Ivabradine for treating chronic heart failure

The committee considered the clinical need for treatment in people with heart failure who are covered by the marketing authorisation of ivabradine. The committee noted that the clinical specialists indicated that ivabradine is primarily a heart-rate-lowering drug for people with left ventricular systolic dysfunction who are in sinus rhythm and for whom beta-blockers are not suitable. The committee heard from the clinical specialists that people with chronic heart failure have a poor quality of life. It also noted the comment from the patient experts that chronic heart failure can impact on everyday tasks, with comorbidities increasing the impact of the disease and usually requiring lifestyle changes. The patient experts also stated that ivabradine may provide symptomatic and prognostic benefit in a small number of chronic heart failure patients unable to take beta-blockers. The committee considered the clinical specialists' comment that it may be difficult to increase beta-blocker dosage for people with low blood pressure, a group who would benefit from ivabradine. It noted that ivabradine is contraindicated in severe hypotension (less than 90/50 mmHg). The committee recognised the impact of chronic heart failure on quality of life and concluded that there were potential treatment benefits with ivabradine for people who are covered by the marketing authorisation.

The committee considered the generalisability of the SHIFT trial to UK clinical practice. The committee was aware that the population covered by the marketing authorisation in SHIFT was younger, included a higher proportion of men and people with more severe chronic heart failure than the typical chronic heart failure population in the UK. It also noted that only a few people from the UK were included in the trial and the use of cardiac devices in the trial was low. The clinical specialists and the ERG indicated that the differences in age and severity of chronic heart failure may be caused by patient recruitment from specialist heart failure centres, which is common with randomised trials. The committee considered the comments from the clinical specialists and the ERG that the results of the trial could be extrapolated to a UK setting because the standard therapies used in SHIFT could be regarded as optimal and were given at similar dosing levels to UK clinical practice. Despite the differences between the trial and the UK population, the committee concluded that SHIFT was relevant to UK clinical practice.

The committee examined the clinical evidence from SHIFT, which compared ivabradine plus standard care with standard care plus placebo. The committee noted that it was a well-conducted clinical trial and that the relevant clinical outcomes of mortality and hospital admission were assessed. It also noted that health-related quality of life data were collected in SHIFT-PRO using both generic and disease-specific instruments, and was aware that improved quality of life was an important outcome for chronic heart failure patients and that this is considered to be one of the main aims of managing chronic heart failure. The committee noted that the committee for Medicinal Products for Human Use had asked the manufacturer to identify the heart rate threshold at which there was a significant mortality benefit with ivabradine, because this benefit was not observed in the main SHIFT population. So the manufacturer then examined a post hoc subgroup of people with a baseline resting heart rate of 75 bpm or more, and this subgroup formed the population for whom ivabradine has a marketing authorisation. The committee noted that the results from this subgroup demonstrated a statistically significant reduction in all primary and secondary endpoints assessed. This included cardiovascular death, which reduced by 17% with ivabradine compared with placebo, unlike in the main SHIFT population, in which the 9% reduction in cardiovascular death was not statistically significant. The committee was aware that baseline resting heart rate was not a stratification factor at randomisation and that this subgroup was identified post hoc, but it was also aware that recommendations could only be made within ivabradine's marketing authorisation. The committee concluded that SHIFT was well conducted and there was it was plausible biologically that a statistically significant mortality benefit will be observed in the subgroup of people with a baseline resting heart rate of 75 bpm or more, which reflects the marketing authorisation of ivabradine. However they were aware the evidence presented should be interpreted with a level of caution because the subgroup was identified post hoc.

