Sample Size in Clinical Cardioprotection Trials Using Myocardial Salvage Index, Infarct Size, or Biochemical Markers as Endpoint

Abstract

Background: Cardiac magnetic resonance (CMR) can quantify myocardial infarct (MI) size and myocardium at risk (MaR), enabling assessment of myocardial salvage index (MSI). We assessed how MSI impacts the number of patients needed to reach statistical power in relation to MI size alone and levels of biochemical markers in clinical cardioprotection trials and how scan day affect sample size.

Methods and results: Controls (n=90) from the recent CHILL-MI and MITOCARE trials were included. MI size, MaR, and MSI were assessed from CMR. High-sensitivity troponin T (hsTnT) and creatine kinase isoenzyme MB (CKMB) levels were assessed in CHILL-MI patients (n=50). Utilizing distribution of these variables, 100 000 clinical trials were simulated for calculation of sample size required to reach sufficient power. For a treatment effect of 25% decrease in outcome variables, 50 patients were required in each arm using MSI compared to 93, 98, 120, 141, and 143 for MI size alone, hsTnT (area under the curve [AUC] and peak), and CKMB (AUC and peak) in order to reach a power of 90%. If average CMR scan day between treatment and control arms differed by 1 day, sample size needs to be increased by 54% (77 vs 50) to avoid scan day bias masking a treatment effect of 25%.

Conclusion: Sample size in cardioprotection trials can be reduced 46% to 65% without compromising statistical power when using MSI by CMR as an outcome variable instead of MI size alone or biochemical markers. It is essential to ensure lack of bias in scan day between treatment and control arms to avoid compromising statistical power.

Keywords: acute myocardial infarction; biochemical markers; cardioprotection; myocardial salvage index; sample size.

© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1

Difference in number of patient needed per treatment arm for different expected treatment effects when using (A) MSI and (B) MI size alone in order to reach sufficient statistical power. Two‐sided probability α=0.05 of type 1 error was assumed. Dashed lines indicate the number of patients needed in each treatment arm to detect a decrease of 25% in outcome variables. MaR indicates myocardium at risk; MI, myocardial infarction; MSI, myocardial salvage index.

Figure 2

Difference in number of patients needed per treatment arm for different expected treatment effects when using (A) AUC hsTnT (B), AUC CKMB (C), peak hsTnT, and (D) peak CKMB in order to reach sufficient statistical power. Two‐sided probability α=0.05 of type 1 error was assumed. Dashed lines indicate the number of patients needed in each treatment arm to detect a decrease of 25% in outcome variables. AUC indicates area under the curve; CKMB, creatine kinase isoenzyme MB; hsTnT, high‐sensitivity troponin T; MaR, myocardium at risk; MI, myocardial infarction.

Figure 3

Distribution of MSI (A), MI size (B), hsTNT AUC (C), CKMB AUC (D), hsTNT peak (E), and CKMB peak (F). Dashed black lines represent the Gaussian distribution assuming that the variables were normally distributed. Red lines represent the actual distribution of the outcome variables in the pooled control subjects from the CHILL‐MI and MITOCARE cardioprotection trials. No variable, except MSI (A), was normally distributed. Thus, performing a power analysis, based on the assumption that the outcome variable is normally distributed, will provide different results compared to the Monte Carlo simulation performed in the present study, which takes the actual distribution into consideration for sample‐size calculation. AUC indicates area under the curve; CKMB, creatine kinase isoenzyme MB; hsTnT, high‐sensitivity troponin T; LVM, left ventricular mass; MI, myocardial infarction; MSI, myocardial salvage index.

Figure 4

Two patient examples showing the impact of relating MI size to MaR when evaluating the efficacy of acute reperfusion therapy. A, An example of patient with MI in the inferior LV wall attributed to occlusion of the right coronary artery. B, An example of a patient with MI in the anteroseptal LV wall attributed to occlusion of the left anterior descending artery. The endocardial borders are delineated in red and the epicardial borders in green. Left panel shows mid‐ventricular short‐axis late gadolinium enhancement images with the infarcted myocardium defined within the yellow delineation. Pink lines represent pixel weighted used for infarct quantification. Red lines indicate microvascular obstruction. Right panel shows corresponding mid‐ventricular short‐axis contrast‐enhanced SSFP images with the MaR delineated in white. Note the similar infarct size (22% and 21% of the LV), but the significantly different MSI (24% vs 53%) attributed to different MaR. Thus, efficacy of acute reperfusion therapy was approximately double in (B) compared to (A) despite similar MI size. LV indicates left ventricle; MaR, myocardium at risk; MI size, myocardial infarct size; MSI, myocardial salvage index; SSFP, steady‐state free precession.

Figure 5

Sensitivity analysis for impact of timing of CMR examination after an acute MI. A, Decrease in hyperenhanced myocardium observed with LGE CMR over the first year in patients with reperfused after first‐time MI as shown by Engblom et al.16 Note the significant decrease observed during the first week after infarction (dashed circle). This is illustrated in (B) by a 3‐chamber LGE image from a patient with an anteroseptal MI (arrows) attributed to an acute proximal LAD occlusion.16 Note the significant reduction of the hyperenhanced myocardium observed between days 1 and 7. C, The increase in sample size needed to avoid committing a type 2 error of rejecting true treatment effect of 25% masked by bias introduced by difference in scan day. CMR indicates cardiovascular magnetic resonance; MaR, myocardium at risk; LAD, left anterior descending artery; LGE, late gadolinium enhancement; MI size, myocardial infarct size; MSI, myocardial salvage index.