Introduction: Ranolazine (RAN) is a late-Na current blocker that is an inhibitor of the P-glycoprotein elimination pathway. The RAID trial tested whether RAN exerts an antiarrhythmic effect in high-risk ICD patients. RAID did not exclude subjects taking digoxin (DIG), a P-glycoprotein substrate, but investigators were advised to reduce the dosage of DIG by 50% to avoid toxic DIG accumulation.
Hypothesis: We asked whether concomitant administration of RAN and DIG impacted the primary endpoint of VT/VF or death.
Methods: The RAID trial was a double-blind, placebo- controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized 1:1 to ranolazine 1,000 mg bid or placebo.
Results: There were 1,012 ICD patients enrolled in RAID (mean age: 64±10 years; 18% women). 170 subjects received DIG (89 in the placebo arm). Subjects receiving DIG had evidence of more advanced cardiovascular disease, including more prevalent atrial fibrillation (31% versus 17%, p<0.001), lower ejection fraction (27.8%±10 versus 32.0%±11.9, p<0.001), and wider QRS duration (136.5 ms±31 versus 130.0 ms±31.5, p=0.012). Nevertheless, DIG was not associated with worse outcome with respect to the primary endpoint in the placebo arm (39% placebo-only versus 40% placebo+DIG, p= 0.83). In the RAN arm, however, DIG use was associated with a significantly worse outcome, with 32% of RAN-only versus 48% of RAN + DIG experiencing the primary endpoint (p=0.004). This difference was driven by a significant increase in mortality (12% RAN-only versus 23% RAN+DIG, p=0.006) and a trend towards increased VT/VF (24% RAN-only versus 31% RAN+DIG, p=0.168). Comparing subjects that did not receive DIG, randomization to RAN was associated with a significant reduction in the primary endpoint (32% RAN-only versus 39% placebo-only, p=0.021). Hazard ratio for primary endpoint for ranolazine vs. placebo in no digoxin patients was 0.76 (95% CI: 0.59-0.97; p=0.025) and in patients on digoxin was 1.37 (95% CI: 0.84-2.25; p=0.295) with interaction p value = 0.034.
Conclusions: Concomitant use of RAN and DIG eliminated the antiarrhythmic effects of ranolazine in high-risk ICD subjects in the RAID trial. Clinicians should avoid combining these agents in ICD patients.