The committee noted that a previous hospital admission for worsening heart failure in the past 12 months was an inclusion criterion for SHIFT. The committee agreed that this was an important consideration because people with a prior hospital admission in the past 12 months may have more severe chronic heart failure than would be observed in clinical practice, with a higher risk of further hospitalisations, which was the key driver of the clinical and cost-effectiveness estimates. The committee noted that the marketing authorisation for ivabradine depended on the efficacy of ivabradine in a specific post hoc subgroup with more severe heart failure (with a baseline heart rate of 75 bpm or more) to demonstrate a cardiovascular mortality benefit. The committee heard from the clinical specialists that prior hospital admission should not be a factor for considering ivabradine treatment because there are no data to prove that the efficacy of ivabradine is limited to the population who have been admitted to hospital in the previous 12 months. The clinical specialists also highlighted that people had to be stabilised for 4 weeks on standard therapy as an entry criterion into the trial. The committee considered that prior hospital admission did not affect mortality and the marketing authorisation did not make any reference to prior admission status. The committee was aware that ivabradine was contraindicated for people with unstable heart failure. Therefore when discussing ivabradine, it understood it could only be initiated after prior stabilisation therapy. The committee concluded that all people for whom treatment with ivabradine is suitable, according to the marketing authorisation, should be able to receive ivabradine regardless of hospital admission status, but that people should be stabilised for 4 weeks on standard therapy first.

The committee considered the adverse event profile associated with ivabradine plus standard care compared with placebo plus standard care. The committee noted that symptomatic bradycardia, atrial fibrillation and phosphenes occurred more frequently in the ivabradine group compared with the placebo group, although other serious adverse events were higher in the placebo group. It noted the comments from the clinical specialists that phosphenes are recognised adverse effects of ivabradine, which usually resolve in most patients during treatment. The clinical specialists also stated that ivabradine appeared to be much simpler and safer to use compared with most heart failure drugs. The committee was concerned that an unusually high proportion of people in the population covered by the marketing authorisation who received a beta-blocker were not treated with the target dose because of hypotension, especially because the mean systolic blood pressure in the population covered by the marketing authorisation was 121 mmHg. It also noted that it would be unusual for people with heart failure to have hypotensive symptoms with this level of blood pressure. It noted the ERG's comment that it has been reported that only 3% to 5% of patients eligible for treatment with beta-blockers are unable to tolerate them because of hypotension or bradycardia. The committee concluded that ivabradine plus standard care had a manageable adverse event profile in the population covered by the marketing authorisation.

The committee examined the exploratory analysis performed by the ERG on the efficacy of ivabradine according to beta-blocker dose received by the population covered by the marketing authorisation in SHIFT. The committee noted the impact of the beta-blocker doses on the effectiveness of ivabradine, particularly in terms of cardiovascular mortality. However, the committee agreed that this analysis was based on subgroups of a subgroup and should be interpreted with caution. The clinical specialists stated that these results further highlight the need for beta-blockers to be used at optimal doses before ivabradine is initiated, because there is good evidence that beta-blockers reduce cardiovascular mortality at optimal doses. They also emphasised that ivabradine would be less effective in people with chronic heart failure who are optimally treated with beta-blockers because both treatments are primarily heart-rate-lowering agents, although beta-blockers are known to have additional effects beyond their heart-rate-lowering properties. The committee concluded that, given the results of these exploratory analyses, the effectiveness of ivabradine with increasing beta-blocker doses is uncertain.

The committee also discussed the exploratory analysis performed according to NYHA class by the ERG for the population covered by the marketing authorisation. It heard from the clinical specialists that it was debatable whether the NYHA class IV subgroup could be considered to be in a stable condition given the severity of their heart failure and that ivabradine is contraindicated in unstable heart failure. The committee also heard from the clinical specialists that the benefit observed in this subgroup of people would be expected because they are the population with the greatest risk of cardiovascular mortality. However, the committee noted that the analysis in this subgroup of people with NYHA class IV heart failure was based on small numbers, which limits the robustness of the results. Therefore the committee concluded that the effectiveness of ivabradine in people with NYHA class IV heart failure was uncertain because of the small patient numbers in the analysis, which meant that these people could not be considered separately as a subgroup.

