Radial access: how do we interpret subgroup analyses

This editorial refers to ‘Radial versus femoral access in patients with acute coronary syndromes with or without ST-segment elevation’†, by P. Vranckx et al., on page 1069. Vascular access selection has been deeply debated in the last 10 years, especially in the context of acute coronary syndromes (ACS). The results from randomized trials suggest that radial access offers better clinical outcomes when compared with femoral access, including access site complications, major bleeding, and major adverse cardiovascular events.1 Current European Society of Cardiology (ESC) guidelines recommend radial access, performed by experienced operators, over femoral access in ACS.2 Also, it is recommended to implement a transition from transfemoral to transradial access in centres treating patients with ACS. It had been thought that radial access may be more beneficial in ST-segment elevation myocardial infarction (STEMI) based on a subgroup of the RIVAL study.3 , 4 This analysis showed a significant interaction and suggested a large benefit for radial access in patients with STEMI for mortality, but no reduction in non-ST-segment elevation acute coronary syndrome (NSTEACS) patients. A potential confounder is that higher volume radial operators tended to randomized STEMI patients, but this interaction persisted after adjusting for radial volume. The Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX (MATRIX access) randomized 8404 ACS patients to radial or femoral access.5 This new large randomized trial provided the opportunity to explore again the subgroups of STEMI vs. NSTEACS reported by RIVAL investigators. Vranckx and collaborators reported in this issue of the journal a pre-specified subanalysis of the MATRIX access study, comparing the effectiveness of radial vs. femoral access in STEMI and NSTEACS.6 Amongst STEMI patients, death, MI, or stroke occurred in 121 (6.1%) with radial access vs. 126 (6.3%) patients with femoral access [relative risk (RR) 0.96, 95% confidence interval (CI) 0.75–1.24; P = 0.76] and amongst NSTEACS patients in 248 (11.3%) with radial access vs. 303 (13.9%) with femoral access (RR 0.80, 95% CI 0.67–0.96; P = 0.016; interaction P = 0.25). Death, MI, stroke, or major bleeding occurred in 142 (7.2%) STEMI patients with radial access and in 165 (8.3%) patients with femoral access (RR 0.86, 95% CI 0.68–1.08; P = 0.18) and in 268 (12.2%) NSTEACS patients with radial access compared with 321 (14.7%) with femoral access (RR 0.82, 95% CI 0.69–0.97; P = 0.023; interaction P = 0.76). The authors conclude that the benefit of radial access was consistent across the ACS spectrum. The findings are different from RIVAL for these subgroups. The most likely explanation is that subgroup analyses are subject to multiple testing error or chance. Another potential explanation is differences in the trial’s design or conduct that would account for differences. We performed an updated meta-analysis to better understand the available evidence. Randomized trials reporting mortality, major cardiovascular outcomes, or major bleeding were considered eligible. We found 18 randomized trials that reported at least one of the outcomes: 15 reported STEMI exclusively, one NSTEACS exclusively, and two STEMI and NSTEACS. We pooled the results and we calculated interaction P-values for STEMI–NSTEACS presentations. Radial vs femoral mortality according to presentation. NSTEACS, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction. The findings of this updated meta-analysis support the benefit of radial access in ACS with the most robust evidence in STEMI. Amongst NSTEACS, there are only three trials with less than half the number of events, leading to much lower power. Not surprisingly, there was heterogeneity between RIVAL and MATRIX for mortality amongst NSTEACS patients. The benefit in both RIVAL and MATRIX was greater in high volume radial centres, suggesting an expertise effect. A potential explanation for the differential findings in RIVAL and MATRIX is that in RIVAL, high volume radial centres due to greater comfort with radial access in STEMI randomized more STEMI patients, potentially confounding this subgroup analysis. As a result, NSTEACS patients tended to be enrolled by lower volume radial centres. The radial volume requirements were overall higher in MATRIX, reducing this source of bias. Subgroup analyses need to have a clear pre-specified biological rationale. The rationale that the effect of radial access is qualitatively different in STEMI and NSTEACS (i.e. beneficial in one and harmful in the other) is less plausible. Furthermore, the power of subgroup analyses is substantially less than the overall trial, and so the overall trial results should stand without significant interactions. Indeed, in our updated meta-analysis, we were not able to detect interactions when pooling all the available evidence from randomized trials. Finally, historically, most subgroup findings have been shown to be spurious when re-tested in subsequent trials. In summary, radial access has proven to be an effective therapy, and this analysis from MATRIX supports current guideline recommendations. Radial expertise is likely to be important for the benefits of radial access so the focus should be improving worldwide expertise for treatment of both STEMI and NSTEACS. Conflict of interest: S.S.J. reports grants from Medtronic, grants from Sanofi, and grants from GlaxoSmithKline, during the conduct of the study.

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