Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery - SYNTAX

Description:

Given the recent advances in the fields of both coronary artery bypass grafting (CABG) as well as percutaneous coronary intervention (PCI) (especially drug-eluting stent [DES] PCI), the goal of this trial was to compare the relative efficacy of CABG versus DES-PCI (using TAXUS stents) in all-comers with severe three-vessel disease (3-VD) or left main (LM) disease, who were deemed eligible for either CABG or PCI.

Contribution to the Literature: The SYNTAX trial showed that in patients with LM disease and/or severe 3-VD, CABG with the use of at least one arterial graft was superior to PCI with TAXUS DES at 5 years.

Study Design

  • Randomized
  • Parallel
  • Stratified

Patients Screened: 4,337
Patients Enrolled: 1,800
Mean Follow-Up: 1, 3, and 5 years
Mean Patient Age: 65.1 years
Female: 22%
Mean Ejection Fraction: Only about 2% had an ejection fraction of <30%.

Patient Populations:

  • De novo coronary artery disease
  • Coronary anatomy suitable for both CABG and PCI

Exclusions:

  • Previous PCI or CABG
  • Acute MI with creatine kinase >2 x ULN
  • ≥50% target vessel stenosis with stable/unstable angina or atypical chest pain
  • If asymptomatic, positive evidence of myocardial ischemia was required
  • Concomitant cardiac surgery

Primary Endpoints:

  • MACCE (all-cause mortality, stroke, MI, or repeat revascularization) at 1, 3, and 5 years

Secondary Endpoints:

  • Death
  • MI
  • CVA
  • Death, MI, or cerebrovascular accident

Drug/Procedures Used:

All patients in the PCI arm received TAXUS (paclitaxel-eluting) stents, whereas all patients in the CABG arm underwent on- or off-pump bypass.

Concomitant Medications:

All patients received aspirin indefinitely. In the PCI arm, thienopyridines were mandatory for 6 months, and 71.1% received them for 12 months. Other medications: statins (81%), beta-blockers (80%), angiotensin-converting enzyme inhibitors (50%). All of these medications were more likely to be used in the PCI arm.

Principal Findings:

Of all the patients who were screened, a team consisting of a surgeon and an interventionalist decided if the anatomy was suitable for both CABG and PCI, CABG only, or PCI only. The patients who were amenable to both options constituted the study population for this study. They were further stratified by the presence of LM disease and diabetes mellitus. The investigators also calculated the SYNTAX score for each patient, based on the coronary lesion complexity.

A total of 1,800 patients were randomized, 897 to CABG and 903 to DES-PCI. About 25.1% were diabetic, with 33% having evidence of prior myocardial infarction (MI). Unstable angina was present in about 28.5% of the patients, and the additive mean EuroSCORE was 3.8. The total SYNTAX score was similar between the CABG and PCI arms (29.1 vs. 28.4, p = 0.19). The time to procedure was significantly shorter in the PCI arm (17.4 vs. 6.9 days, p < 0.0001). Medical management at discharge was better in the PCI arm.

The mean number of lesions was about 4.4, with about 66% having 3-VD only (without LM involvement), and 3.4% having pure LM disease. LM + 1-, 2-, and 3-VD was present in about 5.3%, 11.8%, and 13.7% of the patients, respectively. The number of bifurcation and trifurcation lesions was similar between the two groups (73.3% vs. 72.4%, 10.6% vs. 10.7%).

Of the patients undergoing PCI, the mean number of stents implanted was 4.6, with an average of 3.6 lesions being treated per patient. About 14.1% had a staged procedure. About 15% of the patients in the CABG arm underwent off-pump CABG; at least one arterial graft was used in 97.3% of the patients (95.6% with an arterial graft to the left anterior descending artery). The mean number of grafts per patient was 2.8.

The incidence of the primary endpoint of major adverse cardiac and cerebrovascular events (MACCE) at 12 months was lower in the CABG arm compared with PCI (12.4% vs. 17.8%, p = 0.002), and did not meet the prespecified noninferiority threshold for PCI. This was driven predominantly by a significant reduction in the incidence of repeat revascularization in the CABG arm compared with PCI (5.9% vs. 13.5%, p < 0.001). There was no difference in the incidence of death (3.5% vs. 4.4%, p = 0.37) or MI between the two arms (3.3% vs. 4.8, p = 0.11). The incidence of cerebrovascular accident was significantly higher in the CABG arm (2.2% vs. 0.6%, p = 0.003), whereas the incidence of symptomatic graft occlusion and stent thrombosis was similar between the two arms (3.4% vs. 3.3%, p = 0.89).

