Hot off the presses! Aug 26 Lancet

The Aug 26 issue of the Lancet is now up on Pubget (About Lancet): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• On the horizon in heart failure
  - Lancet 378(9792):637 (2011)
  
• Doctors striking in Israel
  - Lancet 378(9792):638 (2011)
  
• South Africa should step up oversight of maternal care
  - Lancet 378(9792):638 (2011)
  
• Cardiac myosin activation: will theory and practice coincide?
  - Lancet 378(9792):639-641 (2011)
  
• Predictive ability of coronary artery calcium and CRP
  - Lancet 378(9792):641-643 (2011)
  
• Antithrombin alternatives in STEMI
  - Lancet 378(9792):643-645 (2011)
  
• Why not screen for subclinical atherosclerosis?
  - Lancet 378(9792):645-646 (2011)
  
• A low-cost solar-powered blood-pressure device
  - Lancet 378(9792):647-648 (2011)
  
• Pakistan prepares to abolish Ministry of Health
  - Lancet 378(9792):648-649 (2011)
  
• Offline: The great European betrayal
  - Lancet 378(9792):650 (2011)
  
• US physicians urge end to unnecessary stent operations
  - Lancet 378(9792):651-652 (2011)
  
• Laos builds specialty training system through partnerships
  - Lancet 378(9792):653-654 (2011)
  
• The past is never dead
  - Lancet 378(9792):655-656 (2011)
  
• Give me shelter
  - Lancet 378(9792):656 (2011)
  
• John Teerlink: Renaissance man and leader in heart failure research
  - Lancet 378(9792):657 (2011)
  
• Unexpected life lessons from cardiac anatomy and physiology
  - Lancet 378(9792):658-659 (2011)
  
• Kumariah Balasubramaniam
  - Lancet 378(9792):660 (2011)
  
• Radial versus femoral access in acute coronary syndromes
  - Lancet 378(9792):661 (2011)
  
• Radial versus femoral access in acute coronary syndromes
  - Lancet 378(9792):661 (2011)
  
• Radial versus femoral access in acute coronary syndromes – Authors' reply
  - Lancet 378(9792):661-662 (2011)
  
• New antithrombotic drugs and European approval processes
  - Lancet 378(9792):662-663 (2011)
  
• Promise of extended-release naltrexone is a red herring
  - Lancet 378(9792):663 (2011)
  
• Promise of extended-release naltrexone is a red herring – Authors' reply
  - Lancet 378(9792):663-664 (2011)
  
• Injectable extended-release naltrexone for opioid dependence
  - Lancet 378(9792):664-665 (2011)
  
• Injectable extended-release naltrexone for opioid dependence
  - Lancet 378(9792):665 (2011)
  
• Injectable extended-release naltrexone for opioid dependence
  - Lancet 378(9792):665-666 (2011)
  
• Injectable extended-release naltrexone for opioid dependence – Authors' reply
  - Lancet 378(9792):666 (2011)
  
• Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study
  - Lancet 378(9792):667-675 (2011)
  Background Decreased systolic function is central to the pathogenesis of heart failure in millions of patients worldwide, but mechanism-related adverse effects restrict existing inotropic treatments. This study tested the hypothesis that omecamtiv mecarbil, a selective cardiac myosin activator, will augment cardiac function in human beings. Methods In this dose-escalating, crossover study, 34 healthy men received a 6-h double-blind intravenous infusion of omecamtiv mecarbil or placebo once a week for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0·005 to 1·0 mg/kg per h) with a placebo infusion randomised into the sequence. Vital signs, blood samples, electrocardiographs (ECGs), and echocardiograms were obtained before, during, and after each infusion. The primary aim was to establish maximum tolerated dose (the highest infusion rate tolerated by at least eight participants) and plasma concentrations of omecamtiv mecarbil; secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. This study is registered at ClinicalTrials.gov, number NCT01380223. Findings The maximum tolerated dose of omecamtiv mecarbil was 0·5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 [SD 5] ms), the most sensitive indicator of drug effect (r2=0·99 by dose), associated with increases in stroke volume (15 [2] mL), fractional shortening (8% [1]), and ejection fraction (7% [1]; all p<0·0001). Omecamtiv mecarbil increased atrial contractile function, and there were no clinically relevant changes in diastolic function. There were no clinically significant dose-related adverse effects on vital signs, serum chemistries, ECGs, or adverse events up to a dose of 0·625 mg/kg per h. The dose-limiting toxic effect was myocardial ischaemia due to excessive prolongation of systolic ejection time. Interpretation These first-in-man data show highly dose-dependent augmentation of left ventricular systolic function in response to omecamtiv mecarbil and support potential clinical use of the drug in patients with heart failure. Funding Cytokinetics Inc.
• 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(9792):676-683 (2011)
  Background Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure. Methods We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442. Findings 45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9·7 mL) were recorded, associated with a small reduction in heart rate (up to 2·7 beats per min; p<0·0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0·0026) and end-diastolic volumes (16 mL, p=0·0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged. Interpretation Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent. Funding Cytokinetics Inc.
• Associations between C-reactive protein, coronary artery calcium, and cardiovascular events: implications for the JUPITER population from MESA, a population-based cohort study
  - Lancet 378(9792):684-692 (2011)
  Background The JUPITER trial showed that some patients with LDL-cholesterol concentrations less than 3·37 mmol/L (<130 mg/dL) and high-sensitivity C-reactive protein (hsCRP) concentrations of 2 mg/L or more benefit from treatment with rosuvastatin, although absolute rates of cardiovascular events were low. In a population eligible for JUPITER, we established whether coronary artery calcium (CAC) might further stratify risk; additionally we compared hsCRP with CAC for risk prediction across the range of low and high hsCRP values. Methods 950 participants from the Multi-Ethnic Study of Atheroslcerosis (MESA) met all criteria for JUPITER entry. We compared coronary heart disease and cardiovascular disease event rates and multivariable-adjusted hazard ratios after stratifying by burden of CAC (scores of 0, 1–100, or >100). We calculated 5-year number needed to treat (NNT) by applying the benefit recorded in JUPITER to the event rates within each CAC strata. Findings Median follow-up was 5·8 years (IQR 5·7–5·9). 444 (47%) patients in the MESA JUPITER population had CAC scores of 0 and, in this group, rates of coronary heart disease events were 0·8 per 1000 person-years. 74% of all coronary events were in the 239 (25%) of participants with CAC scores of more than 100 (20·2 per 1000 person-years). For coronary heart disease, the predicted 5-year NNT was 549 for CAC score 0, 94 for scores 1–100, and 24 for scores greater than 100. For cardiovascular disease, the NNT was 124, 54, and 19. In the total study population, presence of CAC was associated with a hazard ratio of 4·29 (95% CI 1·99–9·25) for coronary heart disease, and of 2·57 (1·48–4·48) for cardiovascular disease. hsCRP was not associated with either disease after multivariable adjustment. Interpretation CAC seems to further stratify risk in patients eligible for JUPITER, and could be used to target subgroups of patients who are expected to derive the most, and the least, absolute benefit from statin treatment. Focusing of treatment on the subset of individuals with measurable atherosclerosis could allow for more appropriate allocation of resources. Funding National Institutes of Health–National Heart, Lung, and Blood Institute.
• Intravenous enoxaparin or unfractionated heparin in primary percutaneous coronary intervention for ST-elevation myocardial infarction: the international randomised open-label ATOLL trial
  - Lancet 378(9792):693-703 (2011)
