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Extended BEST trial offers insight into murky dispute over optimal long-term revasc strategy in MVCAD

10-year follow-up of BEST study from 2015 latest to show near ‘clinical equipoise’ between contemporary PCI versus CABG for multivessel disease

Findings from the 10-year extended BEST study showed comparable long-term outcomes between coronary artery bypass grafting (CABG) and contemporary percutaneous coronary intervention (PCI) in patients with multivessel coronary artery disease (MVCAD).

As more trials continue to observe smaller differences in long-term clinical outcomes between the two coronary revascularization strategies, the latest study to incorporate advances in second-generation drug-eluting stents (DES) and intracoronary imaging techniques further highlighted the importance of individualizing treatment for MVCAD patients.

The BEST Extended Outcome Study – presented by Jung-Min Ahn, MD (Asan Medical Center, Seoul, South Korea) at TCT 2022 in Boston, Massachusetts on Sept 19 – showed no significant differences between PCI (34.5%) and CABG surgery (30.3%) for the composite primary endpoint (HR 1.18; 95% CI; 0.88-1.56; P=0.26) defined as all-cause death, myocardial infarction (MI) or target-vessel revascularization (TVR) during median follow-up of 11.8 years.

“As anticipated,” rates of spontaneous MI (7.1% vs. 3.8%; HR 1.86; 1.06-3.27; P=0.031) and repeat revascularization (22.6% vs. 12.7%; HR 1.92; 1.58-2.32; P<0.001) were higher with PCI. Findings were published simultaneously in the Circulation.

“The 10-year follow-up of BEST provides important long-term insights that could aid decision-making for an optimal revascularization strategy in patients with MVCAD,” Ahn said at TCT 2022. “In the trial, second-generation everolimus-eluting stents (EES) was the default stent platform and intravascular ultrasound (IVUS) was used in 71.8% of patients who underwent PCI.”

“As anticipated, the PCI group had higher rates of spontaneous MI and repeat revascularization, [since] PCI targets only the narrowed coronary lesion and cannot prevent atherosclerosis progression in non-target lesions over time,” Ahn said. “CABG anastomosed grafts to the coronary vessel beyond the narrowed coronary lesion, targeting potential future culprits and protecting against events arising from de-novo coronary disease progression.”

Although the relative risk of spontaneous MI was higher with PCI, the overall incidence was low (PCI 7.1% vs. CABG 3.0%) when compared to the 5-year SYNTAX trial (10.6% vs. 3.3%) and 5-year FREEDOM trial (13.9% vs. 6.0%), investigators said.

10-year follow-up of BEST provides important long-term insights that could aid decision-making for an optimal revascularization strategy in patients with MVCAD.

Jung-Min Ahn, MD

Fatal spontaneous MI only occurred in 1.8% of the PCI group, indicating that the higher rates with PCI “did not translate to higher mortality found in the ISCHEMIA trial.” A previous meta-analysis of 144 randomized trials on CAD patients also supported the notion that non-fatal MI “may not be a surrogate for mortality.”

However, Ahn warned that “results of randomized trials are not generalizable to a broad spectrum of patients with diverse clinical and lesion complexity” – making heart team discussions crucial. “Revascularization strategy should be individualized in real-world practice,” he said.

‘Best’ long-term strategy for mixed bag of MVCAD patients?

The present trial continued follow-up of the original prospective, multicenter, open-label randomized controlled BEST trial by Seung-jung Park, MD, PhD (Asan Medical Center, Seoul, South Korea) and Korean investigators, which was published in the New England Journal of Medicine (NEJM) in 2015.

The original study randomized 880 patients to test the non-inferiority of PCI compared to CABG for the composite primary outcome of major adverse cardiac events (MACE) defined as mortality, MI or TVR. The study, which first aimed for 1,776 patients, was terminated early due to slow enrollment.

At median follow-up of 4.6 years, initial findings showed clearly improved outcomes with CABG for the composite primary endpoint (PCI 15.3% vs. CABG 10.6%; HR 1.47; 95% CI; 1.01-2.13; P=0.04) but no significant between-group differences for the composite safety endpoint of death, MI or stroke (11.9% vs. 9.5%; P=0.26). Analysis also showed no significant between-group differences for individual endpoints of death (PCI 6.6% vs. CABG 5.0%; P=0.30), stroke (2.5% vs. 2.9%; P=0.72) and MI (4.8% vs. 2.7%; P=0.11) but spontaneous MI was significantly higher with PCI (4.3% vs. 1.6%; P=0.02).

Publishing findings, the BEST investigators called for a longer follow-up to monitor the mortality endpoint in both revascularization arms, citing potential for changes in treatment effectiveness over time.

Lack of mortality difference between the 2 revascularization strategies is partly due to [novel] PCI characteristics like advanced stent technology and frequent intracoronary imaging.

Jung-Min Ahn, MD

For the extended follow-up, principal investigators from 27 international centers of the original trial gathered the status of 880 patients (average age: 64 years; 70% male) between March and May 22 and completed the 10-year follow-up for 99.2% (median follow-up: 11.8 years).

Baseline characteristics of patients randomized to PCI (n=438) and CABG (n=442) included diabetes (PCI 40.4% vs. CABG 42.1%), hypertension (67.6% vs. 66.7%), hyperlipidemia (54.6% vs. 50.2%) and relatively low SYNTAX scores (24.2 vs. 24.6).

Analysis of procedural characteristics showed the average number of stents was 3.4, average stent length was 85.3 mm, and mean stent diameter was 3.1 mm in the PCI group. IVUS was used for 71.8% of patients and about half had complete revascularization.

For the CABG group, 99.3% had a left internal mammary artery (LIMA) graft, 64.3% had off-pump surgery and 71.5% had complete revascularization (average number of grafted vessels: 3; arterial grafts: 2; vein grafts: 1).

