Increase the Ik Channel Ifunny Channel

Summary

I _funny (I _f ), or funny current, channel inhibitors are a class of drugs with heart rate reducing properties (negative chronotropic drugs) and ivabradine is the first representative of this drug class; it was recently tested for the treatment of heart failure (HF).
Based on currently available evidence, it can be interpreted that ivabradine may have a role in the treatment of patients who have a certain form of HF. So for patients with symptomatic HF with reduced ejection fraction (HFrEF) (EF ≤ 35%); that is, with the lower-left part of their heart not contracting well, with a heart rate of 70 beats per minute (bpm) or higher and for patients who are unable to tolerate optimal beta-blocker dosing. Of note, patients with HFrEF who have a heart rate greater than 77 bpm may be the ones to derive the most benefit from initiating ivabradine therapy.
Ivabradine was evaluated in more than 10 clinical trials for a number of cardiovascular (CV) uses including coronary artery disease, angina, myocardial infarction, and HF. While an initial HF study, BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction), did not find significant improvement in cardiac outcomes with ivabradine, findings from a prespecified subgroup of patients with a heart rate of 70 bpm or higher suggested a correlation between the resting heart rate and the risk of CV events; this observation led to further investigation of ivabradine for the treatment of HF.
The clinical development of ivabradine continued with the SHIFT (Systolic Heart failure treatment with the I _f inhibitor ivabradine Trial) study. This study targeted patients with HFrEF, in sinus rhythm (i.e., normal heartbeat) and with a heart rate of 70 bpm or higher. The phase 3 trial evaluated the morbidity and mortality benefits of ivabradine as an add-on therapy to standard treatment for HF, including the use of a beta-blocker if tolerated, compared with placebo. Results showed that when ivabradine is added on to guidelines-based background therapy, there is a statistically significant decrease of 18% in the rate of primary end point (composite of CV death or hospital admission for worsening HF) compared with placebo.
Of note, 89% of patients enrolled in the SHIFT trial were on beta-blockers. However, despite aiming to treat patients at the guidelines-specified target dose for beta-blockers, only 56% of patients were on at least 50% of the target dose and, 26% of patients were at target dose. The most common reasons for suboptimal dosing of beta-blocking therapy were hypotension and fatigue.

Background

HF is a clinical syndrome resulting in the heart's inability to effectively fill with or eject blood from the ventricles, increasing the myocardial oxygen demand.¹ ^– ³ HF is commonly accompanied by the following triad of symptoms: fatigue, dyspnea, and edema.³

According to Canada's Heart and Stroke foundation, HF affects 600,000 Canadians with 50,000 incidences per year.⁴ Considering that there is an aging population in Canada, and that age is one of the factors contributing to the development of HF, the prevalence of HF is expected to grow in the coming years.

Although current treatments improved outcomes over the past two decades, the estimated five-year mortality rate is still high, reaching roughly 50%, which represents a significant health burden on patients.⁴ ^– ⁷ HF is also associated with a number of chronic comorbidities (e.g., hypertension, ischemic heart disease, hyperlipidemia, anemia, and diabetes⁵), which has a further impact on patients' quality of life and puts additional strain on the health care system. HF is a leading cause of hospitalization, with 60,000 hospital visits related to this condition annually.⁴ Consequently, HF is associated with a significant economic burden. Approximately $2.8 billion is spent annually in Canada to cover direct costs such as hospitalization and emergency room visits.⁴

Ivabradine may have a role in patients with HFrEF who have a higher heart rate despite receiving guidelines-based background therapy (including beta-blockers).

The Technology

The pathophysiology of HF (in relation to heart rate) will be briefly discussed to illustrate the putative mechanism of action of I _f channel inhibitors, in particular ivabradine, which is the first representative of this drug class. In a compensatory response to HF, the sympathetic nervous system is activated to increase the heart rate to meet the myocardial (cardiac) oxygen demand.¹ However, the benefit of the high heart rate is short-lived as the disease continues to progress.¹ High resting heart rate is an important risk factor in both the general population and in patients with cardiovascular (CV) disease, as studies have demonstrated an association between high resting heart rate and negative health outcomes.¹ ^, ⁸ Heart rate is mainly directed by conduction across certain parts of the heart, sinoatrial node firing in this case. This process is dependent on the slow diastolic depolarization of action potential.¹ The slow diastolic depolarization is controlled by the opening of the I _f channels, channels that are found in high concentration at the site of the sinoatrial node.¹ ^, ⁹

