Comparison of Coronary Artery Bypass Surgery and Percutaneous Coronary Intervention in Patients with Diabetes: Meta-Anal

1. Comparison of coronary artery bypass surgery andpercutaneous coronary intervention in patients withdiabetes: a meta-analysis of randomised controlled trials Timothy Oh Waikato Cardiothoracic Unit Journal Club

3. Background • Diabetics account for 25% of all revascularisation procedures • CABG vs PCI for diabetics is a constant debate • Limited sufficient powered and specific studies • FREEDOM trial1– first large trial to compare CABG v PCI in diabetics with multi-vessel disease: • CABG lower rates of MACE over 5 years • CABG lower all-cause mortality with borderline significance (p=0.049), due to insufficient power as all-cause mortality was not primary end-point • Since FREEDOM results, other relevant underpowered randomised trials (SYNTAX, CARDia, V CARDS) have been performed2-4 • Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012; 367: 2375–84. • Kappetein AP, Head SJ, Morice MC, et al. Treatment of complex coronary artery disease in patients with diabetes: 5-year results comparing outcomes of bypass surgery and percutaneous coronary intervention in the SYNTAX trial. Eur J CardiothoracSurg 2013;43: 1006–13. • Hall R. CARDia: coronary artery revascularisation in diabetes trial(5-year follow-up data). European Society of Cardiology Congress;Munich, Germany; 2012; Aug 25–29, 2012. • Kamalesh M, Sharp TG, Tang XC, et al. Percutaneous coronary intervention versus coronary bypass surgery in United States veterans with diabetes. J Am CollCardiol 2013; 61: 808–16.

4. AIM / objective • To assess whether all-cause mortalilty different between CABG vs PCI in diabetics, by using meta-analysis of all Randomised controlled trials (RCTs) or sub-group analyses of CABG v PCI in diabetics

5. Data sources • Ovid medline, embase, cochrane central register • 1 Jan 1980 – 12 March 2013 • Search terms: “percutaneous coronary intervention”, “angioplasty”, “coronary artery bypass”, “diabetes mellitus” • Also searched selected articles’ reference lists, conference proceedings, personal files • Searches limited to english language

6. Study selections Inclusion criteria: • Prospective clinical trials • Randomising adults (≥18 years) with multivessel disease and diabetes, to CABG or PCI • to ensure most up-to-date techniques in both intervention groups were being compared: • >80% of patients randomised to CABG had to be bypassed with at least one arterial conduit • >80% of patients randoised to PCI had to have stents used • Reports outcomes separately in diabetic patients with at least 12 months follow-up

7. Study selections Exclusion criteria: • Non-randomised study • Searched citations screened by 2 reviewers & Further screening via full text review by 2 reviewers • Disagreement resolved by consensus amongst 6 reviewers

8. Data extraction & quality assessment • 5 reviewers independently extracted data from included studies • Details of publication were collected and collated • Risk of bias in RCTs was assessed • Disagreements resolved by consensus by 5 reviewers

9. Outcome Measures Primary end-point: • All-cause mortality in patients with diabetes who had CABG vs PCI at 5 years or the longest follow-up duration, pooling trial-level data Secondary end-points: • All- cause mortality at 1-year (or closest) follow-up • Non-fatal myocardial infarction • Non-fatal stroke • Repeat revascularisation at 1-year (or closest) follow-up and at 5 years or longest follow-up duration

10. Data analysis (approach) • Software used: Review Manager (version 5.2) • Used random-effects models incorporating between-trial heterogeneity • Statistical heterogeneity in trials assessed using i2(% of total variability across studies attributale to heterogeneity rather than chance): • Low = 25-49% • Moderate = 50-74% • High ≥ 75%

11. Data analysis (using pooled RR in subgroup analyses) • Risk ratios (RR) used to pool outcomes with two- sided significance level of 5% • Individual trial and summary results reported with 95% CIs • subgroup analysis compared pooled RR of trials using DES in majority of patients vs CABG with pooled RR of trials using BMS in the majority of patients vs CABG • subgroup analysis compared pooled RR in diabetics vs non-diabetics, irrespective of the type of stent used • assessed differences between pooled RR using Z tests

12. Data analysis (publication bias) assess for publication bias: • examined funnel plot comparing effect measure for all-cause mortality vs study precision for evidence of asymmetry • Applied regression tests (Egger’s and modified Macaskill’s)using the metabias command in Stata (version 9.2) • In view of low statistical power of these tests, a more liberal level of significance (p<0·10) was used to suggest possible publication bias

13. Study flow diagram • 4 RCTs used BMS; ERACI II, ARTS, SoS, MASS II • 4 RCTs used DES; FREEDOM, SYNTAX, VA CARDS, CARDia

14. Characteristics of included trials, baseline characteristics of patients, and details of interventions

15. Characteristics of included trials, baseline characteristics of patients, and details of interventions

16. Characteristics of included trials, baseline characteristics of patients, and details of interventions

17. Characteristics of included trials, baseline characteristics of patients, and details of interventions

18. Quality assessment of included RCT

19. Forest plot for all-cause mortality at 5-year (or longest) follow-up

20. Forest plot for all-cause mortality at 1-year (or closest) follow-up

21. Forest plot for outcomes other than mortality at 1-year (or closest) follow-up:(A) NON-FATAL MYOCARDIAL INFARCTION

22. Forest plot for outcomes other than mortality at 1-year (or closest) follow-up:(B) NON-FATAL strokes

23. Forest plot for outcomes other than mortality at 1-year (or closest) follow-up:(c) needforrepeatrevascularisation

24. Forest plot for outcomes other than mortality at 5-year (or lONGEST) follow-up:(A) non-fatal myocardial infarction

25. Forest plot for outcomes other than mortality at 5-year (or lONGEST) follow-up:(B) non-fatal stroke

26. Forest plot for outcomes other than mortality at 5-year (or lONGEST) follow-up:(c) needforrepeatrevascularisation

27. Forest plot for outcomes other than mortality at 5-year (or lONGEST) follow-up, OVERALL

28. Forest plot for outcomes other than mortality at 5-year (or lONGEST) follow-up, OVERALL AND BY DIABETES SUBGROUP (WITH VS WITHOUT DIABETES)

29. Forest plot for outcomes other than mortality at 5-year (or lONGEST) follow-up, OVERALL AND BY DIABETES SUBGROUP (WITH VS WITHOUT DIABETES)

30. DISCUSSIONS • verma’s meta-analysis built upon hlatky’s meta-analysis5: • Hlatky did not include major randomised trials in diabetics (FREEDOM, SYNTAX, VA CARDS, and CARDia) • Hlatky included trials comparing balloon angioplasty • Similar results concluded • Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials. Lancet 2009; 373: 1190–97.

31. DISCUSSIONS • Verma suggested the higher stroke rate in CABG is due to aortic cross-clamping and lower use of antiplatelet therapies (aspirin 99.1% with PCI vs 88.4% with CABG; DAPT 98.4% with PCI v 24.6% with CABG)6 • Verma suggested superiority of CABG is due to longer term durability, more complete revascularisation, and protection from rapid progressive coronary disease in diabetics • Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012; 367: 2375–84.

32. Author’s Conclusion • All 8 trials showed: • CABG was superior to PCI with regard to survival, although a significant difference was only identified in the FREEDOM study and the grossly underpowered VA CARDS trial • The pooled analysis of all trials showed: • survival did not differ at 1-year or shortest follow- up (RR 0·99, 95% CI 0·72–1·37), but CABG resulted in significantly less mortality than PCI after 5 years or longest follow-up (0·67, 0·52–0·86) • The results of this meta-analysis also confirm other findings within secondary outcomes suggested by previous meta-analyses: • The rate of non-fatal stroke was higher with CABG than with PCI at 1 year (RR 2·41, 95% CI 1·22–4·76) and 5 years or longest follow-up (1·72, 1·18–2·53)

33. Strengths of the study • Includes more recent (in 2013) randomised trials that compared CABG with PCI, some exclusively in patients with diabetes, and some involving drug-eluting stents for PCI • Rigorous systematic review

34. Limitations of the study • does not include SYNTAX scores and so it cannot be established whether the benefit of CABG compared with PCI is consistent throughout different complexities of coronary artery disease • Included trials using old stenting techniques, i.e. BMS

35. GENERAL DISCUSSION POINTS • Do these findings translate to a recommendation of CABG in all patients with diabetes? • If not, then who should or should not be referred for CABG? • The role of the heart team

36. Do these findings translate to a recommendation of CABG in all patients with diabetes? • superiority of CABG compared with PCI in the presence of diabetes and coronary artery disease is logical • PCI: only the significant lesion is stented, with the risk of leaving as-yet-insignificant lesions to progress and cause recurrence of symptoms, non-fatal myocardial infarction, or even death • CABG: all existing severe and moderate lesions are bypassed at once, and even though some of these lesions progress to total occlusions, this progression does not lead to symptoms or adverse events because the myocardium remains sufficiently oxygenated through patent grafts • advantage of CABG even more important in patients with diabetes than in those without the disorder, because diabetes accelerates the progression of coronary artery disease

37. Do these findings translate to a recommendation of CABG in all patients with diabetes? NOT NECESSARILY…

38. Do these findings translate to a recommendation of CABG in all patients with diabetes? • pathology of coronary artery disease in patients with three vessel disease is very heterogeneous • for example, patient with occlusion of two coronary arteries in combination with a long lesion in a third artery is more difficult to treat with PCI and has a different prognosis than does a patient with three short lesions • however, in many of the randomised trials that have been done, both types of patients were analysed in the same group

39. Do these findings translate to a recommendation of CABG in all patients with diabetes? • SYNTAX score resolves this shortcoming and quantifies the complexity of coronary artery disease: • Hypothesis- generating subgroup analyses stratified according to SYNTAX score showed that in patients with lesions of low complexity, PCI might be an alternative to CABG • 5-year results from the SYNTAX trial showed that patients with SYNTAX scores of 0–22 had no significant difference in major adverse cardiac and cerebrovascular events with CABG or PCI (33·7% vs 42·5%, respectively; p=0·38) • By contrast, CABG led to better outcomes than did PCI in patients with SYNTAX scores of 23–32 and 33 or higher • Unfortunately, the present meta-analysis does not include SYNTAX scores and so it cannot be established whether the benefit of CABG compared with PCI is consistent throughout different complexities of coronary artery disease

40. Do these findings translate to a recommendation of CABG in all patients with diabetes? • Also, some argue that the benefit of CABG compared with PCI is only apparent in patients with insulin-dependent diabetes • In the 5-year follow-up result from SYNTAX the differences between CABG and PCI were indeed reinforced by insulin dependency • Whereas insulin-dependency did not seem to affect outcomes after CABG, patients who underwent PCI and were insulin-dependent had significantly worse outcomes than did those who were not on insulin • The present meta-analysis could not include such an analysis and this issue will need to be explored in future studies or a meta-analysis that uses pooled individual data

41. who should be referred for revascularisation? • Good question! • Difficult question! • Existing guidelines and clinical decisions are often based on a combination of observational studies, small clinical trials, and expert opinions • Patients with diabetes and coronary artery disease typically often have other organ system comorbidities • Also, decision making and treatment results are also affected by the quality of imaging studies, the expertise of the interventional team, and outcomes specific to each institution

42. The role of the heart team • Different options for different patients • Important that the heart team is able to: • provide best possible treatment recommendations • Represent different treatment options, by having on the team interventional cardiologist, cardiovascular surgeon, and clinical cardiologist • Clearly communicate to the patient: • long-term survival advantage of CABG compared with PCI • short-term disadvantage of an invasive approach