|Year : 2016 | Volume
| Issue : 2 | Page : 73-75
Recent landmark trials in clinical cardiology
Biswajit Paul MD, DNB Cardiology
Department of Cardiology, Jaypee Hospital, Noida, Uttar Pradesh, India
|Date of Web Publication||18-Jul-2016|
Department of Cardiology, Jaypee Hospital, Noida, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Paul B. Recent landmark trials in clinical cardiology. J Clin Prev Cardiol 2016;5:73-5
A few recent trials have attracted the attention of medical fraternity. The foremost being Heart Outcomes Prevention Evaluation-3 (HOPE-3) aimed at primary prevention of individuals at intermediate risk. The trial encompassed individuals of diverse ethnicity and studied the role of a statin and an antihypertensive regimen for the assessment of their effect on lowering cardiovascular risk. Another trial, the Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES) pondered over the role of surgical revascularization in patients of ischemic cardiomyopathy in conferring survival benefit. The Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure studied the role of aliskiren with and without enalapril in patients with left ventricular dysfunction with heart failure. The trial drew attention due to a regulatory mandate curbing aliskiren therapy in diabetic patients on the basis of Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) and Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) as safety concerns were raised. This review summarizes the key findings from these three trials along with their clinical implications.
| Heart Outcomes Prevention Evaluation-3|| |
The role of antihypertensive therapy and statins in lowering cardiovascular risk in patients with high risk is well established. However, their role in intermediate-risk patients (annual rate <1%) without cardiovascular disease is not clear. HOPE-3 was designed to answer these questions. It consisted of over 12,000 patients from 21 countries and 6 continents and spanned over a median period of 5.6 years. The trial had three arms - an antihypertensive regimen (combination plus hydrochlorothiazide), a statin (rosuvastatin), and a combination of the two. In this review, the results from these arms are discussed separately.
Cholesterol lowering in intermediate-risk persons without cardiovascular disease
Yusuf S, Bosch J, Dagenais G, Zhu J, Xavier D, Liu L, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2021-31.
In a 2-by-2 factorial trial, 12,705 participants in 21 countries who did not have cardiovascular disease and were at intermediate risk were randomly assigned to receive 10 mg/day of rosuvastatin or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The second coprimary outcome was revascularization, heart failure, and resuscitated cardiac arrest. The median duration of follow-up was 5.6 years.
A significant reduction in the first coprimary event was seen in the rosuvastatin group (n = 235 [3.7%]) as compared with placebo (n = 304 [4.8%]) group (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.64-0.91; P = 0.002). A significant reduction in the second coprimary event was seen in the rosuvastatin group (n = 277 [4.4%]) as compared with placebo group (n = 363 [5.7%]) (HR 0.75; 95% CI: 0.64-0.88; P < 0.001). Subgroups were defined according to cardiovascular risk at baseline, lipid level, C-reactive protein level, blood pressure, and race or ethnic group. The results were consistent in the subgroups.
In an ethnically diverse population without cardiovascular risk, rosuvastatin 10 mg/day significantly lowers risk of cardiovascular events in intermediate risk subjects.
Blood pressure lowering in intermediate-risk persons without cardiovascular disease
Lonn EM, Bosch J, LÓpez-Jaramillo P, Zhu J, Liu L, Pais P, et al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2009-20.
In a 2-by-2 factorial trial, 12,705 participants were randomly assigned to receive either candesartan (16 mg/day) plus hydrochlorothiazide (12.5 mg/day) or placebo. The participants were at intermediate risk and did not have cardiovascular disease. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The second coprimary outcomes were revascularization, heart failure, and resuscitated cardiac arrest. The median duration of follow-up was 5.6 years.
The mean blood pressure of the participants at baseline was 138.1/81.9 mmHg. A decrement of 6.0/3.0 mmHg was noted in the active treatment group than in the placebo group. The first coprimary event was similar in the active treatment group (n = 260 [4.1%]) than in the placebo (n = 279 [4.4%]) group. The second primary event was also similar between the groups (active group n = 312 [4.9%] vs. placebo n = 328 [5.2%]). In the subgroup for the upper third of systolic blood pressure (>143.5 mmHg), patients who were in the active treatment group had significantly lower rates of the first and second coprimary outcomes than in the placebo group. The effects were neutral in the middle-third and lower-third (P = 0.02 and P = 0.009, respectively, for trend in the two outcomes) subgroups.
In intermediate-risk individuals without cardiovascular disease, therapy with candesartan (16 mg/day) plus hydrochlorothiazide (12.5 mg/day) was not associated with lower rates of major cardiovascular events.
Blood pressure and cholesterol lowering in persons without cardiovascular disease
Yusuf S, Lonn E, Pais P, Bosch J, LÓpez-Jaramillo P, Zhu J, et al. Blood-pressure and cholesterol lowering in persons without cardiovascular disease. N Engl J Med 2016;374:2032-43.
In a 2-by-2 factorial trial, 12,705 participants were randomly assigned to receive rosuvastatin (10 mg/day) or placebo and to candesartan (16 mg/day) plus hydrochlorothiazide (12.5 mg/day) or placebo. The participants were at intermediate risk and did not have cardiovascular disease. The number of participants assigned to the combination therapy (rosuvastatin with candesartan-hydrochlorothiazide; n = 3180) were compared with participants assigned to dual-placebo (n = 3168). The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The second coprimary outcome included heart failure, cardiac arrest, or revascularization. The median follow-up was 5.6 years.
