Elsevier

Journal of the American Society of Hypertension

Volume 2, Issue 5, September–October 2008, Pages 355-365.e2
Journal of the American Society of Hypertension

Research article
Treatment of elderly hypertensive patients with epithelial sodium channel inhibitors combined with a thiazide diuretic reduces coronary mortality and sudden cardiac death

https://doi.org/10.1016/j.jash.2008.04.001Get rights and content

Abstract

No reduction in either coronary mortality or sudden cardiac death (SCD) has been demonstrated in overviews of randomized trials of treatment of hypertension with diuretics. An overview was conducted of coronary mortality and SCD in randomized controlled antihypertensive trials in which an epithelial sodium channel (ENaC) inhibitor/hydrochlorothiazide (HCTZ) combination was used. Secondarily, an analogous overview in which thiazide diuretic was used alone was performed. Randomized trials that used an ENaC inhibitor/HCTZ combination (or, alternatively, thiazide diuretic alone) were identified from previous meta-analyses, searches of PubMed, search of the Cochrane Clinical Trials database, and review of publications that addressed the consequences of treating hypertension. Trials in which participants were randomized to either an ENaC inhibitor combined with a thiazide diuretic (or to a thiazide diuretic alone) or to control treatment for at least 1 year and in which coronary mortality was reported were included. Numbers of events in individual trials were abstracted independently by two authors. Significant reductions in both coronary mortality and SCD were observed in the overview of trials in which elderly patients received an ENaC inhibitor/HCTZ combination. The odds ratio (OR) for coronary mortality was 0.59 (95% confidence interval [CI], 0.44 to 0.78) and for SCD was 0.60 (95% CI, 0.38 to 0.94). In contrast, an overview of the trials using thiazide diuretics alone showed no significant reductions of either coronary mortality (OR, 0.94; 95% CI, 0.81 to 1.09) or SCD (OR, 1.27; 95% CI, 0.93 to 1.75). Use of an ENaC inhibitor combined with HCTZ for treatment of hypertension in the elderly results in favorable effects on coronary mortality and SCD.

Introduction

Diuretic drugs are central to the treatment of hypertension. It is, therefore, appropriate to consider ways in which their benefit can be optimized. Placebo-controlled trials have demonstrated that diuretics are highly efficacious in reducing cerebrovascular accidents and yield a smaller but significant reduction in nonfatal myocardial infarction. However, no significant reduction in coronary deaths has been demonstrated even when the data from all of these trials have been combined by meta-analysis.1

Sudden cardiac death (SCD) constitutes a major subset of coronary deaths in hypertensive patients, and the wasting of potassium induced by diuretics has focused attention on SCD during diuretic therapy. Two case-controlled observational studies have provided evidence that the use of potassium-sparing agents in combination with thiazide diuretics was associated with a reduction in primary cardiac arrest.2, 3 Moreover, potassium wasting enhances the development of experimental ischemic ventricular fibrillation.4, 5, 6 The concerted evidence suggesting that SCD could be an adverse effect of thiazides led us to conduct an overview of coronary mortality and SCD in randomized controlled trials in which hydrochlorothiazide (HCTZ) was combined with an epithelial sodium channel (ENaC) inhibitor.7, 8, 9 Included in the overview are previously unpublished data on SCD from two of these trials.

As a secondary objective, these same endpoints were assessed in an overview of 16 trials that employed a thiazide without mandated use of a potassium-sparing drug.

Section snippets

Selection of the Trials

Randomized controlled clinical trials of diuretic-based antihypertensive treatment that evaluated coronary mortality were sought from the previous and repeated meta-analyses dating back to 1990 that had identified these outcome trials,1, 10, 11, 12, 13 from searches of PubMed from 1985, from the Cochrane Central Register of Controlled Trials (2006, issue 2), and from review of publications addressing the consequences of treating hypertension. Randomized trials that compared treatment of at

Coronary Mortality in Trials Mandating ENaC Inhibitor-HCTZ Combination Therapy

In the three trials employing an ENaC inhibitor together with HCTZ (Table 1), a total of 249 coronary deaths were reported. In the meta-analysis of these trials conducted in elderly patients, a substantial and significant reduction in coronary mortality was observed in the groups receiving the diuretic combination (Figure 1). The OR for coronary mortality in the actively treated group compared to controls is 0.59 (95% CI, 0.44 to 0.78).

SCD in Trials Mandating ENaC Inhibitor-HCTZ Combination Therapy

SCD had been reported as an endpoint in the STOP-HTN Trial,

Discussion

Treatment of elderly hypertensive patients with an ENaC inhibitor combined with HCTZ reduces coronary mortality significantly and substantially. In addition, a parallel and significant reduction in SCD by an ENaC inhibitor/HCTZ combination is demonstrated by meta-analysis. SCD is a major cause of mortality in treated hypertensive patients, constituting 42% of the coronary deaths in the placebo groups of the trials addressed in this report. Accordingly, a therapeutic strategy targeted at its

Conclusion

In conclusion, evidence from controlled clinical trials in concert with observational studies supports the use of an ENaC inhibitor/HCTZ combination as the initial diuretic intervention to reduce sudden coronary death and coronary mortality in elderly hypertensive patients.

Acknowledgments

The authors are indebted to the investigators of the trials that constitute these analyses, to Thomas W. Meade and Valerie McCormack for providing the data from the MRC-Older Adults Trial, and to William D. Dupont for valuable advice.

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  • This work was supported, in part, by a grant from the National Institute of General Medical Sciences (GM 15431). Dr. Oates is the Thomas F. Frist, Sr. Professor of Medicine and is a consultant for Merck. Supplemental Material is available at www.ashjournal.com.

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