Supporters of the trial believe the findings should serve as a slap in the face to clinicians who prematurely decided, long before the results were in, that PCI would be superior, and particularly to centers that declined to randomize patients in the OAT trial on the assumption that medical management would be unethical. Indeed, OAT, which was primarily funded by the National Heart, Lung, and Blood Institute, was plagued with slow enrollment in part due to a lack of equipoise among cardiologists who believed opening the artery to be the only logical treatment.

Dr Judith S Hochman

Presenting the four-year cumulative results here at the American Heart Association 2006 Scientific Sessions, Dr Judith S Hochman (New York University, NY) stressed that in stable MI survivors who do not receive PCI within the first 12 hours, late recanalization of an occluded, infarct-related vessel does not improve on best medical therapy.

"These results support routine use of aggressive secondary prevention without revascularization as the preferred strategy," she said.

Dr Robert Califf (Duke University, Durham, NC), who discussed the OAT results, called the message "straightforward."

"There is no compelling reason to intervene on asymptomatic patients more than 24 hours after infarction with total occlusion of the infarct artery," Califf said.

These results support routine use of aggressive secondary prevention without revascularization as the preferred strategy.

Dr Vladimir Dzavik

Also unveiled during the late-breaking clinical-trial sessions today, the Total Occlusion Study of Canada-2 (TOSCA-2), an OAT substudy looking at the effects of PCI on late artery patency and left ventricular (LV) function, served only to complicate results repeatedly described as unintuitive. As primary investigator Dr Vladimir Dzavik (University Health Network, Toronto, ON) reported, PCI patients were more likely to have patent arteries at one year and also appeared to have less LV enlargement, despite no apparent benefit in clinical outcomes in the overall OAT trial.

"If the remodeling results of TOSCA-2 can be extrapolated to the entire OAT population, we have mild benefit, in terms of reduced LV enlargement, at the same time that we have a trend toward increased MIs that are higher in the angioplasty group, so it's likely there are competing effects," he suggested.

Both the OAT and TOSCA-2 study results were simultaneously published online today in the New England Journal of Medicine and Circulation, respectively [1,2].

In OAT, 2166 stable patients with total occlusions of their infarct-related arteries were randomized to either routine PCI plus stenting and optimal medical therapy (n=1082) or optimal medical therapy alone (n=1082), three to 28 days after their MI. Patients with significant left main or three-vessel disease, angina at rest, hemodynamic or electrical instability, NYHA class 3 or 4 heart failure, or shock were excluded from the trial.

At follow-up, the estimated four-year cumulative primary event rate—a composite of death, reinfarction, or heart failure—did not differ between the PCI group and the medical group, a finding that held up in intention-to-treat analyses. Individually, rates of death and rates of heart failure were also no different between the two groups; however, the rate of nonfatal reinfarction trended to be higher among PCI-treated patients. Indeed, in secondary-end-point analyses based on site-determined event rates (that Hochman described as a more accurate reflection of international definitions of MI), the difference in nonfatal reinfarction rates between the two groups reached statistical significance (p=0.04).

Of note, a nuclear imaging ancillary study of myocardial viability in a subset of 124 patients indicated that 69% of patients had moderate retained viability in the infarct zone.

Fewer patients had angina among the PCI-treated patients at four months and one year, but over time the occurrence of angina declined in the overall study population, and the differences between the two groups disappeared.

As such, PCI is a reasonable strategy to treat persistent angina but not to prevent angina, Hochman clarified. "So if you have a patient who meets the eligibility criteria for OAT and you're not intervening as a routine strategy to make them live longer or prevent MI or HF, and they develop angina that's either severe or affects lifestyle, PCI is an effective therapy."

Referring to the "modest reduction" in angina, Califf called this finding "difficult to place in context" and concluded that it had no impact on the overall results of the study.

A total of 381 patients enrolled in the OAT study were included in the TOSCA-2 ancillary study, in which coronary and LV angiography was performed one year after randomization. Earlier studies have suggested that PCI beyond the accepted period of myocardial salvage might lead to improved left ventricular function and slow LV remodeling.

