If at first you don't succeed try ... a new target in the treatment of angina

Mrinal Saha and Michael S. Marber*

Department of Cardiology, King's College London, Rayne Institute, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK

* Corresponding author. Tel: +44 207 188 1008; fax: +44 207 188 0970. E-mail address: mike.marber{at}kcl.ac.uk

This editorial refers to ‘Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina’{dagger} by J.-C. Tardiff et al., on page 2529

Tardiff et al.1 describe a promising new treatment for angina, ivabradine, that appears to selectively reduce heart rate by blocking the cardiac pacemaker ‘funny’ current, If. In contrast to the existing agents that slow heart rate, there is no accompanying intrinsic negative inotropic effect. Understanding the basis of this unique property requires a brief overview of the underlying physiology.

The cells of the sinoatrial node are the primary pacemaker of the heart. This function is the result of an upward, positive, depolarizing drift in their resting membrane potential during the diastolic phase of the action potential, known as the pacemaker current. Once this drift reaches a threshold potential, the next action potential is triggered by the opening of slow calcium channels and consequent influx of Ca2+ ions. Calcium antagonists reduce Ca2+ influx through slow (L-type) calcium channels and this leads to prolongation of the depolarization phase of the action potential in sinoatrial node cells and diminished myofilament Ca2+ availability in ventricular myocytes. As a net consequence, calcium antagonists are both negatively chronotropic and inotropic. The pacemaker current responsible for automatic depolarization, or automaticity, was thought to be the result of the decay of increased K+ conductance accompanying repolarization (an explanation that still persists in many textbooks). However, studies in the late 1970s or early 1980s demonstrated that it was, in fact, the result of an inward movement of cations (Na+, but also K+ at membrane potentials more negative than its equilibrium potential).2 This current has many unusual or ‘funny’ properties including mixed sodium and potassium conductance, slow kinetics, and activation by hyperpolarization and intracellular cAMP.2 The latter property enables physiological control of heart rate with beta-adrenoceptor Gs-coupled stimulation, and acetylcholine/muscuranic-receptor Gi-coupled inhibition, of adenylate cyclase activity. Thus, beta-adrenoceptor agonists will increase intracellular cAMP, which, through protein kinase A-mediated phosphorylation of key proteins involved in the release or uptake of intracellular calcium and in the increase of myofilament sensitivity to calcium, increases the force of contraction. However, the cAMP will also directly ‘gate’ the funny channel increasing its conductance. Beta-adrenoceptor blockers will have the opposite effect slowing the rate by diminishing cAMP and thus If. However, they will also diminish all the other consequences of beta-adrenoceptor activation, including inotropy. In contrast, a pure If blocker will leave all components of the beta-adrenoceptor signalling cascade intact, apart from the modulation of If and consequently the increase in heart rate.

The ion channel proteins responsible for the If current have been identified and cloned. The proteins form part of the hyperpolarization-activated, cyclic-nucleotide-gated (HCN) channel family, of which four isoforms are identified.2 They are distributed in various tissues such as the heart, retinal photoreceptors, and in neurones where the corresponding current, termed Ih, has been implicated in sensory adaptation and synaptic plasticity. The proportion of each isoform varies according to the tissue location, perhaps the basis for the heterogeneity of the If current in different cells.

On the basis of the summary given earlier, inhibition of If should allow control of heart rate without the deleterious consequences on force of contraction, peripheral circulation, bronchial tone, bowel transit, and glucose and triglyceride metabolism associated with calcium channel or beta-adrenoceptor blockers. However, other unwanted effects secondary to If inhibition may be expected, particularly symptomatic bradycardia, ventricular extrasystoles, and the theoretical suppression of escape rhythms. In addition, there will be extracardiac effects due to If inhibition in other excitable tissues. Such unusual effects were noted in the clinical trials of an earlier If-blocking agent zatebradine (UL-FS 49), which showed no benefit in patients with chronic stable angina, but did cause unusual visual disturbances including photopsia, blurred vision, and stroboscopic effects.3 These symptoms presumably reflect cross-reactivity to HCN channel proteins in the retina where Ih is involved in adaptation to rapid changes in light intensity.4 Nonetheless, it remains unclear why there was no reduction in angina despite a reduction in heart rate.

From a physiological perspective, heart rate reduction alone should reduce angina by at least two principal mechanisms. The first is a decline in myocardial oxygen consumption, providing that the reduction in rate does not produce compensatory changes in the other principal indices of cardiac work, stroke volume, and aortic pressure. The second is an increase in diastolic interval that is known to improve perfusion to the ischaemia-prone subendocardium.5 However, the regional diastolic interval may also be increased by other mechanisms that come into play at the low intracoronary pressures that exist beyond a coronary stenosis.6 Such homeostatic complexities may contribute to the apparent lack of efficacy of zatebradine. Furthermore, they raise the question as to what proportion of the anti-anginal effect of beta-adrenoceptor blockers can be attributed to heart rate reduction and what proportion to negative inotropic or hypotensive actions. This question is best answered by a direct comparison of an If blocker with a beta-adrenoceptor antagonist. It is exactly similar to a trial that is reported by Tardiff et al.

