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PCI no better than optimal medical therapy in persistent
total occlusions three to 28 days post-MI: OAT and TOSCA-2
Chicago,
IL - Defying "logic" and "intuition," performing late
angioplasty on a persistent total occlusion three to 28 days after MI does
not reduce rates of death, reinfarction, or heart failure compared with
optimal medical therapy, results from the Occluded Artery Trial (OAT)
show. Worryingly, OAT patients treated with PCI showed a trend toward more
repeat MIs than patients treated medically. 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.
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.
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].
OAT results 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. Four-year cumulative event rates in OAT 
To download table as a slide, click on slide logo
below 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.
TOSCA 2: Artery patency and LV effects at odds
with clinical outcomes in OAT 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.
What about patients excluded from OAT? 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."
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.
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