368 Ottani et al. JACC VOL. 67, NO.
4, 2016
Cyclosporine A in Reperfused STEMI FEBRUARY 2, 2016:365–74
power to detect a 25% difference in the rates of at admission, day 1, and day 4 were made with the
ST-segment resolution with a 5% dropout rate at a Wilcoxon rank sum test.
2-sided alpha of 5%. The size of the trial also allowed In an attempt to minimize the risk of a false-
us to investigate the effects of treatment on circu- negative result, we not only excluded patients who
lating levels of hs-cTnT on day 4 after pPCI. Assuming did not undergo PCI or who received the wrong dose
a concentration of hs-cTnT of 2,700 ng/l on day 4 of CsA (protocol violations) from the ITT population,
(SD: 2.1) in the control group, it would be possible to thus defining the per-protocol population, but also
detect a 25% difference with 90% power, and a those with incomplete revascularization of the culprit
2-sided alpha of 5%. The study was not powered to artery (i.e., TIMI flow grade <3 at the end of the
detect a treatment effect on the clinical events procedure, thus defining an “optimally reperfused”
defined as secondary endpoints. Cumulative event group) (Figure 1). A 2-sided alpha level of 0.05 was
rates for the secondary endpoints (i.e., events considered to indicate statistical significance. All data
occurring over the 6-month follow-up) were esti- analyses were conducted with SAS software (SAS
mated using the Kaplan-Meier method. Hazard ratios, Institute, Cary, North Carolina), version 9.2 or higher.
95% confidence intervals, and p values for compari-
son of the 2 groups were determined with the Cox RESULTS
proportional hazards regression model. Treatment
effects on echocardiographic parameters related to A total of 410 STEMI patients were enrolled from
ventricular remodeling and on log e-transformed January 19, 2012, to April 30, 2014, in 31 Italian cen-
concentrations of centrally assayed hs-cTnT were ters: 207 received an IV bolus of CsA, and 203, who
examined by analysis of variance. All analysis of served as controls, received conventional treatment.
variance models included the interaction between In all, 80% were male, 40% were active smokers,
study treatment and site of MI and the percentage of and 14% had diabetes. More than one-half of the
left ventricular akinetic/dyskinetic (LV A/D) seg- population was hypertensive. Pre-infarction angina
ments. Between-group comparisons of area under within 48 h before the index event was reported
the curves for the hs-cTnT concentrations measured in approximately one-half of the patients (Table 1).
F I G U R E 1 Patients’ Disposition for Analysis of the Primary Endpoint, ST-Segment Resolution, in the CYCLE Study
410 patients presenting within 6 h from onset of symptoms of
MI were randomized
207 assigned to CsA 203 assigned to Control
ITT analysis ITT analysis
(202 ECG available*‡) (192 ECG available*‡)
4 protocol violations 1 protocol violation
203 PP analysis 202 PP analysis
(199 ECG available‡) (192 ECG available‡)
26 post-PCI TIMI <3 18 post-PCI TIMI <3
177 PP & optimally reperfused 184 PP & optimally reperfused
(174 ECG available‡) (175 ECG available‡)
The population for the per-protocol analysis is defined in the Methods section. Two patients in the CsA group were excluded because of
the concomitant presence of 2 exclusion criteria: PCI not done and study treatment wrong. *CsA arm: 4 patients were excluded for ECG not
measurable for ST-segment resolution and 1 for early death; controls: 9 patients were excluded for ECG not measurable for ST-segment
resolution and 2 for early death. ‡ECG available ¼ baseline and 60-min ECG available and ST-segment measurable. CsA ¼ cyclosporine A;
CYCLE ¼ CYCLosporinE A in Reperfused Acute Myocardial Infarction; ECG ¼ electrocardiogram; ITT ¼ intention-to-treat; MI ¼ myocardial
infarction; PCI ¼ percutaneous coronary intervention; PP ¼ per-protocol; TIMI ¼ Thrombolysis In Myocardial Infarction.
