Obesity Paradox Observed With Hydrochlorothiazide, Not Amlodipine: ACCOMPLISH

May 22, 2012

May 22, 2012 (New York, New York) — A prespecified analysis of the Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial confirms a higher risk of cardiovascular events in lean and overweight patients treated with hydrochlorothiazide but not those treated with amlodipine.

"The background to this analysis is that previous epidemiologic studies, as well as outcomes trials in hypertension, have shown that thin patients, people with normal body-mass index [BMI], tend to have an unexpectedly higher cardiovascular event rate than overweight or obese patients," said lead investigator Dr Michael Weber (SUNY Downstate Medical Center, Buffalo). "Most of the patients from the studies where the obesity paradox was observed were getting thiazide therapy. So the question we asked was whether the excess cardiovascular risk in lean patients could be prevented if nondiuretic treatment were used."

Presenting the results of the analysis here at the American Society of Hypertension 2012 Scientific Sessions in, Weber said the ACCOMPLISH study afforded researchers the opportunity to address the obesity paradox with thiazide therapy, given the trial tested two forms of antihypertensive combination therapies on major fatal and nonfatal cardiovascular events in 11 506 men and women with high blood pressure. Patients were randomized to treatment with the ACE inhibitor benazepril plus the calcium-channel blocker amlodipine or to benazepril and hydrochlorothiazide.

Normal-BMI Patients Fare Poorly on HCTZ

As reported previously by heartwire , the results showed that the single-tablet benazepril/amlodipine combination reduced the risk of morbidity and mortality by 20% compared with conventional therapy. Stratifying patients in the entire cohort by BMI, the primary end point, a composite of cardiovascular death, MI, and stroke, occurred in the 24.7% of patients with a normal BMI, 20.5% of patients considered overweight (BMI 25–30), and in 17.2% of patients considered obese (BMI >30). This translated into a statistically significant 40% increased risk in the lean patients when compared with obese patients.

In a comparison of clinical events in patients treated with hydrochlorothiazide and benazepril only, a comparison of obese vs overweight patients showed a trend toward an increase in the primary end point in the overweight group, but the difference between groups did not reach statistical significance. In a comparison between overweight and normal-weight patients, there was a statistically significant increased risk of the primary end point in the normal-weight patients, particularly an increased risk of cardiovascular death. Finally, the head-to-head comparison between obese and normal-weight patients treated with hydrochlorothiazide showed there was a 69% higher risk of the primary end point in the lean patients.

"The [obesity-paradox] phenomenon is very visibly evident in people treated with the thiazide," said Weber. "When we looked at the people treated with amlodipine, we do not see this phenomenon. If we compare obese and overweight people treated with amlodipine, there is very little difference in the primary end point or any of the other end points. If we compare overweight and normal-weight patients, the overall composite end point, by and large, is not different. Even when we compare obese and normal-weight patients, the extremes, the primary end point is really not different. Quite different from what we saw with the thiazide."

In a head-to-head comparison of the amlodipine-treated patients with those treated with hydrochlorothiazide, there was no difference in the primary end point in the obese patients. In the overweight and normal-BMI cohorts, treatment favored amlodipine, with amlodipine reducing the risk of the primary end point 24% in the obese patients (p=0.03) and 43% in the lean patients (p=0.003). For these normal-weight patients, amlodipine reduced the risk of cardiovascular death 38%, total stroke by 40%, and MI by more than 50%.

"Hypertension in obese patients is associated with excess volume, and a number of people have shown this, so thiazide therapy, as well as calcium-channel-blocker therapy, is appropriate in those patients," said Weber. "But in nonobese patients, thiazides might actually stimulate adverse mechanisms, such as an increased sympathetic activity and renin-angiotensin system activity. That may be why they don't have as good a protective effect in thin patients. So the final conclusion would be that a calcium-channel blocker with amlodipine would be preferred in nonobese high-risk hypertensive patients, particularly lean patients."

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