Clinical outcomes for patients presenting with acute ST-segment elevation myocardial infarction (STEMI) and undergoing primary percutaneous coronary intervention (PCI) have significantly improved over the last decade (1). These improvements result from multiple factors, which include earlier contact for patients with medical staff, better and faster transportation to PCI hospitals, reduced door-to-balloon times, rapid oral antiplatelet therapy, and better anticoagulation regimens. Given these better results, the quest to further optimize outcomes has proven challenging. Recent trials using new pharmacological agents, intracoronary platelet glycoproteins IIb/IIIa receptor inhibitors, intra-aortic balloon pump, or mechanical thrombectomy have been negative or have produced marginal benefit in surrogate endpoints ((2),3).

In this issue of the Journal the RIVAL (Radial vs. Femoral Access for Coronary Intervention) (4) and RIFLE-STEACS (Radial Versus Femoral Investigation in ST Elevation Acute Coronary Syndrome) (5) investigators report a detailed analysis of the 2 large randomized trials comparing radial and femoral approaches in patients with STEMI.

The RIVAL trial was performed in 32 countries and included 7,021 patients with acute coronary syndromes from 2006 to 2010 (6). RIVAL remains the largest trial comparing the radial versus femoral approach to date. Of note, only 122 patients were recruited in the United States. Initially, the RIVAL study was a substudy of the CURRENT (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events) trial (no STEMI), which recruited approximately one-half of its patients before the study continued on its own. Patients with STEMI began to be enrolled after the protocol was amended, and 1,958 patients (28% of the total trial) were included. Results were reported in 2011, and more recently the authors provided a detailed analysis comparing results in patients presenting with STEMI versus those presenting with unstable angina or non-STEMI. Comparison between the characteristics of the 2 trials is provided in (Table 1). It is important to mention that the primary outcome for the overall RIVAL trial was not significantly reduced with the radial approach compared with the femoral approach (3.7% vs. 4.0%; hazard ratio [HR]: 0.92; 95% CI: 0.72 to 1.17; p = 0.50). The rate of TIMI (Thrombolysis In Myocardial Infarction) major non–coronary artery bypass graft (CABG)-related bleeding was low and identical in both groups at 0.5%. Yet using the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) major bleeding definition, the researchers found a significant benefit with the radial approach compared with the femoral approach (1.9% vs. 4.5%; HR: 0.43; 95% CI: 0.32 to 0.57; p < 0.0001). In accordance with recently published meta-analyses, they also found a significant reduction in vascular complications with the radial approach (1.4% vs. 3.7%; HR: 0.37; 95% CI: 0.27 to 0.52; p < 0.0001) (7). Two findings in pre-specified subgroups, however, have generated much discussion. First, the primary outcome was lower among patients assigned to the radial approach at high-volume radial centers (HR: 0.49; 95% CI: 0.28 to 0.87; p = 0.015). Second, among patients with STEMI (the subject of the article under discussion), the radial approach significantly reduced the primary outcome (3.1% vs. 5.2%; HR: 0.60; 95% CI: 0.38 to 0.94; p = 0.026), as well as all-cause mortality (1.3% vs. 3.2%; HR: 0.39; 95% CI: 0.20 to 0.76; p = 0.006). In the primary PCI population, the radial approach produced a 54% relative reduction in mortality at 30 days compared with the standard femoral approach. No such benefits were found in patients without STEMI. Importantly, using the OASIS-5 (Fifth Organization to Assess Strategies in Acute Ischemic Syndromes)–derived major bleeding definition (main definition), neither access site–related nor non–access site–related bleeding were reduced by the radial approach in patients with and without STEMI, whereas access site bleeding was reduced in patients both with and without STEMI with the ACUITY definitions. Conversely, non–access site–bleeding was similar with the radial and femoral approaches in both clinical scenarios.

The RIFLE-STEACS trial was performed at 4 Italian centers from 2009 to 2011 (5). Compared with RIVAL, patients in the RIFLE-STEACS study were at higher baseline risk because the investigators included patients with symptom duration up to 24 h as well as patients presenting with cardiogenic shock. To date, this randomized trial is the only one that has included such a complex population. This was possible because informed consent could be given by family members or relatives. Ultimately, 10% of patients presented in Killip III/IV class and 8% required intra-aortic balloon pump during procedures. Importantly, the RIFLE-STEACS trial was more of a primary PCI trial (99% PCI), whereas RIVAL was more of a STEMI trial (<75% primary PCI). More patients received >300 mg of a clopidogrel loading dose prior to PCI, and platelet glycoprotein IIb/IIIa inhibitors were used in 69% of the RIFLE-STEACS patients versus <35% in RIVAL STEMI patients. Bivalirudin was rarely used in the RIVAL trial and in <10% of the patients in RIFLE-STEACS. Reflecting current practice, ≤6-F sheaths were used in both trials in >90% of the patients. In RIFLE-STEACS, the radial approach was associated with a 36% relative reduction in the primary outcome (13.6% vs. 21%; p = 0.003). Importantly, cardiac death was also reduced with the radial approach compared with the femoral approach (5.3% vs. 9.2%; p = 0.020). The difference was attributed by the researchers to the reduction of bleeding (7.8% vs. 12.2%; p = 0.026), and particularly access site bleeding, because no difference in non–access site bleeding was observed between the 2 groups. It should be noted that using the TIMI non-CABG major bleeding definition, the difference between the 2 groups was no longer significant (1.8% vs. 2.8%; p = 0.399). However, in contrast to the RIVAL study, the radial approach reduced the risk of blood transfusion in RIFLE-STEACS.

