivaroxa­ an 2.5 mg: 1.8% and rivaroxaban b 5 mg: 2.4%, P <0.001), but no increase in fatal bleeding was noted. Most importantly, a highly significant 34% reduction in cardiovascular mortality and a 32% reduction in total mortality was observed for rivaroxaban 2.5 mg twice daily.6 Despite its overwhelming efficacy, this trial reminded us that bleeding continues to be a limiting factor in studies of anticoagulant plus antiplatelet agents and that the window of efficacy needs to be carefully defined. S2  |  JANUARY 2012 Another major trial involved the oral thrombin receptor antagonist vorapaxar. The TRACER trial7 faced issues with bleeding and was terminated early. In this study, 12,944 patients with ACS were randomly assigned to receive vorapaxar or placebo in addition to standard care. Vorapaxar failed to reduce cardio­ ascular death, MI, v stroke, recurrent ischemia, and urgent revasculariza­ ion. This drug led to a 3.4-fold t increased risk for intracranial hemorrhage (P 0.001) and a 35% increase in bleeding.7 The results of this trial highlighted the ever-present hazards of increased bleeding when adding new antithrombotic agents to standard therapy, especially in patients who are at increased risk for intracranial hemorrhage. A second trial (TRA 2°P-TIMI 50) of vorapaxar in patients with stable coronary artery disease will be reported next year; thus the final word on this drug is still to come. Side-by-side comparison of the three major oral anticoagulant trials shows that only the ATLAS ACS 2‑TIMI 56 trial met its primary efficacy end point, reduced mortality, but all studies demon­ trated significant increases s in bleeding (Figure 1). Given the delicate balance between efficacy and bleeding, strategies to identify patients at high risk, and then triaging therapies accordingly, have generated much interest. Mathews et al. included 90,273 patients with ST-segment elevation or ST-segment elevation MI from the ACTION registry– GWTG™ to derive (72,813 patients) and valid­ te (17,960 patients) a bleeding risk a score using only baseline characteristics.8 Twelve patient characteristics and presenting factors emerged as predictors of major bleeding in the model. Notably, history of stroke or transient ischemic attack, which was present in only 8% of this cohort, did not emerge as risk factors for major bleeding in this model, although they have previously been identified as risk factors for intra­ ranial hemorrhage.8 c The risk stratification model by Mathews et al. could guide clinical practice with respect to patient selection for antiplatelet and anticoagulant agents, but the extent to which it can be generalized remains unknown. Ideally, the score should be validated in the setting of randomized trials, various agents, and in high-risk and low-risk patient populations before it is applied widely. The year 2011 was a historic landmark in the treatment of ACS. Major strides were made in diagnostic technology, tailored medical therapy, and the safe use of a very low-dose anticoagulant. Without doubt, the years to come will see many more trials to better educate physicians on how to walk the tightrope between efficacy and bleeding. TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 350 Longwood Avenue, 1st floor office, Boston, MA 02115, USA (P Kohli, C. P Cannon). . . Correspondence to: C. P Cannon . cpcannon@partners.org Competing interests C. P. Cannon declares associations with the following companies: Accumetrics, Alnylam Pharmaceuticals, AstraZeneca, Automedics Medical Systems, BristolMyers Squibb/Sanofi, GlaxoSmithKline, Intekrin Therapeutics, Merck, Novartis, Pfizer, and Takeda. P. Kohli declares no competing interests. 1. 2. 3. 4. Mills, N. L. et al. Implementation of a sensitive troponin I assay and risk of recurrent myocardial infarction and death in patients with suspected acute coronary syndrome. JAMA 305, 1210–1216 (2011). Mega, J. L. et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA 306, 2221–2228 (2011). Price, M. J. et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 305, 1097–1105 (2011). Steg, P . G. et al. RUBY‑1: a randomized, doubleblind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome. Eur. Heart J. 32, 2541–2554 (2011). www.nature.com/reviews
  7. 7. CARDIOLOGY 5. 6. 7. Alexander, J. H. et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N. Engl. J. Med. 365, 699–708 (2011). Mega, J. L. et al. Rivaroxaban in patients with a recent acute coronary syndrome. N. Engl. J. Med. http://dx.doi.org/10.1056/ NEJMoa1112277. Tricoci, P et al. Thrombin-receptor antagonist . vorapaxar in acute coronary syndromes. 8. N. Engl. J. Med. http://dx.doi.org/10.1056/ NEJMoa1109719. Mathews, R. et al. In-hospital major bleeding during ST‑elevation and non‑ST‑elevation myocardial infarction care: derivation and validation of a model from the ACTION Registry®-GWTG™. Am. J. Cardiol. 107, 1136–1143 (2011). ATRIAL FIBRILLATION IN 2011 Stroke prevention in AF Gregory Y. H. Lip In 2011, key trials with oral factor Xa inhibitors in patients with atrial fibrillation highlighted promising data on these novel anticoagulants. Patients with ≥1 stroke risk factors can be considered for oral anticoagulation. These novel, fixed-dose drugs are given without monitoring, so clinicians must learn to balance stroke and bleeding risks. Lip, G. Y. H. Nat. Rev. Cardiol. 9, 71–73 (2012); published online 20 December 2011; doi:10.1038/nrcardio.2011.203 The year 2011 saw the publication of three pivotal phase III trials for two oral direct factor Xa inhibitors, apixaban and rivaroxa­ ban,1–3 as well as important articles on bleeding risk assessment 4 and the net clinical benefit of thromboprophylaxis.5 Novel oral anticoagulants that are viable alternatives to warfarin have clearly changed the landscape of stroke prevention in patients with atrial fibrillation (AF).6 Until recently, the recommended approach was artificially to stratify patients with AF into low, intermediate, and high risk strata—despite stroke risk being a continuum—so that those classed as being at high risk could be targeted for an inconvenient (and potentially dangerous) drug, warfarin. Many studies, however, have shown that the categorization of patients into low, intermediate, or high risk strata has poor correlation with actual warfarin prescribing, and that the predictive value of risk schemes such as the CHADS2 score (Box 1) to identify high-risk patients is suboptimal.7 Consequently, guidelines now recommended the use of the CHA2DS2‑VASc score (Box 1) to complement the older (but simpler) CHADS2 score. Indeed, emphasis is now directed towards identification of ‘truly low-risk’ patients with AF by being more inclusive (rather than exclusive) of common risk factors for stroke, because these patients might not need any antithrombotic therapy. Meanwhile, patients with ≥1 risk factor for stroke should be considered for effective stroke prevention with oral anticoagulation, whether with (very) well-controlled warfarin or one of the KEY ADVANCES IN MEDICINE novel agents, either an oral direct thrombin inhibitor (such as dabigatran) or an oral direct factor Xa inhibitor (for example, rivaroxaban or apixaban). 1 Indeed, the CHA2DS2‑VASc score has consistently been shown to outperform the CHADS 2 score in identification of truly low-risk patients and is as good as—and possibly better than—the CHADS2 score in the identification of high-risk patients who subsequently suffer thromboembolism.7,8 Key advances ■■ In the AVERROES trial, apixaban was superior to aspirin for stroke prevention in patients with atrial fibrillation (AF), with similar rates of major bleeding and improved tolerability1 ■■ In the ARISTOTLE trial, apixaban was superior to warfarin for prevention of stroke and systemic embolism in patients with AF, with significantly less major bleeding and improved survival2 ■■ In the ROCKET‑AF trial, rivaroxaban was noninferior to warfarin for stroke prevention in a high-risk population of patients with AF, with similar rates of major bleeding3 ■■ The HAS‑BLED score is well validated to predict major-bleeding events in patients receiving anticoagulation therapy, and outperforms other bleeding risk assessment schemes4 ■■ ‘Truly low-risk’ patients with a CHA2DS2‑VASc score of 0 do not require thromboprophylaxis; net clinical benefit is greatest in patients with a high HAS‑BLED score, where reduced ischemicstroke risk outweighs the increased intracranial-bleeding risk5 Attention has also been directed to assessment of bleeding risk. Common risk factors for bleeding (as well as potentially correctable risk factors, such as uncontrolled blood pressure and concomitant aspirin use in patients receiving anticoagulation therapy) can inform clinical decision-­ aking, especially m with the novel oral anticoagulants that can come in high-dose and low-dose regimens.9 Investigators in the AVERROES trial1 studied 5,599 patients with AF and ≥1 risk factor for stroke, and who had refused war­ farin or been deemed unsuitable for war­farin by the investigators on the basis of the inclusion criteria. The trial was stopped early because of the clear superiority of apixaban over aspirin, with a 55% reduction in the primary end point of stroke and systemic embolism (HR 0.45, 95% CI 0.32–0.62, P 0.001), but with no significant difference between apixaban and aspirin for major bleeding (HR 1.13, 95% CI 0.74–1.75, P = 0.57) or intracranial hemorrhage. Furthermore, fewer