Best Clinical Trials Reported in 2010




Each year, a number of clinical trials emerge with data sufficient to change clinical practice. Determining which findings will result in practice change and which will provide only incremental benefit can be a dilemma for clinicians. The authors review selected clinical trials reported in 2010 in journals, at society meetings, and at conferences, focusing on those studies that have the potential to change clinical practice. This review offers 3 separate means of analysis: an abbreviated text summary, organized by subject area; a comprehensive table of relevant clinical trials that provides a schematic review of the hypotheses, interventions, methods, primary end points, results, and implications; and a complete bibliography for further reading as warranted. It is hoped that this compilation of relevant clinical trials and their important findings released in 2010 will be of benefit in the everyday practice of cardiovascular medicine.


Prevention


Hypertension


Hypertension continues to represent a major risk factor for coronary artery disease, heart failure, and stroke. As we await new recommendations from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, important new data regarding the treatment of hypertension in patients with diabetes or with impaired glucose tolerance have emerged. The trials of 2010 ( Table 1 ) have added to previous data from the United Kingdom Prospective Diabetes Study (UKPDS) trial, advancing our understanding of this complicated issue. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure (BP) trial was specifically designed to determine the efficacy of intensive BP management in diabetes mellitus. Patients in the intensive arm targeted pressures <120 mm Hg systolic and those in the conventional arm <140 mm Hg. Despite achievement of substantially lower BP in the intensive-therapy arm, no significant improvement was seen in the primary outcome of stroke, myocardial infarction (MI), or cardiovascular death. Moreover, the long-term follow-up data of an International Verapamil SR Trandolapril Study (INVEST) substudy suggest that efforts at tight BP control are associated with signals of harm in this population, particularly if systolic BP is lowered to <110 mm Hg. Pending new directives on BP management from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, it is advisable to avoid reducing systolic BP to <120 mm Hg in patients with diabetes or impaired glucose tolerance.



