The ALLHAT: Thiazide diuretics as first-line antihypertensive therapy [Classics Series]

Classics Series, Landmark Trials in Medicine

1. There were no significant differences in the rates of fatal coronary heart disease or nonfatal myocardial infarction when comparing thiazide diuretics with ACE-Is or CCBs in hypertension management.

2. Thiazide diuretics are the cheapest option amongst common first-line antihypertensives.

Original Date of Publication: December 18, 2002

Study Rundown: Hypertension is considered a major risk factor for cardiovascular disease and blood pressure control is an international priority. Some studies have estimated that 26.4% of the global population suffered from hypertension in 2000, and this number is expected to increase to 29.2% in 2025, affecting an estimated 1.56 billion people. While antihypertensive medication therapy has been shown to reduce the risk of adverse outcomes in hypertensive patients, there are many antihypertensive agents available and questions remained regarding the best choice for initial therapy. The earliest studies demonstrated benefits associated with using thiazides and beta-blockers (BB), though many new agents were subsequently introduced into practice, including angiotensin-converting enzyme inhibitors (ACE-Is) and calcium channel blockers (CCBs).

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, controlled trial published in 2002. The main trial focused specifically on high-risk patients – it sought to determine whether there were significant differences in rates of cardiovascular events when using different first-line antihypertensive agents, such as ACE-Is (i.e., lisinopril), CCBs (i.e., amlodipine), alpha-blockers (i.e., doxazosin), and thiazides (i.e., chlorthalidone). The alpha-blocker arm was terminated early, as chlorthalidone was found to be superior to doxazosin. In summary, there were no significant differences in the rates of fatal coronary heart disease (CHD) or nonfatal myocardial infarction when comparing chlorthalidone with amlodipine (RR 0.98; 95%CI 0.90-1.07) or lisinopril (RR 0.99; 95%CI 0.91-1.08) for hypertension management. Because thiazide diuretics are cheaper than other options, it was recommended that they be considered first-line therapy for hypertension based on the findings of this study.

Click to read the study in JAMA

In-Depth [randomized, controlled study]: The study involved 33,357 participants and had a mean follow-up of 4.9 years. Patients were eligible for the study if they were ≥55 years of age and had stage 1 or 2 hypertension with ≥1 additional risk factor (i.e., previous myocardial infarction, stroke, left ventricular hypertrophy, type 2 diabetes, current cigarette smoking, low high-density lipoprotein). Exclusion criteria were history of heart failure and/or left ventricular ejection fraction <35%. The primary outcome was fatal CHD or nonfatal myocardial infarction, while the secondary outcomes were all-cause mortality, fatal/nonfatal stroke, combined CHD, and combined cardiovascular disease. Chlorthalidone was found to be superior to doxazosin, and the alpha-blocker arm was terminated early.

In the comparison between amlodipine and chlorthalidone, there were no significant differences in the primary (RR 0.98; 95%CI 0.90-1.07) or secondary outcomes. Amlodipine, however, was associated with a significantly higher risk of heart failure, particularly hospitalized/fatal heart failure (p<0.001). The comparison between lisinopril and chlorthalidone again demonstrated no significant differences in the primary (RR 0.99; 95%CI 0.91-1.08) or secondary outcomes; but, lisinopril use was associated with significantly elevated risk of stroke, combined cardiovascular disease, heart failure, hospitalized/treated angina, and coronary revascularization. Moreover, participants in the lisinopril group had significantly higher follow-up systolic blood pressure.

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