- Email: [email protected]
Ivabradine in Coronary Heart Disease—The Emperor Has No Clothes
Accepted Manuscript Ivabradine in Coronary Heart Disease—The Emperor Has No Clothes Franz H. Messerli, MD, Stefano F. Rimoldi, MD, Sripal Bangalore, MD, MHA PII:
S0002-9149(16)30887-6
DOI:
10.1016/j.amjcard.2016.05.033
Reference:
AJC 21885
To appear in:
The American Journal of Cardiology
Received Date: 3 May 2016 Accepted Date: 13 May 2016
Please cite this article as: Messerli FH, Rimoldi SF, Bangalore S, Ivabradine in Coronary Heart Disease—The Emperor Has No Clothes, The American Journal of Cardiology (2016), doi: 10.1016/ j.amjcard.2016.05.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Ivabradine in Coronary Heart Disease—The Emperor Has No Clothes Ivabradine was launched in Europe as a novel anti-anginal known to inhibit the sinus node I-f channel. In doing so the drug produces dose-dependent decrease in heart rate and thereby possibly anti-ischemic
RI PT
effects, presumably without significantly affecting blood pressure, myocardial contractility or vasomotor tone . In early studies ivabradine proved to be non-inferior to first-line anti-anginal agents such as betablockers and calcium channel blockers and superior to placebo. Surprisingly, in 2 large outcome studies of
SC
patients with stable angina, ivabradine conferred no cardioprotective benefits (1, 2). To the contrary, ivabradine was associated with an 18% increase of primary endpoint (cardiovascular death and non-fatal
M AN U
infarction) in the subgroup of patients with angina II to IV in SIGNIFY.
In a recent overview(3) Ohman states that “no clear explanation was provided for the findings” that in SIGNIFY(2) “the rates of death and nonfatal myocardial infarction were higher among patients who received ivabradine than among those who received placebo”. Attempting to further analyze the inefficacy of ivabradine, Beltrame speculated that increased cardiac events in those treated with ivabradine could
TE D
have several potential explanations such as: (i) statistical aberration “if no biologic explanation for the findings can be derived”; (ii) cardiac arrhythmias; (iii) drug interactions; and/or (iv) dose titration (4). None of these explanations has been substantiated and ivabradine’s failure remained essentially
EP
unexplained.
We recently measured central (aortic) blood pressure directly by left heart catheterization at baseline and
AC C
after 6 months in 46 patients with chronic stable coronary artery disease, single-blinded allocated to placebo or ivabradine (5). Ivabradine lowered heart rate by 8.1±11.6 beats/min which however was associated with an increase in central pressure (from 129 ± 22 mmHg to 140 ± 26 mmHg (p=0.02)) and stroke volume (Figure). Double product (central systolic pressure x heart rate), an estimate of myocardial oxygen consumption, remained unchanged. Conceivably heart rate lowering causes a ventricular-vascular mismatch, resulting in the return of the reflected pulse wave from the periphery to the ventricle when it is still in systole, thereby augmenting central pressure (6). This increase in central pressure of 11 mmHg associated with heart rate lowering by ivabradine is prone to mitigate potential benefits. To our way of
ACCEPTED MANUSCRIPT
thinking this is the most likely pathophysiologic mechanism accounting for ivabradine’s failure to reduce outcome in CAD. The good news is that now the problem has been identified, an ample arsenal of antihypertensive agents
RI PT
will lend themselves to be combined with ivabradine to keep central pressure at bay. Suitable partners may be a calcium channel blocker for patients with coronary heart disease and a blocker of the renin
angiotensin system for those with heart failure. Some of these combinations may eventually serve to fully
SC
cloth the emperor again.
AC C
EP
TE D
M AN U
Franz H. Messerli, MD, Stefano F. Rimoldi, MD, Sripal Bangalore, MD, MHA, New York, New York USA 10 May 2016
ACCEPTED MANUSCRIPT
1.
Fox K, Ford I, Steg PG, Tendera M, Ferrari R, Investigators B. Ivabradine for patients with
stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised,
2.
RI PT
double-blind, placebo-controlled trial. Lancet 2008;372:807-816. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Ivabradine in stable coronary artery
disease without clinical heart failure. N Engl J Med 2014;371:1091-1099.
4. 5.
Ohman EM. Chronic Stable Angina. N Engl J Med 2016;374:1167-1176.
Beltrame JF. Ivabradine and the SIGNIFY conundrum. Eur Heart J 2015;36:3297-3299..
SC
3.
Rimoldi SF, Messerli FH, Cerny D, Gloekler S, Traupe T, Laurent S, Seiler C. Selective heart rate
M AN U
reduction with ivabradine increases central blood pressure in stable coronary artery disease. Hypertension 2016 Apr 18. pii: HYPERTENSIONAHA.116.07250. [Epub ahead of print] 6.
Messerli FH, Rimoldi SF, Bangalore S, Bavishi C, Laurent S. When Increase in Central Pressure
FIGURE LEGEND
EP
TE D
Overrides Benefits of Heart Rate Lowering. JACC 2016, in press.
