COMPLETE: Better Outcome With PCI in Nonculprit Lesions After STEMI

Susan Jeffrey

September 01, 2019

PARIS  — Patients who have ST-segment elevation myocardial infarction (STEMI) with multivessel disease benefit from complete revascularization of any other angiographically significant lesions, rather than a strategy of intervention only in the culprit lesion, a new trial shows.

Researchers found a significant reduction in both co-primary endpoints of cardiovascular (CV) death and myocardial infarction (MI) and CV death, MI, and ischemia-driven revascularization. This result was driven mostly by reductions in MI. The benefit was seen regardless of whether nonculprit lesions were addressed during the index hospitalization or shortly after discharge.

"For the first time we have definitive evidence that complete revascularization reduces hard clinical outcomes," Shamir Mehta, MD, Population Health and Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada, told theheart.org | Medscape Cardiology.

"We knew from prior trials that softer outcomes like urgent revascularization were lower, but we didn't know whether or not it would prevent hard outcomes," Mehta said. "This is important because it suggests that the nonculprit lesion is biologically active and can cause recurrent events in the future.

"The other interesting aspect is that these events happen over years — they don't happen immediately, within the first 30 days; they happen over a period of about 5 years. So by adopting this approach, you prevent these downstream events."

Results of the Complete vs Culprit-Only Revascularization Strategies to Treat Multivessel Disease after Early PCI for STEMI (COMPLETE) trial were presented here at the European Society of Cardiology (ESC) Congress 2019 and published simultaneously online September 1 in the New England Journal of Medicine.

COMPLETE Revascularization

STEMI patients undergoing coronary percutaneous coronary intervention (PCI) of the culprit lesion are often found to have multivessel disease, with one or more angiographically significant nonculprit lesions, Mehta told a press conference here. "There's been uncertainty as to how to manage these nonculprit lesions — whether to routinely revascularize them with PCI, or whether to treat them conservatively with guideline-directed medical therapy," he said.

"While prior randomized trials have shown that non-culprit-lesion PCI reduces revascularization, none of these prior trials were adequately powered to detect even moderate reductions in hard clinical outcomes, such as CV death or myocardial infarction," Mehta noted. Meta-analyses have also suggested a possible reduction, he added, but "these results are very fragile and no single RCT [randomized controlled trial] has been adequately powered. The COMPLETE trial was designed to address this evidence gap."

The trial enrolled 4041 patients with STEMI and multivessel coronary artery disease who had undergone successful PCI of the culprit lesion but were found to have nonculprit lesions of at least 70% or a fractional flow reserve measurement of 0.80.

Patients were then randomly assigned to complete revascularization of any additional angiographically significant nonculprit lesions or to no further revascularization. All patients received guideline-directed medical therapy, including aspirin; a P2Y12 inhibitor (usually ticagrelor); and a statin, β-blocker, and risk factor modification.

Enrolling physicians were asked before randomization when they were planning to carry out the non-culprit-lesion PCI: either early during the index hospitalization or within 45 days after discharge from the hospital. Patients were stratified on that basis.

The trial had two co-primary outcomes: a composite of CV death and MI and a composite of CV death, MI, and ischemia-driven revascularization. Follow-up was for a mean of 3 years (range,2 to 5 years).

The nonculprit lesion was located in the left anterior descending (LAD) artery in approximately 40% of cases and in the proximal LAD artery in 10%.

"I think one of the most important parameters of the trial was that complete revascularization was actually achieved in over 90% of patients who were allocated to the nonculprit-lesion PCI arm, and that means that they had a SYNTAX score of 0," Mehta stressed. "There was no significant disease left behind in that group."

At 3 years, the first co-primary endpoint was reduced by a highly significant 26%, with a number needed to treat to prevent one event of only 37, he reported. Kaplan-Meier curves diverged early, but the main benefit was seen over the longer term, with curves continuing to separate between 2 and 3 years of follow-up, 3 and 4 years, and 4 and 5 years.

For the second co-primary endpoint (which included ischemia-driven revascularization), nonculprit PCI reduced the relative risk by 50%, Mehta said. "There are 11 zeros on this P value — it's highly statistically significant," he added.

Table. COMPLETE: Co-Primary Outcomes

Endpoints Complete Revascularization (n = 2016), n (%) Culprit-Lesion-Only PCI (n = 2025), n (%) Hazard Ratio (95% CI) P Value
CV death, MI 158 (7.8) 213 (10.5) 0.74 (0.60 - 0.91) .004
CV death, MI, ischemia-driven revascularization 179 (8.9) 339 (16.7) 0.51 (0.43 - 0.61) <.001

 

The reduction in the primary endpoints was driven by recurrent MI, for which there was a highly significant 32% reduction with the complete revascularization strategy, Mehta said. Reductions were also seen in ischemia-driven revascularization and unstable angina.

