ALLHAT trial

Initial therapy choices for hypertension in diabetes mellitus usually include angiotensin-converting enzyme inhibitors or an angiotensin receptor blocker due to their well documented renoprotective effects. Currently, angiotensin receptor blockers have less robust data to support cardiovascular reduction compared to other therapeutic choices, yet the data that exists appears to be positive in patients with type 2 DM. Also, diuretics have shown superior results to an ACE inhibitor in the ALLHAT trial. The ADA currently recommends the use of any class (ACE inhibitors, angiotensin receptor blockers, /3-blockers, diuretics, or calcium channel blockers) of antihypertensive medication that has shown benefit in prevention of poor cardiovascular outcomes. Choice of monotherapy may not be important, as an average of two to three antihypertensive medications are needed to reach blood pressure goals. 

Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002 288(23) =2981-2997. 

Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group. )AMA 2000 283 1967-1975. 

In high-risk individuals and groups people with clinical evidence of macrovascular disease other than CHD, the Heart Protection Study (HPS) (II) with diabetes, the HPS and Collaborative Atorvastatin Diabetes Study (CARDS) (12) the elderly, Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) (13) or with hypertension, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (14) and Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) (15). 

In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), over 40 000 participants aged 55 years or older with hypertension and at least one other risk factor for coronary heart disease were randomized to chlortalidone, amlodipine, doxazosin, or lisinopril (1,2). Doxazosin was discontinued prematurely because chlortalidone was clearly superior in preventing cardiovascular events, particularly heart failure (2). Otherwise, mean follow-up was 4.9 years. There were no differences between chlortalidone, amlodipine, and lisinopril in the primary combined outcome or allcause mortality. Compared with chlortalidone, heart failure was more common with amlodipine and lisinopril, and chlortalidone was better than lisinopril at preventing stroke. 

Elevated SBP has been shown to be associated with an increased risk of stroke, CHF, myocardial infarction and death [140,141]. The authors of the ALLHAT study suggested that a 3 mm Hg increase in SBP could explain a 10 % to 20% increase in the incidence of CHF [142]. In a meta-analysis of 15, 693 older patients with isolated systolic hypertension from 8 trials, a 10 mmHg higher initial SBP was associated with relative hazard rates of 1.26 (p=0.001) for total mortality, 1.22 (p=0.007) for cardiovascular mortality, and 1.22 (p=0.02) for stroke [143]. The recent meta-analysis by Aw et al [66A] involving 45451 patients found that rofecoxib was associated with a higher risk of developing hypertension compared to celecoxib. 

The results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was the deciding evidence that the JNC7 used to justify thiazide diuretics as first-line therapy." It was designed to test the hypothesis that newer antihypertensive agents (an a-blocker, ACE inhibitor, and dihydropyridine CCB) would be superior to thiazide diuretic therapy. The primary objective was to compare the combined end point of fatal coronary heart disease and nonfatal myocardial infarction. Other hypertension-related complications (e.g., heart failure and stroke) were evaluated as secondary end points. This was the largest hypertension trial ever conducted and included 42,418 patients aged 55 years and older with hypertension and one additional cardiovascular risk factor. This prospective, double-blind trial randomized patients to chlorthalidone (a thiazide diuretic), amlodipine (dihydropyridine CCB), doxazosin (a-blocker), or lisinopril (ACE inhibitor) for a mean follow-up of 4.9 years. 

ACE inhibitors are considered second-line therapy to diuretics in most patients with hypertension. The ALLHAT demonstrated less heart failure and stroke with chlorthalidone versus lisinopril. This difference in stroke is consistent with another outcomes trial, the Captopril Prevention Project (CAPPP). However, other outcome studies have demonstrated similar, if not better, outcomes with ACE inhibitors versus thiazide diuretics." " In the elderly, one study found that they were at least as effective when compared with diuretics and P-blockers, and another study found that they were more effective." In addition, ACE inhibitors have many roles for patients with hypertension and coexisting conditions. Nonetheless, most clinicians will agree that if ACE inhibitors are not first-line therapy in most patients with hypertension, they are a very close second to diuretics. 

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