drug discontinuations occurred with patients taking apixaban, which indicates that this drug is better tolerated than aspirin. Until now, patients who refused or were unsuitable for warfarin were treated with aspirin; therefore, this trial will certainly change clinical practice, especially given that the evidence for a beneficial (and safe) role for aspirin in patients with AF is weak.10 Researchers in the ARISTOTLE trial 2 randomly allocated 18,201 patients with AF to receive either warfarin or apixaban, and reported a 21% reduction in the primary end point of stroke and systemic embolism with apixaban (HR 0.79, 95% CI 0.66– 0.95, P 0.001 for noninferiority, P = 0.01 for superi­ rity), with a 31% reduction in o major bleeding (HR 0.69, 95% CI 0.60–0.80, P 0.001) and an 11% reduction in mortality (HR 0.89, 95% CI 0.80–0.99, P = 0.047). The primary end point was driven by the reduction in hemorrhagic stroke (HR 0.51, 95% CI 0.35–0.75, P 0.001), with no difference in ischemic stroke (HR 0.92, 95% CI 0.74–1.13, P = 0.42) between apixaban and warfarin. Another oral direct factor Xa inhibitor, rivaroxaban, was compared with warfarin in the ROCKET‑AF trial.3 A higher-risk cate­ gory of patients (n = 14,264, mean CHADS2 score = 3.5) was enrolled in ROCKET‑AF compared with the ARISTOTLE and AV E R ROE S t r i a l s ( m e an C HA D S 2 score = 2.1 in both). Also, 55% of the ROCKET‑AF population was a secondary prevention cohort (by contrast with 20% and 14% in the ARISTOTLE and AVERROES trials, respectively). Rivaroxaban was clearly JANUARY 2012  |  S3
  8. 8. CARDIOLOGY Box 1 | Abbreviations and definitions CHADS2 Congestive heart failure (1 point) Hypertension (1 point) Age ≥75 years (1 point) Diabetes mellitus (1 point) Stroke or thromboembolism (2 points) CHA2DS2‑VASc Congestive heart failure (1 point) Hypertension (1 point) Age ≥75 years (2 points) Diabetes mellitus (1 point) Sex, female (1 point) Vascular disease (1 point) Age 65–74 years (1 point) Stroke or thromboembolism (2 points) HAS‑BLED Hypertension (uncontrolled blood pressure) Abnormal renal or liver function Stroke Bleeding history or predisposition Labile international normalized ratio (INR) Elderly (age 65 years) Drugs concomitantly (for example, concomitant aspirin or nonsteroidal antiinflammatory drugs, or alcohol abuse) Net clinical benefit [ISR with no treatment – ISR on treatment] – 1.5*[IHR on treatment – IHR with no treatment] Abbreviations: IHR, intracranial-hemorrhage rate; ISR, ischemic-stroke rate. noninferior to warfarin for the primary end point of stroke and systemic embolism (HR 0.79, 95% CI 0.66–0.96, P 0.001 for non­ nferiority). In the more-conventional i and conservative intention-to-treat analysis, rivaroxa­ an failed to achieve superiority b (HR 0.88, 95% CI 0.74–1.03, P 0.001 for noninferiority, P = 0.12 for superiority), although a per-protocol, on-treatment analysis reported superiority for rivaro­ xaban (HR 0.79, 95% CI 0.65–0.95, P = 0.02). The primary safety end point, major and non­ ajor clinically relevant bleeding, m was not different (HR 1.03, 95% CI 0.96– 1.11, P = 0.44), although hemorrhagic stroke, intracranial hemorrhage, and fatalbleeding events were lower with rivaroxaban than warfarin. Until the advent of novel oral anti­ coagulants, patients with AF who were receiving oral anticoagulation often came under the care of a warfarin clinic, which was responsible for anticoagulation monitoring and doses, rather than cardiologists per se. Now, clinicians will have to make informed decisions on doses of these novel drugs. Of the novel direct thrombin inhibitors, only dabigatran is approved for use for S4  |  JANUARY 2012 stroke prevention in patients with AF, and this drug is licensed at doses of 110 mg or 150 mg twice daily (or 75 mg twice daily for patients with severe renal failure in the USA). Apart from the criteria of age (80 years) and concomitant drug use (such as verapamil), how should the dose of dabigatran be decided on the basis of bleeding risk? To help clinical decision-making, a simple acronym of common risk factors for bleeding (the HAS‑BLED score; Box 1) has been recommended in European and Canadian guidelines. Various validations of the HAS‑BLED score were published in 2011.4,5 In a large, contemporary, anti­ oagulated c population of patients with AF, the HAS‑ BLED score performed best of all the tested bleeding-risk schemes, and more-accurately discriminated patients on the basis of their bleeding risk (whether assessed by the c‑­ tatistic, or estimates of Net s Reclassification Improvement and Integrated Discrimination Improvement), with a stepwise increase in rates of major bleeding with increasing HAS‑BLED score (P 0.0001 for trend).4 Multivariate analyses identified concurrent aspirin use (HR 2.10), renal impairment (HR 1.98), age ≥75 years (HR 1.63), diabetes mellitus (HR 1.47), and heart failure or left ventricular dysfunction (HR 1.32) as significant predictors of bleeding. What does this mean for clinicians in everyday practice, who have to balance the risks of stroke and bleeding? In a large, nationwide, ‘real-world’ cohort study from Denmark (n = 132,372), Olesen and colleagues balanced stroke risk (assessed by the CHADS2 and CHA2DS2‑VASc scores) with bleeding risk (assessed using the HAS‑BLED score), and the net clinical benefit (Box 1) of ischemic-stroke prevention versus intracranial-­ emorrhage risk h was calculated.5 The net clinical benefit was not positive for aspirin at any stroke-risk or bleeding-risk strata, which led the investi­ gators to conclude that “aspirin should not be used for thromboprophylaxis in any patient with AF”.5 Unsurprisingly, the combination of warfarin plus aspirin did not confer any additional benefit in preventing thromboembolism, but substantially increased bleeding risk. In patients treated with warfarin, the only category where the net clinical benefit was negative was patients with a CHA2DS2‑VASc score of 0, which reflects their truly low-risk status. The net clinical benefit was non-­ negative (either neutral or positive) at a CHADS2 score ≥0 and a CHA2DS2‑VASc score ≥1. In addition, the net clinical benefit was clearly positive, in favor of warfarin, in patients with increased risk of stroke or thromboembolism, and was even greater at high HAS‑BLED scores (≥3), which indicates that patients at high risk of bleeding are also at high risk of stroke or thrombo­ mbolism e —and that the absolute benefit of warfarin in reducing the risk of ischemic stroke far outweighs the smaller absolute increase in the risk of serious bleeding. The practical use of the HAS‑BLED score also encourages clinicians to consider bleeding risk factors that can be corrected, such as uncontrolled blood pressure, concomitant use of aspirin or nonsteroidal anti-­ nflammatory i drugs, and time in therapeutic range if the patient is on warfarin (the H, D, and L in HAS‑BLED, respectively). The year 2011 has seen great advances in assessment of stroke and bleeding risks in patients with AF, and exciting new data on the novel oral anticoagulants. Prospects are much improved for patients with AF. University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Dudley Road, Birmingham B18 7QH, UK g.y.h.lip@bham.ac.uk Competing interests The author declares associations with the following companies and organizations: Astellas, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi‑Sankyo, focusAF, Merck, Portola and Sanofi Aventis. See the article online for full details of the relationships. 1. 2. 3. 4. 5. 6. 7. 8. Connolly, S. J. et al. Apixaban in patients with atrial fibrillation. N. Engl. J. Med. 364, 806–817 (2011). Granger, C. B. et al. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 365, 981–992 (2011). Patel, M. R. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 365, 883–891 (2011). Lip, G. Y., Frison, L., Halperin, J. L. Lane, D. A. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS‑BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J. Am. Coll. Cardiol. 57, 173–180 (2011). Olesen, J. B. et al. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: a net clinical benefit analysis using a ‘real world’ nationwide cohort study. Thromb. Haemost. 106, 739–749 (2011). Ahrens, I., Lip, G. Y. Peter, K. New oral anticoagulant drugs in cardiovascular disease. Thromb. Haemost. 104, 49–60 (2010). Karthikeyan, G. Eikelboom, J. W. The CHADS2 score for stroke risk stratification in atrial fibrillation—friend or foe? Thromb. Haemost. 104, 45–48 (2010). Lip, G. Y. Stroke in atrial fibrillation: epidemiology and thromboprophylaxis. J. Thromb. Haemost. 9 (Suppl. 1), 344–351 (2011). www.nature.com/reviews