The committee discussed the position of ivabradine in the treatment pathway for chronic heart failure, noting that it is indicated in chronic heart failure NYHA class II to IV with systolic dysfunction, for people in sinus rhythm whose heart rate is 75 bpm or more, and in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated. The committee heard from the clinical specialists that ACE inhibitors, beta-blockers and aldosterone antagonists used routinely for managing chronic heart failure should always be the initial treatments, because there is robust evidence that they are effective in managing chronic heart failure and improving survival. The clinical specialists all agreed that ivabradine is an additional therapy for a subset of people with chronic heart failure who are in sinus rhythm, and not as a replacement for the recommended standard therapies such as ACE inhibitors, beta-blockers and aldosterone antagonists. They suggested that ivabradine should be considered only when patients are still symptomatic after being stabilised on optimal initial standard therapies at maximally tolerated doses, or when beta-blockers are contraindicated or not tolerated. The clinical specialists expressed their concerns that introducing ivabradine earlier than specified in the marketing authorisation would limit efforts to optimise the use of other standard drugs, particularly beta-blockers. They stressed the need for enough time to titrate beta-blockers to optimal doses according to the 'start low, go slow' recommendations in NICE's guideline on chronic heart failure. The committee concluded that ivabradine should be initiated only after standard treatment with ACE inhibitors, beta-blockers and aldosterone antagonists has been optimised.

The committee explored what optimising standard therapy with beta-blockers meant in clinical practice. It heard from clinical specialists that it can take several months to appropriately titrate beta-blockers to the optimal dose for a patient. The committee was aware that to optimise and ensure adherence to beta-blocker therapy, continuous monitoring and education and support of the patient by members of the heart failure multidisciplinary team are needed. The committee also noted comments from consultees and commentators that there have been misconceptions that beta-blockers are contraindicated in, for example, the elderly, or in people with non-reversible chronic obstructive pulmonary disease, diabetes mellitus, peripheral vascular disease or erectile dysfunction. It noted that, in line with NICE's guidance on chronic heart failure, these groups of people should receive beta-blockers. The committee re-emphasised their conclusion in section 4.9 on the importance of optimising beta-blockers before initiating ivabradine.

The committee also considered the comments from consultees and commentators that there is a recent analysis that shows that digoxin may confer benefits similar to ivabradine for patients in sinus rhythm and with heart failure caused by left ventricular systolic dysfunction. However, the committee noted that digoxin was not included as a comparator in the scope for this appraisal and there was no evidence to support its benefit in this population. The committee concluded that considering digoxin as a comparator to ivabradine is beyond the scope of this appraisal.

The committee also considered the position of cardiac devices, particularly cardiac resynchronisation therapy, in the treatment pathway for chronic heart failure because the manufacturer proposed positioning ivabradine before them. The clinical specialists were uncertain about this and proposed several different options about the most appropriate choice if people still have symptoms after they are treated with ACE inhibitors, beta-blockers and aldosterone antagonists. The committee noted that very few patients in SHIFT received cardiac resynchronisation therapy. It therefore considered that more evidence would be useful to determine the position of ivabradine in relation to cardiac devices, particularly cardiac resynchronisation therapy, in the treatment pathway. However, the clinical specialists said that choosing whether to treat with ivabradine or cardiac resynchronisation therapy will depend on clinical need and that ivabradine will only be considered if the person is in sinus rhythm as indicated in ivabradine's marketing authorisation. The committee was aware that ivabradine is contraindicated in people whose heart rate is dependent on a pacemaker. The committee recognised that there was some uncertainty about the appropriate choice of treatment when people are eligible for both ivabradine and cardiac resynchronisation therapy, and concluded that the decision will likely be based on the judgement of the treating clinician.

The committee considered the comments from the consultees and commentators that ivabradine should only be given to people with a left ventricular ejection fraction of 35% or less. It noted that the patients in SHIFT had left ventricular systolic dysfunction, which was associated with an ejection fraction of 35% or less, and it was aware that this was an entry criterion for the trial. The committee was aware that an ejection fraction level was not specified in the marketing authorisation for ivabradine. However, it considered that ivabradine could not be recommended in people with an ejection fraction that is above 35% because there is no evidence of its effectiveness in that group. The committee discussed how the ejection fraction level will be determined in clinical practice and whether the required tests will be readily available to people who will potentially benefit from ivabradine. It heard that ejection fraction level is usually demonstrated with an echocardiogram and additional tests will not necessarily be required before initiating ivabradine. Therefore, the committee concluded that ivabradine should only be initiated in people with a left ventricular ejection fraction of 35% or less, normally shown on an echocardiogram.