Table 1

Best clinical trials of 2010








































































































































































































































Trial Type of Subjects Subjects Mean Age (years) Men Placebo Control/Blinded Comparison Primary Efficacy Outcome Safety Outcome Other Outcome Clinical Implications
ACCORD BP Type 2 DM, SBP 130–180 mm Hg, <4 BP medications 4,733 62 52% O SBP <140 mm Hg vs <120 mm Hg + HbA 1c <6% vs 7%–8% MI, stroke, or CV death: 1.9% vs 2.1% per year (p = NS) Any stroke: 1.3% vs 1.2% (p = NS) No benefit to aggressive BP control in patients with DM
ACCORD lipid Type 2 DM, LDL-C 60–180 mg/dl, HDL-C <50–55 mg/dl 5,518 62 69% + Simvastatin and (fenofibrate vs placebo) + HbA 1c <6% vs 7%–8% MI, stroke, or CV death: 2.2% vs 2.4% per year (p = NS) Any stroke: 1.5% vs 1.6% (p = NS) No benefit to adding fibrate to statin in patients with DM
AVERROES AF, CHADS score ≥2 in 65% 5,600 60 60% O Apixaban vs ASA Stroke or embolus: 1.7% vs 4.0% per year Major bleeding: 1.6% vs 1.4% per year Intracranial hemorrhage: 0.5% vs 0.4% Apixaban better than ASA in AF
COGENT Requiring dual-antiplatelet for >1 year 3,873 69 68% + Clopidogrel and omeprazole vs clopidogrel alone CV death, MI, stroke or revascularization: 4.9% vs 5.7% (p = NS) Significant GI bleeding or ulcer: 2.9% vs 1.1% Definite or probable stent thrombosis: 0 vs 2 No adverse effect of omeprazole + clopidogrel
CREST Moderate to severe carotid disease, symptomatic or asymptomatic, eligible for stent + surgery 2,522 69 65% O Death, stroke, MI, in 30 days or stroke within 4 years: 5.2% vs 4.5% (p = NS) Death: 0.7% vs 0.3% (p = NS) MI: 1.1% vs 2.3% Similar outcomes for carotid stent vs endarterectomy
CURRENT OASIS 7 NSTEMI or STEMI with catheterization planned <72 hours from diagnosis 25,086 61 73% O Clopidogrel high vs conventional dose + ASA low vs high dose Death, MI, stroke: ASA arm, 4.2% vs 4.4%; clopidogrel arm, 4.2% vs 4.4% (all p = NS) Major bleeding: ASA arm, 2.3% vs 2.3%; clopidogrel arm, 2.5% vs 2.0% (all p = NS) Stent thrombosis: ASA arm, not reported; clopidogrel arm, 1.6% vs 2.3% Similar outcomes for high vs low dose of ASA or clopidogrel
DES-LATE DES >12 months previously, no MI or bleeding since stenting 2,701 62 70% O CV death or MI: 20 vs 12 patients (p = NS) Definite stent thrombosis: 5 vs 4 patients (p = NS) Major bleeding: 3 vs 1 patients (p = NS) No benefit to clopidogrel >12 months, study underpowered
DOSE Hospitalized with CHF, needing ≥48 hours of diuresis 308 66 73% O Creatinine change: admin arm, 0.05 vs 0.07; dose arm, 0.04 vs 0.08 (both p = NS) Urine output: admin arm (p = NS); dose arm, 3.6 vs 4.9 L Bolus diuretics as safe and effective as drip in CHF
EMPHASIS-HF NYHA class II CHF, EF ≤30%, preserved renal function 2,737 69 78% + Eplerenone vs placebo CV death or HF hospitalization: 18% vs 26% Hospitalization for hyperkalemia or renal failure: 1.0% vs 0.8% (p = NS) All-cause death: 13% vs 16% Eplerenone effective in class 2 CHF; NNT = 33 to save 1 life
EVEREST II 3–4+ MR, specific valve anatomy 279 67 64% O Percutaneous valve clip vs valve surgery Death, surgery, reoperation, or MR >2+ at 1 year: 28% vs 12% 30-day MACEs: 10% vs 57% <3+ MR: 82% vs 97% Valve clip not as effective at MR reduction but safer than surgery
IMPROVE-HF Community and university outpatient cardiology clinics 167 clinics O Guideline adherence before use of toolkit vs after toolkit Adherence to core measures for HF (7-measure average): 60% vs 76% Decision-making tools improve use of evidence-based therapy in CHF
NAVIGATOR Impaired fasting glucose, heart disease or risks for same 9,306 64 49% + Valsartan vs placebo Incidence of DM: 33% vs 37% Death, MI, stroke, or HF hospitalization: 8.1% vs 8.1% (p = NS) Valsartan improved BP and incidence of DM but not rate of CV events
PARTNER Severe AS, nonsurgical candidate 358 83 82% O Transcatheter valve vs medicine and valvuloplasty 1-year death: 31% vs 51% Stroke or TIA at 1 year: 11% vs 5% (p = 0.04) Vascular complications: 32% vs7% TAVI superior to standard care of nonsurgical severe AS; NNT = 5 to save 1 life
RACE-2 Permanent AF, rate control strategy 614 68 65% O 3-year death, stroke/emboli, HF hospitalization, or severe arrhythmia: 13% vs 15% Met outpatient rate goal: 98% vs 67% No benefit to aggressive rate control in permanent AF
RAFT NYHA class II–III CHF, EF <30%, QRS duration >120 ms 1,798 66 83% O CRT-ICD vs ICD only Death or HF hospitalization: 33% vs 40% All-cause death: 21% vs 26% CRT-ICD better than ICD alone in CHF + LBBB
SCOUT BMI >25 kg/m 2 , CV risks or disease 9,804 63 58% O Sibutramine vs placebo Weight loss average of 2 kg at 6 months, no further loss thereafter CV death, stroke, or MI: 11% vs 10% Sibutramine withdrawn from United States market
SHIFT NYHA class II–IV CHF, no AF or atrial flutter 6,558 60 76% + Ivabradine vs placebo CV death + HF hospitalization: 24% vs 29% Symptomatic bradycardia: 5% vs 1% CV death alone: 14% vs 15% (p = NS) Ivabradine improves HF hospitalization but not death
STOP-AF AF, failed antiarrhythmic drug 245 57 77% O Cryoballoon vs continued drug therapy Freedom from AF or nonstudy antiarrhythmic drugs: 70% vs 7% Acute phrenic nerve palsy: 11% vs 0% Free of AF without drugs: 58% vs 0% Cryoablation effective in symptomatic AF and failed antiarrhythmic drug

AF = atrial fibrillation; AS = aortic stenosis; ASA = aspirin; BMI = body mass index; CHF = congestive heart failure; COGENT = Clopidogrel and the Optimization of Gastrointestinal Events Trial; CRT = cardiac resynchronization therapy; DES = drug-eluting stent; EF = ejection fraction; HF = heart failure; ICD = implantable cardioverter-defibrillator; LBBB = left bundle branch block; MACE = major adverse cardiac event; MR = mitral regurgitation; NNT = number needed to treat; NSTEMI = non–ST-segment elevation myocardial infarction; NYHA = New York Heart Association; STEMI = ST-segment elevation myocardial infarction; TAVI = transcatheter aortic valve implantation; TIA = transient ischemic attack.


