Friday, December 7, 2012

Relation between Body Weight, Antihypertensive therapy and CV outcome

Clinical trials in high-risk hypertensive patients have noted that paradoxically, higher cardiovascular event rates have been reported in patients of normal weight compared with obese individuals. The obesity paradox has been further evaluated in a prespecified analysis of the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, which aimed to investigate whether the type of hypertension treatment affects patients’ cardiovascular outcomes according to their body size.  Michael Weber and colleagues analyzed data from more than 11,000 patients randomized in the ACCOMPLISH trial to shed light on this problem

On the basis of body-mass index (BMI), the full ACCOMPLISH cohort were divided into the following categories:
• obese (BMI ≥30, n=5709)
• overweight (≥25 to <30 n="4157)</P">
• normal weight (<25 n="1616)</P">

The ACCOMPLISH cohort had already been randomised to treatment with single-pill combinations of either benazepril and hydrochlorothiazide or benazepril and amlodipine. Event rates (adjusted for age, sex, diabetes, previous cardiovascular events, stroke, or chronic kidney disease) were analysed for the primary endpoint of cardiovascular death or non-fatal myocardial infarction or stroke.

According to the intention to treat analysis:

• 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).

• In patients 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 lower with benazepril and amlodipine in overweight patients (hazard ratio 0.76, 95% CI 0.59 to 0.94; p=0.0369) and those of normal weight (0.57, 0.39 to 0.84; p=0.0037).

The researchers conclude from these findings that “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.
An accompanying Comment article notes that there is more to obesity than risk of heart failure; specifically, obese patients commonly present with the metabolic syndrome and hyperuricaemia and are at a 6–12-fold increased risk of diabetes. In addition, thiazide diuretics augment insulin resistance, intra-abdominal fat accumulation, and amount of uric acid in serum, and compared with antihypertensive agents other than β blockers, they confer a 35% increased risk of new-onset diabetes. The authors acknowledge that diuretic-based metabolic abnormalities are mitigated to some extent in the presence of an ACE inhibitor, but seem to persist nonetheless, thereby contraindicating diuretics in the long term, particularly in obese patients. They suggest that if a thiazide is to be used, it should be either chlortalidone or indapamide, for which solid outcome data exist. Based on these concerns, they reject the conclusion of this study that diuretic-based regimens are a reasonable choice in obese patients and surmise that thiazide diuretics are contraindicated in obesity, relatively speaking. They recommend that if the indication is hypertension, then amlodipine-based treatment should be used irrespective of body size but if the indication is prevention or treatment of left-ventricular dysfunction, a diuretic-based regimen should be used, again irrespective of body size. They add that this strategy relegates diuretics to third-line agents for treatment of hypertension, except in patients at risk of heart failure which is a position recognised in the latest NICE guidelines.

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