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Clin. Cardiol. 23, 457-458 (2000)
OPTIME-CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure)
Presenter: Mihai Gheorghiade, M.D., at the American College of Cardiology 49th Scientific Session, Anaheim, California.
Background: The inotropic agent milrinone has a short-term beneficial effect on hemodynamics. Its effect on in-hospital outcomes, however, is unclear.
Purpose and patient population: The purpose of this trial was to determine the effect of intravenous milrinone added to best medical therapy on hospitalization days for cardiovascular events in the intermediate term (60-day) among patients admitted with acute exacerbations of chronic heart failure (CHF) (but not requiring pressor or intotropic support). Patients admitted were >18 years (mean age 65) with ejection fractions <40% (mean 23%). All patients were normotensive, with a mean systolic pressure of approximately 120 mmHg.
Methodology: OPTIME-CHF, a prospective, double-blind placebo-controlled trial, randomized a total of 951 patients in 78 U.S. centers to 48 h of intravenous milrinone (n = 477) 0.5 mcg/kg/min without a bolus dose, or to placebo (n = 472), within 48 h of admission. Patients were followed for 60 days. The primary endpoint was rehospitalization for cardiovascular events within 60 days.
Results: For the primary endpoint, there was no significant difference between milrinone and placebo (12.3 days vs. 12.5 for placebo). The secondary endpoint of proportion of patients achieving target angiotensin-converting enzyme (ACE) inhibitor dose at 48 h and at discharge was similar in the two groups (40.5 and 43%, respectively, for the ACE inhibitor group; 35.8 and 40.9%, respectively, in the placebo group).
Complications, however, were higher with milrinone (12.6 vs. 2.1%, p<0.001), and were attributed to higher rates of treatment-related atrial fibrillation (4.6 vs. 1.5%, p = 0.004) and sustained hypotension (10.7 vs. 3.2%, p<0.001). Mortality rates were similar in the two groups.
Conclusion: Patients admitted for acute exacerbations of chronic CHF not requiring inotropic support do not derive any additional benefit from milrinone therapy.
BARI (Bypass Angioplasty Revascularization Investigation) Seven-Year Outcome by Treatment and Diabetes Status
Presenter: Katherine M. Detre, M.D., at the American College of Cardiology 49th Scientific Session, Anaheim, California.
Background: BARI compared coronary artery bypass graft (CABG) surgery and percutaneous transluminal coronary angioplasty (PTCA) in patients with multivessel coronary artery disease. Results reported at 5 years showed no significant mortality differences, but did show higher in-hospital Q-wave myocardial infarction (MI) in the CABG group and higher repeat revascularization rates in the PTCA group. For diabetics, however, 5-year survival was significantly improved in the CABG group, especially in those receiving an internal mammary graft.
Study population: Patients (n = 1,892) with angiographically documented multivessel coronary artery disease, clinically severe angina, or evidence of ischemia requiring revascularization were enrolled. Patients had to be eligible for either procedure.
Results (7-year): Statistically significant survival differences favoring CABG have emerged (84.4 for CABG vs. 80.9% for PTCA, p = 0.043). The difference, however, is attributable to the better survival with CABG among diabetic patients. For nondiabetic patients, survival was comparable at 86.4% for CABG and 86.8% for PTCA. Among diabetics, survival was 76.4% for CABG and 55.7% for PTCA (p = 0.0011). Outcomes were worse for insulin-treated diabetics in both groups.
Conclusion: Nondiabetic patients with symptomatic multivessel coronary artery disease treated with PTCA or CABG have similar 7-year survival. Diabetic patients in this group treated with CABG have better survival.
Comment: BARI II, a trial designed to evaluate whether aggressive treatment of diabetes and lipids along with early revascularization will result in better outcomes, is underway. BARI II will randomize patients to revascularization or medical therapy, with further randomization in each arm to glycemic control with either insulin or insulin-sensitizing drugs.
PRAISE-2 (Prospective Randomized Amlodipine Survival Evaluation)
Presenter: Milton Packer, M.D., at the American College of Cardiology 49th Scientific Session, Anaheim, California.
Background: PRAISE-1 showed a striking 31% significant (p = 0.04) risk reduction in the primary endpoint of all-cause mortality or cardiovascular morbidity for amlodipine in the subgroup of patients with nonischemic cardiomyopathy. The secondary endpoint of all-cause mortality was reduced by 46% compared with placebo (p<0.001) in this subgroup.
