ANAHEIM, CA — A subgroup analysis of a randomized trial suggests that perioperative low-dose aspirin may reduce the risk of death and nonfatal MI after noncardiac surgery for patients who have undergone a prior PCI[1].
The effect, which was not seen among patients without prior PCI, was driven by a lower risk of MI in these patients.
“For every 1000 patients with prior PCI, perioperative aspirin will prevent 59 myocardial infarctions but cause eight major bleeds,” said Dr Michelle M Graham (University of Alberta and Mazankowski Alberta Heart Institute, Edmonton).
“Among those with prior PCI undergoing noncardiac surgery, perioperative aspirin may be more likely to benefit than to harm patients,” Graham concluded.
The findings, from an unprespecified post hoc analysis of data from the Perioperative Ischemic Evaluation-2 (POISE-2) trial, were presented here at the American Heart Association (AHA) 2017 Scientific Sessions and published in the Annals of Internal Medicine.
Perioperative Risk
Healthcare providers commonly encounter patients with previous PCI who are undergoing noncardiac surgery, Graham told attendees here. “These patients are known to be at increased risk of major perioperative complications, and uncertainty remains about the effects of aspirin in this group of patients.”
The POISE-2 trial, published in 2014 in the New England Journal of Medicine[2], was a randomized trial of aspirin vs placebo in 10,000 patients that showed that aspirin did not prevent the primary composite end point of death and nonfatal MI but did increase the risk of major bleeding.
“At the time POISE-2 was designed, the steering committee did not expect that patients with previous PCI would be randomized, and therefore did not prespecify a PCI subgroup analysis,” Graham noted. However, 470 patients with previous PCI were randomized, and so they looked at the data to see whether perioperative aspirin affected 30-day events vs placebo in this group.
Eligible patients were undergoing noncardiac surgery, were aged 45 years or older, and were considered at risk for vascular complications. They excluded patients with a bare-metal stent implanted less than 6 weeks prior to surgery, a drug-eluting stent within 1 year before surgery, and those who took aspirin within 72 hours before surgery.
Patients were randomized to two aspirin strata: the initiation stratum for patients not chronically on aspirin prior to surgery, and the continuation stratum for those on aspirin at least 6 weeks prior to surgery. The intervention was 200-mg aspirin daily of aspirin or placebo, given just prior to surgery, and continued daily at a dose of 100 mg for 30 days in the initiation stratum, and for 7 days in the continuation stratum, at which point patients reverted to their previous aspirin dose.
The primary outcome was a combination of death or nonfatal MI at 30 days. Major bleeding was defined as a hemoglobin of <70 g/L and receiving two or more units of packed cells, a hemoglobin drop of 50 g/L or more and receiving two or more units of packed cells, receiving four or more units of packed cells in a 24-hour period, bleeding requiring an intervention such as embolization, or retroperitoneal, intraspinal or intraocular bleeding.
The analysis included 470 patients with prior PCI, enrolled at 82 centers in 21 countries; 234 were randomized to aspirin and 236 to placebo. Median duration from PCI to noncardiac surgery was 64 months.
For the combined outcome of death and MI as well as for MI alone, there was no interaction by treatment for the overall POISE-2 trial population or in the subgroup without prior PCI, but event rates indicated a protective effect of aspirin for those with prior PCI, she said.
“In contrast, for the individual component of death, the interactive P value was negative, suggesting that the overall results of the overall trial were the most informative, and not supportive of a subgroup effect,” Graham noted, making the protective effect largely an effect on reducing MI.
POISE-2: Outcomes
| End point | Aspirin (%) | Placebo (%) | Hazard ratio (95% CI) | Interaction P |
|---|---|---|---|---|
| Death and Nonfatal MI | ||||
| Overall trial | 7.0 | 7.1 | 0.99 (0.86–1.15) | 0.036 |
| No prior PCI | 7.1 | 6,9 | 1.03 (0.89–1.20) | |
| Prior PCI | 6.0 | 11.4 | 0.50 (0.26–0.95) | |
| MI | ||||
| Overall trial | 6.2 | 6.3 | 0.98 (0.84–1.15) | 0.021 |
| No prior PCI | 6.2 | 6.1 | 1.03 (0.88–1.21) | |
| Prior PCI | 5.1 | 11.0 | 0.44 (0.22–0.87) | |
| Death | ||||
| Overall trial | 1.3 | 1.2 | 1.05 (0.74–1.49) | 0.61 |
| No prior PCI | 1.3 | 1.2 | 1.07 (0.75–1.53) | |
| Prior PCI | 0.9 | 1.3 | 0.65 (0.11–3.91) | |
In terms of safety, they again found no indication of a subgroup effect, suggesting the overall trial results “are the most informative,” she noted. “In the POISE-2 trial aspirin was associated with an increased hazard ratio for bleeding of 1.22.”
