By Michael H. Crawford, MD, Editor

SYNOPSIS: A combined analysis of six trials comparing radial artery grafts vs. saphenous vein grafts for coronary bypass surgery revealed that patients taking calcium channel blockers for at least one year experienced fewer major cardiac events and fewer radial graft occlusions than those not so treated.

SOURCE: Gaudino M, Benedetto U, Fremes SE, et al. Effect of calcium-channel blocker therapy on radial artery grafts after coronary bypass surgery. J Am Coll Cardiol 2019;73:2299-2306.

The use of radial artery (RA) grafts as conduits for coronary artery bypass graft surgery (CABG) likely will increase now that the results of randomized, controlled trials (RCTs) have shown that they are superior to saphenous vein grafts for reducing subsequent coronary events. However, the role of calcium channel blocker (CCB) therapy and its duration after RA graft placement are unclear.

Investigators pulled data from six RCTs to address this issue. The authors of each trial recommended CCBs postoperatively, although with different agents for different time periods. The primary outcome was a major adverse cardiac event (MACE) at maximum follow-up. The main secondary outcome was RA graft occlusion. The final study population included 732 patients, of whom 502 received CCBs. Angiographic information by protocol was available for 243 patients treated with CCBs, and 200 of those who were not so treated. Median clinical follow-up was 60 months, and angiographic follow-up was 55 months.

Comparing the treated vs. not treated groups, the MACE rate at 36 months was 3.7% vs. 9.3%; at 72 months, 13.4% vs. 17.6%; and at 108 months, 16.8% vs. 20.5% (P = 0.003.). The incidence of RA graft occlusion was 0.9% vs. 8.6% at 36 months, 9.6% vs. 21.4% at 72 months, and 14.3% vs. 38.9% at 108 months (P = 0.001). An adjusted multivariate analysis revealed a significantly lower risk of MACE on CCBs (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.31-0.89; P = 0.02) and lower RA graft occlusion (HR, 0.20; 95% CI, 0.08-0.49; P < 0.001). When specific CCBs were analyzed separately, both diltiazem and amlodipine significantly lowered MACE and increased RA graft patency compared to no CCB therapy. Finally, the use of CCB therapy for one year was associated with lower MACE rates than therapy for less than one year (P = 0.001). Therapy for more than one year was not significant (P = 0.08). Similar results were found for RA patency. The authors concluded that CCB therapy for the first year after RA graft placement was associated with better clinical and angiographic outcomes.

COMMENTARY

The original paper from this compilation of six RCTs showed a significant reduction in MACE and repeat revascularization when the RA was used as the second conduit compared to saphenous veins (Gaudino M, et al. N Engl J Med 2018;378:2069-2077) and certainly influenced the European Society of Cardiology 2018 guidelines on myocardial revascularization, which gave it a class I indication (Neumann FJ, et al. Eur Heart J 2019;40:87-165). Since the six RCTs were randomized on conduit use, this post-hoc analysis of CCB use must be considered observational and hypothesis-generating. Two earlier randomized trials of CCBs vs. placebo in patients with RA grafts failed to demonstrate improved outcomes at one year, but each included ≤ 115 patients and used diltiazem at ≤ 180 mg/day. Consequently, the authors of the current study claim that they were underpowered. Also, most surgeons have empirically prescribed CCBs for patients with RA grafts based on the known enhanced muscularity and vasospastic properties of RAs. One could argue that only those without contraindications to CCB use received them. Indeed, the no CCB group in this combined study was markedly different from the CCB therapy group; they were older and had lower left ventricular function. Perhaps the authors believed this group needed other therapies such as beta-blockers and renin angiotensin system modulators more than they needed CCBs and were not likely to tolerate CCBs. The authors used statistical methods to adjust for these and other differences, but there could be unmeasured confounders that influenced the results.

Ideally, a large randomized trial would answer the controversy over CCB use after RA grafting and its optimal duration. However, because the effect size in this combined observational study was so large, it is unlikely to ever happen. Another strength is that both diltiazem and amlodipine were used in large numbers and showed equivalent effects. Also, the beneficial effects of the CCB were only realized in therapy lasting ≥ 1 year. However, the authors did not provide data on doses or adverse effects of CCB therapy. The authors of other studies have shown peripheral edema in up to 25% of patients on CCBs and headaches in up to 9%. In my experience, most of the adverse effects of CCBs are dose-related. Theoretically, the dose could be adjusted to eliminate adverse effects, but it would be useful to know the least effective dose. At this time, it appears prudent to prescribe a CCB at the highest tolerated dose for at least one year after RA grafting for CABG.