The article by Tardiff et al.1 is the latest study from the INITIATIVE investigators comparing anti-anginal efficacy of ivabradine with atenolol. Patients were randomized to one of the three groups. In the two ivabradine groups, the dose was 5 mg twice per day for 4 weeks and then increasing to either 7.5 mg or 10 mg twice a day for a further 12 weeks, the trial, therefore, lasting 16 weeks in total. In the atenolol group, patients received 50 mg od for 4 weeks and then increasing to 100 mg od until week 16. The primary efficacy endpoint was total exercise duration at trough activity, 12 h after the last ivabradine dose and 24 h after the last atenolol dose. This primary efficacy analysis was done by subtracting the total exercise duration at the end of week 16 from baseline. Secondary efficacy criteria were also included with descriptors of exercise performance and exercise-induced myocardial ischaemia at both trough and peak drug activities at both 4 and 16 weeks. The study clearly demonstrates that at trough activity, ivabradine 5 mg bid is not inferior to atenolol 50 mg od (at the end of week 4) and that both high doses of ivabradine (7.5 mg and 10 mg) are not inferior to 100 mg of atenolol (at the end of week 16). The limit for non-inferiority is total exercise duration within 30–40 s for atenolol.

A potential drawback of the study design is that for regulatory reasons, primary efficacy analyses concentrated on trough activity, and not on maximal efficacy, most likely to coincide with spontaneous physical exertion. Arguably, the latter measure is of most interest to physicians whose patients require anti-anginal protection after, but not prior to, their morning medication. Indeed, atenolol may fare particularly poorly in a trough analysis because of a relatively short half-life of 6–9 h with heart rate-lowering effects attenuated by up to 70% at 24 h.7 Hence, the non-inferiority of ivabradine compared with atenolol was most convincingly demonstrated at trough activity, where it tended to perform better than atenolol. In contrast, at peak drug activity at week 16, 4 h post-morning dose, atenolol tended to perform better than ivabradine, but not sufficient enough to prevent ivabradine showing non-inferiority or no significant difference for all measures apart from time to 0.1 mV ST depression. Despite these criticisms, the study by Tardiff et al. clearly shows that ivabridine at 7.5 mg or 10 mg bid met all criteria for non-inferiority at trough, and thus, the likely additional negative inotropic and observed hypotensive effects of atenolol are not critical to its anti-anginal action.

It is also clear from the current study1 that ivabridine, like zatebradine, causes visual disturbance. For the most part, there seem minor predictable increases in the brightness of limited areas of the visual field (phosphenes) appearing on average after 40 days of treatment. They were only sufficiently disturbing to cause the withdrawal of five of the approximate 600 patients randomized to ivabradine for a total of 112 days.

The potential benefits of ivabradine are clear. However, what remains to be determined is how, once licensed, it will integrate into the drug regimes of patients who are already on several generically available anti-anginal medications. Interactions with calcium channel blockers, potassium channel openers, and beta-blockers are possible. However, the intrinsic properties of ivabradine, such as current-dependent blockade,8 should limit the likelihood of such events. Clearly, after a gap of decades, there is at last a new class of anti-anginal therapy. For those patients who are unable to tolerate beta-blockers, or in whom beta-blockers are contraindicated, there is another way we can try to succeed.

Acknowledgement

M.S. is supported by a British Heart Foundation PhD Fellowship.

Conflict of interest: M.S.M. is an editorial board member of the Heart and Metabolism, an education journal sponsored by Servier, the manufacturers of ivabradine.

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/ehi586 Back

References

  1. Tardiff J-C, Ford I, Tendera M, Bourassa MG, Fox K for the INITIATIVE Investigators. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J 2005;26:2529–2536. First published on October 7, 2005, doi:10.1093/eurheartj/ehi586.[Abstract/Free Full Text]
  2. Baruscotti M, Bucchi A, DiFrancesco D. Physiology and pharmacology of the cardiac pacemaker (‘funny’) current. Pharmacol Ther 2005;107:59–79.[CrossRef][ISI][Medline]
  3. Frishman WH, Pepine CJ, Weiss RJ, Baiker WM. Addition of zatebradine, a direct sinus node inhibitor, provides no greater exercise tolerance benefit in patients with angina taking extended-release nifedipine: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The zatebradine Study Group. J Am Coll Cardiol 1995;26:305–312.[Abstract]
  4. Gargini C, Demontis GC, Bisti S, Cervetto L. Effects of blocking the hyperpolarization-activated current (Ih) on the cat electroretinogram. Vision Res 1999;39:1767–1774.[CrossRef][ISI][Medline]
  5. Ferro G, Duilio C, Spinelli L, Liucci GA, Mazza F, Indolfi C. Relation between diastolic perfusion time and coronary artery stenosis during stress-induced myocardial ischemia. Circulation 1995;92:342–347.[Abstract/Free Full Text]
  6. Merkus D, Kajiya F, Vink H, Vergroesen I, Dankelman J, Goto M, Spaan JA. Prolonged diastolic time fraction protects myocardial perfusion when coronary blood flow is reduced. Circulation 1999;100:75–81.[Abstract/Free Full Text]
  7. Kostis JB. Beta-blocker duration of action and implications for therapy. Am J Cardiol 1990;66:60G–62G.[CrossRef][Medline]
  8. Bucchi A, Baruscotti M, DiFrancesco D. Current-dependent block of rabbit sino-atrial node I(f) channels by ivabradine. J Gen Physiol 2002;120:1–13.[CrossRef][ISI][Medline]

Related articles in EHJ:

Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina
Jean-Claude Tardif, Ian Ford, Michal Tendera, Martial G. Bourassa, Kim Fox, and for the INITIATIVE Investigators
EHJ 2005 26: 2529-2536. [Abstract] [Full Text]  




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