Effects of body size and hypertension treatments on cardiovascular event rates: subanalysis of the ACCOMPLISH randomised controlled trial

Summary

Background

In previous clinical trials in high-risk hypertensive patients, paradoxically higher cardiovascular event rates have been reported in patients of normal weight compared with obese individuals. As a prespecified analysis of the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, we aimed to investigate whether the type of hypertension treatment affects patients' cardiovascular outcomes according to their body size.

Methods

On the basis of body-mass index (BMI), we divided the full ACCOMPLISH cohort into obese (BMI ≥30, n=5709), overweight (≥25 to <30, n=4157), or normal weight (<25, n=1616) categories. The ACCOMPLISH cohort had already been randomised to treatment with single-pill combinations of either benazepril and hydrochlorothiazide or benazepril and amlodipine. We compared event rates (adjusted for age, sex, diabetes, previous cardiovascular events, stroke, or chronic kidney disease) for the primary endpoint of cardiovascular death or non-fatal myocardial infarction or stroke. The analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00170950.

Findings

In patients allocated benazepril and hydrochlorothiazide, the primary endpoint (per 1000 patient-years) was 30·7 in normal weight, 21·9 in overweight, and 18·2 in obese patients (overall p=0·0034). However, in those allocated benazepril and amlodipine, the primary endpoint did not differ between the three BMI groups (18·2, 16·9, and 16·5, respectively; overall p=0·9721). In obese individuals, primary event rates were similar with both benazepril and hydrochlorothiazide and benazepril and amlodipine, but rates were significantly lower with benazepril and amlodipine in overweight patients (hazard ratio 0·76, 95% CI 0·59–0·94; p=0·0369) and those of normal weight (0·57, 0·39–0·84; p=0·0037).

Interpretation

Hypertension in normal weight and obese patients might be mediated by different mechanisms. Thiazide-based treatment gives less cardiovascular protection in normal weight than obese patients, but amlodipine-based therapy is equally effective across BMI subgroups and thus offers superior cardiovascular protection in non-obese hypertension.

Funding

Novartis Pharmaceuticals.

Introduction

Hypertension happens in people of all body sizes, ranging from lean to obese. In general, the choice of treatment to control blood pressure is made without regard to bodyweight. However, recognition of relevant clinical and prognostic differences between weight categories, which potentially could affect selection of treatment, might be important.

The association of obesity with a high incidence of major cardiovascular events, which could be caused by accompanying risk factors and by obesity itself, is widely accepted.1, 2, 3, 4 Despite this knowledge, reports in patients with established cardiovascular disease, particularly those with coronary disease, have suggested that event rates in individuals with normal bodyweight are unexpectedly higher than in heavier patients.5, 6, 7

A similar finding has been noted in hypertension. Findings of epidemiological studies show that lean hypertensive individuals have a higher incidence of adverse cardiovascular outcomes than their obese counterparts.8, 9, 10 The obese phenotype of hypertension might, therefore, be a more benign or protective form of this disorder.8, 9, 10, 11 As likely, however, is that hypertension in lean patients could be associated with the cardiovascular outcomes of greater reactivity of neuroendocrine mechanisms—in particular, the sympathetic and renin-angiotensin systems—to routine stimuli.¹²

In prospective clinical trials of hypertension treatment, increased rates of cardiovascular outcomes have been recorded in lean patients. In a recent study of hypertensive individuals with histories of clinical coronary disease, those who were overweight and obese had a lower risk of major cardiovascular outcomes than did lean people.¹¹ However, since all patients in that trial received active treatment, the researchers could not ascertain whether the reported obesity paradox reflected innate clinical characteristics of individuals in the different weight categories or were the effects of study drugs. Furthermore, augmented risk of cardiovascular death in thin patients (body-mass index [BMI] <20) was reported in the Losartan Intervention for Endpoint reduction in hypertension (LIFE) study, in which an increase in risk for patients who were very obese (BMI >35) was also seen.¹³

Antihypertensive treatment could be an important factor in establishing how body size affects cardiovascular outcomes. In the Systolic Hypertension in the Elderly Program (SHEP), patients randomised to treatment with the diuretic chlortalidone (known also as chlorthalidone) had significantly fewer major events than did those allocated placebo; however, within the group receiving active treatment, a significantly higher rate of death and stroke was recorded in lean versus overweight individuals.¹⁴ No such relation was seen in the placebo group in that study, suggesting that the treatment itself, despite its overall benefit, might have contributed to the increased risk in lean patients.¹⁴

The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial is a further opportunity to study the effects of bodyweight and different treatment regimens in high-risk hypertensive patients. In previous trials in which increased cardiovascular events were noted in lean patients, thiazide diuretics were used as primary or add-on therapy in all or most treated patients.11, 13, 14 However, in ACCOMPLISH, cardiovascular outcomes of diuretic and non-diuretic drug regimens were compared.¹⁵ The prespecified analysis of ACCOMPLISH reported here aims to provide clinical insight into the differential effects of treatment on cardiovascular event rates in hypertensive patients, categorised by BMI.