Clinical Trial Commentary ALLHAT Dr Eric Topol Chairman

Clinical Trial Commentary ALLHAT Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

ALLHAT The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial Eligibility - Men and women > 55 years with systolic BP > 140 mm. Hg and/or diastolic BP > 90 mm Hg, or medicated for hypertension - at least one additional risk factor for coronary heart disease (CHD) Risk factors for CHD -myocardial infarction, stroke, left ventricular hypertrophy by ECG or echo, type II diabetes, smoking, low HDL

ALLHAT Patients 42 448 participants recruited from 625 centers Patients were randomized to the following antihypertensive treatments (relative number of patients per group in parentheses). chlorthalidone (1. 7) lisinopril (1) amlodipine (1) doxazosin (1) A substudy looks at lipid-lowering using pravastatin. Treatment goal BP systolic < 140 and diastolic < 90 mm Hg

ALLHAT Primary endpoint composite fatal CHD and nonfatal MI Secondary endpoints (1) all-cause mortality (2) combined CHD (death, nonfatal MI, revascularization, hospitalization for angina) (3) stroke (4) combined CVD The doxazosin arm was discontinued in January 2000 based on the recommendations of an independent review committee. For the remaining treatment arms, follow-up is scheduled to end in March 2002.

ALLHAT doxazosin vs chlorthalidone Outcomes for blood pressure control Year of study chlorthalidone doxazosin Baseline 145/83 145/84 1 137/79 140/79 2 136/78 138/78 4 135/76 137/76 Mean blood pressure, seated ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. JAMA 2000; 283: 1967 -1975

ALLHAT doxazosin vs chlorthalidone Outcomes for primary and secondary endpoints Relative risk (RR) for doxazosin shown Endpoint CHD RR 1. 03 95% CI (0. 9 - 1. 17) p value 0. 71 all-cause mortality 1. 03 (0. 9 - 1. 15) 0. 56 Combined CVD 1. 25 (1. 17 -1. 33) <0. 0001 CHF 2. 04 (1. 79 -2. 32) <0. 0001 Non-CHF events 1. 13 (1. 06 -1. 21) <0. 001 Stroke 1. 19 (1. 01 -1. 40) 0. 04 ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. JAMA 2000; 283: 1967 -1975

ALLHAT Study outcome Compared with doxazosin, chlorthalidone reduces the risk for combined CVD events, particularly CHF, in high-risk hypertensive patients. The study did not have a placebo arm, so the effect of doxazosin compared to no treatment cannot be determined. The use of blood pressure as a surrogate marker in the treatment of hypertension, without regard for the antihypertensive drug used, is called into question.

ALLHAT “To me the take home message to the practitioner is that if you have a patient on an alpha-blocker alone or doxazosin alone in particular, and there's an alternative, and it hasn't been a complicated step to get where you are in the antihypertensive regimen, then switch to the other alternative. ” Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

ALLHAT “So it's ironic too that here is a men's health drug, to improve quality of life for patients with large prostates, and coming out the same week as the Women's Health Initiative for estrogen replacement. You wonder all kinds of things that are in the pharmacologic environment that because they haven't been adequately tested when they get to large scale trials you start to learn about the truth. ” Dr Eric Topol Chairman and Professor Department of Cardiology Cleveland Clinic

Demographics in cardiology The average American now be expected to live until age 76. 4 (80 years for females, 73 years for males). In 1995, 737 000 deaths were secondary to heart disease (HD). 615 000 or 84% of these deaths occurred in people 65 years or older. The population is projected to increase 43. 4% and deaths attributable to HD are projected to increase by 112. 7% over the next 50 years. Foot DK, et al. J Am Coll Cardiol 2000; 35: 10667 -1081