AC C
Effects of ivabradine on heart rate, central systolic blood pressure,and stroke volume in patients with stable coronary heart disease.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S0002-9149(16)30887-6
DOI:
10.1016/j.amjcard.2016.05.033
Reference:
AJC 21885
To appear in:
The American Journal of Cardiology
Received Date: 3 May 2016 Accepted Date: 13 May 2016
Please cite this article as: Messerli FH, Rimoldi SF, Bangalore S, Ivabradine in Coronary Heart Disease—The Emperor Has No Clothes, The American Journal of Cardiology (2016), doi: 10.1016/ j.amjcard.2016.05.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Ivabradine in Coronary Heart Disease—The Emperor Has No Clothes Ivabradine was launched in Europe as a novel anti-anginal known to inhibit the sinus node I-f channel. In doing so the drug produces dose-dependent decrease in heart rate and thereby possibly anti-ischemic
RI PT
effects, presumably without significantly affecting blood pressure, myocardial contractility or vasomotor tone . In early studies ivabradine proved to be non-inferior to first-line anti-anginal agents such as betablockers and calcium channel blockers and superior to placebo. Surprisingly, in 2 large outcome studies of
SC
patients with stable angina, ivabradine conferred no cardioprotective benefits (1, 2). To the contrary, ivabradine was associated with an 18% increase of primary endpoint (cardiovascular death and non-fatal
M AN U
infarction) in the subgroup of patients with angina II to IV in SIGNIFY.
In a recent overview(3) Ohman states that “no clear explanation was provided for the findings” that in SIGNIFY(2) “the rates of death and nonfatal myocardial infarction were higher among patients who received ivabradine than among those who received placebo”. Attempting to further analyze the inefficacy of ivabradine, Beltrame speculated that increased cardiac events in those treated with ivabradine could
TE D
have several potential explanations such as: (i) statistical aberration “if no biologic explanation for the findings can be derived”; (ii) cardiac arrhythmias; (iii) drug interactions; and/or (iv) dose titration (4). None of these explanations has been substantiated and ivabradine’s failure remained essentially
EP
unexplained.
We recently measured central (aortic) blood pressure directly by left heart catheterization at baseline and
AC C
after 6 months in 46 patients with chronic stable coronary artery disease, single-blinded allocated to placebo or ivabradine (5). Ivabradine lowered heart rate by 8.1±11.6 beats/min which however was associated with an increase in central pressure (from 129 ± 22 mmHg to 140 ± 26 mmHg (p=0.02)) and stroke volume (Figure). Double product (central systolic pressure x heart rate), an estimate of myocardial oxygen consumption, remained unchanged. Conceivably heart rate lowering causes a ventricular-vascular mismatch, resulting in the return of the reflected pulse wave from the periphery to the ventricle when it is still in systole, thereby augmenting central pressure (6). This increase in central pressure of 11 mmHg associated with heart rate lowering by ivabradine is prone to mitigate potential benefits. To our way of
ACCEPTED MANUSCRIPT
thinking this is the most likely pathophysiologic mechanism accounting for ivabradine’s failure to reduce outcome in CAD. The good news is that now the problem has been identified, an ample arsenal of antihypertensive agents
RI PT
will lend themselves to be combined with ivabradine to keep central pressure at bay. Suitable partners may be a calcium channel blocker for patients with coronary heart disease and a blocker of the renin
angiotensin system for those with heart failure. Some of these combinations may eventually serve to fully
SC
cloth the emperor again.
AC C
EP
TE D
M AN U
Franz H. Messerli, MD, Stefano F. Rimoldi, MD, Sripal Bangalore, MD, MHA, New York, New York USA 10 May 2016
ACCEPTED MANUSCRIPT
1.
Fox K, Ford I, Steg PG, Tendera M, Ferrari R, Investigators B. Ivabradine for patients with
stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised,
2.
RI PT
double-blind, placebo-controlled trial. Lancet 2008;372:807-816. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Ivabradine in stable coronary artery
disease without clinical heart failure. N Engl J Med 2014;371:1091-1099.
4. 5.
Ohman EM. Chronic Stable Angina. N Engl J Med 2016;374:1167-1176.
Beltrame JF. Ivabradine and the SIGNIFY conundrum. Eur Heart J 2015;36:3297-3299..
SC
3.
Rimoldi SF, Messerli FH, Cerny D, Gloekler S, Traupe T, Laurent S, Seiler C. Selective heart rate
M AN U
reduction with ivabradine increases central blood pressure in stable coronary artery disease. Hypertension 2016 Apr 18. pii: HYPERTENSIONAHA.116.07250. [Epub ahead of print] 6.
Messerli FH, Rimoldi SF, Bangalore S, Bavishi C, Laurent S. When Increase in Central Pressure
FIGURE LEGEND
EP
TE D
Overrides Benefits of Heart Rate Lowering. JACC 2016, in press.
AC C
Effects of ivabradine on heart rate, central systolic blood pressure,and stroke volume in patients with stable coronary heart disease.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT