Ivabradine in Stable Coronary Artery Disease without Clinical Heart Failure

Fox, Kim; Ford, Ian; Steg, Philippe Gabriel; Tardif, Jean‐Claude; Tendera, Michał; Ferrari, Roberto

doi:10.1056/nejmoa1406430

Cited by 441 publications

(368 citation statements)

References 19 publications

(25 reference statements)

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“…Occurrence of bradycardia was reported in 2.2-4.2% of patients with chronic stable angina. The rate of bradycardia was much higher (18.0%) in the SIGNIFY trial 39 . Of note, the therapeutic regimen in SIGNIFY (7.5 mg uptitrated to 10.0 mg twice daily) significantly differs from current clinical practice, and 4.6% of patients were treated with diltiazem or verapamil, which are moderate inhibitors of cytochrome P450 P3A4, which metabolizes ivabradine.…”

Section: Key Points For Nicorandilmentioning

confidence: 82%

“…Diltiazem and verapamil should, therefore, not be used in combination with ivabradine owing to the risk of severe bradycardia 39 .…”

Section: Key Points For Calcium-channel Blockersmentioning

confidence: 99%

“…The observed phosphenes are reported to occur in 5.4% of patients, are mild and transitory, and only rarely lead to treatment withdrawal (<1%) 39 .…”

Section: Key Points For Nicorandilmentioning

confidence: 99%

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A 'diamond' approach to personalized treatment of angina

et al. 2017

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Chronic stable angina pectoris is the most prevalent symptomatic manifestation of ischaemic heart disease, and its management is a priority (BOX 1). Current clinical guidelines recommend antianginal therapy to control symptoms, before considering coronary artery revasculariza tion [1][2][3][4] . However, revascularization by either percutaneous coronary angioplasty or CABG surgery is indicated in patients who have significant artery steno sis (50% left main narrowing or proximal three-vessel disease) to reduce myocardial ischaemia and its adverse clinical manifestation. Antianginal agents are approved by documenting that they improve total exercise duration, together with a reduction in daily frequency of chronic stable angina compared with placebo and/or equivalence to an active comparator. Cardiovascular outcomes, although highly advocated, are not a pre requisite for regulatory approval. None of the antianginal drugs has been proved to reduce cardiovascular mortality or the rate of myocardial infarction. When patients are optimally treated, mortality for chronic stable angina is low, which might explain why all trials designed to improve prognosis have been negative. Guidelines recom mend a first-choice and a second-choice approach, based more on tradition and expert opinion, rather than evidence. This categorical approach has been questioned in the past couple of years 5-8 . Newer antianginal drugs, which are classified as second choice, have more evidence-based clinical data that are more contemporary to support their use than is available for the traditional first-choice drugs. Equally, the often-needed combin ation of double or triple therapy is based on expert opinion and not related to the underlying pathophysio logy. What constitutes optimal antianginal treatment, therefore, varies considerably between countries, and the majority of doctors treat their patients according to their own preconceptions.A group of experts with experience and interest in chronic stable angina met at the University of Ferrara, Italy, to discuss an individualized approach to medical treatment of chronic stable angina, on the basis E X P E RT C O N S E N S U S D O C U M E N TA 'diamond' approach to personalized treatment of angina Abstract | In clinical guidelines, drugs for symptomatic angina are classified as being first choice (β-blockers, calcium-channel blockers, short-acting nitrates) or second choice (ivabradine, nicorandil, ranolazine, trimetazidine), with the recommendation to reserve second-choice medications for patients who have contraindications to first-choice agents, do not tolerate them, or remain symptomatic. No direct comparisons between first-choice and second-choice treatments have demonstrated the superiority of one group of drugs over the other. Meta-analyses show that all antianginal drugs have similar efficacy in reducing symptoms, but provide no evidence for improvement in survival. The newer, second-choice drugs have more evidence-based clinical data that are more contemporary than is available for tr...

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Section: Key Points For Nicorandilmentioning

confidence: 82%

“…Diltiazem and verapamil should, therefore, not be used in combination with ivabradine owing to the risk of severe bradycardia 39 .…”

Section: Key Points For Calcium-channel Blockersmentioning

confidence: 99%

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A 'diamond' approach to personalized treatment of angina

et al. 2017

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“…SIGNIFY, which studied patients with stable coronary artery disease and without LV dysfunction, showed that patients treated with ivabradine did not have improved outcomes in terms of mortality from cardiovascular causes and myocardial infarction 48. In patients with significant angina, ivabradine even increased cardiovascular mortality and nonfatal myocardial infarction.…”

Section: Discussionmentioning

confidence: 99%

Heart Rate Reduction With Ivabradine Protects Against Left Ventricular Remodeling by Attenuating Infarct Expansion and Preserving Remote‐Zone Contractile Function and Synchrony in a Mouse Model of Reperfused Myocardial Infarction

O’Connor

Smith

Piras

et al. 2016

JAHA

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BackgroundIvabradine selectively inhibits the pacemaker current of the sinoatrial node, slowing heart rate. Few studies have examined the effects of ivabradine on the mechanical properties of the heart after reperfused myocardial infarction (MI). Advances in ultrasound speckle‐tracking allow strain analyses to be performed in small‐animal models, enabling the assessment of regional mechanical function.Methods and ResultsAfter 1 hour of coronary occlusion followed by reperfusion, mice received 10 mg/kg per day of ivabradine dissolved in drinking water (n=10), or were treated as infarcted controls (n=9). Three‐dimensional high‐frequency echocardiography was performed at baseline and at days 2, 7, 14, and 28 post‐MI. Speckle‐tracking software was used to calculate intramural longitudinal myocardial strain (Ell) and strain rate. Standard deviation time to peak radial strain (SD Tpeak Err) and temporal uniformity of strain were calculated from short‐axis cines acquired in the left ventricular remote zone. Ivabradine reduced heart rate by 8% to 16% over the course of 28 days compared to controls (P<0.001). On day 28 post–MI, the ivabradine group was found to have significantly smaller end‐systolic volumes, greater ejection fraction, reduced wall thinning, and greater peak Ell and Ell rate in the remote zone, as well as globally. Temporal uniformity of strain and SD Tpeak Err were significantly smaller in the ivabradine‐treated group by day 28 (P<0.05).ConclusionsHigh‐frequency ultrasound speckle‐tracking demonstrated decreased left ventricular remodeling and dyssynchrony, as well as improved mechanical performance in remote myocardium after heart rate reduction with ivabradine.

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“…These promising data have been challenged however, as despite 90% of patients receiving β‐blockers, only 26% of patients were successfully titrated to full doses, and up to 40% of patients were not managed with a mineralocorticoid receptor antagonist, suggesting sub‐optimal concomitant conventional medical therapy (Teerlink, 2010). Indeed, in a recent and much larger study of 19 102 patients with stable coronary artery disease without clinical evidence of HF, targeted heart rate reduction to a mean of 61 bpm conferred no demonstrable benefit in the treatment arm, and in fact, a conflicting increase was observed in the composite primary endpoint of cardiovascular death and non‐fatal acute myocardial infarction in patients with severe activity‐limiting angina (Fox et al ., 2014). The debate on the role of ivabradine in cardiovascular disease is therefore ongoing.…”

Section: Evidence‐based Pharmacological Agentsmentioning

confidence: 99%

Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm

Loudon

Noordali

Gollop

et al. 2016

British J Pharmacology

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Many conditions culminate in heart failure (HF), a multi‐organ systemic syndrome with an intrinsically poor prognosis. Pharmacotherapeutic agents that correct neurohormonal dysregulation and haemodynamic instability have occupied the forefront of developments within the treatment of HF in the past. Indeed, multiple trials aimed to validate these agents in the 1980s and early 1990s, resulting in a large and robust evidence‐base supporting their use clinically. An established treatment paradigm now exists for the treatment of HF with reduced ejection fraction (HFrEF), but there have been very few notable developments in recent years. HF remains a significant health concern with an increasing incidence as the population ages. We may indeed be entering the surgical era for HF treatment, but these therapies remain expensive and inaccessible to many. Newer pharmacotherapeutic agents are slowly emerging, many targeting alternative therapeutic pathways, but with mixed results. Metabolic modulation and manipulation of the nitrate/nitrite/nitric oxide pathway have shown promise and could provide the answers to fill the therapeutic gap between medical interventions and surgery, but further definitive trials are warranted. We review the significant evidence base behind the current medical treatments for HFrEF, the physiology of metabolic impairment in HF, and discuss two promising novel agents, perhexiline and nitrite.

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Ivabradine in Stable Coronary Artery Disease without Clinical Heart Failure

Cited by 441 publications

References 19 publications

A 'diamond' approach to personalized treatment of angina

A 'diamond' approach to personalized treatment of angina

Heart Rate Reduction With Ivabradine Protects Against Left Ventricular Remodeling by Attenuating Infarct Expansion and Preserving Remote‐Zone Contractile Function and Synchrony in a Mouse Model of Reperfused Myocardial Infarction

Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm

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