  9. 9. CARDIOLOGY 9. [ESC] Working Group on Thrombosis. Thromb. Haemostat. 106, 997–1011 (2011). 10. Lip, G. Y. The role of aspirin for stroke prevention in atrial fibrillation. Nat. Rev. Cardiol. 8, 602–606 (2011). Lip, G. Y. H. et al. Bleeding risk assessment and management in atrial fibrillation patients: executive summary of a position document from the European Heart Rhythm Association [EHRA], endorsed by the European Society of Cardiology HEART FAILURE IN 2011 Heart failure therapy—technology to the fore John J. V. McMurray Studies published in 2011 in the field of heart failure have reinforced the benefit of cardiac resynchronization therapy in patients with mild symptoms and confirmed the value of left ventricular assist devices and CABG surgery in selected patients. Conversely, the efficacy of nesiritide in acute heart failure has been questioned. McMurray, J. J. V. Nat. Rev. Cardiol. 9, 73–74 (2012); doi:10.1038/nrcardio.2011.212 KEY ADVANCES IN MEDICINE trials, in which recurrent events that are frequent and of great clinical significance than first HF events are ignored. A report from INTERMACS 2 also re-­ inforced the impressive technological progress made with left ventricular assist devices (LVADs). In a post-approval study required by the FDA, outcomes in the first 169 consecutive patients receiving a HeartMate II® (Thoratec Corporation, Pleasanton, CA, USA) device as a bridge-to-transplant were compared with those in 169 patients receiving different LVADs for the same indication over the same time period. The proportion of patients transplanted, recovered, or receiving continuing LVAD support at 6 months was 91% in the HeartMate II® group and 80% in the comparator group (85% and 70%, © Newlight | Dreamstime.com Although many interesting studies on epidemio­ogy, pathophysiology, and biol markers in heart failure (HF) were published in 2011, my focus in this article is on treatments that are available for use and can make an impact in everyday practice. Five important studies, covering device and drug therapy, and surgery in patients with HF will be discussed. In August 2011, a follow-up report from MADIT-CRT1 reinforced the impressive effect of cardiac resynchronization therapy (CRT) on outcomes among patients with HF, even in those with mild symptoms. The investigators showed that CRT plus a defibrillator, compared with a defibrillator alone, reduced the risk of a first episode of worsening HF by 46% (P 0.001) and, importantly, also reduced the risk of subsequent episodes by 38% (P = 0.003). Because patients experiencing a first episode of worsen­ ng i HF were at a substantially elevated risk of a further event, the absolute reduction in risk of subsequent episodes with CRT was large (from 72 to 44 events per 100 patient years of follow-up). The benefit was greatest in patients with left bundle branch block. In addition, a 19-fold increase in mortality risk was reported in patients experiencing a second episode of worsening HF.1 These findings are important for several reasons. Clearly, worsening of HF is extremely unpleasant for patients and usually leads to hospital admission with major consequences (economic and otherwise) for health-care systems, and is associated with an increased risk of death.1 These findings also highlight the limitations of the conventional ‘time to first-event’ analysis of respectively, at 1 year). These excellent outcomes from ‘real-world’ practice at 77 centers in the USA are consistent with the findings of the pivotal, randomized HeartMate II® trial,3 which showed that this continuousflow device was superior to the comparator pulsatile-flow device. Monitoring devices are currently of immense interest in HF research and the findings of the CHAMPION study 4 were notable. This moderate-sized trial showed that a small, implantable hemodynamic monitor improved outcomes in patients with NYHA class III HF who had been hospitali­ ed for HF in the previous year z and were optimally treated. The monitor was placed transvenously in a pulmonary artery branch and allowed wireless non­ invasive measurement of pulmonary artery pressure. Physicians in the control group and patients in both groups did not have knowledge of pressure measurements; however, site investi­gators, the trial principal investi­ ators, and sponsor (CardioMEMS, g Atlanta, GA, USA) employees had access to pressure measurements and these were used to adjust therapy. Addition of nitrates and hydralazine and adjustment of diuretic therapy, including use of intravenous diure­ tics, were more frequent in the inter­ ention v group. The primary outcome was the rate of HF hospitaliza­ ion over 6 months; t 83 hospitaliza­ ions occurred among 55 of t the 270 patients in the intervention group, compared with 120 among 80 of the 280 patients in the control group (rate 0.31 vs 0.44; HR 0.70, 95% CI 0.60–0.84, P 0.0001). In absolute terms, 12.5 fewer hospitaliza­ tion events per 100 patients occurred over JANUARY 2012  |  S5
  10. 10. CARDIOLOGY Key advances ■■ Cardiac resynchronization therapy reduced not only the first, but also subsequent, episodes of worsening heart failure (HF) in patients with systolic dysfunction and mild symptoms1 ■■ Use of the HeartMate II®(Thoratec Corporation, Pleasanton, CA, USA) continuous-flow left ventricular assist device was associated with excellent 6-month and 12-month survival in a ’real-world’ registry study2 ■■ Pharmacological intervention prompted by noninvasive pulmonary artery monitoring may reduce the risk of HF hospitalization in patients with moderately severe symptoms and previous admission for HF4 ■■ In selected patients with ischemic systolic HF and a life expectancy of more than 2 years, CABG surgery may reduce cardiovascular mortality and morbidity6 ■■ Nesiritide has a small and clinically insignificant effect on dyspnea and no effect on mortality or worsening HF in patients with acute HF7 6 months in the intervention group, meaning that eight patients needed to be treated to prevent one hospitalization. 4 Although these results are impressive, the trial has been criticized because of the active involvement of the sponsor in encouraging treatment changes in the intervention group, and whether the benefit would be as substantial when used in ordinary practice has been questioned. Nevertheless, the positive findings of the CHAMPION trial4 contrasted strikingly with those of other studies, such as the negative study DOT-HF5 in which an implantable intrathoracic impedance detection device was used. Another study that raised as many questions as answers was the STICH trial.6 In this study, 1,212 patients with a left ventric­ lar u ejection fraction 35%, coronary artery disease amenable to surgery, and no indica­ tion for revascularization (that is, left main disease or Canadian Cardiovascular Class III angina or greater) were randomly assigned to receive medical therapy or CABG surgery. The primary end point was death from any cause. Over a median follow-­ p of u 56 months, 218 of the 610 patients assigned to surgery and 244 of the 602  patients alloca­ ed to medical therapy died (36% vs t 41%; HR 0.86, 95% CI 0.72–1.04, P = 0.12). However, occurrence of the key secondary end points (cardiovascular death and death or cardiovascular hospitalization) was signifi­ antly less common in the surgical c S6  |  JANUARY 2012 group, as was all-cause mortality in an adjusted intention-to-treat analysis and in a per protocol analysis. As in prior trials of CABG surgery, there was an initial mortality excess in the surgery group and benefit from surgery was not apparent until after approximately 2 years of follow-up.6 On balance, the STICH trial probably was a positive study, although the patients were highly selected and atypically young (mean age 60 years) for the majority with HF; two-thirds had symptoms of angina. Unexpectedly, pre­ operative evaluation of myocardial viability did not help to identify patients who would benefit from revascularization. The takehome message seems to be that, in carefully selected patients with systolic HF and coronary artery disease likely to survive for more than 2 years, CABG surgery leads to reduced long-term mortality and morbidity compared with medical therapy alone. The list of treatments that are ineffective in acute HF grew longer in 2011 with the publication of the results of ASCEND-HF,7 which showed that nesiritide (recombinant human B‑type natriuretic peptide) had only a small effect on dyspnea at 6 h and 24 h and no effect on mortality or worsening HF at 30 days. This trial ended a long-running controversy about the safety and efficacy of nesiritide and highlighted the difficulty of demonstrating a benefit for novel therapies over and above that of conventional treatment with diuretics and nitrates, which is rapid and substantial.8 Despite the lack of success with treatments for acute HF to date, interesting new drugs continue to be developed. One of these, with intriguing proof-of-concept data in patients, is a ‘first-in-class’ cardiac myosin activator, omecamtiv mercarbil, which is thought to improve cardiac performance by increasing the rate of transition from the weak myosin-acting binding state to the strongly bound (that is, force-generating) state. This agent increases the duration of systole without increasing heart rate or myocardial oxygen consumption.9 Finally, I would like to mention an important study relevant to the holistic care of patients with HF. Peterson and colleagues10 looked at health literacy in 1,494 patients with an emergency room visit or hospitaliza­ tion with HF using three brief screening questions—how often do you have someone help you read hospital materials; how often do you have problems learning about your medical condition because of difficulty reading hospital materials; and how confident are you filling out forms by yourself? More than one in six patients showed a low level of health literacy, which was an indepen­ ent predictor of all-cause mortald ity, after taking account of other prognostic variables.10 These findings argue for testing of the effect of interventions thought to improve health literacy on outcomes in HF. In summary, 2011 has been largely a year of consolidation for HF therapeutics. We have an array of effective drugs, devices, and surgical procedures for patients with systolic HF, but substantial progress has yet to be made in the treatment of patients with preserved ejection fraction and those with acute decompensation. British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK. john.mcmurray@glasgow.ac.uk Competing interests The author declares associations with the following companies: Amgen and Johnson Johnson/Scios. See the article online for full details of the relationships. 