Effects of bisoprolol and verapamil in non-obstructive hypertrophic cardiomyopathy

Background Evidence for beta-blocker and verapamil therapy in non-obstructive hypertrophic cardiomyopathy (HCM) from randomized trials is absent. Purpose To assess the effects of bisoprolol and verapamil on functional capacity and symptoms in non-obstructive HCM. Methods A randomized, double-blind, placebo-controlled, triple-crossover trial performed at two tertiary referral centers. HCM patients without left ventricular outflow tract obstruction (< 30 mmHg during any conditions) and with a maximal left ventricular wall thickness ≥15 mm, having ≥1 marker of disease severity: NYHA class ≥II, NT-proBNP >300 ng/l, or documented non-sustained ventricular tachycardia were eligible for study participation. Patients were randomized into six different sequences of bisoprolol-, verapamil- and placebo-treatment. Patients underwent three treatment periods with target doses of bisoprolol 7.5 mg, verapamil 360 mg, and placebo, respectively, or maximal tolerable doses. Outcomes were evaluated after two weeks of steady-state treatment. The primary outcome, peak oxygen consumption (pVO2) in comparison between bisoprolol and verapamil treatment, was obtained through cardiopulmonary exercise testing. Secondary outcomes were symptoms (KCCQ-OSS) and NT-proBNP. Both treatments were compared to placebo. Results Thirty-two patients, age 54±15 years, 11 females, were included. The pVO2, was 25.7±8.7 ml/kg/min with bisoprolol versus 28.6±9.8 ml/kg/min with verapamil, with an adjusted mean difference of 2.3 ml/kg/min (95% CI: 0.7 to 3.8, p= 0.004). The adjusted mean difference in KCCQ-OSS was 4.3 points (95% CI: 0.7 to 8.0, p= 0.019) and in NT-proBNP, 275 ng/L (CI 95%: 221 to 320, p<0.001), both in favor of verapamil. Compared to placebo, bisoprolol reduced pVO2 by 2.5 ml/kg/min (95% CI: 1.0 to 4.1, p=0.005), while verapamil only reduced it by 0.2 ml/kg/min (95% CI: -1.3 to 1.8, p=1.000). The adjusted mean differences to placebo in KCCQ-OSS was 6.6 points, (95% CI: 3.0 to 10.3, p=0.001) with bisoprolol and 2.3 points (95% CI: -1.4 to 6.0, p=0.668) with verapamil. Verapamil reduced NT-proBNP by 155 ng/L (95% CI: 81 to 242, p<0.001), whereas bisoprolol increased NT-proBNP by 132 ng/L (95% CI: 52 to 200 ng/L, p=0.006) compared to placebo (Figure 1). Conclusion Bisoprolol reduces functional capacity and increases symptoms as well as NT-proBNP compared to verapamil and placebo in non-obstructive HCM. Verapamil reduces NT-proBNP, but no differences in functional capacity or symptoms was identified compared to placebo.