On subgroup analysis of the LM patients, the overall 12-month MACCE event rate was lower with CABG (13.7% vs. 15.8%), although patients with LM only (8.5% vs. 7.1%) and LM + 1-VD (13.2% vs. 7.5%) seemed to do slightly better with PCI. Patients with LM + 2-VD (14.4% vs. 19.8%), LM + 3-VD (15.4% vs. 19.4%), or 3-VD alone (11.5% vs. 19.2%) seemed to do better with CABG than PCI. When stratified by diabetes status, patients with diabetes had lower 12-month MACCE event rates with CABG than with PCI (14.2% vs. 26.0%, p = 0.0025), whereas nondiabetic patients showed a trend toward a benefit with CABG, but it was not statistically significant (11.8% vs. 15.1%, p = 0.08).

Three-year follow-up: The incidence of the primary endpoint of MACCE was still lower in the CABG arm as compared with the PCI arm (20.2% vs. 28.0%, p < 0.001), once again driven by a significant reduction in repeat revascularization with CABG (10.7% vs. 19.7%, p < 0.0001). Interestingly, the rates of MI were also lower in the CABG arm at 3 years (3.6% vs. 7.1%, p = 0.0002); strokes were numerically higher with CABG, but no longer statistically significant (3.4% vs. 2.0%, p = 0.07). On subgroup analysis, no difference in the primary endpoint was noted in the LM subset (22.3% vs. 26.8%, p = 0.20), but was statistically lower with CABG in the 3-VD subset (18.8% vs. 28.8%, p < 0.0001). When stratified by SYNTAX score, all patients with low (0-22) and some patients with intermediate (23-32) SYNTAX scores did equally well with PCI as compared with CABG.

Five-year follow-up: The incidence of the primary endpoint of MACCE was still lower in the CABG arm as compared with the PCI arm (26.9% vs. 37.3%, p < 0.0001). Reductions were also noted in the incidence of repeat revascularization (13.7% vs. 25.9%, p < 0.0001) and MI (3.8% vs. 9.7%, p < 0.0001); strokes remained numerically higher with CABG, but not statistically significant (3.7% vs. 2.4%, p = 0.09). The incidence of stent thrombosis or graft occlusion was similar (4.0% vs. 5.5%). All-cause mortality was similar between CABG and PCI (11.4% vs. 13.9%, p = 0.1). However, CABG was superior to PCI for CV (5.8% vs. 9.6%, p = 0.008) and cardiac (5.3% vs. 9.0%, p = 0.003) mortality. MI-related mortality was particularly low with CABG (0.4% vs. 4.1%, p < 0.0001).

On subgroup analysis, no difference in the primary endpoint was noted in the LM subset (31.0% vs. 36.9%, p = 0.12), but was statistically lower with CABG in the 3-VD subset (24.2% vs. 37.5%, p < 0.0001). When stratified by SYNTAX score, all patients with low (0-22) and the LM subset of patients with intermediate (23-32) SYNTAX scores did equally well with PCI as compared with CABG.

In the overall LM subset, MACCE rates at 5 years were similar between PCI and CABG (36.9% vs. 31.0%, p = 0.12), with higher rates of stroke with CABG (1.5% vs. 4.3%, p = 0.03) and higher rates of repeat revascularization with PCI (26.7% vs. 15.5%, p < 0.01).

In the overall 3-VD subset, MACCE rates at 5 years were higher in the PCI arm compared with CABG (37.5% vs. 24.2%, p < 0.001), including a higher risk of all-cause mortality (14.6% vs. 9.2%, p = 0.006), MI (9.2% vs. 4.0%, p = 0.001), and repeat revascularization (25.4% vs. 12.6%, p < 0.001), with a similar risk of stroke (3.0% vs. 3.5%). When stratified by SYNTAX score, patients with low (0-22) SYNTAX scores had comparable MACCE rates with PCI or CABG (33.3% vs. 26.8%, p = 0.21), with a higher rate of repeat revascularization (25.4% vs. 12.6%, p = 0.038) with PCI.

Cost-effectiveness: Total procedure costs were lower in the CABG arm compared with PCI ($8,504 vs. $11,919) due to a large number of stents required (mean 4.6). However, overall hospitalization costs were higher in the CABG arm ($33,190 vs. $23,154; Δ = $10,036; p < 0.001). Over 5 years of follow-up, the cumulative cost difference narrowed to $5,619. The lifetime analysis demonstrated that CABG was likely to be highly cost-effective (incremental cost-effectiveness ratio = $16,537 per quality-adjusted life-year gained). On subgroup analysis, PCI was the dominant strategy in patients with LM disease and those with a low SYNTAX score; CABG was cost-effective in patients with 3-VD and intermediate and high SYNTAX scores.

