The Role of Chlorthalidone in Patients With High‐Risk Hypertension

Abstract

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) investigators found that patients with essential hypertension and one additional risk factor for coronary artery disease events when randomized to the thiazide diuretic chlorthalidone had a significant reduction in the incidence of hospitalization for heart failure (HHF) compared with those randomized to the angiotensin-converting enzyme inhibitor (ACEI) lisinopril, the dihydropyridine calcium channel blocker (CCB) amlodipine, or the a-adrenergic receptor– blocking agent doxazosin, independent of its effect on lowering blood pressure (BP). In this issue of the Journal, the authors present evidence refuting the criticism that differences in therapy prior to randomization may have influenced the results. The finding that chlorthalidone was more effective than the other randomized strategies in preventing HHF has important implications since HHF is associated with an increased risk of subsequent mortality and has important health cost implications since HHF is the most frequent and expensive cause of hospitalization in patients older than 65 years. The finding that chlorthalidone was more effective than the other strategies in preventing HHF is plausible since high-risk patients with hypertension often develop myocardial fibrosis and hypertrophy resulting in diastolic dysfunction and a decrease in ventricular compliance such that a relatively small increase in dietary sodium intake and ⁄or a decrease in renal function with a resultant increase in sodium retention and an increase in plasma volume could lead to a marked increase in left ventricular end-diastolic pressure with resultant pulmonary congestion and peripheral edema. An increase in sodium excretion and decrease in plasma volume associated with diuretic use might prevent this sequence of events better than with the other recommended strategies. It is important to ask, however, how these results should influence the treatment of patients with high-risk hypertension. While chlorthalidone has been shown to be effective in reducing HHF in ALLHAT, a large percentage of high-risk patients with hypertension will require >1 antihypertensive agent (40.7% of patients in ALLHAT randomized to chlorthalidone were taking >1 antihypertensive agent at 5 years). If one considers that at least 2 drugs are necessary to control BP in many high-risk patients with hypertension, should 1 be a diuretic such as chlorthalidone? The recent Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial showed that the combination of an ACEI + amlodipine was more effective in reducing cardiovascular (CV) events including CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina pectoris, and need for coronary revascularization but not HHF in high-risk patients with hypertension compared with an ACE-I+ the thiazide diuretic hydrochlorothiazide (HCTZ) at equal BP reduction (confirmed in a subset by ambulatory BP monitoring [ABPM]). It can From the University of Michigan School of Medicine – Cardiology, Ann Arbor, MI Address for correspondence: Bertram Pitt, MD, University of Michigan School of Medicine – Cardiology, 1500 East Medical Center Drive, Ann Arbor, MI 48104 E-mail: bpitt@umich.edu