Dyslipidemia


New data have also emerged regarding the role of fibrates as second-line agents in high-risk patients with diabetes. The ACCORD lipid trial evaluated the addition of fenofibrate to simvastatin and found no improvement in MI, stroke, cardiovascular death, or all-cause mortality. These findings confirm the primacy of statins in the management of these patients and call into question what role, if any, fibrates play in cardiovascular risk management.


Obesity


The search for a safe, effective weight management drug continues after the Sibutramine Cardiovascular Outcomes Trial (SCOUT) resulted in the manufacturer’s withdrawal of sibutramine from the United States market. Patients taking sibutramine were found to have only minimal reductions in weight and an absolute increase in the rate of death, stroke, or MI. On the basis of number-needed-to-harm calculations, 1 of every 71 patients taking the drug is expected to have a death, stroke, or MI beyond those taking only placebo. Orlistat thus remains the only medication approved by the United States Food and Drug Administration for the long-term management of weight. The focus in weight management should continue to be on diet and exercise. For those with morbid obesity who have demonstrated compliance with behavior modification programs, bariatric surgery may be an option.


Diabetes mellitus


The Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial evaluated the progression from impaired fasting glucose to diabetes mellitus in patients receiving valsartan and nateglinide. As noted in previous trials, but now with convincing evidence, a renin-angiotensin-aldosterone system inhibitor, in this case valsartan, appears to decrease the incidence of diabetes. This occurred without an associated improvement in cardiovascular outcomes, although longer term follow-up and/or an even larger patient population might still demonstrate a positive influence on cardiovascular events. Nateglinide was not associated with a reduction in the incidence of diabetes in this trial but remains a reasonable consideration for glycemic control.




Treatment


Coronary and carotid artery disease


Many trials emerged this year to further the art and science of coronary intervention, with some extending their influence well beyond the scope of interventional cardiology. The Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events–Optimal Antiplatelet Strategy for Interventions (CURRENT-OASIS 7) trial simultaneously evaluated low-dose (75 to 100 mg) and high-dose (300 to 325 mg) aspirin alongside low and high doses of clopidogrel in patients with either non–ST-segment elevation or ST-segment elevation MI. Presuming, as this study did, that a single loading dose of aspirin is given at the time of presentation, an immediate transition to low-dose aspirin on day 2 appears to be as effective as maintaining a higher dose for the next 30 days. Conversely, however, the study also showed that there is no increased risk in using the more conventional higher dose for this period, leaving the matter to practitioner discretion. Although high-dose clopidogrel for the first 30 days does not appear to affect mortality or major morbidity, the higher dose demonstrated a 0.7% reduction in the secondary end point of stent thrombosis at the expense of a trend toward nonfatal major bleeding.


Cardiologists worldwide continue to await a clear answer to the safest duration of dual-antiplatelet therapy for patients receiving drug-eluting stents. Two trials formerly known as Evaluation of the Long-Term Safety After Zotarolimus-Eluting Stent, Sirolimus-Eluting Stent, or Paclitaxel-Eluting Stent Implantation for Coronary Lesions–Late Coronary Arterial Thrombotic Events (ZEST-LATE) and Correlation of Clopidogrel Therapy Discontinuation in Real-World Patients Treated With Drug-Eluting Stent Implantation and Late Coronary Arterial Thrombotic Events (REAL-LATE) were combined under the new name Optimal Duration of Clopidogrel Therapy After Drug-Eluting Stent (DES-LATE) and published in 2010. These data suggest that 1 year of postprocedural dual-antiplatelet therapy is noninferior to prolonged dual-antiplatelet therapy on the end point of very late stent thrombosis. Despite the importance of these findings, it is as yet too soon to change practice. The statistical power of these trials is hampered by the small number of reported events and the open-label nature of the design. Clinicians are advised to continue their current management strategies while more rigorous data are obtained. At present, >20,000 patients are being enrolled in the Dual Antiplatelet Therapy (DAPT) trial ( NCT00977938 ), estimated to be completed in December 2013. This trial is designed specifically to address the duration of dual-antiplatelet therapy. Two other trials being conducted in non-American populations, Safety and Efficacy of Six Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE; NCT00661206 ) and Optimized Duration of Clopidogrel Therapy Following Treatment With the Endeavor Zotarolimus-Eluting Stent in the Real World Clinical Practice (OPTIMIZE; NCT01113372 ) will also contribute to our understanding.