1. Goldenberg, I. et al. Reduction of the risk of recurring heart failure events with cardiac resynchronization therapy: MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). J. Am. Coll. Cardiol. 58, 729–737 (2011). 2. Starling, R. C. et al. Results of the post‑US Food and Drug Administration-approval study with a continuous flow left ventricular assist device as a bridge to heart transplantation: a prospective study using the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). J. Am. Coll. Cardiol. 57, 1890–1898 (2011). 3. Slaughter, M. S. et al. Advanced heart failure treated with continuous-flow left ventricular assist device. N. Engl. J. Med. 361, 2241–2251 (2009). 4. Abraham, W. T. et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 377, 658–666 (2011). 5. van Veldhuisen, D. J. et al. Intrathoracic impedance monitoring, audible patient alerts, and outcome in patients with heart failure. Circulation 124, 1719–1726 (2011). 6. Velazquez, E. J. et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N. Engl. J. Med. 364, 1607–1616 (2011). 7. O’Connor, C. M. et al. Effect of nesiritide in patients with acute decompensated heart failure. N. Engl. J. Med. 365, 32–43 (2011). 8. Felker, G. M. et al. Diuretic strategies in patients with acute decompensated heart failure. N. Engl. J. Med. 364, 797–805 (2011). 9. Cleland, J. G. et al. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet 378, 676–683 (2011). 10. Peterson, P . N. et al. Health literacy and outcomes among patients with heart failure. JAMA 305, 1695–1701 (2011). www.nature.com/reviews
  11. 11. CARDIOLOGY HYPERTENSION IN 2011 New insights—from risk factors to treatment implications George L. Bakris The results of several hypertension studies published in 2011 have contributed to our knowledge on the risks of and treatment for this condition, including the effects of slow-wave sleep, nocturnal dosing of medication, variability in post-stroke blood-pressure reduction, and the impacts of a low-sodium diet. Bakris, G. L. Nat. Rev. Cardiol. 9, 75–77 (2012); published online 13 December 2011; doi:10.1038/nrcardio.2011.202 Four key studies, completed and published in 2011, should affect the evaluation of patients with hypertension and practice patterns in this population. In one such trial, conducted in Spain, medications were dosed at night in order to improve the dipping status of blood pressure (BP). In this trial 661 patients with hypertension who were at various stages of chronic kidney disease (CKD) were randomly assigned to take all prescribed hypertension medications upon awakening or at least one drug before going to bed.1 At the end of follow-up (median 5.4 years), patients who took the nocturnal dose had an adjusted risk for total cardiovascular events that was approximately onethird that of patients who took medication upon awakening. 1 Patients who received nocturnal treatment also had a significantly lower mean BP during sleep and a greater proportion of these indivi­ uals demond strated controlled ambulatory BP compared with those taking medication upon awakening.1 These data are consistent with those from a shorter-term study of patients with stage 2–3 CKD and no signifi­ ant proteinc uria.2 However, a pilot study in the African American Study of Kidney Disease (AASK) cohort of ~100 patients with stage 4 CKD and proteinuria using similar methodo­ ogy l as the Spanish group failed to show this benefit on BP dipping status or BP control in the morning after 1 year of dosing antihypertensive medications at night.3 One of the major differences between the studies was that 100% of the patients in the AASK cohort had proteinuria at various levels and stage 4 nephropathy, whereas only about 10% of the patients in the Spanish study fit this description. A nocturnal dosing strategy was also tested in the large CONVINCE trial, 4 but failed to show a reduction in cardio­ ascular risk. However, the CKD and v dipping status of the individuals enrolled in KEY ADVANCES IN MEDICINE the trial was unknown. Given the increased cardiovascular risk among patients with stage 3 CKD, ambulatory BP monitoring (ABPM) is required to assess dipping status and indivi­dualize dosing regimens in people who meet the criteria as nondippers. As yet no ABPM data are available from large cohorts with stage 4 CKD and so the recom­ mendation cannot be extended to this group of patients. The second major advance in 2011 was the finding of an association between poor sleep quality and the development of hyper­ tension.5 This relationship is unrelated to sleep apnea and has more to do with the amount and type of sleep. Fung et al. evaluated whether incident hypertension is associ­ated with polysomnography measures of sleep-disordered breathing, sleep duration, and sleep architecture in older men (mean age 75 years).5 Participants included 784 community-dwelling, ambulatory men from the Outcomes of Sleep Disorders in Older Men Study who did not have Key advances ■■ Among patients with moderate-stage nephropathy, dosing medications at night has the advantage of improving blood pressure (BP) goal attainment in the early morning when cardiovascular risk is highest1 ■■ Failure to recognize insufficient quality of sleep secondary to frequent disturbances of awakening is a major contributing risk for hypertension development and poor BP control5 ■■ Lowering BP by more than 15–20% in patients with hypertension early in the post-stroke period can result in long-term cognitive consequences6 ■■ Low-sodium diets clearly reduce BP, but tend only to reduce cardiovascular events in trials; in populations, low-sodium diets reduce mortality8 hypertension at the time of their in-home sleep studies and who returned for followup after 2–4 years. By the end of follow-up (mean 3.4 years), 243 men met the criteria for incident hypertension. After adjustment for age, nonwhite race, study site, and BMI, the only sleep index to remain signifi­ cantly associated with incident hyper­tension was decreased stage N3 (or slow-wave) sleep. No attenuation of this association was seen after accounting for sleep duration, sleep fragmentation, and indices of sleepdisordered breathing. Thus, failure to get an appropriate amount of slow-wave sleep each night is a risk factor for development of hyper­ ension. Reduced amounts of slowt wave sleep are seen commonly in elderly patients and could be related to increased frequency of waking to urinate. Physicians should be aware of decreased deep sleep as a risk factor for hypertension and ensure that patients get an extended rest period at night by decreasing stimuli, such as caffeine and liquid intake. This strategy is used in my practice with a fair amount of success. A third important trial published in 2011 provides new information on the consequences of aggressive BP management in the setting of acute stroke. In SCAST,6 2,029 patients from northern Europe with acute ischemic or hemorrhagic stroke and systolic BP 140 mmHg were randomly assigned within 30 h of symptom onset to cande­sartan or placebo for 7 days. The dose was increased from 4 mg on day 1 to 16 mg on days 3–7. During the 7‑day treatment period, BP was 5/2 mmHg lower in the candesartan group than in the placebo group (mean BP 147/82 mmHg vs 152/84 mmHg). At the end of the 6 month follow-up, the risk of the primary composite vascular end point did not differ between treatment groups. The co-primary end point of functional outcome (modified Rankin scale), however, was associ­ ted with a higher risk of poor a outcome in the candesartan group. The results were interpreted by the investigators to suggest some harm and no benefit for BP lowering after acute stroke.6 To understand this finding, clinicians should be aware that current BP guidelines for the post-stroke period differ according to whether the stroke is hemorrhagic or ischemic. 7 In addition, the approach to BP management for the prevention of stroke is totally different from its management post stroke. In hemorrhagic stroke, current guidelines suggest cautious lowering of BP by no more that 20% in the first 24 h.7 Agents with rapid, short-term JANUARY 2012  |  S7
