Comparative effects of ivabradine, a selective heart rate-lowering agent, and propranolol on systemic and cardiac haemodynamics at rest and during exercise

Abstract

Aim: To compare in humans the effects of ivabradine and propranolol on cardiac and systemic haemodynamics at rest, during tilt and exercise.

Methods: Nine healthy volunteers randomly received single oral doses of ivabradine (Iva, 30 mg), propranolol (Propra, 40 mg) or placebo (Plac) during a double-blind cross-over study. Doses were selected to be equipotent in heart rate (HR) reduction. HR, systolic and diastolic blood pressure (SBP, DBP), cardiac index (CI, bioimpedance), rate pressure product (RPP), plasma epinephrine (E) and norepinephrine (NE), were measured at rest at baseline, before and after two tilt and exercise tests, started 2 and 5 h after drug intake. Heart rate variability (low to high frequency ratio LF/HF) was evaluated at rest and at 5 th minute of tilt.

Results: At rest, HR and RPP decreased similarly with Iva and Propra (both P < 0.01). During tilt, HR increased less with Iva than Propra (P < 0.01), LF/HF decreased after Iva (P < 0.03), SBP and mean blood pressure decreased after Propra (both P < 0.01), RPP decreased similarly after Iva and Propra (both P < 0.01) and CI decreased to a greater extent with Propra than with Iva or Plac (both P < 0.04). During exercise, Iva and Propra similarly decreased HR (both P < 0.01) and RPP (P < 0.01).

Conclusions: These results demonstrate that for a similar decrease in HR at rest and during sympathetic stimulation, acute administration of ivabradine, a selective heart rate-lowering agent, decreased myocardial oxygen demand to the same extent as a reference beta-blocker, propranolol, but without evidence of depressant effect on cardiac function.

Figure 1

Mean (± SEM) values of heart rate (HR), cardiac index (CI), systolic blood pressure (SBP) and rate pressure product (RPP) obtained 2 and 5 h after administration of placebo (○), ivabradine (•) and propranolol (□) at baseline and at the 5th minute of tilt test. P, Time effect. *P < 0.05 vs. placebo, †P < 0.05 vs. propranolol

Figure 2

Mean (± SEM) values of heart rate (HR), cardiac index (CI), systolic blood pressure (SBP) and rate pressure product (RPP) obtained 2.25 and 5.25 h after administration of placebo (○), ivabradine (•) and propranolol (□) at baseline and at maximal load during exercise test. P, Time effect. *P < 0.05 vs. placebo, †P < 0.05 vs. propranolol

Figure 3

Relationships between plasma norepinephrine and heart rate (left), plasma epinephrine and cardiac index (middle) and plasma epinephrine and mean blood pressure (right), using individual values obtained at rest, during tilt tests and during exercise, after administration of placebo (○), ivabradine (•) and propranolol (□). The r-values correspond to the univariate correlation coefficients obtained for each significant treatment group relationship

Figure 4

Mean (± SEM) values of low-frequency component (LF/T), high-frequency component (HF/T) and low- to high-frequency ratio (LF/HF) of heart rate spectra obtained at rest before (time 0) and at rest, 2, 5 and 8 h after administration of placebo (○), ivabradine (•) and propranolol (□)

Figure 5

Mean (± SEM) values of low-frequency component (LF/T), high-frequency component (HF/T) and low- to high-frequency ratio (LF/HF) of heart rate spectra obtained 2 and 5 h after administration of placebo (□), ivabradine (▪) and propranolol () at baseline (base) and at the 5th minute of tilt test (tilt). P, Time effect. *P < 0.05 vs. placebo