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European Heart Journal Advance Access originally published online on August 31, 2009
European Heart Journal 2009 30(19):2300-2301; doi:10.1093/eurheartj/ehp360
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org

A BEAUTIFUL lesson—ivabradine protects from ischaemia, but not from heart failure: through heart rate reduction or more?

Gerd Heusch*

Institut für Pathophysiologie, Universitätsklinikum Essen, D-45122 Essen, Germany

* Corresponding author. Tel: +49 201 723 4480, Fax: +49 201 723 4481, Email: gerd.heusch{at}uk-essen.de

This commentary refers to ‘Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial’{dagger}, by K. Fox et al., on page 2337

Heart rate is a major determinant of cardiac output, myocardial oxygen consumption, and coronary blood flow under physiological and pathological conditions.1 Increased heart rate contributes to myocardial ischaemia distal to a severe coronary stenosis by abbreviation of diastole and by unfavourable flow redistribution from post-stenotic into normally perfused myocardium through collaterals2 and, within the post-stenotic myocardium, from subendo- to subepicardium.3 Increased heart rate possibly4 contributes to left ventricular dysfunction in failing myocardium through a negative Treppe phenomenon.5

The BEAUTIFUL investigators have previously reported, using a prospective study design, that in patients with coronary artery disease and left ventricular dysfunction, a heart rate >70/min is associated with greater risk than a heart rate <70/min for cardiovascular mortality, hospitalization for heart failure or myocardial infarction, and for coronary revascularization;6 of note, the discrimination by a heart rate >70/min was stronger for heart failure than myocardial ischaemia endpoints. In the randomized, double-blind, placebo-controlled BEAUTIFUL trial in >10 000 patients with coronary artery disease and left ventricular dysfunction, ivabradine did not affect the primary composite endpoint of cardiovascular death and hospitalization for heart failure or myocardial infarction, but significantly reduced hospitalization for myocardial infarction and coronary revascularization in patients with a heart rate >70/min; the heart rate reduction was only 7/min when placebo corrected.7

Now the BEAUTIFUL investigators present a retrospective, subgroup analysis in 13.8% of the original patient population who had limiting symptomatic angina—as characterized by pain, fatigue, palpitations, or dyspnoea—at baseline.8 The essential conclusions from the original BEAUTIFUL study were largely confirmed and further emphasized: now with a just borderline-significant reduction in the composite endpoint, ivabradine had no effect on mortality and hospitalization for heart failure, but significantly reduced the hospitalization for myocardial infarction and coronary revascularization, and this reduction was more pronounced in patients with a heart rate >70/min than in the entire population with limiting angina; the placebo-corrected heart rate reduction was only 4/min and 7/min in the entire population with limiting angina and in those with limiting angina and a heart rate >70/min, respectively.

The investigators appropriately acknowledge the limitations of their retrospective approach to analyse a subgroup of a trial which was entirely negative in its primary endpoint and advocate their analysis as hypothesis generating and in need of large-scale prospective testing. Unfortunately, they do not say precisely which hypothesis they generate from their subgroup analysis, possibly that ivabradine provides greater protection from ischaemia in patients with coronary artery disease and limiting angina than in those without angina; to test such a hypothesis would require a huge trial.

Somewhat surprisingly, the investigators fail to discuss critically their choice of limiting angina as the entry criterion for their subgroup analysis. While they expand in detail on the impact of angina on prognosis, this is obviously not true for the BEAUTIFUL patients with limiting angina who had a mortality of 10.0% with placebo as compared with 10.1% in the entire BEAUTIFUL population with placebo. The reasons for the lack of impact of angina on prognosis in this study population remain unclear: the excellent antianginal background medication7,8 or potential cardioprotective phenomena related to repeated episodes of reversible ischaemia/reperfusion, such as ischaemic pre-conditioning9 or—in conjunction with left ventricular dysfunction10—myocardial hibernation,11 might have offset the otherwise adverse effects of angina on prognosis.

Notwithstanding the above limitations, the current subgroup analysis in patients with limiting angina confirms the findings of the original BEAUTIFUL trial, in that ivabradine protects from ischaemia and not from heart failure, and that protection is more pronounced in patients with a heart rate >70/min. However, the placebo-corrected heart rate reduction by no more than 7/min, respectively, with ivabradine strikes me as modest and difficult to reconcile with the profound protection. Also difficult to reconcile are the facts that a heart rate >70/min was a stronger discriminator for heart failure than ischaemia outcome,6 but then there was no protection from heart failure but only from ischaemia endpoints with heart rate reduction. So is there protection from ischaemia by ivabradine beyond that by heart rate reduction? Experimental studies in pigs clearly revealed a significant reduction in infarct size with ivabradine, not only when given before ischaemia but also when given just at reperfusion, and such infarct size reduction was largely preserved when heart rate reduction was offset by atrial pacing.12 This pleiotropic protective action of ivabradine beyond its bradycardic effect13 puts ivabradine into the context of cardioprotection and its signal transduction,14 notably into the context of post-conditioning, since ivabradine is still protective when given just at reperfusion. The mechanism(s) underlying the pleiotropic protection by ivabradine are largely unclear; attenuation of damage by reactive oxygen species13 and reduced sodium influx through the If current with secondary reduction of sodium–calcium exchange and ultimate reduction in calcium overload15 have been suggested.