The committee considered how ivabradine will be prescribed in clinical practice. It heard from clinical specialists that a heart failure specialist in secondary care with access to a multidisciplinary team should initiate ivabradine. The clinical specialists also stated that titration and monitoring of ivabradine could then take place in primary care by a GP with a special interest in heart failure or a heart failure specialist nurse, supported by a multidisciplinary team. They highlighted that this may help ensure the appropriate patients are treated with ivabradine after optimising treatment and stabilising patients on maximally tolerated doses of ACE inhibitors, beta-blockers and aldosterone antagonists. However, the manufacturer anticipated that ivabradine would be prescribed by a clinician experienced in managing chronic heart failure as recommended in the summary of product characteristics. The committee discussed the emergence of increasing heart failure expertise outside secondary care. It noted that NICE's guideline on chronic heart failure defined a specialist as a physician with a subspecialty interest in the management of heart failure and who leads a specialist multidisciplinary heart failure team of professionals with appropriate competencies from primary and secondary care. The committee concluded that ivabradine should be initiated by a heart failure specialist (in line with the NICE clinical guideline) with access to a multidisciplinary heart failure team and dose titration and monitoring should then be carried out by a heart failure specialist or in primary care by either a GP with a special interest in heart failure or a heart failure specialist nurse.

The committee considered the manufacturer's economic model and the ERG's critique of this model. The committee was aware that the manufacturer had based the economic evaluation on the subgroup of patients with a baseline resting heart rate of 75 bpm or more. The committee noted that this was the subgroup for whom ivabradine has a UK marketing authorisation. The committee concluded that the appropriate population for the economic evaluation of ivabradine for treating chronic heart failure had been captured in the model.

The committee discussed the assumptions made by the manufacturer in developing the economic model. The committee noted the ERG's comment that the manufacturer's model was transparent and made use of patient-level data in the base-case analysis. It agreed with the ERG that the standard care treatments used in the economic model reflected UK clinical practice. The committee was satisfied that the utility values applied in the model were derived from SHIFT, which was the pivotal trial used in the economic analysis, and considered the approach taken by the manufacturer to obtain the final utility estimates to be plausible and robust. The committee was also satisfied with the costs used by the manufacturer and that the clinical inputs to the model reflected UK practice. The committee was aware that the sensitivity analyses conducted by the manufacturer were robust for the base-case estimate, except for the risk of cardiovascular mortality (see section 3.33 and 3.35), and that the ICERs for all the subgroup analyses were below £11,000 per QALY gained. The committee concluded that the manufacturer's model was robust and the assumptions were realistic and conservative.

The committee considered the uncertainty around the benefit of ivabradine on cardiovascular mortality given that the ICER ranged between approximately £5,600 and £40,600 per QALY gained when the risk of cardiovascular mortality was varied using the 95% confidence interval around the mean from the trial data. The committee noted the ERG's comments that there were uncertainties associated with the regression analyses for cardiovascular and heart failure mortality used in the economic model presented by the manufacturer. The committee noted that the treatment effect of ivabradine in the regression analysis had a p value of 0.38 for cardiovascular mortality and a p value of 0.06 for heart failure mortality. For the population covered by the marketing authorisation in the clinical effectiveness analysis, the p value for cardiovascular mortality was 0.02, and for heart failure mortality was less than 0.01. On the other hand, beta-blockers given at 50% or more of the target dose were associated with a statistically significant reduction in the risk of cardiovascular mortality, and beta-blockers at all doses were associated with statistically significant reductions in the risk of heart failure mortality. The committee considered that this further highlights the importance of optimising beta-blocker therapy before treatment with ivabradine. However, the committee noted the ERG's comment that the absence of a statistically significant effect with ivabradine in the model may be a result of the adjustment of patient characteristics not accounted for in the clinical analysis. The committee was also aware that the manufacturer's regression analyses were conservative in favour of placebo, which made the analyses likely to underestimate the risks of cardiovascular and heart failure mortality, and so generated different results from those observed in the population covered by the marketing authorisation of the SHIFT trial. The committee concluded that the additional treatment effect of ivabradine was uncertain compared with the effect of beta-blocker doses.