Although these trials have many differences, both showed that the radial approach was associated with a striking relative reduction in mortality, 44% in all-cause death in RIVAL STEMI and 60% in cardiac death in RIFLE-STEACS. Should we conclude that the case is closed and that the radial approach should now become the preferred and standard access site for treating all patients presenting with STEMI?

Although the radial approach for diagnostic angiography and interventions was described 20 years ago, it is only recently that there has been renewed interest in the technique (8). There is firm and convincing evidence that the radial approach reduces vascular complications and access site–related bleeding, accelerates ambulation, and is largely preferred by patients over the femoral approach ((6),9). In an era of cost containment, these benefits allow faster hospital discharge and hence substantial cost benefits for health systems (10). These undisputed benefits create selection bias (radial bias) because patients at higher risk of bleeding are typically no longer enrolled in those trials either because of exclusion criteria (such as in these trials) or simply because interventional cardiologists do not want any more of these patients to randomize. Hence, the risk exists that lower-risk patients get randomized, and underpowered trials and type II errors result.

But how can simply changing the arterial access site from femoral to radial reduce mortality? A simplistic view is that the reduction in major bleeding is the likely mechanism of the mortality benefit. Although periprocedural bleeding after the radial or femoral approach is clearly associated with worse outcomes, that does not mean that bleeding reduction might automatically reduce mortality ((11),12). Furthermore, recent evidence suggests that non–access site bleeding is more deleterious than access site bleeding (13). Two important observations from the studies can be made: 1) the impact on bleeding is highly dependent of the definitions used; and 2) it is likely that the radial approach minimizes access site bleeding regardless of the definition, but any impact on non–access site bleeding remains undetermined and unlikely.

It seems biologically implausible that the reduction of access site–related bleeding/complications with the radial approach could explain the >50% relative reduction in 30-day mortality after primary PCI ((7),9). Although we do not have the detailed causes of deaths in RIVAL, they are provided in the appendix for RIFLE-STEACS. Because most patients in the radial and femoral arms died early after PCI and most often from pump failure, it is difficult to understand the mechanisms by which the radial approach provided its benefit. Other potential mechanisms of the benefits of the radial approach could lie in earlier ambulation (lower risk of venous thromboembolism and pulmonary embolism), rapid hospital discharge (lower risk of nosocomial infection), lower risk of renal dysfunction (secondary to periprocedural renal embolization), or other unknown factors (14).

Although the exact impact of the radial approach on mortality remains unclear, this should not delay the efforts to promote and increase the use of the radial approach (15). Indeed, although the industry has invested hundreds of millions of dollars to find new pharmacological compounds or devices, there is no need to develop costly new devices to practice transradial PCI (16). In fact, this is one of the major challenges to performing large randomized trials comparing the radial with femoral approach because the industry has little incentive to invest in those studies. In the United States for the first time, investigators at the Duke Clinical Research Institute have combined industry funding with funding provided by the Food and Drug Administration Office of Women's Health to support the conduct of a multicenter trial comparing the radial and femoral approach in women undergoing PCI (SAFE-PCI for Women [Study of Access Site for Enhancement of PCI for Women]; NCT01406236).

Another teaching point from these 2 studies is the relationship among radial experience, PCI volumes, and outcomes. Although RIVAL operators were not primarily radial operators, the investigators observed better results at sites with more radial experience, whereas RIFLE-STEACS operators were using the radial approach in >50% of patients prior to study initiation. Hence, this might suggest that the benefit observed for the treatment of patients with STEMI with the radial approach does not necessarily require expert radial operators and that default radial operators could even possibly obtain better results. To maximize benefit, it is crucial that fellows get exposed early in their training to the radial approach (15). Finally, it should be noted that crossover from the radial approach occurred in >5% in both trials. This should remind us that the radial approach to patients with STEMI should be used only after adequate training and exposure, but interventional cardiologists are still required to master both access sites to provide optimal care to patients presenting with acute coronary syndromes. Furthermore, given the low participation of U.S. sites in previous trials comparing radial versus femoral approaches, there is a need for well-designed, large clinical trials including patients from the United States. Meanwhile, ongoing trials comparing radial versus femoral approaches for patients with STEMI will soon further define the exact benefits of the radial approach (STEMI-RADIAL trial [ST Elevation Myocardial Infarction Treated by Radial or Femoral Approach] NCT01136187, SAFARI-STEMI trial [Safety and Efficacy of Femoral Access Versus Radial for Primary Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction] NCT01398254, MATRIX trial [Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX] NCT01433627). Before these data become available, the researchers discussed here and investigators throughout the world must be congratulated on providing this important clinical information to the cardiology community.

⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily reflect the views of JACC or the American College of Cardiology.