Faint PRAISE: 13 Year Delay In Publication Of A Major Clinical Trial Sparks Criticism Reply

13 years after first being presented the results of the PRAISE-2 trial finally have been published in JACC: Heart Failure. The trial itself is now largely irrelevant to current clinical practice, as the hypothesis it tested has long been abandoned, but the long delay in publication may serve to bring even more awareness to the issue of the delay or complete absence of publication of many clinical trials.

An accompanying editorial, by Marc Pfeffer and Hicham Skali, is highly critical of the delay:

Although standards for conduct and reporting of clinical trials have improved since 2000, the failure to fully vet the results of a clinical trial of human volunteers in a peer-reviewed journal was and remains unacceptable.

PRAISE-2 had its origins in the first PRAISE trial, which was first presented in 1995 and subsequently published in the New England Journal of Medicine in 1996. In that trial there was no difference between amlodipine (Norvasc, Pfizer) and placebo in the rate of mortality or cardiovascular hospitalization in patients with heart failure. However, a prespecified subgroup analysis turned up the highly surprising result that heart failure patients with a nonischemic etiology who received amlodipine had a highly significant 46% reduction in the risk of death compared with placebo patients.

Click here to read the full post on Forbes.

Milton Packer

Milton Packer

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Should Body Weight Influence Choice of Antihypertensive Therapy? 1

The hypertension field has been troubled by repeated observations that normal weight patients have more cardiovascular (CV) events than obese patients. Now a new analysis of a large hypertension trial confirms this finding but also suggests that it may be explained by either an adverse effect of diuretics or a protective effect of calcium-channel blockers in non-obese hypertensives.

Michael Weber and colleagues analyzed data from more than 11,000 patients randomized in the ACCOMPLISH trial to shed light on this problem. In 2008 the main results of the trial showed that the combination of benazepril and amlodipine (calcium channel blocker group, CCB) was superior to the combination of benazepril and hydrochlorothiazide (diuretic group) in reducing CV events in high risk hypertensive patients.

The new analysis, published online in the Lancet, confirmed earlier observations and found significant differences in outcome based on weight. However, the differences in outcome occurred mostly in the diuretic group. In the diuretic group, the rate for the primary endpoint was significantly different between the groups (30.7 events per 1,000 patient-years in normal weight patients, 21.9 in overweight patients, and 18.2 in obese patients, p=0.0034). In the CCB group the rates were not significantly different (18.2, 16.9, and 16.5).

To explain their finding the investigators proposed that “hypertension in obese and lean patients is probably mediated by different forms of underlying pathophysiology.” Obese patients, who are more likely to have increased plasma volume and cardiac output, will be responsive to diuretics, while lean patients are more likely to have involvement of the sympathetic and renin-angiotensin systems. They concluded that “diuretic-based regimens seem to be a reasonable choice in obese patients in whom excess volume provides a rationale for this type of treatment, but thiazides are clearly less protective against cardiovascular events in patients who are lean. An alternative therapeutic regimen that includes a calcium channel blocker such as amlodipine, which works equally well across all BMI categories, provides an advantage with respect to clinical outcomes in patients who are not obese.”

In an accompanying comment, Franz Messerli and Sripal Bangalore write that the effectiveness of hydrochlorothiazide in obese people in ACCOMPLISH “has little if anything to do with obesity per se, but simply reflects the fact that among obese patients there was a preponderance of individuals at risk for heart failure who were prone to respond well to diuretic treatment.” They argue that “amlodipine-based treatment should be used irrespective of body size” for the indication of hypertension. Diuretics, on the other hand, should be used for the prevention of left-ventricular dysfunction.
Click here to read the press release from the Lancet…