The committee considered whether the base-case ICER of approximately £8,500 per QALY gained (incremental cost of approximately £2,400 and incremental QALY of 0.28) of adding ivabradine to standard care estimated by the manufacturer was the most plausible ICER. The committee considered that the ICER suggested that ivabradine was cost effective if a threshold of £20,000 per QALY gained was applied. The committee considered that the effect of ivabradine on the hospital admission endpoints was the key driver of the cost effectiveness of ivabradine plus standard care compared with standard care alone. It noted that ivabradine plus standard care was more effective and cost more than standard care. Additionally it noted that ivabradine was still accruing more QALYs when the confidence interval for the hazard ratio for mortality crossed 1 and favoured standard care alone in the model, which suggested that ivabradine has a large impact in reducing hospital admissions. The committee agreed that the wide range of sensitivity and subgroup analyses conducted by the manufacturer sufficiently addressed any areas of uncertainty in the economic analysis, including the beta-blocker subgroups, and all produced ICERs below £11,000 per QALY gained. It also considered that the modelled results and most of the model assumptions were conservative and biased against ivabradine. The committee therefore concluded that the manufacturer's ICER estimate of approximately £8,500 per QALY gained was plausible and was likely to represent the expected cost effectiveness of adding ivabradine to standard care for treating chronic heart failure in the population covered by the marketing authorisation.

The committee recognised the novel mode of action of ivabradine as a heart-rate-lowering agent for patients in sinus rhythm for whom beta-blockers are contraindicated or not tolerated. It also considered the manufacturer's comment that ivabradine is the only non-surgical treatment available for people with chronic heart failure whose prognosis remains poor after recommended optimised therapy for chronic heart failure. However, the committee considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations. The committee therefore concluded that the innovative aspects of ivabradine were already incorporated in the economic model and analyses.

The committee discussed potential equality issues and gave particular consideration to avoid unlawful discrimination against any group of people on the grounds of race, gender, disability, religion or belief, sexual orientation, age, gender reassignment, pregnancy and maternity. The committee noted the potential equality issue raised by the patient experts about the higher prevalence of non-revascularisable coronary artery disease in the Asian population because of the impact of diabetes as a risk factor. It highlighted that higher prevalence rates are not an equality issue that technology appraisal guidance can address. Nevertheless, the committee did not consider that the wording of the recommendations affected access to treatment by this group. The committee also noted that older people and women were under-represented in SHIFT. But it considered that the recommendation for ivabradine was not based on sex or age, does not vary according to the sex or age of the patient, and that all patients would benefit from ivabradine. The committee considered that these were not equality issues under the legislation. The committee therefore concluded that its recommendations do not have a particular impact on any of the groups whose interests are protected by the legislation and that there is no need to alter or add to its recommendations.

Overall the committee considered the effectiveness of ivabradine in the subgroup of patients with a resting heart rate of 75 bpm or more derived from SHIFT, the generalisability of the trial to UK clinical practice, the adverse event profile of ivabradine, the position of ivabradine in the treatment pathway of chronic heart failure (that is after optimisation on standard care therapy with ACE inhibitors, beta-blockers and aldosterone antagonists) and the way ivabradine will be prescribed in clinical practice. It also considered the robustness of the economic model, the realistic nature of the assumptions used in the model, the plausibility of the base-case ICERs and the range of sensitivity analyses presented by the manufacturer. The committee noted that there were uncertainties associated with the effectiveness of ivabradine with increasing beta-blocker doses. However, it was convinced of the benefits of adding ivabradine to the standard care therapies for chronic heart failure in the group of people covered by the marketing authorisation. The committee therefore concluded that ivabradine could be considered a cost-effective use of NHS resources for treating chronic heart failure in people covered by the marketing authorisation.