Purpose: Because the nonischemic subgroup was small (n = 119), and no plausible mechanism of benefit could be put forward, PRAISE-2 was launched to evaluate the effects of amlodipine in a larger cohort of patients with nonischemic cardiomyopathy.
Patient population: PRAISE-2 included patients with chronic heart failure (left ventricular ejection fraction <30%) attributed to nonischemic cardiomyopathy and New York Heart Association class IIIB or IV symptoms despite therapy with diuretics, digoxin, and ACE inhibitors. Mean age was nearly 60 years.
Study design: PRAISE-2 duplicated PRAISE-1 design, with patients (n = 1,652) randomized to amlodipine, first receiving 5 mg daily, then 10 mg daily after 2 weeks.
Results: All-cause mortality was similar in the two arms at 31.7% for placebo and 33.7% for amlodipine. A stratified analysis including patients from both PRAISE trials also showed no benefit for amlodipine.
Conclusion: PRAISE-2 results do not confirm the survival benefit for amlodipine in nonischemic cardiomyopathy patients that was seen in PRAISE-1.
Comment (Milton Packer, M.D.): The failure to show benefit in PRAISE and other recent heart failure drug trials shows that more rigorous standards need to be met before findings of a single trial can be considered substantial enough to warrant a change in clinical practice.
Dr. Packer proposed: "...results of a single trial are most likely to represent a true treatment effect if (1) they reflect a primary hypothesis, (2) they have a very small p value of ¾0.01, (3) they are associated with narrow confidence intervals, and most important, (4) they are concordant with other results."
ACUTE 1 (Assessment of Cardioversion Using Transesophageal Echocardiography [TEE]) Multicenter Study: Clinical Outcomes at Eight Weeks
Presenter: Allan Klein, M.D., at the American College of Cardiology 49th Scientific Session, Anaheim, California.
Background: The anticoagulation regimen used in conventional therapy for atrial fibrillation (AF) increases bleeding risk and requires inconvenient and expensive repeat visits for monitoring of INR. It entails anticoagulation treatment 3 weeks prior to and 4 weeks subsequent to cardioversion. It was thought that use of TEE to screen patients for pre-existing thrombi would allow a reduced period of anticoagulation, and lower embolic events and bleeding complications.
Objective: The trial was undertaken for prospective comparison of short-term anticoagulation using TEE-guided echocardiography versus conventional AF therapy.
Study population: Population consisted of patients >18 years of age eligible for cardioversion with >48 h AF or atrial flutter with documented history of AF.
Study design: Patients were randomized to conventional therapy or TEE, and received immediate anticoagulation with heparin or warfarin. If no left atrial thrombus was detected, cardioversion ensued with anticoagulation being continued for 4 weeks. The primary endpoints of stroke, transient ischemic attacks (TIA), or peripheral embolism were evaluated at 8 weeks.
Procedural characteristics: Because of scant funding for the study, the trial was stopped after 1,222 of the intended 2,900 patients were enrolled, with 619 randomized to TEE. Of 551 patients ultimately receiving TEE, cardioversion was not performed in 124 for various reasons, including thrombi (79 patients) and spontaneous conversion (31 patients). Among the 427 patients undergoing both TEE and cardioversion, cardioversion was successful in 344 (80.1%). In the conventional group (n = 603), cardioversion was not carried out in 236 patients, with successful cardioversion in 293 of 367 patients (79.8%). The difference was not significant.
Results: The primary endpoint occurred similarly in the two arms, at a rate of 0.81% for TEE and 0.5% for conventional therapy. All events consisted of either stroke or TIA. There was, however, a trend toward more major (1.5% conventional, 0.81% TEE) and minor (4 vs. 2.3%) bleeding events in the conventional therapy arm, with the combined bleeding events significantly more common for conventional therapy (5.5 vs. 3.1%). While cardiac mortality was similar for the two groups, there was a strong trend toward higher all-cause mortality for TEE (2.42 vs. 1%).
Conclusion: A TEE-guided strategy with shorter anticoagulation does not appear to lower embolic events over an 8-week study period, but tends to decrease major and minor bleeding complications.