Ivabradine exerts a negative chronotropic effect (i.e., a reduction in heart rate) by inhibiting the open I _f channels, which delays the slow depolarization of action potential, and ultimately reduces heart rate.¹ ^, ⁹ Studies have shown that ivabradine selectively targets the open I _f channels and does not exert effects on other channels in the heart or the vascular system (at the therapeutic dose).¹ ^, ⁸ Given its specific effect at the I _f channels of the sinus node, ivabradine reduces heart rate without affecting myocardial contractility, relaxation, and peripheral vascular resistance.¹⁰ ^, ¹¹ Clinically, ivabradine can reduce heart rate without much impact on blood pressure.¹¹

The effect of ivabradine on the heart rate of patients with HF is dose dependent; it is also dependent on the baseline heart rate before treatment.¹ ^, ¹² With respect to the latter, a higher baseline heart rate (more open I _f channels) leads to a greater decrease in heart rate (by ivabradine), while a lower baseline heart rate (less open I _f channels) leads to less of a decrease in heart rate — a property referred to as use dependence.¹ ^, ⁸ ^, ¹³

The I _f channel inhibitor's mechanism of action has been used and studied for various clinical conditions, including in the treatment of chronic stable angina pectoris/coronary artery disease (CAD) and for symptomatic chronic HF.¹¹ ^, ¹⁴ ^, ¹⁵ Of note, selective heart rate reduction through I _f inhibition decreases myocardial oxygen demand and improves ventricular filling time; that is, time to fill the lower chambers of the heart, allowing increased coronary blood flow and leading to improved oxygen supply.² ^, ⁸ ^, ¹⁶ ^, ¹⁷

Regulatory Status

Ivabradine is the first drug of its class to be marketed in Europe, Australia, and the US,¹⁴ ^, ¹⁵ ^, ¹⁸ In Canada, the drug was granted its notice of compliance (NOC) on December 23, 2016; the trade name is Lancora.¹⁹ Ivabradine is indicated in Canada for the treatment of stable chronic HF with reduced left ventricular ejection fraction (LVEF) (≤ 35%) in adult patients with New York Heart Association (NYHA) Classes II or III who are in sinus rhythm with a resting heart rate ≥ 77 beats per minute (bpm), to reduce the incidence of CV mortality and hospitalizations for worsening HF.²⁰

In Europe, the European Medicines Agency (EMA) first approved ivabradine in 2005 for the treatment of chronic stable angina pectoris and approved it again in 2012 for the treatment of HF.¹⁴ Similarly in Australia, the Therapeutic Goods Administration (TGA) first approved ivabradine for chronic stable angina pectoris in 2006, and approved it again in 2012 for HF.¹⁵ In the US, the Food and Drug Administration (FDA) approved ivabradine on April 2015 for the treatment of chronic HF with left ventricular EF < 35%.¹⁸ As of August 2016, ivabradine has been approved for HF in 103 countries and marketed in 92 countries (Frederic Fasano, CEO Servier Canada Inc., Laval, QC: personal communication, 2016 Aug 16). Although ivabradine has been available in Europe and Australia for more than a decade for stable angina, this drug is not available in Canada for this indication. Of note, the EMA recently stated that the use of ivabradine in patients with angina is limited to the alleviation of symptoms as available evidence does not indicate that this drug provides benefits on CV outcomes such as myocardial infarction or CV death in this population.²¹

Patient Group

To explain I _f channel inhibitors' potential role in HF, the HF population will be briefly examined in this section. First, when considering EF, it is possible to categorize HF in two main types: HFrEF and HF with preserved ejection fraction (HFpEF).⁵ ^, ²² Of note, EF measures the volume expelled from the ventricles (lower heart chambers) with each contraction.³ Each category makes up approximately 50% of the overall HF population; as there are about 600,000 individuals in Canada with HF, it may be extrapolated that approximately 300,000 Canadians have HFrEF. Of note, each HF type has its own treatment algorithm.²³ While there is a clearly outlined algorithm for HFrEF (EF ≤ 40%) in the Canadian Cardiovascular Society (CCS)'s guideline, there is limited evidence in existence for outcome-modifying therapies for HFpEF.²³ There are also varying degrees of HF severity.⁵ ^, ²³ A commonly used monitoring tool called the NYHA Functional Classification identifies the severity of HF according to the degree of burden this condition has on patient's physical activities – ranging from Class I (least severe) to Class IV (most severe).⁵

