Operational aspects of terminating the doxazosin arm of The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized, practice-based trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI). The double-blind, active-controlled component of ALLHAT was designed to determine whether the rate of the primary outcome-a composite of fatal coronary heart disease and nonfatal myocardial infarction-differs between diuretic (chlorthalidone) treatment and each of three other classes of antihypertensive drugs: a calcium antagonist (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin) in high-risk hypertensive persons ages 55 years and older. In addition, 10,377 ALLHAT participants with mild to moderate hypercholesterolemia were also enrolled in a randomized, open-label trial designed to determine whether lowering serum LDL cholesterol with an HMG CoA reductase inhibitor (pravastatin) will reduce all-cause mortality as compared to a control group receiving "usual care." In January 2000, an independent data review committee recommended discontinuing the doxazosin treatment arm. The NHLBI director promptly accepted the recommendation. This article discusses the steps involved in the orderly closeout of one arm of ALLHAT and the dissemination of trial results. These steps included provisional preparations; the actual decision process; establishing a timetable; forming a transition committee; preparing materials and instructions; informing 65 trial officers and coordinators, 628 active clinics and satellite locations, 313 institutional review boards, over 42,000 patients, and the general public; reporting detailed trial results; and monitoring the closeout process. Control Clin Trials 2001;22:29-41

Exploring the minimal dose of amiodarone with antiarrhythmic and hemodynamic activity.

Amiodarone in doses of 200 to 400 mg/day has shown promise in secondary prevention trials for reducing mortality in patients surviving myocardial infarction who have complex ventricular ectopy or nonsustained ventricular tachycardia, or both. In an attempt to explore the lowest dose of amiodarone with antiarrhythmic and hemodynamic activity, we studied 48 patients (mean age 53 +/- 11 years, ejection fraction 23 +/- 9%, clinical heart failure in 85%) with nonsustained ventricular tachycardia. This was a 3-month, randomized, parallel, double-blind pilot study comparing placebo (n = 16) with amiodarone 50 mg/day (n = 15) and 100 mg/day (n = 17). Patients randomized to amiodarone received a mean loading dose of 422 mg/day for the first study week. At the end of the 12 weeks, amiodarone (100 mg) significantly reduced ventricular premature complexes (177 +/- 64 to 98 +/- 38/hour), couplets (8 +/- 3 to 4 +/- 2/hour), and runs of nonsustained ventricular tachycardia (13 +/- 7 to 3 +/- 2/day), all p < 0.01 versus baseline. In addition, 10 of 14 patients taking 100 mg/day had total suppression of nonsustained ventricular tachycardia compared with 4 of 15 taking placebo, p = 0.021. Left ventricular ejection fraction improved by > or = 7% (absolute) in 11 of 29 patients taking amiodarone as compared with only 1 of 15 placebo patients (p = 0.02). In these 11 patients with the greatest measurable hemodynamic improvement, amiodarone significantly increased ejection fraction (21 +/- 7% to 33 +/- 11%, p < 0.01), stroke volume index (28 +/- 9 to 40 +/- 7 ml/m2, p < 0.01) and decreased end-systolic volume index (116 +/- 48 to 92 +/- 44 ml/m2, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous fenoldopam in heart failure: comparing the hemodynamic effects of dopamine1 receptor agonism with nitroprusside.

Dopamine1 receptors mediate hemodynamic effects that may be beneficial in patients with congestive heart failure. We infused the selective dopamine1 receptor agonist, fenoldopam mesylate (SKF 82526 J), to evaluate hemodynamic and neurohumoral changes during continuous intravenous infusion in patients with congestive heart failure and compared them with the effects of nitroprusside, a traditional vasodilator that works by a distinctly different mechanism. In 15 patients with a mean radionuclide ejection fraction of 17%, the agents were infused in a random-ordered, double-blinded, crossover, active drug-controlled protocol after optimal dosing was determined during a titration period. Hemodynamic changes were induced in minutes with both drugs during a mean (+/- standard deviation) infusion dose of 1.45 +/- 1.66 micrograms/kg/min for fenoldopam and 2.99 +/- 1.59 micrograms/kg/min for nitroprusside. At 1 hour, mean blood pressure decreased and cardiac index rose with both drugs, and the effect lasted throughout the 6-hour infusion period. Nitroprusside, but not fenoldopam, reduced right heart filling pressures (including mean pulmonary capillary wedge, mean right atrial, and mean pulmonary artery pressures) during the infusion period. Both drugs caused significant reduction in systemic vascular and pulmonary arteriolar resistances. No significant change occurred in plasma norepinephrine levels. Fenoldopam ameliorates some of the adverse hemodynamic changes that occur during heart failure but does not reduce right heart filling pressures as does nitroprusside. Because of fenoldopam's unique characteristics, it may benefit certain patients with heart failure.