The meta-analyzes of the muses on the ISCHEMIA message lasted longer


He ISCHEMIA judgment is the compass for conservative care, it now remains stable coronary artery disease (CAD) if the follow-up of the primary outcome had been a few more years? This question may have helped inspire a new meta-analysis of 25 trials, with nearly 20,000 patients, who faced coronary revascularization plus drug drug therapy in stable CAD populations alone.

ISCHEMIA showed no significant difference between the two strategies for their primary clinical value after a mean follow-up of about 3 years. The trial and these provocative the findings have been influential and have been widely debated since its presentation in 2019.

In contrast, in the new meta-analysis: almost half of the trials were followed by patients for 5 to 15 years, and a much longer – the risk of cardiac death with invasive treatment fell by 21% overall and was seen to decrease by 19% for every 4 years of follow-up versus a conservative strategy.

The benefits of invasive treatment depended on the optimization of medical therapy and the duration of follow-up, and were partly driven by a 26% reduction in the risk of spontaneous suffering. myocardial infarction (MI), reported Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland, this week during the 2021 Virtual Congress of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR).

The analysis suggests that in patients with stable CAD and myocardial ischemia, “the benefits of revascularization and optimization of medical therapy are additive, and their combination may reduce cardiac mortality and spontaneous MI,” he said.

“Based on these findings, which are solid and consistent, I think it should be considered strongly, and it will probably be very unethical not to offer revascularization to stable patients with coronary artery disease,” explains Navarese, lead author of the study. Published May 18 at European Heart Journal, he said at a roundtable after his presentation.

ISCHEMIA had assigned 5179 stable patients with moderate to severe ischemia to stress tests to invasive strategy or conservative care, i.e., to optimal medical therapy with vs without cardiac catheterization and possible coronary revascularization. The researchers found no significant difference between strategies for the primary endpoint, a cardiovascular death compound (CV), MI, hospitalization for heart attack or unstable angina, the resuscitated cardiac arrest.

As has often been pointed out, the main ISCHEMIA curves do not show any significant difference between management strategies at an average of 3.2 years crossed after about 2 years in an apparent trajectory to show superiority after the strategy. invasive.

Although the trial could not draw conclusions about individual clinical criteria, Navarese observed, it produced a benefit signal for the outcome of CV death at 5 years in patients assigned to the invasive strategy.

“Recommendations for medical therapy alone based on trials with limited follow-up have likely underestimated the benefits of revascularization plus medical therapy,” states the meta-analysis publication on the management of patients with stable CAD, which is likely noted by ISCHEMIA.

“The weight of the evidence suggests that revascularization in the SCC [chronic coronary syndromes] should be considered a non-prognostic procedure, “except in patients with left primary coronary heart disease or severe ventricular impairment,” said Christopher Cook, MD, National Heart and Lung Institute, Imperial College London, United Kingdom, as guest speaker after the presentation in Navarre.

“But do the results of the current meta-analysis justify a change?” The new analysis, he said, “is clearly methodologically robust. Second, the findings identify longer time horizons as a potential reason for the lack of effect in the original study.” Finally, “their results in reducing cardiac mortality and spontaneous MI are consistent with other data sets.”

Four decades of testing

Questioning the relevance of a meta-analysis of mostly ancient trials for current practice, Cook wondered about the role of “contemporary optimal medical therapy, in particular the impact of important drugs such as SGLT-2 inhibitors, which are underrepresented in current test data. “

Another of the debaters, Davide Capodanno, MD, a doctor at the University of Catania, Italy, noted that the trials that contributed to the meta-analysis date back to 1979, with half conducted more than a decade ago. In addition, extensive studies contributed to the meta-analysis to varying degrees.

“Five studies had significant weight as drivers of the full outcome” for the endpoint of cardiac mortality, which made the overall data less widely representative. The reduction in spontaneous MI was driven primarily by three studies, he said.

Navarese said this weighting did not appear to matter in successive analyzes that omitted the contribution of a trial successively. “No matter the weight of the study, the results were always the same, always strongly consistent.”

He also said that the chronological order of the trials and, therefore, their variation in the state of the art CV technique represented each, had no significant effect on the meta-analysis results.

“In addition, it has been argued that, by current standards, older trials had a lower percentage of drug use, that medical therapies were not optimal in these trials,” Navarese said. But within each trial, the state of medical therapy was always the same in both arms of treatment, “and the percentage of medical therapy was generally comparable,” which made it possible to assess the difference made by revascularization.

But the vintage of many trials in meta-analysis is one of its main flaws, said William E. Boden, MD, Boston University School of Medicine and VA New England Healthcare System. | Cardiology Medscape.

“Frankly, it’s what I would call garbage meta-analysis,” he said. “They mix apples, oranges and pears” by including some “old and obsolete” studies from the 1980s, which were followed by seismic changes in the medical therapy landscape for patients with CAD.

“I would say that sharing data before 2000 is useless, because you will share old data from lower medical therapy,” said Boden, who chaired the COURAGE trial and was a co-principal investigator for ISCHEMIA.

“This is the great critique, the high degree of selection that was carried out, a kind of indiscriminate grouping of very heterogeneous and disparate studies over a time horizon of 30 to 40 years.”

Selection of end points

The 25 meta-analysis trials included 10,023 patients with stable CAD who had been randomly assigned to invasive intervention in addition to medical therapy and 9783 who were managed with medications alone; their mean follow-up was 5.7 years.

The relative risk (RR) of cardiac death in the invasive cohort compared with conservatively managed was 0.79 (95% confidence interval) [CI], 0.67 – 0.93; Pg <0.01) and for spontaneous MI was 0.74 (95% CI: 0.64 - 0.86; Pg <.01). The study did not show significant differences in mortality risk or cause of all-cause mortality stroke.

The reduction in cardiac death risk in revascularization cohort patients was linearly associated with follow-up duration, Navarese reported, for an RR of 0.81 (95% CI, 0.69 – 0.96). ; Pg = .008) for each additional 4 years of follow-up.

The selection of results in the meta-analysis is another of its weaknesses, Boden said. “For starters, the whole analysis depends on the endpoints that were never the main endpoints of the test.” Cardiac mortality is an example. In ISCHEMIA, “the reason we have used mortality for all causes is that there is no doubt. Cardiac mortality, on the other hand, is very complicated because it usually has to be determined.”

It is unclear, he said, “how cardiac mortality was defined in these studies, how it was measured, or whether it was awarded or not.”

In another example, the MI result in the meta-analysis is limited to spontaneous MI only. “At ISCHEMIA we had a global MI endpoint with six subtypes,” Boden said, referring to the MI typing system in the latest iterations of the Universal Definition of Myocardial Infarction. Limiting the analysis to spontaneous MI, for example, would exclude periprocedural MI.

They “chose” their endpoints, he said. “It’s about manipulating the data so that the result you want to achieve is achievable.”

2021 Congress of the European Association of Percutaneous Cardiovascular Interventions, presented on 18 May.

Eur Heart J. Published online May 18, 2021. Full text.

Navarese revealed receipt of grants for Abbott and Amgen research, and conference fees or Astra fees Zeneca, Bayer, Pfizer and Sanofi-Regeneron. Boden disclosed the receipt of consultant fees or fees AbbVie, Amgen, AstraZeneca and Janssen, and Amarin Scholarships for research.

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