As previously mentioned, rising heart rate is a part of the HF disease progression and elevated heart rate has been associated with increased risk of the following negative CV outcomes: myocardial infarction, left ventricle remodelling, CAD disease progression, and increased risk of CV death.¹⁶ ^, ¹⁷ ^, ²⁴ Several studies have indicated that resting heart rate is a strong prognostic risk factor for increased CV mortality and morbidity in the general population, as well as for patients with hypertension, CAD or chronic HF.¹⁷ More specific to HF patients, a relatively recent ancillary study of the BEAUTIFUL trial showed that patients with a heart rate of 70 bpm or higher were at a 34% increased risk of CV death and a 53% increased risk of hospital admission for HF compared with patients with a heart rate lower than 70 bpm.¹⁶ ^, ¹⁷ The analysis also showed that there was an 8% increase in the risk of CV death and 16% increase in the rate of admission to hospital for HF for every 5 bpm increase in heart rate.¹⁷

Current Practice

For the purpose of this report, only the treatments for HFrEF will be discussed. While there is no cure for HFrEF at the moment, current therapies address symptomatic relief and improve outcomes through non-pharmacological and/or pharmacological interventions. Pharmacologic interventions include the use of the following classes of medications: diuretics, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), beta-blockers, and mineral corticoid receptor antagonists (MRAs); the angiotensin receptor/neprilysin inhibitor (ARNI), digoxin; and/or a combination of hydralazine and nitrates.²³ ^, ²⁵

The 2016 CCS HF companion guideline states that the standard (first-line) pharmacological intervention should consist of triple therapy with an ACEI or an ARB, a beta-blocker, and an MRA. Additional drug therapies are considered if patients continue to experience NYHA Class II to Class IV symptoms and meet certain criteria; these therapies may include ivabradine (pending regulatory approval), ARNI, digoxin, and hydralazine/nitrate. Diuretics are also used to relieve congestion.²⁵ Of note, several clinical trials (e.g., CIBIS-II, MERIT-HF, COPERNICUS, SENIORS, and MOCHA) have shown the benefit of beta-blockers in morbidity and mortality; that is, the improvement in left ventricular remodelling, reduction in sudden death, and improvement in LVEF.¹ ^, ⁶ ^, ⁸ ^, ¹⁶ ^, ²⁶ The negative chronotropic property of beta-blockers may, in part, be attributed to these CV benefits.²⁷ It has been reported, however, that reaching target doses of beta-blockers may not be possible for all patients.¹ ^, ⁶ ^, ⁸

A number of reasons can explain patients' intolerance to target doses of beta-blockers or inability to take beta-blockers, reflective of symptoms or conditions commonly encountered in clinical practice (e.g., fatigue, hypotension, dyspnea, dizziness, asthma, chronic obstructive pulmonary disease).⁶ ^, ⁸ In a large (n = 7,363) observational registry called IMPROVE HF (Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting), the percentage of patients on an optimal beta-blocker dose was approximately 20%, which is close to the percentage reported in SHIFT (26%).¹

The Evidence

Several clinical trials were conducted to evaluate ivabradine as a treatment for various CV populations. As an overview, the stable CAD population was studied in SIGNIFY²⁸ and BEAUTIFUL;²⁴ angina patients in ASSOCIATE,²⁹ INITIATIVE,¹¹ RESPONSIfVE,³⁰ and REDUCTION;³¹ myocardial infarction patients in VIVIFY;³² and HF patients in BEAUTIFUL,²⁴ CARVIVAHF, ³³ INTENSIFY,³⁴ and SHIFT.⁶ The latter study evaluated morbidity and mortality benefits of ivabradine specifically in HFrEF patients with a heart rate of 70 bpm or higher.⁶ The FDA approved ivabradine for HF based on findings from the SHIFT trial.⁶ ^, ³⁵ Prior to the SHIFT trial, the BEAUTIFUL trial had been completed. This study aimed to assess the morbidity and mortality benefits of ivabradine in patients with CAD and LVEF less than 40%.¹⁷ ^, ²⁴ While the results from the BEAUTIFUL study itself showed no significant improvement in cardiac outcomes with ivabradine, findings from a prespecified subgroup of patients with a heart rate of 70 bpm or higher¹⁸ from this trial suggested a correlation between the resting heart rate and the risk of CV events. More specifically, compared with placebo, ivabradine reduced the rate of secondary end points; namely, admission to hospital for MI (fatal and non-fatal) (hazard ratio [HR] 0.64; 95% confidence interval [CI], 0.49 to 0.84), MI (fatal or non-fatal) or unstable angina (HR 0.78; 95% CI, 0.62 to 0.97), and coronary revascularization (HR 0.70; 95% CI, 0.52 to 0.93). Of note, 84% of the patients in this subgroup were on a beta-blocker.¹⁷ ^, ²⁴ Given that these observations were derived from a subgroup analysis, no definitive conclusion could be made. They appear, however, to have informed the generation of the hypothesis and the design of the SHIFT study. SHIFT was a phase 3 trial that studied the effect of ivabradine on CV outcomes in patients with chronic HF (Table 1).⁶