TOSCA-2 results indicated that 83% of PCI-treated patients had patent infarct-related arteries at one year, compared with 25% in the medical therapy group (p<0.001). LV ejection fraction improved in both groups by roughly 4%, but with no significant differences between the two groups. Change in LV end-diastolic volume index was lower in the PCI group, at 3.2 mL/m², vs 5.3 mL/m² in the medical-therapy-only group, suggesting that PCI had a favorable effect in terms of reducing ventricular enlargement. This finding only trended toward statistical significance, however, and Dr Eric R Bates (University of Michigan, Ann Arbor), the discussant for the TOSCA-2 trial, emphasized that this observation, while intriguing, was drawn from a subset of a subset, since only 42% of the TOSCA-2 cohort underwent volume determination studies.

In an interview with heartwire, Dzavik acknowledged that one-year follow-up in the TOSCA-2 substudy may not have been enough. "The real question is, will that tendency for the PCI to reduce expansion of the heart override the MI results over long-term follow-up? Or will the tendency of the procedure to cause more infarcts be the overriding factor?"

Califf agreed: "It would be great to have more follow-up—the intriguing small difference in end-diastolic volume: could that enable the PCI group to look better over time, or could the more impressive excess MI rate in the PCI group, if that continues, [provide] more persuasive evidence not only of failure to benefit but actual harm of invasive, aggressive treatment?" Out to three years, he added, the event curves for reinfarctions show no signs of coming together.

Also unanswered by OAT are questions about higher-risk and unstable-MI patients who were excluded from the OAT and TOSCA-2 studies.

"The criticism will be, well, you didn't enroll high-enough-risk patients," Dzavik acknowledged, noting that this will be sufficient for some operators to justify continuing to use angioplasty outside the recommended therapeutic window. But the fact remains, he noted, that the types of patients currently being referred for PCI outside the guideline-recommended 12-hour period are precisely the types of patients included in OAT. "It is in this large group of patients where there should be an impact [of OAT and TOSCA-2]. There should be a reduction in procedures, which are probably unnecessary in this group."

Indeed, during a media briefing, Hochman estimated that approximately 100 000 MI patients per year in the US would meet the OAT criteria. However, both Hochman and Dzavik stressed repeatedly to the press that the OAT findings do not apply to higher-risk patients.

"Nobody has any doubt that high-risk patients need to have their arteries opened," Dzavik told heartwire. But in the two groups of patients who might be expected to benefit—patients with infarcts in left anterior descending (LAD) arteries and patients with lower ejection fractions—"we found no differences in clinical outcomes in these patients," he said.

Most experts commenting on the study expressed the hope that physicians, armed with these new results, would put aside their previous biases.

Dr Paul Armstrong (University of Alberta, Edmonton) described OAT and TOSCA-2 as a lesson in what not to do. "We've learned some important lessons, and they should help us in reallocating resources, when even in the great US cost containment has become an important issue," he said.

Bates, discussing the TOSCA-2 findings, emphasized that despite earlier studies suggesting a benefit of improved LV function following PCI, these have not translated into better clinical outcomes: "It should be very clear that there is no role for routine delayed PCI in improving LVEF in stable patients with an occluded infarct artery after MI. This [information] probably should immediately be transferred into clinical practice. I have no doubt that it will be embraced by the guidelines committee, and I bet the appropriateness boys will use this when they evaluate our future performance of PCI."

To heartwire, Dr Kim Fox (London, UK) hinted that old habits die hard, and he expressed his "sincere hope" that clinicians will change their minds about using PCI in stable patients three days post-MI. "They may not—there is a great wish and desire to do angioplasty on an occluded vessel simply because you see it's occluded: it's easy to do, and the results are good. But I certainly hope this causes people to think about this problem."

I would raise the question, is this an issue of knowing an answer to the scientific question, or was it a case of putting the pocketbook . . . over the interests of patients?

Califf had even stronger words, particularly for American cardiologists and investigators, who he suggested had unwittingly compromised the generalizability of the OAT results to the US population by doing such a lousy job of enrolling patients.

"Let me browbeat my colleagues in the US," Califf said. Over five years, he noted, US sites enrolled only 489 patients. "If anything, this trial points out that we are in serious trouble in the conduct of clinical trials in the US."

Worse still, some of the "nation's best centers" refused to participate because they believed they already knew the answers, Califf said. "Unfortunately they had it backward, and I would raise the question: Is this an issue of knowing an answer to the scientific question, or was it a case of putting the pocketbook, the ability to reap financial rewards from doing the procedures, over the interests of patients being given the opportunity to participate in a clinical trial that would answer a very important question?" Califf asked.

Ultimately, Califf chided, OAT was a study funded by US taxpayers, yet the majority of patients were randomized outside the US.