  12. 12. © Elena Babushkina | Dreamstime.com CARDIOLOGY action such as labetalol, nicardipine, and fenoldapam are preferred as nitroglycerin and nitroprusside can increase intra­ ranial c pressure. For patients with ischemic stroke who are not receiving thrombolytic therapy, BP should be lowered if markedly elevated (220/120 mmHg). 7 In SCAST, baseline BP was 171/90 mmHg,6 so a reduction to ~140 mmHg is excessive given the recommendation and, therefore, the lack of benefit is not surprising. The fourth notable study published in 2011 is a meta-analysis in which the investigators aimed to assess the long-term effects of dietary salt reduction on mortality and cardiovascular morbidity and whether BP reduction is an explanatory factor in any effect of such dietary interventions.8 A total of 7 studies were included, 3 in normo­ tensive individuals, two in patients with hyper­ ension, one in a mixed population, t and one in patients with heart failure with end of trial follow-up of 7–36 months and longest observational follow up to 12.7 years. The data failed to show strong evidence for a reduced risk of all-cause mortality or cardio­ ascular morbidity in normo­ ensive v t indivi­ uals and patients with hyper­ ension d t on low-salt diets. The investigators suggest their review had insufficient power to exclude clinically important effects, since only 665 deaths occurred in 6,250 participants. They further state that their estimates of benefits from dietary salt restriction are consistent with the predicted small effects on clinical events attributable to the small BP reduction achieved. This information puts into perspective the limitations of clinical trials. The evidence that salt reduction lowers BP is clear and consistent. Since BP reduction is critical for reducing the risk of stroke and progression of CKD, low-salt diets should also be of benefit. S8  |  JANUARY 2012 However, most people do not consistently maintain a low sodium intake leading to fluctu­ation in BP, which is a major risk factor for stroke. The real impact of low sodium intake on mortality has been demonstrated in Japan and Finland where sodium reduction policies have been instituted for all foods sold in stores. In the USA, reducing dietary salt by 3 g per day is projected to reduce the annual number of all-cause deaths from 44,000 to 92,000.9 Hence, large numbers of indivi­ duals and years of follow-up are required to see the effect of consistent reduced sodium intake. Not surprisingly, therefore, trial data and even meta-­ nalyses cannot adequately a demon­ trate these effects. Clinicians should s focus on the established fact that BP reduction is consistently associ­ated with reductions in cardio­vascular event rates and continue to stress the importance of a low-sodium diet to patients with hypertension. Finally, the multicenter, prospective, randomized Symplicity HTN‑2 trial, which was published in late 2010, 10 provided ground-breaking results for a new concept of treatment for refractory hypertension. Participants with systolic BP ≥160 mmHg (or ≥150 mmHg for those with type 2 diabetes mellitus) were randomly allocated to undergo renal denervation together with continuation of previous treatment or maintain previous treatment alone. Office-based BP measurements were reduced by 32/12 mmHg (baseline 178/96 mmHg) in the renal denervation group, control group BP values did not differ from the baseline of 178/97 mmHg, and between-group differences in BP at 6 months were 33/11 mmHg. No serious procedure or device-related complications occurred and adverse events did not differ between groups. The investi­ ators concluded that catheterg based renal denervation is a safe and viable treatment for patients who cannot achieve BP goals with pharmaco­ herapy.10 In 2011, t recruitment for the Symplicity HTN‑3 trial started in the USA; with a protocol that is more stringent than Symplicity HTN‑2 and involves more frequent ABPM. This new trial will include between-group differences in ABPM as a prespecified secondary end point. Hypertension management prior to study enrollment will be more intense and will include spironolactone. If the results of the Symplicity HTN‑3 trial are as gratifying as that of Symplicity HTN‑2, a true alternative to medications will exist for refractory hypertension. Many other ongoing clinical trials have been designed to address and, hopefully, answer important questions about specific approaches to reducing cardio­ vascular risk and the progression of CKD in patients with hypertension. Hypertensive Diseases Unit, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, MC 1027, Chicago, IL 60637, USA. gbakris@medicine.bsd.uchicago.edu Competing interests The author declares associations with the following companies: Abbott, CVRx, Eli Lilly, FDA, Forest Laboratories, Johnson Johnson, Medtronic, Novartis, Relypsa, Servier, and Takeda. See the article online for full details of the relationships. 1. 2. 3. 4. 5. 6. 7. 8. Hermida, R. C., Ayala, D. E., Mojon, A. Fernandez, J. R. Bedtime dosing of antihypertensive medications reduces cardiovascular risk in CKD. J. Am. Soc. Nephrol. http://dx.doi.org/10.1681/ASN.2011040361. Minutolo, R. et al. Changing the timing of antihypertensive therapy to reduce nocturnal blood pressure in CKD: an 8‑week uncontrolled trial. Am. J. Kidney Dis. 50, 908–917 (2007). Rahman, M. Appel, L. J. Should reducing nocturnal blood pressure be a therapeutic target in CKD? The time is ripe for a clinical outcomes trial. Am. J. Kidney Dis. 50, 901–903 (2007). Black, H. R. et al. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA 289, 2073–2082 (2003). Fung, M. M. et al. Decreased slow wave sleep increases risk of developing hypertension in elderly men. Hypertension 58, 596–603 (2011). Sandset, E. C. et al. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebocontrolled, double-blind trial. Lancet 377, 741–750 (2011). Aiyagari, V. Gorelick, P Management of . B. blood pressure for acute and recurrent stroke. Stroke 40, 2251–2256 (2009). Taylor, R. S., Ashton, K. E., Moxham, T., Hooper, L. Ebrahim, S. Reduced dietary salt for the prevention of cardiovascular disease: a meta-analysis of randomized controlled trials (Cochrane review). Am. J. Hypertens. 24, 843–853 (2011). www.nature.com/reviews
  13. 13. CARDIOLOGY 9. Bibbins-Domingo, K. et al. Projected effect of dietary salt reductions on future cardiovascular disease. N. Engl. J. Med. 362, 590–599 (2010). 10. Esler, M. D. et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN‑2 trial): a randomised controlled trial. Lancet 376, 1903–1909 (2010). VALVULAR DISEASE IN 2011 Breakthrough for intervention? Volkmar Falk In 2011, both the PARTNER‑A trial, in high-risk patients with severe aortic stenosis, and EVEREST II, in patients with mitral insufficiency, showed noninferiority of transcatheter interventions compared with surgery for the chosen primary end points. However, both of the trials, and important registry data, identified limitations of transcatheter valve interventions. Falk, V. Nat. Rev. Cardiol. 9, 77–78 (2012); published online 20 December 2011; doi:10.1038.nrcardio.2011.204 Data from two major randomized, controlled trials in which interventional therapy was compared with conventional surgery for the treatment of aortic stenosis in high-risk patients1 and for selected patients with mitral insufficiency 2,3 were published in 2011. Both trials showed noninferiority for their respective primary end points, but (together with data from national registries4,5) also highlighted limitations of interventional therapy. The most-important trial in the field of valvular heart disease that was published in 2011 was the PARTNER‑A trial,1 in which transcatheter aortic-valve implantation (TAVI) was compared with surgical aorticvalve replacement (SAVR) in a high-risk population of patients with severe aortic stenosis. From a total of 3,105 screened patients, 699 individuals (23%) were randomly allocated to either SAVR (n = 351) or TAVI (n = 348, transfemoral or trans­ pical) a using the Edwards SAPIEN ® (Edwards Lifesciences Corporation, Irvine, CA, USA) balloon-expandable valve. Patients were considered high risk on the basis of coexisting conditions associated with a risk of death ≥15% at 30 days. In the intention-to-treat analysis, death from any cause (the primary end point) was not different between the TAVI and SAVR groups at 30 days (3.4% vs 6.5%, respectively) or 1 year (24.2% vs 26.8%, respectively), which led to the conclusion that TAVI was non­ nferior to SAVR. Patients in i the TAVI group had a shorter length of stay in the intensive-care unit and a shorter index hospitalization compared with patients undergoing SAVR. Bleeding and new onset of atrial fibrillation were more frequent in the surgical group, whereas rates of vascular and neuro­ ogical complications were higher in l KEY ADVANCES IN MEDICINE the TAVI group. The rates of major stroke were 3.8% and 2.1% at 30 days, and 5.1% and 2.4% at 1 year, in the TAVI and surgical groups, respectively. At 1 year, TAVI was associated with a lower mean aorticvalve gradient compared with the surgical group, but with a higher rate of moderate or severe paravalvular regurgitation at 30 days (12.2% vs 0.9%) and 1 year (6.8% vs 1.9%). Functional improvement was significant for both groups after 1 year and not different between the groups. The results of the PARTNER‑A trial 1 demonstrate that TAVI is not only superior to medical therapy in non­surgical candidates, but also a true alternative to surgical replacement for a selected, high-risk subgroup of patients with aortic stenosis. Data from a number of national TAVI registries were published in 2011. The FRANCE registry 6 included data on 244 patients who received an Edwards SAPIEN® (68%) or CoreValve® (Medtronic CV Luxembourg S.a.r.l., Luxembourg; 32%) in 2009. Device success rate was 98.3% and 30‑day mortal­ity Key advances ■■ In high-risk patients with severe aortic stenosis, transcatheter aortic-valve implantation (TAVI) can be performed with similar 1‑year survival and functional outcomes as conventional surgery1 ■■ Moderate and severe paravalvular leakage after TAVI is an independent predictor of late mortality4,5 ■■ Percutaneous edge-to-edge