Experimental studies, e.g. with ivabradine on top of sodium–calcium exchange blockade or antioxidant regimes, are required to elucidate the potential pleiotropic protective mechanism of ivabradine. Clinical studies are required to confirm the experimental data on protection by ivabradine against reperfusion injury; a similar study design to that in the most recent trial on cyclosporine A in patients with acute myocardial infarction16 would be most useful. The incidental observation that ivabradine confers a disadvantage to patients without angina and with heart rate <70/min requires confirmation with more thorough testing and further emphasizes the need to characterize pleiotropic effects of ivabradine which may also have a downside.

Conflict of interest: G.H. has received funding for his experimental studies and honoraria for educational lectures from Servier.

Footnotes

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

{dagger} doi:10.1093/eurheartj/ehp358 Back

References

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  2. Heusch G, Yoshimoto N. Effects of heart rate and perfusion pressure on segmental coronary resistances and collateral perfusion. Pflügers Arch (1983) 397:284–289.[CrossRef][Web of Science][Medline]
  3. Guth BD Jr., Heusch G, Seitelberger R, Ross J Jr. Elimination of exercise-induced regional myocardial dysfunction by a bradycardic agent in dogs with chronic coronary stenosis. Circulation (1987) 75:661–669.[Abstract/Free Full Text]
  4. Neumann T, Ravens U, Heusch G. Characterization of excitation–contraction coupling in conscious dogs with pacing-induced heart failure. Cardiovasc Res (1998) 37:456–466.[Abstract/Free Full Text]
  5. Hasenfuss G, Holubarsch C, Hermann HP, Astheimer K, Pieske B, Just H. Influence of the force–frequency relationship on haemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy. Eur Heart J (1994) 15:164–170.[Abstract/Free Full Text]
  6. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet (2008) 372:817–821.[CrossRef][Web of Science][Medline]
  7. Fox K, Ford I, Steg PG, Tendera M, Ferrari R. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet (2008) 372:807–816.[CrossRef][Web of Science][Medline]
  8. Fox K, Ford I, Steg Ph G, Tendera M, Robertson M, Ferrari R, on behalf of the BEAUTIFUL Investigators. Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur Heart J (2009) 30:2337–2345. First published on 31 August 2009. doi:10.1093/eurheartj/ehp358.[Abstract/Free Full Text]
  9. Heusch G. Nitroglycerin and delayed preconditioning in humans. Yet another new mechanism for an old drug? Circulation (2001) 103:2876–2878.[Free Full Text]
  10. Guth BD, Schulz R, Heusch G. Time course and mechanisms of contractile dysfunction during acute myocardial ischemia. Circulation (1993) 87(Suppl.):IV-35–IV-42.
  11. Heusch G, Schulz R, Rahimtoola SH. Myocardial hibernation: a delicate balance. Am J Physiol Heart Circ Physiol (2005) 288:H984–H999.[Abstract/Free Full Text]
  12. Heusch G, Skyschally A, Gres P, van Caster P, Schilawa D, Schulz R. Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabradine—protection beyond heart rate reduction. Eur Heart J (2008) 29:2265–2275.[Abstract/Free Full Text]
  13. Heusch G. Pleiotropic action(s) of the bradycardic agent ivabradine: cardiovascular protection beyond heart rate reduction. Br J Pharmacol (2008) 155:970–971.[CrossRef][Web of Science][Medline]
  14. Heusch G, Boengler K, Schulz R. Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation (2008) 118:1915–1919.[Free Full Text]
  15. Gewirtz H. ‘Funny’ current: If heart rate slowing is not the best answer, what might be ? Cardiovasc Res (2009) doi:10.1093/cvr/cvp245.
  16. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, Andre-Fouet X, Revel D, Kirkorian G, Monassier J-P, Derumeaux G, Ovize M. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med (2008) 359:473–481.[Abstract/Free Full Text]

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Related articles in EHJ:

Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial
Kim Fox, Ian Ford, Ph. Gabriel Steg, Michal Tendera, Michele Robertson, Roberto Ferrari, and on behalf of the BEAUTIFUL Investigators
EHJ 2009 30: 2337-2345. [Abstract] [FREE Full Text]  




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