Dr William E Boden

But one of the most burning unresolved questions, at least for the ACC, is who said what about the COURAGE trial at a sponsored satellite symposium on Sunday night, leading to a Wall Street Journal (WSJ) story Monday that prompted the ACC to lift the trial embargo one day early.

"There was a statement [Sunday] night . . . that violated the embargo of this particular trial," ACC spokesperson Dr James Dove told heartwire. "It was reported in the media, and we felt it was egregious enough that the rest of the media should not be held accountable to the embargo. . . . We are very upset by the fact that the embargo was broken; it's an ethical violation of the practice of medicine, and we do not condone that kind of activity. Once we investigate the individual or individuals involved, then we'll decide what the sanction should be."

Dr James Dove

One of those "individuals" singled out in the WSJ story was Dr Martin Leon (Columbia University, New York), who was a speaker at the Boston Scientific-sponsored symposium and who also participated in a panel discussion. Leon is quoted in the WSJ today as saying, during the symposium, that COURAGE was "rigged to fail, and it did."

To heartwire, however, Leon denied saying anything inappropriate. "During the course of that panel discussion questions were asked about [our] interpretation of what we imagined the COURAGE trial results might be, and several speakers on the panel made statements about the COURAGE trial. We did not know who was in the audience, of course. . . . No data from the study were discussed, no reference to where the study was being published was discussed, none whatever."

But Leon also acknowledged to heartwire that he did say, during the symposium, that he was a reviewer for the COURAGE paper, which presumably could be construed as tainting any hypothetical discussion of how the trial might turn out.

We are very upset by the fact that the embargo was broken; it's an ethical violation of the practice of medicine.

"I was asked by someone in the audience who was upset about the way that interventional cardiology seems to be on the defensive to make some comments, and several of us on the panel made comments. I said that we know, from decades of experience, that it's difficult to apply medical therapy in all patients with good results, which is why interventional cardiology and surgery are appropriate in many patients. And yes, I said that we've been very passive, and that it's time we mobilized our forces to work together as a group to [go] on the offensive to try to defend some of the virtues of PCI. All of these comments were taken out of context and woven into a story, which is a distortion of what went on at that meeting. Nothing went on at that meeting that should justify the embargo having been broken. People commented on the trial design and what they expected the results to show, and everyone agreed we expected that there would be no difference."

Quality of life data William S Weintraub During the late-breaking clinical-trial session this morning, Boden presented the primary end point and hard clinical secondary end points from COURAGE: all of the data that are now published in the NEJM, as reported by heartwire yesterday. Next, Weintraub took the stage to present other prespecified secondary-end-point data, including QoL, healthcare economics, and utility data. As Weintraub showed, three QoL questionnaires were used, with data collected at one, three, six, and 12 months, then annually thereafter. For the Seattle Angina Questionnaire, results for three of the most important domains—physical limitation, angina frequency, and overall quality of life—all pointed to a slight advantage of PCI over optimal medical therapy out to three years of follow-up, with differences between the two being statistically significant at most of the time points. Similar results were seen for the RAND-36 questionnaire, Weintraub said. In the healthcare economics analysis, resource utilization and costs were compared for the two treatment arms, and then an incremental cost-efficacy analysis was performed. Seattle Angina Questionnaire* results Domain PCI Medical therapy p Physical limitation 6 mo 76 73 0.0019 12 mo 76 72 0.010 36 mo 74 71 0.046 Angina frequency 6 mo 85 82 0.0041 12 mo 87 83 0.0001 36 mo 88 86 0.0777 QoL 6 mo 73 70 0.0005 12 mo 75 71 0.0006 36 mo 77 75 0.051 *Score 0-100, higher is better Out to three years, optimal medical therapy cost significantly less than PCI, although the difference between the two narrowed over time, a reflection of the one third of medically treated patients who ended up undergoing PCI during follow-up. Utility was no different between the two groups at any time point. As a result, quality-of-life-year-gained analyses showed a difference of 0.024, or approximately eight days, Weintraub said. This translated into a cost of $217 000 per quality of life-year gained. Thus, in cost-efficacy analyses, less than 1% of patients treated with PCI would be deemed a cost-effective approach, he said. "Over 99% of estimates of cost effectiveness were in excess of the common benchmark of $50 000," he said. Cost of therapy Time point PCI ($) Medical therapy ($) p Baseline 7771 1751 <0.0001 1 y 10 051 4153 <0.0001 3 y 19 605 6661 <0.0001 To download tables as slides, click on slide logo below "Angina will improve with either PCI plus optimal medical therapy or optimal medical therapy alone," Weintraub stated. "PCI plus optimal medical therapy does offer an incremental benefit over optimal medical therapy alone in treating angina, but compared with optimal medical therapy, PCI plus optimal medical therapy as a first-choice therapy for stable CAD is expensive." -SW

Both investigators and outside experts commenting on the trial observed over and over that no one had expected medical therapy to do so well.

"Medical therapy has received kind of a bad rap in recent years, it's kind of old-fashioned, kind of ho-hum," Boden acknowledged. "The most surprising result in COURAGE was how well medical therapy did in terms of relieving angina."

Dr David Cohen

Likewise, Dr David Cohen (Saint Luke's Mid America Heart Institute, Kansas City, MO), told heartwire, "Maybe that's the major message to interventional cardiologists. If I were to say what surprised me most about this study, it would be the magnitude of angina relief and quality-of-life benefit that was seen with medical therapy. . . . Angioplasty was better, but medical therapy was pretty darn good."