mitral-valve repair can be safely performed with low periprocedural complications2 ■■ Residual moderate mitral regurgitation is more frequent after percutaneous edge-to-edge repair than surgery and might impair long-term results3 was 12.7%. Stroke and vascular complications occurred in 3.6% and 7.3% of patients, respectively. Data from the FRANCE 2 registry,7 which included 2,419 patients treated between January 2010 and July 2011, were presented at the ESC Congress in 2011. Device success rate was 97.1%, and 30‑day and 6‑month mortality were 9.9% and 17.2%, respectively. The stroke rate of 4.0% was similar to the rates reported in the PARTNER trials.1 The high incidence of stroke after TAVI is concerning, and might result from a substantial embolic load during the TAVI procedure, as has been demonstrated using transcranial Doppler imaging during implantation and cerebral MRI after the procedure. The UK TAVI registry 8 included 890 patients. Procedural success (97.2%) and stroke rate (4.1%) were similar to the French experience. Mortality at 30 days was 7.1%, and 1‑year and 2‑year survival were 78.6% and 73.7%, respectively. A degree of paravalvular aortic regurgitation (AR) regarded as suboptimal or unacceptable occurred in 61% of patients. The presence of moderate or severe AR (13% of patients) was an independent predictor of mortality at 1 year. In the German TAVI registry, 4 which comprised 690 patients (84% Medtronic CoreValve ® system), the rate of AR ≥2 was 17.2% and its presence was a strong, in­ ependent predictor of in-hospital death d (adjusted OR 2.43). In the Italian, multicenter registry 5 of 663 patients who underwent transfemoral TAVI with the third-generation 18 Fr CoreValve® device, the rate of paravalvular leak ≥2 after implantation was 21%, and independently associated with mortality between 30 days and 1 year (HR 3.79). Therefore, data from three national registries have shown that paravalvular leakage is an independent risk factor for mortality after TAVI.4,5,8 The development of improved prosthetic implants and implantation techniques is required. In the absence of long-term follow-up data after TAVI, the results of the PARTNER‑A trial1 and the data from the national registries4–8 must be interpreted with caution. Recommendations to individual patients must balance the obvious advantages of a less-invasive transcatheter approach compared with SAVR, with the increased risk of stroke and unfavorable longterm consequences of paravalvular leakage after TAVI. The landmark mitral-valve trial published in 2011 was EVEREST II.2 In total, 279 patients with severe mitral regurgitation JANUARY 2012  |  S9
  14. 14. CARDIOLOGY V a b 10 Figure 1 | Images from a patient in NYHA class IV because of ischemic cardiomyopathy with poor LV ejection fraction (20%) and mitral-valve insufficiency III–IV, who underwent a MitraClip® (Abbott Vascular, Abbott Park, IL, USA) procedure. a | The preprocedural LV end-diastolic volume was assessed as 550 ml. b | At 1 year follow-up after the procedure, LV end-diastolic volume was reduced to 480 ml, the patient had improved to NYHA class II, and residual mitral-valve regurgitation was 1+. Abbreviation: LV, left ventricular. (MR; grade 3+ or 4+) were randomly allocated to either surgery or percutaneous edgeto-edge clipping using the MitraClip® device (Abbott Vascular, Abbott Park, IL, USA). Acute procedural success was not achieved with the MitraClip® in 23% of patients, the majority of whom underwent subsequent mitral-valve surgery. The transvenous–­ transseptal approach was associated with fewer adverse events at 30 days compared with surgery. The composite end point of major adverse events was reached in 9.6% and 57% of patients in the MitraClip® and surgical groups, respectively. This striking difference was almost exclusively driven by the need for blood transfusion (8% vs 53%, respectively). Noninferiority for the clinicaleffectiveness 1‑year end point (freedom from death, mitral-valve surgery, mitral-valve dysfunction 90 days after the index procedure, and MR 2+ at 12 months) was met, despite the fact that 18.5% and only 3% of patients had residual mitral insufficiency 2+ at 1 year in the MitraClip® and surgical groups, respectively. Another 33% of patients in the MitraClip® group had residual mitral insufficiency = 2+, and more than 15% of patients in the device arm subsequently underwent mitral-valve surgery because of persistent, severe MR. The arbitrary end point of freedom from mitral insufficiency 2+ has triggered lively discussion. Residual mitral insufficiency 1+ after mitral repair is clearly unacceptable, and is an independent predictor of late mortality. If the EVEREST II investi­ gators had chosen presence of mitral insufficiency 2+ instead of absence of mitral S10  |  JANUARY 2012 insufficiency 2+ as part of the effectiveness end point, fewer than half of the patients (47.9%) treated with the MitraClip® would have fulfilled the combined criteria. Statistical noninferiority for effectiveness at 1 year was reached by definition, but the debate whether this result can be regarded as noninferior from a clinical perspective is likely to continue—particularly because the intention-to-treat analysis revealed that the primary composite end points at 2 years were still significantly better with surgery than percutaneous intervention.3 Longterm data are needed before the indication for this therapy can be extended to patients with degenerative mitral-valve disease, in whom the success rate of endoscopic surgical mitral-valve repair is 95%, with excellent short-term and long-term results.9 Mitralvalve repair after previous clip placement is often not possible because the device is encapsulated over time by fibrous tissue; the use of the MitraClip® should, therefore, be restricted to patients who are at high surgical risk. The unconvincing long-term results of downsizing annuloplasty in patients with severe leaflet tethering make the MitraClip® an attractive option in patients with functional MR. In the PERMIT trial,10 51 severely symptomatic nonresponders to cardiac resynchronization therapy with severe left ventricular dysfunction and functional MR underwent treatment with the MitraClip®. Residual MR ≥2+ was present in 20% of patients at discharge, and in only about 10% at 1 year follow-up. Periprocedural mortality was 5.8%, but was not less than surgery in similar groups of patients. The NYHA functional class had already improved at discharge in 73% of patients. Reverse remodel­ ing was observed to continue at 6 months and 1 year (Figure 1). A randomized trial with larger patient numbers than in the PERMIT trial10 will be needed to confirm these findings and determine the role of the MitraClip® in patients with functional MR. The treatment of valvular heart disease continues to progress with the evolution of percutaneous approaches as alternatives to surgical therapy in selected patients. To provide patients with the best-possible treatment, short-term effectiveness must be balanced with long-term outcomes. Division of Cardiovascular Surgery, University of Zurich, Rämistrasse 100, Zurich CH‑8091, Switzerland. volkmar.falk@usz.ch Competing interests The author declares associations with following companies: Edwards Lifesciences, Medtronic, Philips, St Jude Medical, and Valtech. See the article online for full details of the relationships. 1. Smith, C. R. et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N. Engl. J. Med. 364, 2187–2198 (2011). 2. Feldman, T. et al. Percutaneous repair or surgery for mitral regurgitation. N. Engl. J. Med. 364, 1395–1406 (2011). 3. George, J. C., Varghese, V., Dangas, G. Feldman, T. E. Percutaneous mitral valve repair: lessons from the EVEREST II (Endovascular Valve Edge-to-Edge REpair Study) and beyond. JACC Cardiovasc. Interv. 4, 825–827 (2011). 4. Abdel‑Wahab, M. et al. Aortic regurgitation after transcatheter aortic valve implantation: incidence and early outcome. Results from the German transcatheter aortic valve interventions registry. Heart 97, 899–906 (2011). 5. Tamburino, C. et al. Incidence and predictors of early and late mortality after transcatheter aortic valve implantation in 663 patients with severe aortic stenosis. Circulation 123, 299–308 (2011). 6. Eltchaninoff, H. et al. Transcatheter aortic valve implantation: early results of the FRANCE (FRench Aortic National CoreValve and Edwards) registry. Eur. Heart J. 32, 191–197 (2011). 7. Gilard, M. et al. FRANCE 2: FRench Aortic National CoreValve and Edwards Registry http://spo.escardio.org/eslides/ view.aspx?eevtid=48fp=3126 (2011). 8. Moat, N. E. et al. Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis: The U.K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation) Registry. J. Am. Coll. Cardiol. 58, 2130–2138 (2011). 9. Mihaljevic, T. et al. Robotic repair of posterior mitral valve prolapse versus conventional approaches: potential realized. J. Thorac. Cardiovasc. Surg. 141, 72–80 (2011). 10. Auricchio, A. et al. Correction of mitral regurgitation in nonresponders to cardiac resynchronization therapy by MitraClip improves symptoms and promotes reverse remodeling. J. Am. Coll. Cardiol. 58, 2183–2189 (2011). www.nature.com/reviews
