Diuretics and CV prevention: not all that glitters is gold.

The reader surfing PubMed by using the key word “diuretics” in combination with “hypertension” and/or “outcomes” might be surprised by the very large number of recent papers (mainly editorials or comprehensive reviews) re-considering the problem of the efficacy profile of these old drugs. The very last trigger has been the publication of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. . The purpose of this trial was to determine whether in patients with type 2 diabetes and high risk profile the achievement of SBP values <120 mm Hg produced a better outcome when compared to SBP <140 mm Hg. The study enrolled 4733 patients and the mean follow-up time was 4.7 years. The difference in BP reduction between groups was 14.2⁄6.1 mm Hg for SBP and DBP respectively. Based on the results of the available meta-analyses, this reduction in systolic BP should have decreased the incidence of stroke by 38% and coronary heart disease by 24%. Conversely, the results of the study were unable to show any benefit on the primary composite end point, with only a significant decrease in the incidence of stroke (P<0.01) that is the most BP-sensitive event associated with hypertension. Thus, the negative outcome of the ACCORD study lies mainly with the lack of a beneficial effect of aggressive BP lowering on the incidence of coronary events. An important aspect for the understanding of the results is to scrutinize the strategy recommended to reduce BP in the two groups of patients. In particular, in the ‘‘intensive treatment arm’’, investigators were advised to start the treatment with a regimen including an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) plus the thiazide-type diuretic, chlorthalidone. Such a prescriptive advice was not given to the less intensively treated group. In the intensive treatment group, diuretics were used in 83% and 89% of the patients at 12 months and at the last visit respectively, while in the standard care group, the percentages were reduced to 52% and 56% of the population. Thus, after 12 months the use of diuretics was 33% higher in the intensive arm and the difference may account for the greater incidence of hypokalemia seen in the intensive treatment group (P=.01). , Analysis of data from the Systolic Hypertension in the Elderly Program (SHEP) trial, suggest that this degree of hypokalemia would largely offset the expected benefit of BP reduction on CHD thus providing a reliable explanation for the differences observed in the ACCORD trial where a beneficial effect on stroke might be counterbalanced by the adverse effects of drug therapy on CHD, arrhythmias and sudden death. A similar concern was raised a couple of years ago, after the publication of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial. In this trial, the combination of benazepril plus amlodipine was compared with that of the same ACE-inhibitor with the diuretic hydrochlorothiazide in terms of cardiovascular outcomes. The primary end point was the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization. The study enrolled 11,506 patients, and the BP control (clinic BPs and 24-hour ambulatory BP monitoring) was virtually identical in the two treatment arms. The study was discontinued early because of a greater benefit in the amlodipine arm in comparison to the diuretic group. Since the study does not have placebo or control arm, one could argue that the results were a measure of the superiority of the CCB over the diuretic, Nevertheless the same would apply by considering that the difference in outcomes was due to a negative effect of the diuretic hydrochlorothiazide. Very similar considerations were raised nearly ten years ago also by the publication of the results of the largest trial of antihypertensive drugs ever conducted, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), that enrolled 33,357 patients. The purpose of the study was to determine whether the treatment with the CCB amlodipine, or the ACE inhibitor lisinopril, would reduce the incidence of coronary heart disease or other cardiovascular disease events when compared with the treatment with the diuretic chlorthalidone. At the end of the trial (mean follow-up 4.9 years), there was no difference in the primary outcome between the treatment arms even whether the Authors concluded that thiazide-type diuretics should be preferred as first-line antihypertensive drugs because of their superiority in preventing major cardiovascular complications at a more reasonable price (“less expensive”). The results of ALLHAT study are puzzling in their interpretation since the diuretic arm of the trial was associated with a significantly larger systolic BP reduction (on average of 1-to-2 mmHg when compared with the ACE inhibitor or CCB treatment arms) that reached 4 to 5 mmHg at some point of the study. Surprisingly, the better BP control was not associated with a superior prevention of the primary outcome, i.e., fatal and non-fatal myocardial infarction despite the sample size of the trial and the 2-mmHg reduction in SBP would support an expected reduction in the rate of myocardial infarction by 7% and stroke by 10% would be. One possible way to explain the surprising results of the ALLHAT trial would be to again that the diuretic treatment attenuated the cardiovascular benefits that would be expected with this reduction in systolic BP. Some could argue that the results observed in these large clinical trials would be the consequence of the ever-elusive ‘‘J-shaped’’ curve of CV events. However we do believe that it is of paramount importance that when a more successful lowering of BP does not result in the expected beneficial result, it should be considered the possibility that the regimen used to lower BP might have had a negative effect. Probably, the problem will be better clarified by the results of the recently started Systolic Blood Pressure Intervention Trial (SPRINT) sponsored by the NIH. SPRINT will test the hypothesis that lowering BP below current recommendations can reduce the risk of age-related cognitive decline, but also the risk of cardiovascular and kidney diseases. The study will involve 7500 people 55 years and older followed for a minimum of 4 years during which participants with a systolic BP of ≥130 mm Hg will be randomized either to a group taking more intensive drug therapy (3 or 4 medications) or a control group taking about 2 medications to maintain BP at the currently recommended 140 mm Hg. In conclusion, a careful review of the results of some large randomized clinical trials testing the efficacy of diuretics suggest the paradoxical evidence hat the treatment with such drugs might effectively reduce blood pressure even whether some of the benefit is offset by the adverse effects of drugs. This suggests a primary role for RAS inhibitors and calcium channel blockers as a suitable starting regimen for the uncomplicated patients as well as for those at high CV risk high risk who deserve multiple drugs to achieve an aggressive blood pressure control.