Fewer cardiovascular and all-cause deaths were seen with the complete revascularization strategy. The difference did not reach statistical significance, but the trial was not powered for these endpoints, Mehta noted.

The researchers found no interaction with outcomes whether the nonculprit-lesion PCI was done early during the index hospitalization or later after discharge. "The benefits on hard outcomes —– CV death or MI — are preserved, and the reason for that likely is that the benefits again of complete revascularization occur over the long term," Mehta said.

Similarly, there was no interaction of procedure timing with the composite of CV death, MI, and ischemia-driven revascularization.

Strategies did not significantly differ in terms of safety outcomes, including stroke, stent thrombosis, bleeding, New York Heart Association class IV heart failure, and clinically nonsignificant bleeding.

The number of contrast-induced nephropathy cases was higher with complete vs culprit-only revascularization, but the difference was not significant (30 vs 19; hazard ratio, 1.59 [95% CI, 0.89 - 2.84]; P = .11).

The researchers note that although cardiogenic shock was not an exclusion criterion for the trial, "no patients with cardiogenic shock were enrolled in the trial and the results should not be extrapolated to such patients."

Results of the CULPRIT-SHOCK study, published in 2017, showed 30-day mortality from any cause or renal replacement therapy — the primary endpoint — was reduced by 17% (P = .01) with the culprit-only approach. The 1-year data from that trial, presented at the ESC meeting last year, showed the early benefit was maintained. However, there was a surprising fourfold increase in rehospitalization for heart failure in the culprit-lesion-only group.

Mehta said he and his coauthors plan a full cost analysis of this approach, factoring in the additional cost of the initial intervention as well as the potential savings from reducing later events. "But if you perform the procedure the next day, patients are usually in hospital at least 48 hours for their heart attack, you're not really prolonging the hospitalization to any significant extent, and they would need an additional stent. But on the other side, you prevent rehospitalization, you prevent unstable angina, you prevent recurrent myocardial infarction," he said in an interview.

He noted that the MIs prevented in this trial were type 1, "so these are life-changing events. These are events that bring patients to hospital with chest pain, they often result in an admission to hospital, they result in a second procedure being done, so when you look at it from that perspective, I think it probably is favorable."

Suitable Nonculprit Lesions

In an editorial accompanying the publication, Lars Køber, MD, and Thomas Engstrøm, MD, from the Department of Cardiology, Rigshospitalet, University of Copenhagen, Denmark, point out that up to half of patients with STEMI have multivessel disease, and current American Heart Association/American College of Cardiology/ESC guidelines give treatment of nonculprit lesions a class IIb recommendation.

They caution that the patients in trials are often different from sicker patients seen in the clinical setting, so extrapolating these results to patients at risk for great complications "may not be safe."

For patients in the COMPLETE trial, the SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score, which expresses risk associated with revascularization by taking into account the complexity of coronary artery disease, was relatively low. "More complex nonculprit lesions (associated with higher SYNTAX scores) may be different physiologically and may be less suitable for routine treatment," they write.

Some patients may benefit from treatment with high-potency dual antiplatelet therapy with prasugrel or ticagrelor, they note, adding that in this trial one quarter of patients were on clopidogrel, "which may not be the more effective therapy in patients with acute coronary syndromes."

Still, they conclude, "Since this strategy appears to be safe and reduces the composite outcome of cardiovascular  death or recurrent myocardial infarction, as well as the risk of future revascularization, it appears appropriate to recommend complete revascularization for patients similar to those included in the COMPLETE trial.

"We hope that the investigators will be able to obtain data from longer follow-up in order to evaluate whether the tendency toward a small reduction in all-cause mortality becomes significant over time," they note, suggesting that better selection of high-risk patients may better define which patients are most likely to benefit from complete revascularization.

"Regardless, in light of the results of the well-planned and well-executed trial by Mehta et al., the guidelines should recommend a strategy of full revascularization in patients with STEMI and multivessel disease, at least in those who have suitable nonculprit lesions," they conclude.

The study was funded by the Canadian Institutes of Health Research, with additional support from AstraZeneca, Boston Scientific, and the Population Health Research Unit. Mehta reports grants and other from AstraZeneca and grants from Boston Scientific during the conduct of the study, as well as grants from AstraZeneca outside the submitted work. Disclosures for coauthors are available at www.nejm.org . Engstrøm reports personal fees from Abbott, AstraZeneca, Bristol-Myers Squibb, and Bayer AS outside the submitted work. Køber reports personal fees from Novartis and Bristol-Myers Squibb and grants and other support from AstraZeneca.

N Engl J Med. Published online September 1, 2019. Article, Editorial

European Society of Cardiology (ESC) Congress 2019. Presented September 1, 2019.

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