Prevention of heart failure mortality and hospitalizations in SPRINT, EMPA-REG, ALLHAT and HYVET: are diuretics the clue?

What do the recently published SPRINT [1] and EMPA-REG Outcome [2] trials have in common with the ALLHAT [3] and the HYVET [4] trials? All four demonstrated significant clinical benefits in terms of cardiovascular morbidity and mortality of either lowering blood pressure (BP) in high-risk hypertensive patients (ALLHAT, SPRINT) or very elderly patients with hypertension (HYVET) or treating patients with type 2 diabetes with an inhibitor of renal sodium/glucose cotransport (EMP-REG trial). Another common finding of these trials is that all of them reported a very significant reduction in either death or hospitalizations due to heart failure. The third common point maybe the potential role of diuretics or drugs with diuretic properties such as SGLT2 inhibitors in mediating the reduction of heart failure mortality and/or hospitalizations.

In ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), the main objective was to determine whether a calcium channel blocker (CCB) or an angiotensin converting enzyme inhibitor (ACEI) was more effective in preventing coronary heart disease (CHD) than the diuretic chlorthalidone [3]. Despite a slightly but significantly greater reduction in BP with chlorthalidone than with the CCB and the ACEI, there was no difference between treatments in the primary outcome or in all-cause mortality but the risk of heart failure was increased by 38% in the CCB-treated patients and by 19% in the ACEI-treated group when compared to the diuretic-treated group. Overall, the lowest rates of hospitalization and death due to heart failure were observed in the groups receiving a diuretic or an ACE inhibitor, with a greater (albeit not significantly greater) reduction in the diuretic group. Even taking into consideration the limitations of the ALLHAT trial [5], these data suggest that diuretics are very effective in reducing the risk of hospitalizations and death associated with heart failure.

In HYVET (Hypertension in the Very Elderly Trial) [4], the objective was to test the usefulness of treating hypertensive patients older than 80 years for the prevention of stroke. Enrolled patients were randomly assigned to receive either the diuretic indapamide (sustained release, 1.5 mg) or matching placebo. The ACEI perindopril (2 or 4 mg), or matching placebo, was added if necessary to achieve the target BP of  <150/80 mm Hg. The primary end point was fatal or nonfatal stroke. Besides the significant 30% reduction in fatal or nonfatal stroke and 21% decrease in death from any cause, the most striking finding of this trial was the 64% reduction in heart failure, which led to the early interruption of the trial. Although only 25% of patients on active treatment were on indapamide alone at the end of the study, these data once again emphasize the potential clinical benefits of diuretics in preventing heart failure when prescribed alone or in combination with a blocker of the renin-angiotensin system (RAS).

The SPRINT trial (Systolic Blood Pressure Intervention Trial) [1] was designed to assess the most appropriate targets for systolic BP to reduce cardiovascular morbidity and mortality in patients with hypertension and a high risk for cardiovascular events but without diabetes. At enrollment patients had a systolic BP >130 mmHg. They were randomly allocated to a target systolic BP of  <120 mmHg or  <140 mmHg. To achieve these targets physicians could use diuretics, CCBs and RAS blockers. The protocol encouraged the use of drug classes such as thiazide-type diuretics (chlorthalidone was encouraged as the first-line agent), loop diuretics (for participants with chronic kidney disease), and beta-adrenergic blockers (for those with coronary artery disease). In order to reach the predefined targets diuretic therapy might have been withheld to obtain a systolic BP between 120 and 140 mmHg in some patients and intensified in those patients who were allocated to the <120 mmHg target. Thus in the low target group, the prescription of diuretics increased by 24%. In comparison, the prescription of CCB, beta-blockers and RAS blockers increased by 21.5, 10 and 22% respectively. In the latest visit, 76% of patients received a RAS blocker, 67% a diuretic, 57% a CCB and 41% a beta-blocker in the intensive treated group. The results of the trial showed a 25% reduction in death and major cardiovascular events in patients of the intensive-treatment group with no significant impact on stroke, myocardial infarction or acute coronary artery syndrome. Interestingly, however, 50% of primary endpoints were due to incident heart failure. Although the majority of patients included in the intensive-treatment group of the protocol were treated simultaneously with a diuretic and a RAS blocker, one may wonder how determinant was the increase in the intensity of diuretic therapy in reducing the mortality and the heart failure incidence. As observed in HYVET, it appears that diuretics in association with a RAS blocker have a major impact on incident heart failure.

The most recent trial is the EMPA-REG Outcome trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) [2], a study aiming at examining the effects of the SGLT2 inhibitor empagliflozin on cardiovascular morbidity and mortality as compared with placebo, in patients with type 2 diabetes at high risk for cardiovascular events. The primary outcome was a composite of death from cardiovascular causes, non-fatal myocardial infarction (excluding silent myocardial infarction), or non-fatal stroke. This trial demonstrated for the first time a significant reduction in the risk of death from any cause and death from cardiovascular causes (hazard ratio of 0.62 and 0.68 respectively p < 0.001) in patients with type 2 diabetes. However, empagliflozin had no effect on stroke, myocardial infarction or coronary events. The reduction in mortality was independent of the presence or absence of antihypertensive therapy, of the prescription of diuretics or RAS blockers (80% of patients were on a RAS blocker and 42% on a diuretic) and of diabetes control. The reduction in the risk of hospitalization for heart failure was the prominent feature of the study, the majority of cardiovascular events in this trial being due to heart failure.

SGLT2 inhibitors are not considered as classic diuretics but they do have an impact on renal function causing an osmotic diuresis. The decrease in glucose reabsorption in the proximal tubule of the nephron and the resulting persistent glucosuria lead to an increase in urinary volume and probably also in urinary sodium excretion, though this latter has not been formerly demonstrated. In any case, administration of SGLT2 inhibitors was associated with a 4.8 to 5% increase in hematocrit in EMPA-REG suggesting hemoconcentration, and in a decrease in both systolic and diastolic BP. The empagliflozin effects on BP and diuresis and natriuresis may have contributed to the reduction in heart failure hospitalizations via an intensification of diuretic therapy. Other metabolic hypotheses have also been proposed to explain the benefits of SGLT2 inhibitors in heart failure, which need to be tested [6]. At the last meeting of the American College of Cardiology, the results of the CVD-REAL survey were presented. The survey included more than 150,000 patients treated with SGLT2 inhibitors and as many patients not treated with an SGLT2 inhibitor. The results confirmed the major impact of this antidiabetic class on the prevention of heart failure hospitalizations (−39%) and all cause death (−51%). The survey also demonstrated that this is a class effect [7].

These data obtained in various populations with a high risk of incident heart failure suggest that diuretics may play an important role in the prevention of death and hospitalizations due to heart failure. European heart failure guidelines [8] recommend diuretics only to reduce the signs and symptoms of congestion [8]. Yet a Cochrane meta-analysis has shown that in patients with chronic heart failure, loop and thiazide diuretics reduce the risk of death and worsening heart failure compared with placebo. In their last heart failure guidelines, the ESC has introduced the possibility to use empagliflozine in patients with type 2 diabetes “to prevent or delay the onset of heart failure and to prolong life” [8]. Thus, the role of diuretics in preventing heart failure and its complications should probably be reassessed in the light of most recent trials in high cardiovascular risk patients.

Michel Burnier [email protected]University Hospital, Lausanne, Switzerland Krzysztof Narkiewicz Medical University of Gdansk, Poland Sverre E. Kjeldsen University of Oslo, Ullevaal Hospital, Oslo Norway

Disclosure statement

MB, KN and SEK are editors of Blood Pressure and report no relevant conflicts of interest to disclose related to this commentary.