The primary endpoint was defined as 10-year MACE (composite of all-cause death, MI or TVR). Secondary endpoints included the composite safety outcome (death, MI or stroke) and the composite outcome of death, MI, stroke or any repeat revascularization. Other secondary endpoints included the individual components of the composite endpoints.

Results showed no significant difference between PCI and CABG for the composite primary endpoint (34.5% vs. 30.3%; HR 1.18; 95% CI; 0.88-1.56; P=0.26) or the composite secondary safety endpoint (28.8% vs. 27.1%; HR 1.07; 0.75-1.53; P=0.70) and all-cause mortality (20.5% vs. 19.9%; HR 1.04; 0.65-1.67; P=0.86).

As-treated analysis comparing patients actually treated with PCI (n=464) or CABG (n=401) showed consistent findings for the primary endpoint (HR 1.20; 0.92-1.56; P=0.17) and all-cause death (HR 0.89; 0.65-1.22; P=0.47) in addition to other secondary endpoints.

Although PCI reported higher rates of spontaneous MI (7.1% vs. 3.8%, HR 1.86; 1.06-3.27; P=0.03), investigators noted that both target vessel-related incidences (2.5% vs. 1.8%; HR 1.40; 0.86-2.28; P=0.18) and non-target vessel-related incidences (4.6% vs. 2.0%; HR 2.27; 0.97-5.31; P=0.06) were statistically insignificant, albeit higher for PCI.

The timely adoption of updated medical therapy and crossover from PCI to CABG due to recurrent events during follow-up may have also neutralized the treatment effect.

Jung-Min Ahn, MD

For repeat revascularizations, analysis showed TVR (13.5% vs. 9.5%; HR 1.47; 1.12-1.93; P=0.005) and non-target lesion revascularization rates were significantly higher with PCI (16.2% vs. 5.9%; HR 2.94; 1.99-4.34; P<0.001). Target lesion revascularization rates were also higher with PCI but the difference was statistically not significant (10.5% vs. 8.4%; HR 1.28; 0.90-1.82; P=0.16).

Ahn and investigators wrote: “The increased risk of spontaneous MI and repeat revascularization after PCI was related to non-target vessels, possibly as a result of the lower rate of complete revascularization in the treatment group (PCI 50.9% vs. CABG 71.5%). Incomplete revascularization has been associated with a higher risk of cardiac events and may be a risk modifier for spontaneous MI according to revascularization strategies.”

For patients with diabetes, prespecified subgroup analysis showed a clear increase in the primary endpoint risk with PCI (42.9% vs. 31.7%; HR 1.52; 1.12-2.07; P=0.007), although overall mortality rates were similar between PCI and CABG (26.0% vs. 27.4%; HR 0.96; 0.60-1.54; P=0.87).

Compounded by the lack of between-group differences in patients without diabetes (28.7% vs. 29.3%; HR 0.97; 0.67-1.39; P=0.79), investigators noted “significant interaction” between revascularization strategy and diabetes mellitus (P=0.009) “backed the notion” of CABG superiority for the subgroup.

Narrowing mortality difference between CABG vs PCI with DES, IVUS

Although not without faults, the randomized data may aid decision-making between contemporary revascularization techniques – that have both evolved significantly over time – and better define decision-making factors for a heterogenous MVCAD population, investigators said.

Results of randomized trials are not generalizable to a broad spectrum of patients with diverse clinical and lesion complexity, making heart team discussions crucial.

Particularly, the evidence may bridge gaps in data on contemporary PCI versus CABG and update both older studies conducted before second-generation DES and even the contemporary BEST, SYNTAX, FREEDOM and SYNTAXES trials.

“In the original BEST trial, the survival curves appeared to initially favor CABG at 5-years but they did not diverge further, remaining statistically insignificant during late follow-up,” Ahn said. “This lack of mortality difference between the two revascularization strategies may be partially explained by the variety of PCI strategies, such as the use of advanced stent technology and intracoronary imaging.”

“Second-generation EES – the default stent platform of the BEST trial – has also been shown to reduce the risk of stent thrombosis and subsequent post-PCI long-term cardiac mortality compared to first-generation DES. IVUS use has been associated with lower risk of mortality and cardiac events (HR 0.45; 0.33-0.61; P<0.001).

“Contrary to previous randomized trials using DES, the extended BEST study showed no significant difference in mortality between PCI and CABG. The timely adoption of updated medical therapy and crossover from PCI to CABG due to recurrent events during follow-up may have also neutralized the treatment effect to some extent.”

To further equalize outcomes between the two strategies, Ahn noted the ability to achieve complete revascularization and guideline-directed medical therapy (GDMT) were potential key factors. Population aging during “very long-term follow-up” could also mitigate the mortality endpoint.

“In this study, there was no between-group difference in cardiac events in patients with ejection fraction (EF) ≤40%, but this was a subgroup analysis with a limited sample size,” he said. “The ongoing Canadian CABG or PCI in Patients With Ischemic Cardiomyopathy (STICH3C) trial is expected to shed more insight.”

Limitations of the extended BEST trial included underpowered endpoints due to the premature termination of the original trial (partially offset by the long-term follow-up), open-label design and few patients with a high SYNTAX score (16.5%).

Edited by

Jung-Min Ahn
Jung-Min Ahn , MD

Asan Medical Center, Korea (Republic of)

Written by

YoonJee Marian Chu
YoonJee Marian Chu, Medical Journalist
Read Biography

The BEST Extended Outcome Study was funded by the CardioVascular Research Foundation (Seoul, South Korea) and Abbot Vascular (Santa Clara, California, USA); neither participated in study design, data collection, analysis, interpretation or writing of the report.

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