Published. Swedberg K et al. “Ivabradine and outcomes in chronic heart failure ( SHIFT): a randomised placebo-controlled study”. Lancet. Systolic Heart failure treatment with the lf inhibitor ivabradine Trial. Effect of ivabradine on the primary composite endpoint (A), heart and heart failure hospitalizations (C) in the SHIFT trial.
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Michel Komajda; Prognostic and symptomatic benefits with ivabradine: Ivabradine, a funny current If inhibitor, has been developed for symptomatic therapy of angina and in stduy heart failure CHF with low ejection fraction. Ivabradine improved health-related quality of life significantly and reduced the number of recurrent hospitalizations for HF.
Sub-studies conducted in subgroups with important co-morbidities, i.
The acute cardiac effect is characterized by a reversal of the abnormal force—frequency relationship, thus resulting in preserved contractile function and increased stroke volume despite heart rate reduction. The chronic cardiac effect is characterized by a reverse remodelling of the left ventricle with reduced cardiac dimensions which result from unloading of the left ventricle.
The publication of the positive results of the large outcome trial SHIFT Systolic Heart Failure Treatment with the If inhibitor ivabradine trial has led to the registration of this new molecule for the management of chronic heart failure CHF in countries including the recent approval in the USA and in China and ivabradine is listed as a recommended medication in the latest version of the European Society of Cardiology guidelines.
Following the main publication of the trial, a number of sub-studies have sift conducted in order to address key issues such as role on quality of live, mechanism of action and, most importantly, efficacy and safety in patients with comorbidities which can affect management of heart failure HF and make it more complex.
The purpose of this review is i to summarize the key findings of the SHIFT trial and ii to discuss its implications for daily practice. This beneficial effect was observed in a well-treated population: Studg, the incremental benefit observed with ivabradine on HF outcomes was obtained in a population of patients well treated by evidence-based therapies. The beneficial effect on the outcomes detailed above occurred rapidly, and the survival curves show that the separation was rapid after randomization.
This mirrored heart rate reduction, which occurred early on: The difference in heart rate between the two groups was 8 b. The benefit was also similar in patients with or without an ischaemic aetiology of HF. Visual side effects were also uncommon and led to treatment discontinuation in only a few cases.
Patients included in this safety analysis are those who had taken at least one dose of study drug. P -values are calculated on the basis of the number of patients.
One shif point of interest for safety is sshift tolerability on cardiac rhythm since both beta-blockers and ivabradine reduce heart rate. It was therefore legitimate, to conduct a h Holter sub-study beyond the overall safety evaluation.
Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
Heart rate reduction tended to be more pronounced during walking hours than during sleep. No episode of third-degree AV block was observed. On the pro-arrhythmic side, the percentage of patients with episodes of supraventricular tachycardia was also similar Finally, atrial fibrillation was identified in six patients in the ivabradine group and five in the placebo group. Despite modern therapy, people with Ivabtadine are frequently readmitted to hospital because of worsening of their symptoms.
Rehospitalization is associated with a substantially increased risk of subsequent death and the sift is more important in the early phase after hospitalization.
Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
Finally, ivabradine reduced substantially the risk of early readmission for HF ivabradin 30 days 4. Heart failure is a disabling condition associated with a poor quality of life. Multiple comorbidities are frequent in patients with HF and are the rule in elderly patients over 65 years. The presence of dhift makes management of HF more complex due to an increase in the risk of poor tolerability of HF iabradine or of contra-indications.
An extensive series of sub-analyses was therefore made in the SHIFT population in order to evaluate the efficacy and the safety of ivabradine in subgroups of patients presenting with important comorbidities. Chronic obstructive pulmonary disease was reported in patients who were older and had an overall increased risk of death, cardiovascular death, all-cause and HF hospitalization than patients without chronic obstructive pulmonary disease.
Adverse events were overall more frequent in chronic obstructive stjdy disease patients than in non-chronic obstructive pulmonary disease patients but were not significantly different in the ivabradine ivavradine placebo arms of either group. This sub-study shows that ivabradine is similarly effective and safe in CHF patients with or without chronic obstructive pulmonary disease and can be safely combined with beta-blockers in this high-risk population.
Importantly, no differences in changes in renal function over time were found between ivabradine- and placebo-treated patients. The presence of low SBP shif complicates the management of HF and is a challenge for the uptitration of recommended medications.
Patients with low SBP had a lower ejection fraction and were less likely to be at target beta-blockers dose than patients in the other SBP groups. Similar results were found for cardiovascular mortality and hospitalization for HF.
There was no evidence of a differential safety profile of ivabradine according to SBP. This post hoc analysis confirms that the efficacy of ivabradine is independent of the level of SBP. This finding is in line with the mechanism of action of the If current inhibitor that does not affect the vascular bed and has therefore no vasodilatory action. This may have implications for the management of HF with low SBP and elevated heart rate, a condition where uptitration of beta-blockers is often difficult due to hypotension.
