Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
JAMA 2002;288:2981-2997
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
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
ALLHAT
JAMA 2002;288:2981-2997
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)
* Discontinued prior to study completion
Chlorthalidone vs Amlodipine
Primary Endpoint
RR = 0.98
p = 0.65
ALLHAT: Primary Endpoint*
Chlorthalidone
JAMA 2002;288:2981-2997
Amlodipine
* Primary Endpoint = Fatal CHD or nonfatal MI
Chlorthalidone vs Lisinopril
Primary Endpoint
RR = 0.99
p = 0.81
Chlorthalidone
Lisinopril
All Cause Mortality
RR = 0.96
p = 0.20
ALLHAT: Secondary Endpoints
Chlorthalidone
JAMA 2002;288:2981-2997
Amlodipine
Heart Failure
RR = 1.38
p < 0.001
Chlorthalidone
Amlodipine
Chlorthalidone vs Amlodipine
All Cause Mortality
RR = 1.00
p = 0.90
ALLHAT: Secondary Endpoints
Chlorthalidone
JAMA 2002;288:2981-2997
Lisinopril
Heart Failure
RR = 1.19
p < 0.001
Chlorthalidone vs Lisinopril
Chlorthalidone
Lisinopril
Chlorthalidone
Lisinopril
Stroke
RR = 1.15
p = 0.02
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
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