  15. 15. CLINICAL ONCOLOGY OVARIAN CANCER IN 2011 Mutations and non-inferiority analyses show a way forward Maurie Markman Highly clinically relevant ovarian cancer clinical research in 2011 focused on an increased understanding of the biology of the malignancy, limitations of strategies for early detection and screening, and the provocative reports of alternative primary and second-line management strategies. Markman, M. Nat. Rev. Clin. Oncol. 9, 69–70 (2012); published online 20 December 2011; doi:10.1038/nrclinonc.2011.200 Although there were a number of very interesting preliminary reports of thera­ eutic p advances in ovarian cancer in 2011 (for example, bevacizumab in the first-line and second-line management of the malignancy, and olaparib as maintenance therapy for high-grade serous cancers), as of the writing of this commentary these studies have not appeared in the peer-reviewed oncology literature. Despite the absence of major advances in the realm of treatment, several papers published in 2011 provide highly clinically relevant insight into the management and unique biology of ovarian cancer. Perhaps the most important paper in 2011 was the long-awaited final report from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening randomized controlled trial dealing specifically with ovarian cancer.1 The study, involving 78,000 women with ages ranging from 55 to 74 years, randomly assigned participants to what was classified as ‘usual care’ or a rather-intensive screening strategy that included annual serum CA125 determinations and trans­ vaginal ultrasounds. It should be noted that this study did not specifically target women identified as being at ‘high risk’ for the develop­ment of ovarian cancer (for example, those with a family history of ovarian cancer). The screening protocol, undertaken from November 1993 to July 2001, was performed at one of 10 centers in the USA and the median follow-up period for the population was 12.4 years, with patients being followed until death or for a maximum of 13 years. The primary study end point was the rate of mortality from ovarian cancer (including primary peritoneal or fallopian tube cancer), with secondary end points of disease incidence and complications associ­ ted with a KEY ADVANCES IN MEDICINE Table 1 | Influence of BRCA1 or BRCA2 on outcome in high-grade serous ovarian cancer6 Mutational status 3-year PFS (%) 5-year PFS (%) HR compared with WT patients 3-year OS (%) 5-year OS (%) HR compared with WT patients BRCA1 mutation 22 13 0.81 (P = 0.44) 64 44 0.76 (P = 0.35) BRCA2 mutation 44 39 0.40 (P = 0.004) 83 61 0.33 (P = 0.003) BRCA WT 16 10 – 58 25 – Abbreviations: HR, hazard ratio; OS, overall survival; PFS, progression-free survival; WT, wild type. the screening strategy. The study revealed no difference in deaths from ovarian cancer or other causes between the screening and usual-care groups. Specifically, there were 212 cases of ovarian cancer and 118 deaths from the malignancy in the screening group versus 176 cases and 100 deaths in the routine-care population. Furthermore, and of considerable relevance, 1,080 surgeries were performed among the 3,285 women with false-positive screening tests, and 163 of these individuals developed at least a single ‘serious complication’.1 The important data from this screening trial provide no support for the routine use of annual CA125 determinations or vaginal ultrasounds for completely asymptomatic women as a screening strategy to detect ovarian cancer. However, it is again rele­ ant v to acknowledge that this trial did not specifically address the issue of screening a more high-risk population, nor did it attempt to define the utility of these tests in the detection of ovarian cancer in indivi­duals presenting with symptoms (for example, several weeks of persistent mild abdominal pain). A study that is somewhat related to the PLCO trial attempted to address the important question of whether an earlier diagnosis of ovarian cancer in a sympto­ atic m individual might be associated with an improved outcome.2 Australian investigators retrospectively examined the survival of 1,300 patients with ovarian cancer seen by a physician within varying time intervals (55%, 70% and 92% of the women presented within 1, 2 and 6 months, respectively) from the onset of their initial symptoms. The investigators were unable to find any difference in survival based on the duration of symptoms before the time of diagnosis. Importantly, these data do not support the hypothesis that a somewhat earlier diagnosis (timeline measured in ‘months’) will be associ­ ted with superior a ovarian cancer-specific survival,3 although the more-timely recognition of the correct diagnosis will likely result in more-rapid initiation of a management plan that will hopefully favorably impact serious symptoms and the individual’s overall quality of life. It is well established that mutations in BRCA1 and BRCA2 are associated with an increased lifetime risk for the development of ovarian cancer. 4 Furthermore, highly provocative data from a number of ovarian cancer investigators have suggested that within the population of women with docu­ mented advanced-stage ovarian cancer, patients with BRCA mutations experience an overall superior survival (compared with patients with wild-type BRCA), a difference that is possibly related to increased sensiti­ vity to platinum-based chemotherapy.5 In a most-provocative report, investigators JANUARY 2012  |  S11
  16. 16. CLINICAL ONCOLOGY Key advances ■■ There are currently no evidence-based data supporting the clinical utility of any ovarian cancer screening strategy in non‑high-risk populations1 ■■ Provocative data suggest there may be a clinically meaningful difference between the presence of a BRCA1 or a BRCA2 mutation in influencing outcome in ovarian cancer6 ■■ Under specific circumstances (for example, neuropathy) it might be reasonable to substitute pegylated liposomal doxorubicin for paclitaxel in the front-line chemotherapy management of ovarian cancer7 conducted an observational study involving 316 women with high-grade serous ovarian cancer whose BRCA mutational status was established, to evaluate the impact of such mutations on outcome.6 Although the total sample size was limited (37 and 29 patients with BRCA1 and BRCA2 mutations, respectively), there was a rather striking difference in both the inherent chemosensitivity and survival between the two mutation groups, and compared with women without mutations (Table 1). Patients with BRCA2 mutations experienced a statistically significant improvement in 5‑year survival compared with BRCA1 deficient and BRCA ‘wild-type’ cases. Although these results will need to be confirmed by other investigative groups with larger sample sizes, they suggest the potential that these two genetic abnormalities might exert quite different influences on outcome in high-grade serous ovarian cancer. At the present time, there are no known thera­peutic implications associated with these findings, but it is possible that future research may result in recommendations for different management strategies for patients with BRCA1 or BRCA2 mutations. Finally, it is relevant to note an interesting (although unfortunately flawed) phase III randomized trial that directly compared a regimen of carboplatin plus paclitaxel to carboplatin plus pegylated liposomal doxorubicin as primary treatment for epithelial ovarian cancer.7 Although this potentially paradigm changing study included a total of 820 patients, it was specifically designed to demonstrate the therapeutic superiority (rather than non-inferiority with possibility an improved toxicity profile) of the investi­ gative pegylated liposomal doxorubicincontaining regimen. In fact, although the study demonstrated similar median progression-free survival times (19.0 months and 16.8 months) and median overall survival times (61.6 months and 53.2 months) S12  |  JANUARY 2012 for the carboplatin–pegylated liposomal doxorubicin and carboplatin–paclitaxel study arms, respectively, the trial failed to achieve its primary end point (the documentation of ‘superiority’ for the experimental arm over the established therapy arm). As a result of this failure, the investigators appropriately concluded that the investigative regimen “was not superior to carboplatin– paclitaxel which remains the standard firstline chemo­ herapy for advanced ovarian t cancer.”7 However, it is reasonable to suggest that for patients unable to tolerate the taxane (for example, patients who develop neuro­ pathy early in the treatment course or severe paclitaxel-associated hypersensitivity reaction) the substitution of pegylated liposomal doxorubicin is not an unreasonable option. Thus, it is reasonable to characterize the ovarian cancer peer-reviewed literature in 2011 as providing modestly useful information regarding disease management and including important discussions of the limitations in our ability to modify the relatively early natural history of the malignancy. It is rather striking that in a clinical research world where unique targets have been discovered in multiple cancers (for example, HER2 overexpression in breast cancer, EGFR mutations in lung cancer, and BRAF mutations in melanoma) leading to exciting new treatment strategies, there remain no such molecular targets in ovarian cancer, the presence of which would lead to specific management paradigms to favorably impact outcome. It is clear that much work needs to be done to improve our understanding of the fundamental biology of ovarian cancer to change this current state-of-affairs. Cancer Treatment Centers of America, Eastern Regional Medical Center, 1331 East Wyoming Avenue, Philadelphia, PA 19124, USA. maurie.markman@ctca-hope.com Competing interests The author declares an association with the following company: Genentech. See the article online for full details of the relationship. 