Background: Few studies have examined the efficacy of drug-eluting stents (DES) for reducing aortocoronary saphenous vein bypass graft (SVG) failure compared with bare-metal stents (BMS) in patients undergoing stenting of de-novo SVG lesions. We assessed the risks and benefits of the use of DES versus BMS in de-novo SVG lesions. Methods: Patients were recruited to our double-blind, randomised controlled trial from 25 US Department of Veterans Affairs centres. Eligible participants were aged at least 18 years and had at least one significant de-novo SVG lesion (50–99% stenosis of a 2·25–4·5 mm diameter SVG) requiring percutaneous coronary intervention with intent to use embolic protection devices. Enrolled patients were randomly assigned, in a 1:1 ratio, by phone randomisation system to receive a DES or BMS. Randomisation was stratified by presence or absence of diabetes and number of target SVG lesions requiring percutaneous coronary intervention (one or two or more) within each participating site by use of an adaptive scheme intended to balance the two stent type groups on marginal totals for the stratification factors. Patients, referring physicians, study coordinators, and outcome assessors were masked to group allocation. The primary endpoint was the 12-month incidence of target vessel failure, defined as the composite of cardiac death, target vessel myocardial infarction, or target vessel revascularisation. The DIVA trial is registered with ClinicalTrials.gov, number NCT01121224. Findings: Between Jan 1, 2012, and Dec 31, 2015, 599 patients were randomly assigned to the stent groups, and the data for 597 patients were used. The patients' mean age was 68·6 (SD 7·6) years, and 595 (>99%) patients were men. The two stent groups were similar for most baseline characteristics. At 12 months, the incidence of target vessel failure was 17% (51 of 292) in the DES group versus 19% (58 of 305) in the BMS group (adjusted hazard ratio 0·92, 95% CI 0·63–1·34, p=0·70). Between-group differences in the components of the primary endpoint, serious adverse events, or stent thrombosis were not significant. Enrolment was stopped before the revised target sample size of 762 patients was reached. Interpretation: In patients undergoing stenting of de-novo SVG lesions, no significant differences in outcomes between those receiving DES and BMS during 12 months of follow-up were found. The study results have important economic implications in countries with high DES prices such as the USA, because they suggest that the lower-cost BMS can be used in SVG lesions without compromising either safety or efficacy. Funding: US Department of Veterans Affairs Cooperative Studies Program.
Bibliographical noteFunding Information:
We did not find a significant difference between DES and BMS in the incidence of the combined endpoint of cardiac death, target vessel myocardial infarction, or target vessel revascularisation during the first 12 months and over the entire length of follow-up (median 2·7 years) among patients undergoing stenting of de-novo SVG lesions. There was also no difference in the risk for stent thrombosis or bleeding. DIVA did not mandate angiographic follow-up, which is known to increase the rates of repeat revascularisation in favour of DES. 25 DIVA had higher use of embolic protection devices (69% [409 of 597 patients]) than any previous SVG stenting trial. Our findings are in contrast with those of three 11–13 of the four randomised controlled trials done to date that showed benefit with DES over BMS in SVGs. The ISAR-CABG trial 12 randomly assigned 610 participants to a first-generation DES or a BMS, and reported lower 12-month incidence of target vessel revascularisation in the DES group (7% vs 13%, p=0·01), and no significant differences in all-cause mortality, myocardial infarction, and definite or probable stent thrombosis as compared with BMS. ISAR-CABG had planned angiographic follow-up as did two smaller studies. 9–11 The first study 9 showed harm (higher mortality with DES compared with BMS at 3 years [29% vs 0%, p=0·001], although most deaths were due to non-cardiac events) and similar target vessel revascularisation in both groups. The second study 10,11 showed lower risk for myocardial infarction and target lesion revascularisation with DES than BMS. The BASKET-SAVAGE trial 13 randomly assigned 173 patients to receive either DES or BMS, had no planned angiographic follow-up, and had lower incidence of target vessel revascularisation in the DES group (4·5% vs 19·1% at 3 years, p<0·001). The absence of improved outcomes with DES in DIVA was observed despite the use of second-generation DES in 256 (88%) of 292 patients in the DES group, whereas first-generation DES were used in all previous studies. 9,11–13 The absence of benefit with DES in DIVA could be related to the different pathophysiology of SVG atherosclerosis (more concentric and diffuse with less well defined fibrous cap) compared with native coronary artery atherosclerosis. 