Author + information
- Franz H. Messerli, MD* ()
- ↵*Hypertension Program, Division of Cardiology, St. Luke's-Roosevelt Hospital, Columbia University College of Physicians and Surgeons, 1000 10th Avenue, Suite 3B-30, New York, New York 10019
- Sripal Bangalore, MD, MHA
To the Editor:
“…but did not reduce the rate of cardiovascular events…” were the concluding words in the abstract of the recently published NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) study (1), which assessed the effects of valsartan on the incidence of diabetes and cardiovascular events in more than 9,000 patients. Although blood pressure (BP) was significantly lower by 2.8/1.4 mm Hg in the valsartan arm when compared with placebo and the risk of diabetes was lessened, disappointingly the coprimary cardiovascular outcomes (composite of death from cardiovascular cause, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, and hospitalization for unstable angina) were similar between the groups. Similar to NAVIGATOR, the National Heart, Lung and Blood Institute–sponsored ACCORD (Action to Control Cardiovascular Risk in Diabetes) study (2) in 4,733 patients with type 2 diabetes showed that targeting systolic BP to <120 mm Hg as compared with <140 mm Hg “did not reduce the rate of a composite outcome of fatal and non-fatal major cardiovascular events.” And, finally, we should remember that in the DREAM (Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication) study (3), in more than 5,000 patients with impaired fasting glucose levels or impaired glucose tolerance, “the use of ramipril for 3 years did not significantly reduce the incidence of diabetes or death…” nor did ramipril “reduce the risk of the cardiorenal composite outcome.” Not uncommonly, the concluding line of the abstract of a landmark study becomes the one and only line that sticks in the practicing clinician's mind. Thus, the nihilistic conclusions from the 3 major recent studies in patients with diabetes or impaired fasting glycemia are that aggressive lowering of BP to systolic goals below 140 mm Hg (achieved BP of 133, 128, and 119 mm Hg in NAVIGATOR, DREAM, and ACCORD, respectively) confers no benefits whatsoever. This certainly is a disturbing finding given our teaching over more than 2 decades, ever since Syst-Eur (Systolic Hypertension in Europe) (4) and HOT (Hypertension Optimal Treatment) (5) trials, that diabetes renders patients particularly susceptible to the effects of BP lowering and that indeed a given fall in BP conferred distinctly more benefits in the patient with diabetes than in the patient without. In Syst-Eur (6), for instance, active treatment reduced all cardiovascular events by 69% in patients with diabetes as opposed to only 26% in patients without diabetes (4). Not surprisingly, most, if not all, recent hypertension guidelines adopted significantly lower BP goals for the patient with diabetes than for the hypertensive patient without diabetes. Obviously, these unexpected findings in 3 major recent trials are prone to have a major impact on the state of the art of antihypertensive therapy in patients with impaired glucose tolerance or type 2 diabetes. However, because stroke is the most BP-dependent cardiovascular outcome, we decided to scrutinize the 3 recent landmark studies for cerebrovascular events. The results from 19,309 patients with diabetes or impaired fasting glucose suggest that intensive BP control is associated with a 28% reduction in the risk of stroke (odds ratio: 0.72; 95% confidence interval: 0.28 to 0.89) when compared with routine control (Fig. 1). Treatment of 174 patients with aggressive BP control for 4.8 years will prevent 1 stroke.
High BP certainly remains a powerful risk factor for coronary heart disease and for congestive heart failure. However, many studies have shown that BP reduction confers distinctly more benefit for prevention of strokes than for prevention of heart disease (7,8). The reason for this discrepancy is not entirely clear, although it may be related to the extensive use of thiazide diuretics in many studies. Evidence has been put forward that thiazides are particularly efficacious for stroke prevention (9) and mutatis mutandis particularly inefficacious for prevention of coronary artery disease. This cerebroprotective effect, first observed by Brown and Brown (10), seems to be, at least to some extent, independent of the thiazides' BP-lowering effect and may be related to stimulation of the AT2 receptor (9). Regardless of the exact mechanism for stroke reduction (and the lack of coronary artery disease reduction) in the 3 major landmark trials, these results deserve our attention. It stands to reason that cardiologists are more concerned with coronary artery disease than with cerebrovascular disease. However, stroke remains the most devastating complication of hypertensive cardiovascular disease. Clearly, a 28% reduction of cerebrovascular events cannot be swept under the rug. As a post hoc finding in a meta-analysis, it is by no means hypothesis testing but seems to mandate a thorough reinterpretation of the seemingly disappointing results in DREAM, ACCORD, and NAVIGATOR.
Please note: Dr. Messerli serves on the Speakers' Bureaus of Abbott, GlaxoSmithKline, Novartis, Pfizer, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Forest, Sankyo, and Sanofi; has served as an ad hoc consultant for GlaxoSmithKline, Novartis, Boehringer Ingelheim, Forest, Daiichi Sankyo, Sanofi, and Takeda; and has received research grants from GlaxoSmithKline, Pfizer, Novartis, and CardioVascular Therapeutics. Dr. Bangalore has reported that he has no relationships to disclose.
- American College of Cardiology Foundation