Effects of Verapamil on Top of Trandolapril on Exercise Tolerance and Cardiac Performance in Patients with Hypertension and Reduced Left Ventricular Function (2001)

Calcium antagonists and angiotensin-converting enzyme (ACE) inhibitors act synergistically in reducing blood pressure through additive hemodynamic and vasculoprotective effects. <i>Objectives:</i> The aim of this study was to investigate the hemodynamic and neurohumoral effects of combined verapamil SR plus trandolapril treatment (verapamil SR/trandolapril) versus trandolapril monotherapy at rest and during exercise in patients with essential hypertension (WHO I–II) and mild left ventricular dysfunction. <i>Methodology:</i> The investigation was performed in patients with a diastolic blood pressure ≧90 mm Hg and impaired left ventricular ejection fraction of 35–50%. A total of 84 patients (18–75 years) were randomized to double-blind treatment (42 in the verapamil SR/trandolapril and 42 in the trandolapril group) to whom verapamil SR (180 mg) plus trandolapril (2 mg) or trandolapril alone (2 mg) were administered orally once daily for 2 weeks. Hemodynamic and neurohumoral variables were estimated after a screening phase (baseline) and after 2 weeks of therapy at rest and during supine exercise by using right heart catheterization. <i>Results:</i> The heart rate was slightly reduced in the verapamil SR/trandolapril group compared to the trandolapril group both at rest (–9.4 ± 9.8 vs. 7.8 ± 11.3 bpm, nonsignificant) and at maximal comparable workload (–2.4 ± 10.8 vs. –1.9 ± 8.6 bpm, p > 0.05). Mean reduction of systolic blood pressure at rest was insignificantly higher in the verapamil SR/trandolapril group than in the trandolapril group both at rest (–20.6 ± 19.3 vs. –18.1 ± 14.4 mm Hg, p > 0.05) and at maximal comparable workload (–17.2 ± 23.7 vs. –13.1 ± 15.1 mm Hg, p > 0.05). Furthermore, mean reduction of diastolic blood pressure from baseline was slightly higher in the verapamil SR/trandolapril group than in the trandolapril group, both at rest (–13.8 ± 12.1 vs. –9.2 ± 7.8 mm Hg) and at maximal comparable workload (–12.0 ± 13.3 vs. –4.5 ± 11.0 mm Hg). Cardiac output showed a decrease in both groups at rest (–0.45 ± 1.44 vs. –0.57 ± 1.03 liter/min) and during exercise (–0.43 ± 2.88 vs. –0.21 ± 2.89 liter/min). Mean reduction of pulmonary capillary wedge pressure was significantly higher in the trandolapril group compared to the verapamil SR/trandolapril group both at rest (–1.6 ± 5.3 vs. –0.8 ± 4.6 mm Hg, p < 0.05) and during exercise (–2.9 ± 8.7 vs. –1.7 ± 8.5 mm Hg, p < 0.05). A decrease of norepinephrine between baseline and endpoint was registered when measured at rest both in the verapamil SR/trandolapril and the trandolapril group (–23 vs. –10%, p < 0.05, baseline median values 324 vs. 283 pg/ml). Renin increased under verapamil SR/trandolapril and trandolapril treatment, both at rest (+4.20 vs. +62%, p < 0.05, initial values 1.1 vs. 0.6 ng/ml/h). Angiotensin II experienced a decrease under verapamil SR/trandolapril and trandolapril administration, both at rest (–52 vs. –21%, p < 0.05, initial values 4.6 vs. 2.7 pg/ml). Atrial natriuretic peptide decreased significantly more under trandolapril than under verapamil SR/trandolapril (–14 vs. –2%, p < 0.05, baseline median values 101 vs. 111 pg/ml). No significant differences were registered for aldosterone (–74 vs. –57%, baseline values 107 vs. 97 pg/ml). As to hormones, values of both groups at a comparable workload did not show any significant difference either. <i>Conclusion:</i> ACE inhibitors and Ca<sup>2+</sup> antagonists have additive hemodynamic and neurohumoral actions. Verapamil does not appear to reduce exercise tolerance, invasive measures at rest and during exercise on left ventricular function, even in patients with reduced left ventricular function.