AVERT trial design and findings in the hot seat: investigators insist AVERT reflects current practices

Shelley Wood

July 21, 2000

Fri, 21 Jul 2000 14:30:51

St Louis, MO - Criticism continues to dog the Atorvastatin VErsus Revascularization Treatment (AVERT) trial following an editorial published in the July 2000 issue of the American Heart Journal. The authors of the editorial, Drs Balkrishna M Singh, Sanjeev Puri, Jorge Saucedo, and J David Talley (University of Arkansas for Medical Science, Little Rock, AR), listed problems they identified with the study design, and with the generalizations made by the AVERT investigators when they published their findings last year. On their part, the AVERT investigators insist that their trial had valid findings that they hope will spur further studies and perhaps have an influence on engrained physician practices.

The AVERT study was published in the July 8, 1999 issue of the New England Journal of Medicine by Dr Bertram Pitt (Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI) and colleagues, on behalf of the AVERT investigators. In their concluding remarks, Pitt et al hypothesize that, with additional results results from additional long-term, large-cohort trials, "aggressive lipid lowering with atorvastatin appears to be as safe and as effective as angioplasty and usual care in reducing the incidence of ischemic events."

 

By contemporary cardiology standards, the sample size of 341 patients in the AVERT trial was incredibly small to make the kind of broad generalizations that the authors make

 

In an interview with heart wire , Singh said firmly that the AVERT trial, as it was conducted, "wasn't the right trial design." The choice of outcomes and the small patient cohort, says Singh, profoundly compromise the generalizability of the study findings. He and his fellow editorialists write: "By contemporary cardiology standards, the sample size of 341 patients in the AVERT trial was incredibly small to make the kind of broad generalizations that the authors make."

Who needs revascularization, anyhow?
 

One can even question whether these patients even needed revascularization at all

 

A major bone of contention for Singh and colleagues was the number of patients randomized to participate in the study who had few or no symptoms of ischemic disease, combined with the omission of symptom relief as an endpoint in the study. Given the inclusion of patients with "very minor disease ... one can even question whether these patients even needed revascularization at all," Singh told heart wire .

Speaking to heart wire about the editorial, Pitt conceded that the patient numbers were small, but defended the inclusion of patients with mild disease. "If you look at what's happening in practice throughout the country, there are many people with class I, class II angina that are getting revascularization. So this is not off the wall, these people are being done."

 

If you look at what's happening in practice throughout the country, there are many people with class I, class II angina that are getting revascularization. So this is not off the wall, these people are being done.

 

Singh et al also disagreed with the exclusion of symptom relief within the composite endpoint of the AVERT study. They write, "Although improvement in angina with angioplasty was significantly higher in the AVERT trial, this was not included in the end points." In Singh's opinion, "They clearly took away the thing that benefited from revascularization."

 

There really is no evidence that doing revascularization in these people has lowered the risk of dying because most of the heart attacks occur not in the vessel they're fixing but from minimally narrowed vessels that are lipid rich and lead to rupture

 

Pitt counters that relief of angina is not usually included in the composite endpoint for trials of this kind. Symptom relief can only do so much, and many patients, if given the choice, might opt for medical treatment over angioplasty, even if their symptoms, on drugs, did not go away overnight. "There are a lot of people [getting angioplasty] that probably could have been given a choice and would have done well on medicine, and if they show progressive symptoms, they can be done later. But there really is no evidence that doing revascularization in these people has lowered the risk of dying because most of the heart attacks occur not in the vessel they're fixing but from minimally narrowed vessels that are lipid rich and lead to rupture."

Angioplasty vs drugs: not an "either-or"
 

Clearly if you have an angioplasty you should also be getting medicine, but that's not what happens all the time in practice where [physicians] say: what a good job I did, I fixed this vessel, and they forget about the other things

 

Ongoing trials, cited by Singh and colleagues, will provide evidence on angioplasty in combination with lipid-lowering medication, and on what the degree of LDL reduction is optimal. Pitt is the first to agree that these will be extremely important, and insists that the AVERT findings should not be interpreted as an "either-or" study: "Clearly if you have an angioplasty you should also be getting medicine, but that's not what happens all the time in practice where [physicians] say: what a good job I did, I fixed this vessel, and they forget about the other things."

Singh and colleagues are not the first to express their concerns about the trial and particularly the broad statement made by the study authors. In a letter to the editor following publication of the NEJM study, Dr David J Cohen and colleagues (Beth Israel Deaconess Medical Center, Boston, MA) point out that several published studies preceding AVERT showed lipid-lowering therapy to be superior to PTCA (not merely "as safe and effective as"). As such, choosing "a PTCA-based strategy as the control therapy in patients with minimal (if any) myocardial ischemia would thus seem to be a straw man that inherently biased the study toward a positive result for medical therapy, with or without aggressive lipid lowering"

Pitt responds by insisting that the AVERT trial reflects current physicians practices and that the conclusions reached in the published study can only express what they found. "Angioplasty may be inferior, but we couldn't say that, we weren't statistically different, we were sort of equivalent as it were. Our study is a small study, as pointed out, and it's really hypothesis-generating, the first one looking at this issue, and it really has to be followed up by bigger studies. What we wanted to do was make people think."

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