Wednesday, April 2, 2008

The Disease Management Care Blog Dishes Up Some Straight Dope on Obesity, Heart Disease & Rimonabant

The Disease Management Care Blog thinks the Vytorin food fight from the 2008 American College of Cardiology meeting is not only overdone but it’s obscuring other news, such as this tasty morsel on rimonabant. This is a promising weight loss drug that blocks “cannabinoid” receptors. If that term sounds familiar, it should. There is another well known drug that shares the philology but stimulates the cannabinoid receptors; this accounts for its appetite-provoking “munchies” side effect. Because rimonabant blocks those receptors, it leads to a decrease in appetite. Rimonabant is manufactured by sanofi-aventis and is available in Europe. Not so in the U.S: after one unsuccessful attempt at getting it approved, the U.S. Food and Drug Administration sent it back because concerns about side effects. More on that later.

So that readers of the DMCB don't have to read the entire article, the rimonabant study summary is served up over the next 4 paragraphs. The DMCB then weighs in with some additional opinions. Tie on a bib and read on…..

This study was cooked up to determine if the appetite blocking effects of rimonabant was not only enough to lead to weight loss but to treat coronary artery disease. The study was done in classic state of the art fashion: volunteers across multiple clinics agreed to be randomly assigned one of two menu options: the drug rimonabant or an identical placebo.

And what were the ingredients? Volunteers had to have heart symptoms severe enough to warrant a cardiac catheterization. Other criteria included having a partial 20% or more blockage of at least one artery during that catheterization, a waist circumference of either 34.6 or 40.2 inches for women or men, respectively and to either a) have the “metabolic syndrome” or b) use tobacco. If those criteria were met, the study arranged for an ultrasound device to be placed into a coronary artery once the regular cardiac catheterization was finished. It was used to take sequential ultrasound pictures of the artery as it was slowly pulled out. The extent and thickness of the atherosclerosis, otherwise known as plaque, of the artery was measured. The volunteers were then randomized to drug or placebo. All saw a dietician at least once and were also expected to use local options for other weight loss. They were then let to age in a “blinded” fashion over approximately 18 months.

That’s when another ultrasound was ordered up. The measure used was the average “percent atheroma volume.” This is the amount of cross sectional area occupied by plaque versus normal artery. Atherosclerosis is a progressive disease, so the increase in percent atheroma volume should be greater in persons on placebo compared to the rimonabant users. That turned out to be the case, but the difference was not enough to be statistically significant; it could have happened as a result of random variation. For those of you with a taste for the actual the numbers, it was a 0.25% increase vs. a 0.51% increase, while the likelihood that random variation accounted for the difference was 22%.

The authors baked in other measures of plaque and found 3 dimensional “total volume” of the plaque was less at 18 months among the rimonabant users. This turned out to be statistically significant. However, there was no difference in heart attack, stroke, hospitalizations or death rates between the two groups. Rimonabant users lost just under 10 lbs and about 4 ½ inches of waist versus about a pound and 1 inch for the placebo users. This came at a price, though: 43.4% of the rimonabant users had a psychiatric issue come up during the study versus 28.4% in the placebo patients. Most of the issues were anxiety and depression. Suicide was rare: one person in the placebo group attempted it and one person in the rimonabant group succeeded.

So what can the Disease Management Care Blog bring to the table in thinking about this?

“Percent atheroma volume” (PAV) as a measure may taste great but it isn’t filling.

a) It’s a short-term or “surrogate” measure for the severity of heart disease. If the study had been carried out longer with more volunteers, the frequency of heart attacks themselves could have been better studied and we might have a good understanding of how rimonabant really performs. Studies like this are underway, so stay tuned.
b) While PAV predicts problems in the future, that predictive performance is best correlated with statin treatment for cholesterol, not calorie restriction treatment for weight. See a) above
c) Heart attacks seem to be a function of plague rupture more than plaque thickness. Even if rimonabant resulted in thinner plaques, that doesn’t necessary mean users will be better served by living longer. See a) above.

Secondly, rimonabant was not ala carte. It was accompanied by a helping of dietary counseling and follow-up. If this drug ever is approved by the FDA, the DMCB hopes that its use will be linked to meaningful dietary and activity coaching. Assuming such counseling is eventually “covered” by insurers at the prevailing fee schedules for similar evaluation and management (E&M) services, the DMCB will be very surprised if many physicians will want to fill their appointments with calorie counting and activity logs. They could hire a nurse or a dietician to do it, but it remains to be seen if the E&M revenue exceeds that cost. Rather, this sounds like a job for scalable “industrial strength” obesity (which may be a disease) management programs tailored by a menu of personalized care options.

The incidence of side effects gave the DMCB dyspepsia. Egads, there was a greater than 40% rate of psychiatric illness, probably from blockade of the “mellow” receptors. The FDA declined to approve rimonabant the first time because of reports of adverse mood changes and this report will likely not satiate their appetite for a better margin of patient safety. Since these patients may need mental health monitoring, the DMCB wonders if disease management can also fill that void - and appease the FDA.

To wrap things up: looks like rimonabant’s weight loss doesn’t necessarily benefit obese persons with heart blockages. However, that benefit was measured using a dubious surrogate measure. Whatever benefit may exist is linked to the type of care that can be provided by disease management. Given the 40% psychiatric illness rate, the advantages and disadvantages will need to be carefully assessed on a patient-by-patient basis and close follow-up may be warranted, perhaps also by disease management companies.

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