Interpretation:

The results of the much-awaited SYNTAX trial demonstrate that in patients with LM disease and/or severe 3-VD, CABG (with the use of at least one arterial graft) is superior to PCI with TAXUS DES. This is especially true for reducing 12-month MACCE rates, which were predominantly driven by the need for repeat revascularization in the PCI arm. CABG is, however, associated with a higher risk of CVA at 12 months, compared with PCI.

Importantly, there is no difference in the incidence of death, MI, or graft occlusion/stent thrombosis between the two arms. The largest benefit from CABG seems to be in patients with diabetes mellitus. The results of this trial also suggest that patients with LM only, LM + 1-VD, and nondiabetics may do as well with both CABG and PCI, although the trial was not powered to study these differences individually.

This is obviously one of the biggest questions in cardiology today, since many significant advances in both surgery and PCI have occurred since the BARI and ARTS trials, which showed superiority for CABG over angioplasty in patients with 3-VD and LM disease. It is unknown if the use of newer-generation stents (everolimus-eluting stents) instead of paclitaxel-eluting stents, would be associated with better outcomes in patients who undergo PCI.

Long-term results indicate that adverse clinical outcomes are lower with CABG as compared with PCI, due to a reduction in repeat revascularization, MI, and MI-related mortality. Not all MIs in the two arms were periprocedural; the higher rate in the PCI arm versus CABG requires further study. Cost-effectiveness analyses also demonstrate a benefit with CABG over PCI at 5 years, but in patients with LM disease and low SYNTAX scores, PCI was the dominant strategy.

The SYNTAX score is increasingly becoming a valuable tool to risk-stratify patients with respect to the optimal revascularization strategy. Patients with LM disease and low and intermediate SYNTAX scores, for example (i.e., lesser complexity), may do equally well with PCI and CABG over 5 years of follow-up. On the other hand, patients with complex 3-VD may do better with CABG. These are very important findings, and could result in a paradigm shift in how LM disease is treated.

References:

Milojevic M, Head SJ, Parasca CA, et al. Causes of Death Following PCI Versus CABG in Complex CAD: 5-Year Follow-Up of SYNTAX. J Am Coll Cardiol 2016;67:42-55.

Cohen DJ, Osnabrugge RL, Magnuson EA, et al. Cost-Effectiveness of Percutaneous Coronary Intervention with Drug-Eluting Stents vs. Bypass Surgery for Patients with 3-Vessel or Left Main Coronary Artery Disease: Final Results from the SYNTAX Trial. Circulation 2014;Aug 1:[Epub ahead of print]

Head SJ, Davierwala PM, Serruys PW, et al. Coronary artery bypass grafting vs. percutaneous coronary intervention for patients with three-vessel disease: final five-year follow-up of the SYNTAX trial. Eur Heart J 2014;May 21:[Epub ahead of print].

Morice MC, Serruys PW, Kappetein AP, et al. Five-Year Outcomes in Patients With Left Main Disease Treated With Either Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting in the SYNTAX Trial. Circulation 2014;129:2388-94.

Presented by Dr. David J. Cohen at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2013), San Francisco, CA, October 28, 2013.

Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013;381:629-38.

Kappetein AP, Feldman TE, Mack MJ, et al. Comparison of coronary bypass surgery with drug-eluting stenting for the treatment of left main and/or three-vessel disease: 3-year follow-up of the SYNTAX trial. Eur Heart J 2011;Jun 22:[Epub ahead of print].

Serruys PW, Morice MC, Kappatein AP, et al., on behalf of the SYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:961-72.

The Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery: The SYNTAX Study. Presented by Dr. Patrick Serruys at the European Society of Cardiology Congress, Munich, Germany, August/September 2008.

Clinical Topics: Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Aortic Surgery, Interventions and Coronary Artery Disease

Keywords: Coronary Artery Disease, Myocardial Infarction, Stroke, Follow-Up Studies, Drug-Eluting Stents, Immunosuppressive Agents, Sirolimus, Angioplasty, Percutaneous Coronary Intervention, Stents, Paclitaxel, Thrombosis, Research Personnel, Coronary Artery Bypass, Diabetes Mellitus


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