The decrease in low-density lipoprotein (LDL) cholesterol level was 33.7 mg/dl greater and the decrease in systolic blood pressure was 6.2 mmHg greater than in the dual-placebo group. In the combined therapy group a significant lower rates of the first and second coprimary events were observed than in the dual-placebo group (First coprimary event: Combined therapy group [n = 113; 3.6%] vs. dual-placebo [n = 157; 5%] HR 0.71, 95% CI: 0.56-0.90; P = 0.005. Second coprimary event: Combined therapy group [n = 136; 4.3%] vs. dual-placebo [n = 187; 5.9%] HR 0.72, 95% CI: 0.57-0.89, P = 0.003).
In individuals with intermediate risk and without cardiovascular disease, combination of rosuvastatin (10 mg/day) and candesartan-hydrochlorothiazide (16 mg/day plus 12.5 mg/day) was associated with significantly lower rates of cardiovascular events.
Heart outcomes prevention evaluation-3 perspective
The results support a risk-based approach to statin use rather than an approach that is based primarily on LDL cholesterol levels. It emphasizes that even in intermediate-risk individuals without cardiovascular disease, statins reduce cardiovascular events. However, in this population, blood pressure by antihypertensive therapy does not appear to provide any benefit. The possibility of lowering cardiovascular events with better and more powerful regimen has not been ruled out. However, this needs to be weighed by the drug-related adverse events in this low-risk population. An important feature of the HOPE-3 trial was that it encompassed an ethnically diverse population as opposed to the western population in most trials.
| Surgical Treatment for Ischemic Heart Failure Extension Study Trial: Coronary Artery Bypass Surgery in Patients with Ischemic Cardiomyopathy|| |
Velazquez EJ, Lee KL, Jones RH, Al-Khalidi HR, Hill JA, Panza JA, et al. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N Engl J Med 2016;374:1511-20.
STICHES trail was undertaken to study the survival benefit of coronary artery bypass grafting (CABG) added to guideline-directed medical therapy as compared with medical therapy alone in patients with coronary artery disease, heart failure, and severe left ventricular dysfunction. In between July 2002 and May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease were amenable to CABG along with guideline-directed medical therapy (n = 610) or medical therapy alone (n = 612). The primary outcome was death from any cause. Major secondary outcomes were death from cardiovascular causes, death from any cause or hospitalization for cardiovascular cause, death from any cause or hospitalization for heart failure.
A significant survival benefit was observed in primary and secondary outcomes in patients subjected to CABG along with guideline-directed medical therapy (Death from any cause: CABG group n = 359 [58.9%] vs. medical therapy group n = 398 [66.1%], P = 0.02. Death from cardiovascular cause: CABG group n = 247 [40.5%] vs. medical therapy group n = 297 [49.3%], P = 0.006. Death from any cause or hospitalization for cardiovascular cause: CABG group n = 467 [76.6%] vs. medical therapy group n = 524 [87%], P ≤ 0.001. Death from any cause or hospitalization for heart failure: CABG group n = 404 [66.2%] vs. medical therapy group n = 450 [74.8%], P = 0.002). A median survival of 18 months was noted in patients of the CABG group. The number needed to treat to prevent one death due to any cause was fourteen. The number needed to treat to prevent one death due to cardiovascular cause was eleven.
Lack of blinding led to patients and the investigators being aware of the treatment assignments. This could have affected the rates of revascularization procedures.
In patients with ischemic cardiomyopathy, CABG along with guideline-directed medical therapy confers survival benefit as compared with medical therapy alone.
| Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure Trial|| |
McMurray JJ, Krum H, Abraham WT, Dickstein K, KØber LV, Desai AS, et al. Aliskiren, enalapril, or aliskiren and enalapril in heart failure. N Engl J Med 2016;374:1521-32.
The trial compared angiotensin-converting enzyme (ACE) inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction. The trial was funded by NOVARTIS. More than 7000 patients with heart failure New York Heart Association class 2-4 and an left ventricle ejection fraction ≤35% were randomized to one of the three arms: Enalapril (n = 2336) at a dose of 5 or 10 mg once daily, aliskiren (n = 2340) at a dose of 300 mg once daily, and the combination therapy (n = 2340). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure.
After a median follow-up of 36.6 months, cardiovascular death or hospitalization occurred in 770 patients (32.9%) in the combination therapy group and 808 (34.6%) in the enalapril group (HR 0.99, 95% CI: 0.90-1.10). The prespecified requirement of P < 0.01 for noninferiority was not met. In the combination therapy group, a higher risk of hypotensive symptoms (13.8% vs. 11%; P = 0.005), a higher risk of elevated serum creatinine level (4.1% vs. 2.7%; P = 0.009), and an elevated serum potassium level (17.1% vs. 12.5%; P < 0.001) were observed with the enalapril group.
The findings of the trial indicate that renin inhibitor aliskiren is not an effective alternative to ACE inhibitor enalapril in patients of heart failure.
Controversy about this trial
Because of safety concerns in diabetic patients in ALTITUDE and ASTRONAUT trials, BfArM (German Federal Institute for Drugs and devices) wanted to review the unblinded data of the trial. The data monitoring committee refused to do, so fearing the outcome of the trial may be compromised. This was when the Clinical Trial Facilitation Group stepped in and announced that any participant with baseline diabetes is switched immediately to standard therapy and no further diabetics could be enrolled. This action has raised questions regarding the role of regulatory bodies interfering with trials.