  Background Primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction has traditionally been supported by unfractionated heparin, which has never been directly compared with a new anticoagulant using consistent anticoagulation and similar antiplatelet strategies in both groups. We compared traditional heparin treatment with intravenous enoxaparin in primary PCI. Methods In a randomised open-label trial, patients presenting with ST-elevation myocardial infarction were randomly assigned (1:1) to receive an intravenous bolus of 0·5 mg/kg of enoxaparin or unfractionated heparin before primary PCI. Wherever possible, medical teams travelling in mobile intensive care units (ambulances) selected, randomly assigned (using an interactive voice response system at the central randomisation centre), and treated patients. Patients who had received any anticoagulant before randomisation were excluded. Patients and caregivers were not masked to treatment allocation. The primary endpoint was 30-day incidence of death, complication of myocardial infarction, procedure failure, or major bleeding. The main secondary endpoint was the composite of death, recurrent acute coronary syndrome, or urgent revascularisation. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00718471. Findings 910 patients were assigned to treatment with enoxaparin (n=450) or unfractionated heparin (n=460). The primary endpoint occurred in 126 (28%) patients after anticoagulation with enoxaparin versus 155 (34%) patients on unfractionated heparin (relative risk [RR] 0·83, 95% CI 0·68–1·01, p=0·06). The incidence of death (enoxaparin, 17 [4%] vs heparin, 29 [6%] patients; p=0·08), complication of myocardial infarction (20 [4%] vs 29 [6%]; p=0·21), procedure failure (100 [26%] vs 109 [28%]; p=0·61), and major bleeding (20 [5%] vs 22 [5%]; p=0·79) did not differ between groups. Enoxaparin resulted in a significantly reduced rate of the main secondary endpoint (30 [7%] vs 52 [11%] patients; RR 0·59, 95% CI 0·38–0·91, p=0·015). Death, complication of myocardial infarction, or major bleeding (46 [10%] vs 69 [15%] patients; p=0·03), death or complication of myocardial infarction (35 [8%] vs 57 [12%]; p=0·02), and death, recurrent myocardial infarction, or urgent revascu! larisation (23 [5%] vs 39 [8%]; p=0·04) were all reduced with enoxaparin. Interpretation Intravenous enoxaparin compared with unfractionated heparin significantly reduced clinical ischaemic outcomes without differences in bleeding and procedural success. Therefore, enoxaparin provided an improvement in net clinical benefit in patients undergoing primary PCI. Funding Direction de la Recherche Clinique, Assistance Publique-Hôpitaux de Paris; Sanofi-Aventis.
• In search of new therapeutic targets and strategies for heart failure: recent advances in basic science
  - Lancet 378(9792):704-712 (2011)
  Chronic heart failure continues to impose a substantial health-care burden, despite recent treatment advances. The key pathophysiological process that ultimately leads to chronic heart failure is cardiac remodelling in response to chronic disease stresses. Here, we review recent advances in our understanding of molecular and cellular mechanisms that play a part in the complex remodelling process, with a focus on key molecules and pathways that might be suitable targets for therapeutic manipulation. Such pathways include those that regulate cardiac myocyte hypertrophy, calcium homoeostasis, energetics, and cell survival, and processes that take place outside the cardiac myocyte—eg, in the myocardial vasculature and extracellular matrix. We also discuss major gaps in our current understanding, take a critical look at conventional approaches to target discovery that have been used to date, and consider new investigational avenues that might accelerate clinically relevan! t discovery.
• Medical therapy for chronic heart failure
  - Lancet 378(9792):713-721 (2011)
  Understanding of contemporary pharmacological therapy for chronic heart failure continues to evolve. In this Review, we discuss how findings from clinical trials have caused the roles of old therapies to be expanded and past treatment algorithms to be challenged. Several trials investigating preserved ejection fraction as a measure of heart failure had disappointing results, although important studies are in progress. Many novel therapeutic approaches for heart failure have emerged and are discussed in this review. The pharmacological treatments for heart failure continue to change, with many exciting possibilities for the future.
• Implantable cardioverter defibrillators and cardiac resynchronisation therapy
  - Lancet 378(9792):722-730 (2011)
  Implantable cardioverter defibrillators and cardiac resynchronisation therapy (CRT) have become standard of care in modern treatment for heart failure. Results from trials have provided ample evidence that CRT, in addition to its proven benefits in patients with symptomatic heart failure (New York Heart Association [NYHA] class III), might also reduce morbidity and mortality in those with mildly symptomatic heart failure (NYHA class II). As a result, the 2010 European Society of Cardiology guidelines now recommend CRT for both patient populations. In this review we summarise and critically assess the landmark randomised clinical trials REVERSE, MADIT-CRT, and RAFT. Furthermore, we discuss the rationale and available evidence for other emerging indications of CRT, including its use in patients with a mildly reduced left ventricular ejection fraction (>35%), in those with a narrow QRS complex (≤120 ms), and in those with concomitant bradyarrhythmic pacemaker indication! s. We also focus on patients who do not respond to CRT, and on CRT optimisation.
• Telemedicine and remote management of patients with heart failure
  - Lancet 378(9792):731-739 (2011)
  Advances in telecommunication technologies have created new opportunities to provide telemedical care as an adjunct to medical management of patients with heart failure. Meta-analyses suggest that telemedicine can reduce morbidity and mortality in such patients; however, two prospective clinical trials not included in the analyses do not support these findings. Therefore, the effectiveness of telemedicine in heart failure is not established. Telemedicine approaches range from computer-based support systems to programmes led by nurses and physicians. Standardisation and appropriate classification of telemedical systems are needed to enable accurate interpretation of clinical trials. Here we propose a classification of four generations of telemedicine in heart failure. Not all approaches are the same and not every patient with heart failure will need telemedicine. Crisis prevention and treatment, and stabilisation and self-empowerment of patients are focuses of telemedic! ine in heart failure. The profile of patients who can potentially benefit from telemedicine is unknown and should be investigated in adequately powered randomised clinical trials. We are optimistic that telemedicine is an efficient approach and will become an important feature of management in heart failure.
• Coagulation: cascade!
  - Lancet 378(9792):740 (2011)