26,27 The absence of benefit with DES could also be because of the large burden of comorbidities among patients with a previous CABG, 14 or the use of thin-strut bare-metal stents that might have lower risk for restenosis as compared with thicker strut stents that were used in previous SVG PCI studies; 9,11–13 it is unlikely to be because of differences in stenting technique and concomitant medications, since those characteristics were similar in both groups. Unknown confounders could have played a role, but are unlikely given randomisation. The study results have important economic implications in countries with high DES prices such as the USA, because they suggest that the lower cost BMS can be used in SVG lesions without compromising either safety or efficacy. The financial implications of the study might differ between countries, depending on local stent pricing. An alternative treatment approach would be to recanalise the native coronary artery instead of the diseased SVG, 4,28 although such interventions can be technically challenging. 29,30 Our study has limitations. As is typical in Veterans Affairs studies, nearly all study participants were men, which limits the extrapolation of the results to women, although most patients undergoing PCI after CABG are men. 31 The interventionalists doing the index SVG PCI were not masked to the type of stent used, although the patients, clinicians, and event adjudicators were masked. The study was stopped before completion of the revised enrolment target, yet the number of patients recruited was greater than originally planned and the post-hoc power (86%) was similar to the pre-hoc power (90%) to detect the originally hypothesised HR of 0·556. In summary, in our evaluation of the clinical outcomes of 597 patients undergoing PCI of de-novo SVG lesions, we found no significant difference in the 12-month and long-term (median 2·7 years) incidence of cardiac death, target vessel myocardial infarction, or target vessel revascularisation. Contributors ESB, RE, DLB, SGo, DRH, SVR, KS, BVR, TAC, TW, YL, M-CS, and SB designed the study, analysed and interpreted data, and wrote and revised the manuscript. KM, KR, AAB, SGa, FL, EA, and HJ, implemented the study, enrolled patients, interpreted data, and wrote the manuscript. JK, BV, and AA analysed and interpreted data and wrote the manuscript. RE, LU, M-CS analysed data, did the statistical analyses, and wrote the manuscript. ESB wrote the first draft and submitted the final version of the manuscript. All authors approved the final version of the manuscript. Declaration of interests ESB consults for and receives speaker honoraria from Abbott Vascular, Amgen, Asahi, Boston Scientific, Cardinal Health, CSI, Elsevier, GE Healthcare, Medicure, Medtronic, and Nitiloop, and receives research support from Boston Scientific, InfraRedx and Osprey. ESB's spouse was an employee of Medtronic. DLB is an advisory board member of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; is on the board of directors of Boston VA Research Institute and Society of Cardiovascular Patient Care; is chair of the American Heart Association Quality Oversight Committee; is on the data monitoring committees of Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, and Population Health Research Institute; receives honoraria from the American College of Cardiology, Belvoir Publications, Duke Clinical Research Institute, Harvard Clinical Research Institute, HMP Communications, Journal of the American College of Cardiology, Population Health Research Institute, Slack Publications, Society of Cardiovascular Patient Care, and WebMD; is deputy editor of Clinical Cardiology, and chair of the NCDR-ACTION registry steering committee and VA CART research and publications committee; receives research funding from Abbott, Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi Aventis, and The Medicines Company; receives royalties from Elsevier; is a site co-investigator for Biotronik, Boston Scientific, and St Jude Medical (now Abbott); is a trustee of the American College of Cardiology; and does unfunded research for FlowCo, Merck, PLx Pharma, and Takeda. SG receives research support from the National Institutes of Health, the VA Cooperative Studies Program, the Arizona Biomedical Research Commission, and Merck Pharmaceuticals, and is the co-founder of Avery Therapeutic. SVR consults for Medtronic. KS consults for Medeon Bio Inc, TransAortic Medical, and Terumo, and receives research support from Siemens Medical Systems and Medinol. AAB consults for the American College of Cardiology. SG receives research grants from Edwards Lifesciences and VA Office of Research and Development, and consults for Medtronic, Boston Scientific, Osprey Medical, and Surmodics. FL is a speaker for Abbott Vascular, and consults for Medicure. EA consults for Abbott Vascular, Boston Scientific, Cardiovascular Systems, Medtronic, and Spectranetics. BVR receives a research grant from InfraRedx and the Spectranetics Corporation, and salary support from the VA Cooperative Studies Program. YL consults for PTC Therapeutics and PaxVax. SB receives speaker honoraria from AstraZeneca, CSI, Gore, and Medtronic, and institutional research grants from Boston Scientific Corporation, and Merck. All other authors declare no competing interests. Acknowledgments This study was funded by the US Department of Veterans Affairs Cooperative Studies Program (125). The views expressed in this Article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or any US Government agency.