Journal of the American Society of Hypertension
Research articleTreatment of elderly hypertensive patients with epithelial sodium channel inhibitors combined with a thiazide diuretic reduces coronary mortality and sudden cardiac death
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(HCTZ) was combined with an epithelial sodium channel (ENaC) inhibitor.7, 8, 9 Included in the overview are previously unpublished data on SCD from two of these trials.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.