1. 2. 3. 4. 5. 6. 7. Buys, S. S. et al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening randomized controlled trial. JAMA 305, 2295–2303 (2011). Nagle, C. M. et al. Reducing time to diagnosis does not improve outcomes for women with symptomatic ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J. Clin. Oncol. 29, 2253–2258 (2011). Anderson, M. R. et al. Combining a symptoms index with CA125 to improve detection of ovarian cancer. Cancer 113, 484–489 (2008). King, M. C. et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302, 643–646 (2003). Tan, D. S. et al. “BRCA-ness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J. Clin. Oncol. 26, 5530–5536 (2008). Yang, D. et al. Associations of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA 306, 1557–1565 (2011). Pignata, S. et al. Carboplatin plus paclitaxel versus carboplatin plus pegylated liposomal doxorubicin as first-line treatment for patients with ovarian cancer: The MITO‑2 randomized phase III trial. J. Clin. Oncol. 29, 3628–3635 (2011). PROSTATE CANCER IN 2011 Hitting old targets better and identifying new targets Yu Chen and Howard I. Scher Options to treat late-stage castration-resistant prostate cancer continued to increase in 2011, as three agents with different mechanisms of action prolonged life and a fourth reduced the morbidity of skeletal metastases. These outcomes contrasted with the heightened controversy generated by the recommendation against PSA screening and other early detection strategies. Chen, Y. Scher, H. I. Nat. Rev. Clin. Oncol. 9, 70–72 (2012); published online 10 January 2012; doi:10.1038/nrclinonc.2011.213 In the Western world, one in six men will be diagnosed with prostate cancer and, of these, one in six will die of metastatic disease. Improving outcomes for men with prostate cancer depends on the one hand on developing more-effective systemic therapies and, on the other hand, on early diagnosis and treatment, before the disease has metastasized. 2011 is the 70 th anniversary of when Charles Huggins established that prostate cancer is an androgen-dependent www.nature.com/reviews
  17. 17. CLINICAL ONCOLOGY malignancy and, until recently, docetaxel was the only non-hormonal therapy to prolong life. In 2010, sipuleucel‑T and cabazitaxel were shown to confer a survival benefit and were subsequently approved by the FDA. This trend continued in 2011, as three therapies, CYP17 inhibitor abiraterone acetate,1 bone-targeting agent radium‑223, 2 and androgen-signaling inhibitor MDV3100,3 were shown to prolong life in definitive phase III clinical trials (Figure 1), and the RANKL inhibitor, denosumab, was shown to be superior to zoledronic acid in reducing the morbidity associated with bone metastases.4 The demonstration that agents targeting unique aspects of the malignant process associated with tumor cell growth and survival could provide meaningful clinical benefits has highlighted the importance of understanding the biology of castrationresistant prostate cancer (CRPC). The trials established important principles, which will be discussed. The first principle is that CRPCs are not hormone refractory. CRPCs acquire diverse mechanisms to reactivate the androgen receptor signaling pathway in the environment of castrate levels of androgens, including an increase in the androgen biosynthetic machinery and overexpression of androgen receptor. Thus, further decreasing androgen levels by inhibiting steroid synthesis enzymes in the adrenal glands and tumor may be of benefit. CYP17 is a cytochrome P450 enzyme that catalyzes the rate-limiting step of androgen synthesis; abiraterone acetate is a structural analog of the CYP17 substrate pregnenolone that is rationally designed to be a specific and irreversible inhibitor of CYP17. A large international phase III trial (Cougar AA‑301) that compared abiraterone acetate plus prednisone (to prevent mineralocorticoid excess) and placebo plus prednisone in patients with CRPC who had received docetaxel showed an increase in median overall survival from 10.9 to 14.8 months (hazard ratio = 0.65; P 0.001).1 All major subgroups of patients benefitted and treatment was well tolerated. A separate trial assessing abiraterone acetate in chemotherapy-naive patients has completed accrual and the results are awaited (NCT00887198). Another drug supporting the principle that CRPCs are not hormone refractory is MDV3100, a next-generation anti-androgen that was rationally designed to overcome several deficiencies of available agents including modest receptor binding and agonist properties that can promote tumor KEY ADVANCES IN MEDICINE Localized disease Rising PSA Clinical metastasis Non-castrate Rising PSA Castrate Non-castrate prostate cancer Castrate prostate cancer Trial drug shown to improve survival in phase III trials Clinical metastases Castrate Pre-docetaxel Sipuleucel-T Clinical metastases Castrate First-line chemotherapy Docetaxel Clinical metastases Castrate Post-docetaxel Cabazitexel Abiraterone Radium-223 MDV3100 Figure 1 | Clinical states model of prostate cancer progression and systemic therapies shown to improve survival for castrate disease. Blue text represents FDA approved therapies. growth. The drug displays no androgen receptor activation, blocks nuclear trans­ location of the receptor and completely inhibits the ability of androgen receptor to bind to DNA. 3 Promising activity of MDV3100 was demonstrated in a phase I– II trial in 140 patients, which led to the phase III AFFIRM trial in patients with chemotherapy-treated CRPC that compared MDV3100 with placebo. 3 This trial was stopped by the Data Safety and Monitoring Board in November 2011 when the first planned interim analysis showed a 37% reduction in mortality, and superior overall survival (median 18.4 versus 13.6 months) in favor of MDV3100.3 The second principle was that targeting the bone environment can confer benefits, independent of an effect on prostate-specific antigen (PSA). Bone is the most common site of prostate cancer spread and is responsible for the highest morbidity burden from the disease. Therapies directed at the bone microenvironment can be divided into three classes: osteoclast inhibitors of bone resorption, radiopharmaceuticals that target bone, and kinase inhibitors. Despite the radiographic appearance of osteoblastic lesions, there is heightened osteoclastic activity and bone turnover in metastatic prostate cancer lesions. Osteoclast inhibitors, including zoledronic acid, are used as an adjuvant therapy to maintain bone density and to decrease skeletal-related events (SRE) in patients with CRPC. Denosumab is a humanized monoclonal antibody that blocks RANKL, which is required for osteoclast activation and survival. In 1,904 patients with CRPC that had meta­ tasized to the bone, denosumab s delayed the median time to first SRE from 17.1 to 20.7 months (P = 0.008) compared to zoledronic acid, leading to FDA approval.4 The beta-emitting bone-seeking radioisotopes strontium‑89 and samarium‑153 lexidronam are approved for the palliation of pain, but neither has been shown to prolong life. Radium‑223 is a unique bone-directed radioisotope that emits high-energy alpha particles that penetrate only several cell layers in tissue, significantly improving the radiation delivery to areas of sclero­ tic bone where the tumor resides while minimizing radiation to hematopoietic tissue. In a phase III trial in 922 patients with CRPC and bone pain, 6-monthly doses of radium‑223 conferred a significant overall survival benefit over placebo (14.0 versus 11.2 months; P = 0.00185);2 it is the first bone-directed agent to prolong overall survival. Multiple signaling cascades are critical for bone homeostasis and turnover. Two promising investigational agents targeting this axis deserve mention. Dasatinib inhibits kinases including Src family tyrosine kinases that are important for bone turnover; a single-agent phase II trial in patients with CRPC showed a marked decrease in bone turnover, disease stabilization5 and additive effects with docetaxel. A phase III trial comparing dasatinib with placebo in combination with docetaxel has completed accrual. Cabozantinib inhibits kinases including Ret, Met, and VEGFR2; in a randomized phase III discontinuation trial in patients with CRPC, treatment with cabozantinib was associated with normalization of radionuclide bone scans in 86% of patients, improvement of bone pain in 64% of patients, decline in bone marker levels, improvement of anemia, and a marked reduction in bone pain independent of an effect on PSA.6 Two phase III trials will be opened for recruitment soon: the first for an indication for the palliation of pain and a second for an improvement in overall survival in patients with CRPC. Limiting the use of agents shown to prolong life to men with advanced metastatic CRPC will not considerably decrease the number of men who die from prostate cancer. To do so requires the identification and treatment of those cancers that are destined to metastasize, produce symptoms and ultimately shorten a patient’s anticipated life expectancy when tumor burdens JANUARY 2012  |  S13

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