POISE-2 Substudy: Safety
| End point | Aspirin (%) | Placebo (%) | Hazard ratio (95% CI) | Interaction P |
|---|---|---|---|---|
| Overall trial | 4.6 | 3.8 | 1.22 (1.01–1.48) | 0.50 |
| No prior PCI | 4.7 | 3.8 | 1.24 (1.02–1.51) | |
| Prior PCI | 3.4 | 3.8 | 0.85 (0.33–2.20) |
They looked at the primary outcome in the prior PCI patients by type of stent used, whether bare-metal or drug-eluting stent, timing of the stent placement relative to the noncardiac surgery, whether less or more than a year, and whether or not additional antiplatelet medication was used within 7 days prior to the noncardiac surgery, Graham noted, and none of these analyses indicated a subgroup effect.
“I will, however, point out that these were of very low power, and this does not completely exclude that a subgroup effect may exist,” she said.
Finally, they performed a subgroup analysis of the overall POISE-2 population based on a history of coronary artery disease, a total of 2268 patients. “This was done to assess whether our finding of a PCI subgroup effect was simply reflective of the presence of coronary artery disease,” Graham said. “In contrast to the PCI subgroup analyses that I’ve shown you here today, the CAD subgroup analysis demonstrated no support for a subgroup effect, with negative P values (interaction P values >0.45).
Provocative Analysis
Invited discussant for this analysis was Dr Bernard Gersh (Mayo Clinic, Rochester, Minnesota).
“First of all, I think subset analyses post hoc are potentially dangerous but also interesting, and I congratulate Dr Graham and her colleagues on I think a really fascinating, provocative analysis,” Gersh said.
The current analysis shows a “very large effect” on the end point of death and MI, driven by the effect on MI. “I think the magnitude of this benefit is surprising—this is a doubling of the rate of MI, with a hazard ratio of 0.44, but I would point out the very large and wide confidence intervals,” he noted.
The subanalysis in the CAD patients was “very interesting,” he said, and “really does emphasize that the differences that were seen were due to prior PCI and stenting as opposed to coronary disease per se.”
The researchers concluded that for every 1000 patients with prior PCI, perioperative aspirin will prevent 59 MIs and cause eight major bleeds, he noted, “and I might add, this is certainly my clinical practice and the clinical practice of most, and that is, I’m not going to stop aspirin for a noncardiac surgery unless it’s absolutely essential,” such as surgery on the brain.
The findings have to be regarded as hypothesis generating, but the numbers are “quite persuasive,” Gersh said. “The numbers are small, but the effect size is large, and it’s biologically plausible—I can perfectly understand why aspirin would be beneficial in the perioperative period, which is a prothrombotic state in patients undergoing noncardiac surgery.”
Still, not only was the analysis post hoc and nonprespecified, but “this one is really unique because . . . these 500-odd patients weren’t even meant to be in the trial,” he added. “The numbers are small, the confidence intervals are wide, and we don’t have information with regard to the causes of MI, and were these due to stent-stent thrombosis, and what stents were used in the patients who had a myocardial infarction? “
“So in closing, the question that I would ask Dr Graham is, do we need another clinical trial based upon this analysis and the small numbers, or is there sufficient evidence to justify current clinical practice? And the majority of current clinical practice is by and large not to withhold aspirin in patients undergoing noncardiac surgery, unless it’s critical,” Gersh asked.
“Do we need a clinical trial?” she responded. “Based on all the evidence that’s out there, I’m wondering whether people would be willing to withdraw aspirin in this population.”
“I agree with you totally,” Gersh added. “I would not do a clinical trial. I think this supports my practice.”
Important Contribution
In an accompanying editorial[3], Dr Raffaele Piccolo and Dr Stephan Windecker (Bern University Hospital, University of Bern, Switzerland) consider how the results of this substudy should be interpreted.
“The data suggest that the hypothesized benefit to continue or resume low-dose aspirin during the perioperative period among patients with previous PCI undergoing noncardiac surgery is likely true,” they write. “Guidelines on both sides of the Atlantic recommend to continue, if possible, low-dose aspirin among patients undergoing noncardiac surgery with previously implanted coronary stents (class I, level of evidence B in ESC guidelines and class I, level of evidence C in ACC/AHA guidelines, respectively).”
The results provide “direct evidence that aspirin effectively prevents ischemic events even several years after PCI irrespective of stent type (median time from PCI to noncardiac surgery 5.5 years) and that the ischemic benefit related to aspirin outweighs the bleeding risk,” they note.
“Therefore, this information should be taken into consideration by the multidisciplinary expert team when the management of antiplatelet therapy is discussed during the perioperative period in patients with prior PCI.”
While there are caveats, they conclude, “the POISE-2 PCI substudy is an important contribution to the field of cardiovascular management of patients who require noncardiac surgery. In the absence of a very high bleeding risk, low-dose aspirin should be continued or resumed during the perioperative period among patients with previous coronary stents, whereas it remains dispensable in patients at increased risk of vascular events but without coronary stents.”
The study was supported by the Canadian Institutes of Health Research. Graham reports no relevant. Disclosures for the coauthors are listed in the paper. Windecker has received research grants to the institution from Bracco, Boston Scientific, and Terumo. Piccolo reports no relevant financial relationships.
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