COURAGE at 15 Years: Still No Survival Advantage for PCI

Extended follow-up from COURAGE—a pivotal trial that tested PCI’s effect on long-term mortality in stable CAD—shows no survival benefit with early revascularization over optimal medical therapy (OMT) alone. However, the analysis involves only about half of the patients initially enrolled and is missing key data points, with even the study authors admitting important limitations. 

The findings were published in the November 12, 2015, issue of the New England Journal of Medicine.

COURAGE, originally published in 2007, randomized 2,287 stable CAD patients to OMT with or without PCI at 50 US and Canadian centers between 1999 and 2004. Both groups received pharmacologic and lifestyle interventions consistent with existing clinical practice guidelines. The trial found no difference between the 2 strategies for the outcomes of death, nonfatal MI, and hospitalization for ACS at a median follow-up of 4.6 years.

For the new analysis, Steven P. Sedlis, MD, of New York VA Healthcare Network (New York, NY), and colleagues examined survival information on patients from the original COURAGE cohort by searching the VA’s Corporate Data Warehouse and the National Death Index through 2012.

Extended follow-up data were available for 53% of the original population at a median duration of 11.9 years, compared with a median of 6.2 years for all trial participants. In the original trial, 4% of patients assigned to PCI did not undergo revascularization at all and 21.1% of patients in the PCI group and 32.6% of those in the OMT group had additional revascularization. However, no data were available on any revascularizations that occurred during extended follow-up.

Overall, 25% of the population died (180 during the original trial and 381 during extended follow-up), with no difference in mortality rates between the PCI and OMT-only groups for either time span.

The results for death from any cause in the PCI group vs the OMT group were confirmed by Cox regression analysis, which accounted for all baseline variables and design variable (HR 1.03; 95% CI 0.83-1.21). Furthermore, there were no significant interactions between treatment effect and any of the subgroup variables.

No Late Trend

Sedlis and colleagues say the results are consistent with those of the BARI 2D trial. Over a median follow-up of 5.3 years, that trial also failed to “show a survival benefit with PCI for the primary endpoint of death from any cause,” they note.

“In the original [COURAGE] trial, the survival curves appeared to separate at 5 years in favor of PCI … which suggested that a late survival benefit with an initial management strategy of PCI may have emerged toward the end of the follow-up period,” the study authors write. “However, after 15 years of extended follow-up, nearly half the VA patients and one quarter of the non-VA patients in the study had died, and no late trend had emerged to suggest a survival benefit with initial PCI.”

During the initial COURAGE trial, 32.6% of patients crossed over from OMT to revascularization. The lack of information on how many patients in the OMT group later underwent revascularization during extended follow-up is a key drawback to the current analysis, Sedlis and colleagues acknowledge. Without this element, there can be no answer to the question of whether patients initially treated with medical therapy alone are likely to require PCI or CABG in later years.

In an interview with TCTMD, Ajay J. Kirtane, MD, SM, of NewYork-Presbyterian Hospital/Columbia University Medical Center (New York, NY), said that omission makes the results “minimally informative.”

Sedlis and colleagues also note that, due to issues of permission and informed consent for survival tracking, the extended follow-up mainly included veterans and a small number of non-VA trial participants from the United States. No extended data from Canadian patients could be collected.

“This is a very important point,” Kirtane observed. “We know from the original trial that there were differences based on where patients were enrolled and in fact, the patients who did the best with PCI were at non-VA sites, particularly in Canada. So, the fact that those patients are missing further obscures the question of any potential benefit of PCI.”

Other limitations of COURAGE as a whole include little, if any, use of invasive physiologic measurements, limited use of IVUS or other newer imaging modalities, little use of DES, and a restriction in the protocol against CABG as a revascularization option. The authors say that taken together, the limitations underscore the importance of the ongoing ISCHEMIA trial. The primary hypothesis for the newer study is that an invasive approach to stable ischemic heart disease can reduce hard clinical outcomes.

Kirtane said he has already enrolled 2 patients in ISCHEMIA and predicts it will be “far more relevant than this study.”  
 

Source: 
Sedlis SP, Hartigan PM, Teo KK, et al. Effect of PCI on long-term survival in patients with stable ischemic heart disease. N Engl J Med. 2015;373:1937-1946. 

Disclosures:

• The COURAGE trial was supported by Department of Veterans Affairs Cooperative 
• Studies Program, with additional funding provided by the Canadian Institutes of Health Research and supplemental corporate support in the form of unrestricted research grants from AstraZeneca, Bristol-Myers Squibb, Datascope, First Horizon, Fujisawa, GE Healthcare, Key Pharmaceutical, Kos Pharmaceuticals, Merck, Pfizer, and Sanofi-Aventis payable to the Department of Veterans Affairs. 
• Dr. Sedlis reports no relevant conflicts of interest. 
• Dr. Kirtane reports receiving institutional grant/research support from Abbott Vascular, Abiomed, Boston Scientific Corporation, Eli Lilly and Company, Medtronic, St. Jude Medical, and Vascular Dynamics.