The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) demonstrated efficacy of carotid stenting in those with moderate to severe carotid artery disease, but safety questions remain. Stenting (compared to surgical endarterectomy) was associated with a 1.2% decrease in MI but a 1.8% increase in stroke. Furthermore, the long-term durability of stent repair beyond 4 years remains unknown, a particular concern given that the noninferiority of stenting is driven primarily by the youngest patients studied. Patients aged >70 years continue to fare better with endarterectomy. Follow-up of the CREST patient cohort out to 10 years is ongoing.


Heart failure


The Systolic Heart Failure Treatment With the I f Inhibitor Ivabradine Trial (SHIFT) study examined the effect of ivabradine, a drug of interest for its heart rate–lowering effects, on the outcomes of patients with heart failure in sinus rhythm. When added to a regimen that included β blockers (but not consistently at target doses), ivabradine improved a composite outcome of cardiovascular death and heart failure hospitalization, with the benefit largely attributable to reductions in hospitalization in those with heart rates at rest >77 beats/min. This study demonstrates the potential importance of heart rate slowing (perhaps a mechanism of β blockers) in the treatment of heart failure. Whether the same improvements might have occurred simply with ideal dose titration of current evidence-based β blockers remains a provocative question. The Diuretic Optimization Strategies Evaluation (DOSE) trial revives the long-held discussion regarding optimal strategies for diuresis in acute decompensated heart failure and demonstrates that a priori continuous administration of furosemide may not yield superior patient outcomes compared to conventional bolus dose therapy. The Improving Evidence-Based Care for Heart Failure in Outpatient Cardiology Practices: Primary Results of the Registry to Improve Heart Failure Therapies in the Outpatient Setting (IMPROVE-HF) registry followed centers after interventions intended to increase adherence to current evidence-based guidelines across 7 critical quality domains of heart failure treatment and demonstrated substantial improvements in 5 of these domains.


The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) has now demonstrated convincingly that the addition of an aldosterone antagonist to a conventional heart failure regimen in mild to moderate heart failure (New York Heart Association class II) is associated with significant morbidity and mortality advantages. The body of accumulated evidence addressing the benefit of aldosterone antagonists in heart failure is now sufficient to warrant a stronger embrace of this regimen, with the proviso that careful patient selection regarding renal function and risk for hyperkalemia is necessary. Hesitancy to use this approach in heart failure is no longer warranted.


Taken together, these studies illustrate potential additions in heart failure management but once again reinforce the primacy of adherence to already proved evidence-based guideline-driven therapy for heart failure. Given the recent dearth of positive heart failure trials, it is reassuring to witness a resurgence of interest in the study of novel compounds and unique processes of care that may improve the care of patients with heart failure. Upcoming results from ongoing studies, including the revascularization–versus–medical therapy arm of the Surgical Treatment for Ischemic Heart Failure (STICH) trial and Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT), will further define the care of patients with heart failure.


Finally, the publication of Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT) has substantially extended the subset of patients for whom a mortality benefit of cardiac resynchronization therapy can be expected. Looking at patients with ischemic and nonischemic New York Heart Association class II and III heart failure with ejection fractions ≤30% and wide QRS intervals, resynchronization therapy was found to be superior to defibrillator alone, with a number needed to treat of only 19 to save 1 life. Hospitalizations were also reduced. As in previous studies, the benefit was driven exclusively by those with QRS duration >150 ms and left-bundle morphology.