Overall, patients with diabetes were older, had a poorer renal function, and are more severely symptomatic HF than patients without diabetes. Regardless of diabetic status, the incidence of serious adverse events was not significantly different between ivabradine and placebo. The conclusion of this analysis is that ivabradine can ivabdadine used safely and is efficient in patients with CHF and diabetes.
Management of severely symptomatic HF NYHA class IV and of patients with very low ejection fraction is often difficult due to poor tolerability of HF medications and optimization of treatment is ivabradne. These findings suggest that ivabradine can be safely ivabraeine in severe HF and may improve clinical outcomes, independently of disease severity. It has been known for long studdy the force—frequency relationship is positive in the normal heart i.
This unfavourable effect can be reverted by ivabradine as ivabradihe both in the experimental setting and in patients with advanced HF. The only mechanism of action of ivabradine is to reduce heart rate when elevated through blockade of the If channel in the sinoatrial node.
SHIFT Study Overview | Corlanor® (ivabradine) tablets
The effect of this pure heart rate-lowering effect on cardiac function has been assessed in an echocardiographic sub-study. This reduction was also observed on LV end-diastolic index and there was a 2. This mechanistic study shows that ivabradine reverses cardiac remodelling and this reversal is associated with improved outcomes. One potential explanation for the beneficial effect of heart rate reduction on cardiac dimensions is the reduction of afterload.
Contractility remained unchanged and ventricular-arterial coupling was improved, resulting in a higher stroke volume in ivabradine-treated patients. This second mechanistic study therefore suggests that isolated heart rate reduction with ivabradine unloads the left ventricle of a failing heart and contributes to the beneficial effect observed in patients. Despite the considerable amount of information generated by experimental and clinical studies, some questions remain open and deserve further consideration:.
Little progress has been made in the management of these two conditions. Acute HF is associated with a high mortality rate in hospital and early after discharge.
Reverting the force—frequency relationship by ivabradine might be beneficial in this unstable situation, particularly when heart rate is markedly elevated and this hypothesis needs to be tested. In HFpEF, prolonging diastole in an abnormally stiff left ventricle might result in an improved LV filling with potential clinical benefit. In the clinical setting, earlier administration has been tested in individual cases. A study comparing early to late administration of ivabradine is therefore needed to see whether this results in an optimization of titration and in potential clinical benefit.
The introduction of ivabradine in the management of HF with low ejection fraction, in sinus rhythm and with elevated heart rate is associated with improved clinical outcomes, quality of life and reduced rehospitalizations for this condition. A number of studies in specific populations demonstrate that this drug is efficient and safe on top of contemporary HF medications.
This includes patients with chronic obstructive pulmonary disease, renal dysfunction, diabetes, and patients with low SBP. Important clinical questions remain regarding early initiation and potential extension of indications which need to be addressed in future clinical trials.
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Rehospitalizations for heart failure. Efficacy and safety of ivabradine in specific populations.
Mechanism of action of ivabradine in heart failure. Prognostic and symptomatic benefits with ivabradine: Abstract Ivabradine, a funny current If inhibitor, has been developed for symptomatic therapy of angina and in chronic heart failure CHF with low ejection fraction. Chronic heart failureIvabradineSstudy treatmentClinical trials.
View large Download slide. Short-term haemodynamic effect of beta-blocker and ivabradine in chronic heart failure. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure Heart rate reduction with ivabradine and health related quality of life in patients with chronic heart failure: Effects of selective heart rate reduction with ivabradine on left ventricular remodeling and function: Selective heart rate reduction with ivabradine unloads the left ventricle in heart failure patients.
Clinical profiles and outcomes in patients with chronic heart failure and chronic obstructive pulmonary disease: The effect of heart rate reduction with ivabradine on renal function in patients with chronic heart failure: Efficacy and safety of ivabradine in patients with chronic systolic heart failure according to blood pressure level in SHIFT. Efficacy and safety of ivabradine in patients with chronic systolic heart failure and diabetes: Twenty-four-hour heart rate lowering with ivabradine in chronic heart failure: Effect of ivabradine on recurrent hospitalization for worsening heart failure ivabraadine patients with chronic systolic heart failure: Health related quality of life in patients with congestive heart failure comparison with other chronic diseases and relation to functional variables.
Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: Epidemiology of multimorbidity and implications for health care, research, and medical education: Renal impairment, worsening renal function and outcome in patients with heart failure: Current management and ivabraeine directions for the treatment of patients hospitalized for heart failure with low blood pressure.
Diabetes mellitus and heart failure: Heart failure due to systolic dysfunction and mortality in diabetes: Influence of the force-frequency relationship on haemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy.
Long-term heart rate reduction induced by the selective I f current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure.
Favourable effects of heart rate reduction with intravenous administration of ivabradine in patients with advanced heart failure.