The Role of Chlorthalidone in Patients With High‐Risk Hypertension

The Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) investigators ¹ 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 α‐adrenergic receptor–blocking agent doxazosin, independent of its effect on lowering blood pressure (BP). ² 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. ³ 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, ¹ 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 ⁴ 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]). ⁵ It can be argued that HCTZ is not as effective in lowering BP as chlorthalidone. However, the BP reduction with an ACEI + amlodipine in ACCOMPLISH ⁴ was similar to that with an ACEI + HCTZ. If one were to use chlorthalidone and achieve a BP reduction greater than with an ACEI + HCTZ one could increase the dose of the ACEI‐amlodipine combination to achieve a similar reduction in BP. In this instance I would anticipate results similar to that seen in ACCOMPLISH, ⁴ ie, superiority of the ACEI‐amlodipine combination. While chlorthalidone is more effective than HCTZ in lowering BP it shares all of the potential adverse effects of thiazide diuretics such as a reduction in serum potassium with all of its adverse consequences including myocardial fibrosis, an increase in sudden cardiac death, and the development of diabetes mellitus, as recently shown in a reanalysis of the Systolic Hypertension in the Elderly Program (SHEP) trial. ⁶ Thiazide diuretics including chlorthalidone activate the renin‐angiotensin‐aldosterone system and the sympathetic nervous system thereby increasing oxidative stress and decreasing nitric oxide (NO) availability. These neurohumoral mechanisms may be blunted but not eliminated by combining a diuretic with an ACEI. Thiazide diuretics, when added to an ACEI in rats post–myocardial infarction, have been shown to have a detrimental effect on renal function and structure compared with an ACEI alone. ⁷ Thiazide diuretics have also recently been shown to increase the ratio of visceral to subcutaneous fat, ⁸ which has important long‐term implications for vascular and myocardial inflammation and fibrosis, as well as for the development of diabetes mellitus. Thiazide diuretics have not been shown to improve the availability of NO or to improve endothelial function, ⁹ whereas both an ACEI and amlodipine improve NO availability, with the combination being more effective than either alone. ¹⁰ It should also be pointed out that while the prevention of HHF is important, heart failure comprises only a minority of CV events in high‐risk patients with hypertension. While the ACEI‐amlodipine combination did not reduce the incidence of HHF in ACCOMPLISH ⁴ it was as effective as the ACEI‐HCTZ combination. Thus, there is no compelling evidence to support the use of a diuretic or chlorthalidone in particular in combination with an ACEI in contrast to ACEI + amlodipine in high‐risk patients with hypertension, a large percentage of whom will require at least 2 antihypertensive agents. When considering an antihypertensive agent for monotherapy in a patient with low‐risk hypertension, chlorthalidone appears to have an advantage in preventing HHF. One might wish to consider a potassium‐sparing diuretic, however, to avoid the consequences of hypokalemia, including diabetes mellitus, myocardial fibrosis, and sudden cardiac death, which begin to occur at a serum potassium level <4.0 meq/L, ⁸ or to consider a combination of chlorthalidone and a potassium‐sparing diuretic. It should be emphasized that these suggestions are contrary to current guidelines that recommend diuretic therapy with a thiazide as initial therapy in many patients with hypertension and as part of combination therapy in high‐risk patients with HHD. However, until there is contrary evidence, the review of the potential adverse effects of thiazide diuretics, including chlorthalidone, and the results of ACCOMPLISH, ⁴ in my opinion, favor the use of an ACEI or ARB + a dihydropyridine CCB such as amlodipine in high‐risk patients with hypertension who often require more than 1 antihypertensive drug to control BP.