But while many agreed that the medical-therapy results were unexpectedly good, most believed the overall findings from COURAGE are completely in keeping with what cardiologists should have expected, and not a bolt from the blue, as many media reports are suggesting.

"We've seen this before; this is the same song, different verse," Dr William O'Neill (University of Miami, FL) told heartwire, pointing to studies dating back 20 years. "I think the lay press will hype this far beyond the scientific import."

Boden, for one, disagrees. "It's interesting that the interventional community seems to be rising up and saying, this doesn't tell us something that we didn't already know. 'Gosh, the only reason we do this is to alleviate angina.' Well, I don't know if that's so true," Boden said. "I think many patients who are confronted with the at-times surprising news that they have blockages or narrowings in their coronary arteries and who are agreeing to undergo such procedures do so with the implicit belief that the angioplasty procedure is going to improve more than just angina or more than just decrease nitroglycerine consumption. Rather, their expectation is that, if I undergo PCI and stenting, I'm going to be less likely to have a heart attack or I'll live longer. That has been the implicit belief that all of us have labored under for many years."

Many experts who spoke with heartwire expressed concern that COURAGE will be seen as the triumph of one therapy over another, when in fact the study gives physicians and patients the option of delaying, perhaps indefinitely, an interventional approach.

"I'm not up here to in any way denigrate PCI," Boden told a press conference. "It is a better approach, initially, for alleviating angina. But to balance the rest of the discussion, one of the unexpected findings was just how well medical therapy did."

Instead, says Cohen, "It's not unreasonable to ask patients their opinion: Would you rather take medications, or would you rather have angioplasty? We can reasonably counsel them that the angioplasty is likely to provide better symptomatic relief both in the short and intermediate term, but a trial of medical therapy does not burn any bridges, doesn't expose them to any excess risk, and if they're not doing well on medical therapy, they can certainly have the angioplasty at a later time."

Dr Gregory Dehmer

But many may be reluctant to treat COURAGE as offering choices. "People are making this out to be the battle of the century between PCI and medical therapy, and it's really not that at all," Dr Gregory Dehmer (Texas A&M School of Medicine, Temple) told heartwire.

Yet, rising to the defense of stents, interventional cardiologists, Dehmer among them, are swift to point out that the medical-management arm of COURAGE was as good as it gets. "If you've ever been given 10 days of antibiotics to take care of a sore throat, you probably haven't remembered to take every single pill on time," Dehmer pointed out. "That's the difficulty. The medical therapy they prescribe is excellent, no question about it, but it's very difficult in practice for patients to stay on that level of medical therapy day in and day out."

Dr Eric Cohen (Sunnybrook Health Sciences Centre, Toronto, CA), pointing to the same problem, says that COURAGE "may be hard to reproduce in routine practice, and on this basis, some may challenge the generalizability of the COURAGE results and downplay its relevance. However, I think that will be missing the point, because the real issue—and opportunity—that is presented here is to ensure that this type of aggressive risk-factor modification for coronary patients is translated into routine practice."

Dr Eric Cohen

The major stent manufacturers have also chimed in, reminding cardiologists that COURAGE was not a trial of drug-eluting stents, which could have led to a more radical reduction in angina symptoms as compared with medical therapy. Likewise, the Society for Cardiovascular Angiography and Interventions (SCAI) in a press statement vowed that the COURAGE results "are unlikely to alter the approach that interventional cardiologists take in treating most patients with chronic stable angina."

Even Boden, questioned about how COURAGE would have an impact in his hospital, acknowledged he doesn't expect PCI rates to would change, at least for the time being.

"I don't think there will be a short-term impact. This result, although unexpected in the minds of many, will need to be digested, and the study will need to be carefully reviewed," Boden said. What might change sooner, however, is that many patients may now opt to delay PCI, first trying medical therapy rather than proceeding directly to the cath lab.

O'Neill, by contrast, predicts a short-term dip, followed by business as usual. When the CASS trial results first came out in the 1980s, suggesting that CABG was no more effective than medical therapy, there was a decline in bypass that subsequently recovered, he pointed out. "So what I think might happen is in the short term there may be a small decline in the rate of PCI, but I don't think it's going to be long term," he told heartwire.

Angioplasty is likely to provide better symptomatic relief both in the short and intermediate term, but a trial of medical therapy does not burn any bridges.

The true impact of COURAGE will depend, ultimately, on how cardiologists view the applicability of the results to their patients and on the larger financial pressures they face. According to Weintraub and Boden, "The results of COURAGE apply broadly to the great majority of patients out there with symptomatic CAD and ischemia."

But PCI proponents are unconvinced, pointing out that more than 35 000 patients were screened for COURAGE yet only 3021 met eligibility criteria. "The fact is . . . 32 000 patients were excluded," Dehmer told heartwire. "One of potential criticisms of this study is its applicability to the general population."

By contrast, advocates for medical management point to the cost savings of avoiding PCI and, on the flip side, the financial incentives that keep stenting procedure rates higher than warranted, medically. PCI, Dr Salim Yusuf (McMaster University, Hamilton, ON) pointed out following the COURAGE late-breaker, is a $15 billion to $20 billion industry in North America. "There are huge vested interests that are going to push you back," he warned Boden and Weintraub. "And they've already begun to do so."

According to Yusuf, physicians and patients have been "brainwashed and deluded" into thinking that PCI will save them, while interventionalists fear that if they turn patients away, their referral base will dry up. "The reason for PCI is not scientific, it's not medical, it's sociological, and—we all know it, although we don't want to say it—it's economic. It's really time to confront this because medicine here has gone wrong."

Easier said than done, Yusuf acknowledged. "We're going to have a hell of a time putting the genie back in the bottle."