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The addition of cyclosporine A to percutaneous coronary intervention (PCI) did not confer protective effects against reperfusion injury, which may occur during the process of myocardial salvage, the CYCLE trial showed.

At 6 months, ST-elevation myocardial infarction (STEMI) patients treated with cyclosporine A fared no better than their control counterparts when it came to reperfusion efficacy, with greater than 70% after 60 minutes of complete perfusion (52.0% versus 49.0%, P=0.76).

The CYCLE study seems to refute "the previous findings of a marked cardiac protective effect of cyclosporine A in the setting of timely reperfused acute myocardial infarction by means of primary PCI," wrote Roberto Latini, MD, of Istituto di Ricerche Farmacologiche Mario Negri in Milan, Italy, and colleagues in the Journal of the American College of Cardiology.

The data "support our observation that cyclosporine A does not reduce ischemia/reperfusion injury when given intravenously just before primary PCI in acute MI treated within 6 hours from the onset of symptoms," they concluded.

Worse, because cyclosporine A recipients trended toward higher incidences of 6-month mortality and cardiogenic shock, the data from CYCLE "raise the ominous possibility that cyclosporine A might even exert harmful effects," Carol Chen-Scarabelli, PhD, and , both of University of Alabama at Birmingham, noted in an accompanying editorial.

Cyclosporine A blocks the mitochondrial permeability transition pore [MPTP], the opening of which "spawns a lethal chain of events" that result in cell death, they noted.

They added that the compound had been "the epitome of the cardiovascular drugs that pharmacologically mimic the effects of ischemic post-conditioning," or the "repeated cycles of brief reperfusion/re-occlusion, resulting in substantial salvage of ischemic myocardium from infarction."

Even though the compound also recently failed in STEMI in the CIRCUS trial, Chen-Scarabelli and Scarabelli weren't ready to give up on post-conditioning yet.

"The negative outcome of the CYCLE trial should not be seen as the ultimate coup de grace to ischemic post-conditioning," they wrote, given that for several years, many cardiologists "underestimated, or even refused to believe in the existence of reperfusion injury."

The open-label CYCLE study randomized 410 STEMI patients to PCI with or without a single intravenous bolus of cyclosporine A between 2012 and 2014. At 6 months post-PCI, there was no difference between groups in rates of the following:

• Death (5.7% cyclosporine A recipients versus 3.2% control, P=0.17)
• Cardiac death (4.4% versus 2.2%, P=0.18)
• Heart failure (9.7% versus 10.4%, P=0.75)
• Cardiogenic shock (2.4% versus 1.5%, P=0.33)
• Cardiovascular rehospitalization (14.3% versus 14.6%, P=0.84)

The groups likewise had similar levels of high-sensitivity cardiac troponin T (P=0.85) as a marker of infarct size. Additionally, left ventricular remodeling was comparable among patients, as left ventricular ejection fraction and the proportion of left ventricular A/D segments were no different between the two cohorts (P=0.29 and P=0.77, respectively).

The investigators acknowledged that the study was "slightly underpowered," having failed to enroll a target of 444 patients. They were also unable to "estimate a myocardial salvage index" due to their use of echocardiography instead of magnetic resonance imaging.

Chen-Scarabelli and Scarabelli criticized the use of ST-resolution as endpoint, given that "new work raised the possibility that successful reperfusion and infarct size reduction may occur without any appreciable change in ST-resolution."

They also noted that infarct size could have been better assessed by cardiac MRI – "currently the test of choice to assess the cardioprotective efficacy of different drugs used to curb reperfusion injury."

Despite raising additional concerns regarding the study's open-label design, however, the editorialists ceded that "the CYCLE trial is unmistakably neutral."

"There is more to post-conditioning than MPTP," the pair emphasized. "Mitochondria are central, although not the only effectors of the conditioning phenomenon."