Valvular heart disease


The year 2010 witnessed the evolution of percutaneous treatment strategies for valvular heart disease that heretofore had been primarily in the domain of surgical approaches. With these new innovations, the sphere of interventional cardiology has now been extended to valvular heart disease. The Placement of Aortic Transcatheter Valve (PARTNER) trial evaluated the use of transcatheter aortic valve implantation in patients with severe aortic stenosis. Results from the group deemed inoperable have been reported and demonstrate that transcatheter aortic valve implantation decreases mortality at 1 year from 51% to 31%, with decreased transvalvular pressure gradients by echocardiography. Durability of the valve and longer term outcomes remain to be determined. The Second Endovascular Valve Edge-to-Edge Repair Study (EVEREST II) addressed moderately severe to severe mitral valve disease in patients who were also suitable for operative repair or replacement. This randomized study demonstrated a safety benefit over surgery (primarily driven by reduced need for transfusion) for percutaneous mitral valve repair (via an Alfieri-type clip) although surgery is superior for reduction in mitral regurgitation severity. The available data are encouraging and represent an expansion of nonsurgical options for patients with severe valvular heart disease. Although both of these proof-of-concept trials are “positive,” important questions remain regarding precise indications for intervention, durability of percutaneous approaches, and the likely need to limit these complex procedures to highly skilled, high-volume centers of excellence in valvular heart disease. It is expected that product iterations already under development will address many of the residual questions. Nevertheless, these data have ushered in a new area of interventional cardiology and deserve our watchful eye over the coming year.


Cardiac arrhythmias


The arrhythmia trials are largely focused on the issues surrounding the risk and management of atrial fibrillation. In 2009, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial demonstrated superiority of the twice-daily oral direct thrombin inhibitor dabigatran over conventional adjusted-dose warfarin sodium. One year later, dabigatran is now approved by the Food and Drug Administration to lower stroke risk in atrial fibrillation, even as new trials pave the way for another class of oral anticoagulants in this population. The Apixaban Versus ASA to Reduce the Risk of Stroke (AVERROES) trial of apixaban, a twice-daily oral factor Xa inhibitor, showed significant superiority to aspirin in the prevention of strokes in high-risk patients with atrial fibrillation. The patients studied were all deemed or demonstrated to be unsuitable for warfarin; the important comparison of apixaban to warfarin is currently under way in the Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE) trial. The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism in Atrial Fibrillation (ROCKET AF) trial evaluated the once-daily oral factor Xa inhibitor rivaroxaban in patients with atrial fibrillation with a very high risk for stroke (>90% of patients had CHADS scores >3) and found rivaroxaban noninferior to warfarin for the prevention of stroke. Although this therapy appears promising, further enthusiasm will have to await full publication of the trial data. Head-to-head comparisons of any of these new agents to each other have not been completed, and the data should be reviewed with respect to the populations studied and not in a comparison format. The emergence of these novel anticoagulants with separate and unique mechanisms of action are potentially transformative changes in the management of atrial fibrillation.


The Second Rate Control and Rhythm Control in Patients With Recurrent Persistent Atrial Fibrillation (RACE-2) trial extends the application of rate control strategies (see Atrial Fibrillation Follow-Up Investigation of Rhythm Management [AFFIRM] ) by demonstrating that more lenient rate control is no worse than intensive efforts at lowering heart rate over periods of ≥3 years. It is thus reasonable to use a rate control strategy targeting only a rest heart rate <110 beats/min. For patients in whom rhythm control is desired, the Sustained Treatment of Paroxysmal Atrial Fibrillation (STOP-AF) trial extends the momentum regarding ablative therapies for atrial fibrillation and demonstrates clear superiority of a new cryoballoon ablation technique over medical therapies, although not yet superior suppression of atrial fibrillation versus more conventional radiofrequency-based ablation techniques. There was also a significant periprocedural risk for phrenic nerve palsy. Candidate selection and careful follow-up will be key elements of care going forward.


Cardiopulmonary resuscitation


Three new clinical trials have demonstrated the efficacy and safety of compression-only cardiopulmonary resuscitation in patients in cardiac arrest. Analyzed in aggregate, using compressions only, more patients survived than with the previously taught combination of compressions and so-called rescue breaths, with a number needed to treat of 41 patients to save 1 life. On the basis of these new data, the International Liaison Committee on Resuscitation issued new guidelines recommending compression-only cardiopulmonary resuscitation to laypersons and those assisting them.


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Dec 16, 2016 | Posted by in CARDIOLOGY | Comments Off on Best Clinical Trials Reported in 2010
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