Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

1. ALLHAT Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial JAMA 2002;288:2981-2997

2. ALLHAT • 42,418 patients with hypertension • SBP >140mmHg and/or DBP >90 mmHg OR • Took medication for hypertension and had at least one additional risk factor for CHD • Age >55 years • NHLBI funded trial Calcium Channel Blocker Amlodipine 2.5-10 mg/day (n=9,048) ACE Inhibitor Lisinopril 10-40 mg/day (n=9,054) Alpha Blocker Doxazosin* 2-8 mg/day (n=9,061) Diuretic Chlorthalidone 12-25 mg/day (n=15,255) • Endpoints: • Primary – Fatal coronary heart disease and nonfatal MI • Secondary – All-cause mortality, stroke, and major cardiovascular disease events (CHF, coronary revascularization, angina, and peripheral artery disease) • Mean follow-up 4.9 years JAMA 2002;288:2981-2997 * Discontinued prior to study completion

3. ALLHAT: Primary Endpoint* Chlorthalidone vs Lisinopril Primary Endpoint RR = 0.99 p = 0.81 Chlorthalidone vs Amlodipine Primary Endpoint RR = 0.98 p = 0.65 Lisinopril Chlorthalidone Chlorthalidone Amlodipine JAMA 2002;288:2981-2997 * Primary Endpoint = Fatal CHD or nonfatal MI

4. ALLHAT: Secondary Endpoints Chlorthalidone vs Amlodipine All Cause Mortality RR = 0.96 p = 0.20 Heart Failure RR = 1.38 p < 0.001 Amlodipine Chlorthalidone Chlorthalidone Amlodipine JAMA 2002;288:2981-2997

5. ALLHAT: Secondary Endpoints Chlorthalidone vs Lisinopril All Cause Mortality RR = 1.00 p = 0.90 Stroke RR = 1.15 p = 0.02 Heart Failure RR = 1.19 p < 0.001 Chlorthalidone Lisinopril Chlorthalidone Chlorthalidone Lisinopril Lisinopril JAMA 2002;288:2981-2997

6. ALLHAT: Summary Prespecified primary endpoint of fatal CHD or nonfatal MI did not differ between initial use of the diuretic chlorthalidone vs initial use of the ACE inhibitor lisinopril or the calcium antagonist amlodipine for the treatment of hypertension • Secondary outcome of heart failure was lower among patients treated with chlorthalidone vs lisinopril or amlodipine • Each of the 3 drugs reduced blood pressure from baseline, although chlorthalidone use was associated with larger SBP reductions vs lisinopril or amlodipine • Increased risk of heart failure in lisinopril arm unexpected and in contrast to the benefits of ACE inhibitors observed in other trials for the treatment of heart failure such as SOLVD

7. ALLHAT: Limitations Diabetic risk • Important side effect in the chlorthalidone arm was higher fasting glucose levels vs lisinopril or amlodipine arms in all patients and in non-diabetics • Impact of chlorthalidone on diabetes and cardiovascular disease may not be fully manifested in the relatively short follow-up period of 4 years • ACE inhibitors have previously been associated with a reduction in the development of diabetes and the progression of diabetic nephropathy Add-on therapy • ACE inhibitor arm potentially at a disadvantage since the first add-on therapy specified by the trial treatment algorithm for this arm was a beta-blocker rather than a diuretic or calcium channel blocker, both of which are more commonly used in clinical practice Large crossover rate by 4 year follow-up