Remote Ischemic Conditioning Fails in MI: CONDI-2/ERIC-PPCI

Patrice Wendling

September 10, 2019

PARIS — Remote ischemic conditioning (RIC) prior to contemporary primary PCI does not improve clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI), according to results of the CONDI‑2/ERIC‑PPCI study.

RIC prior to primary percutaneous coronary intervention (PPCI), compared with standard management, had no effect on the primary endpoint of cardiac death or heart failure hospitalization at 1 year (9.4% vs 8.6%; hazard ratio, 1.10; P = .32).

Nor was there an effect on any of the secondary endpoints, including the individual components of the primary endpoint, major adverse cardiovascular and cerebral events, implantable cardioverter-defibrillator use within 1 year, or troponin release. The finding was consistent across subgroups.

"Our adequately powered, multicenter trial yielded robust and consistent data across different study organizations, which demonstrate that remote ischemic conditioning did not improve clinical outcomes after 12 months in STEMI patients undergoing primary PCI," coprimary investigator Hans Erik Bøtker, MD, Aarhus University Hospital, Denmark, said during an ESC Congress 2019 hotline session.

The results are disappointing because RIC — achieved with four 5-minute cycles of upper arm blood pressure cuff inflations and deflations — appeared to have cardioprotective effects on ischemia-reperfusion injury in animal models and prior studies, he said.

In the proof-of-concept CONDI-1 trial, RIC applied before PPCI in STEMI patients improved myocardial salvage and reduced median overall infarct size from 7% to 4% of the left ventricle, and anterior infarcts from 16% to 8%. The beneficial effect seemed strongest in those with the largest infarcts.

The current study randomly assigned 5401 patients in Denmark, the United Kingdom, Spain, and Serbia to receive PPCI alone or PPCI plus RIC (autoRIC; CellAegis) administered in the ambulance en route to the hospital or in the hospital, either before or during the PPCI. The results were published concurrently in The Lancet.

Speculating on why RIC failed to improve clinical outcomes, Bøtker suggested that patients with STEMI are so well treated nowadays with PCI that it has diminished ischemia reperfusion as a target for protection substantially because the magnitude seems to be small and infarct size is small.

It may also be that longer follow-up is needed to observe a benefit, he said. Although not prospectively designed or powered for clinical events, increased myocardial salvage with RIC was associated with fewer major cardiovascular and cerebral events at a median follow-up of 3.8 years in CONDI-1, and with fewer major adverse cardiac events at a median follow-up of 3.6 years in the LIPSIA CONDITIONING trial.

"I think that the study provides a definitive answer in uncomplicated STEMI patients undergoing modern reperfusion therapy with primary PCI in an optimal pre- and in-hospital setting," Bøtker told | Medscape Cardiology. "I cannot exclude that RIC might work in more severely affected patients, such as those with cardiogenic shock and cardiac arrest patients."

"For this reason and because RIC is a simple and safe treatment modality — we observed no adverse effect in our study — there is no reason to abandon the treatment," he said.

Bøtker noted that there are several ongoing trials, including the RESIST trial in stroke and the CORIC-MI trial in STEMI, that use the same approach as the present study but continue RIC for a variable time after revascularization. Other ongoing trials in heart failure and stroke use a more extended period of RIC or "chronic RIC."

Invited discussant Bernard Gersh, MBChB, DPhil, of the Mayo Clinic in Rochester, Minnesota, said "results of this trial are emphatic and there would appear to be no role for routine remote ischemic preconditioning in the management of most — and I will emphasize most, perhaps not all — but most patients with STEMI undergoing primary PCI. The results may not be what we hoped to hear, and I share Dr Bøtker's disappointment, but the data appear to be conclusive in regard to the majority of the primary PCI population. It is what it is."

He suggested something might be "lost in translation" between animal models and humans, possibly related to existing comorbidities, age, or the timing of reperfusion and RIC, but said the main reason for the neutral results is that the window of opportunity is limited.

"When you have a cardiac mortality, as in this trial of about 2%, it's very difficult to ever demonstrate a difference, even if you can make a difference, and I think that is the era we now live in," he said.

Gersh took up Bøtker's suggestion of a possible benefit in other patient populations, highlighting a recent study he coauthored examining delays in primary PCI in patients with STEMI, in which 30-day mortality was 2.8% overall, 50% in patients with cardiogenic shock and cardiac arrest, and 23.4% in those with cardiogenic shock and no cardiac arrest.

Of the latter patients, he said, "This is the group where there may still be a therapeutic target. We know that cardiogenic shock is an evolving process, and with this 23% mortality perhaps myocardial salvage may still make a difference."

In a "Meet the Trialist" session at the congress, Gersh also questioned whether RIC might have a role outside the "sophisticated environments" where it was tested, noting that many patients with STEMI live very far from a revascularization center and that even those nearby may be delayed for hours by weather or traffic.

In a commentary accompanying the study, Andrew Peter Vanezis, MD, Royal Alexandra Hospital, Edmonton, Canada, writes that the findings clearly show that RIC adds no clinical benefit to outcomes but that "a cautionary note pertains to the follow-up time of only 1 year: our current understanding of cardiac remodeling post-STEMI is that the clinical benefits derived from cardioprotective interventions might not manifest until after 2 years, or perhaps longer, and as such the trial could have benefited from a longer follow-up time."

Nevertheless, Vanezis concludes, "It might be time to abandon this form of cardioprotection in favor of more effective therapies to extend and improve the lives of these patients."

The study was funded by the British Heart Foundation, University College London, Danish Innovation Foundation, Novo Nordisk Foundation, and Trygfonden. Bøtker reports being a shareholder in CellAegis. Vanezis has disclosed no relevant financial relationships.

European Society of Cardiology (ESC) Congress 2019: Presentation 2303. Presented September 1, 2019.

The Lancet. Published September 6, 2019. Full text, Editorial

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