The multinational SHIFT trial was designed to evaluate the effect of ivabradine, in addition to guidelines-based treatment, on CV outcomes, symptoms, and quality of life in patients with chronic HF and systolic dysfunction.⁶ It was a randomized, double-blind, placebo-controlled, parallel-group study that included 6,558 HFrEF patients with the following characteristics: adults 18 years or older, heart in sinus rhythm, resting heart rate of 70 bpm or higher, stable symptomatic chronic HF on stable background treatment for four weeks or longer, admission to hospital for worsening HF within the previous 12 months, and a LVEF of 35% or lower. Of these, data were available for 6,505 patients.⁶ Patient exclusion criteria were the following: MI within the previous two months, pacemakers pacing for 40% of the day or more; atrial fibrillation or flutter, symptomatic hypotension, and HF caused by congenital heart disease or primary severe valvular disease.⁶ Administration of non-dihydropyridine calcium channel blockers, Class I antiarrhythmics, and strong cytochrome CYP3A4 enzyme (CYP3A4) inhibitors or inducers were prohibited throughout the study.⁶

Patients who were randomized received either ivabradine 5 mg twice daily or a matching placebo dose in addition to their guidelines-based background HF therapy; in particular, the latter included a beta-blocker if tolerated.⁶ The ivabradine dose was adjusted by investigators accordingly to the patient's resting heart rate on days 14 and 28 and then every 4 months until study closure. The median follow-up duration was 22.9 (interquartile range 18 to 28) months.⁶

The primary end point was the composite of CV death or hospital admission for worsening HF.⁶ Secondary end points included three single mortality end points (all-cause death, any CV death, death from HF) and four other end points (all-cause hospital admission; hospital admission for worsening HF; any CV hospital admission; and composite of CV death, hospital admission for worsening HF, or hospital admission for non-fatal MI).⁶ Of note, the composite end point of CV death or hospital admission for worsening HF was also measured in a subgroup of patients receiving at least 50% of the target (daily) dose of a beta-blocker (as defined by the European Society of Cardiology guidelines) at randomization.⁶ For simplicity, this subgroup will be referred to as the beta-blocker_50% subgroup in the rest of this text.

Patient's functional capacity was assessed using the NYHA classification. In regard to addressing the mortality end points of the study, all deaths were considered CV-related unless a definite non-CV cause was found. In terms of hospital admissions for worsening HF, this was defined as patients being admitted for new or increasing signs and symptoms of HF.⁶ The average patient age of the combined population (treated + placebo) was 60.4 years old, 75% of enrolled patients were men, and 89% were white.⁶ In terms of cardiac parameters, the mean heart rate was 79.9 bpm and EF was 29%.⁶ The distribution of patients between NYHA classes II, III, and IV was 49%, 50%, and 2%, respectively. Of the HF cases, 68% were related to an ischemic cause.⁶ In addition, 91% of patients were on ACEIs or ARBs, while 89% were on beta-blockers. Despite aiming to treat patients at the guidelines-specified target dose for beta-blockers, only 56% of patients were on at least 50% of the target dose (as defined by the European Society of Cardiology guidelines), and 26% of patients were at target dose. The most common reasons for not reaching the target dose of beta-blocker therapy were hypotension and fatigue.⁶ Because of comorbidities (e.g., chronic obstructive pulmonary disease, asthma, hypotension) or other reasons, 11% of patients did not receive any beta-blocker.⁶ Other considerations include the low number of patients recruited from North America (30 patients enrolled in Canada only) as well as the low use of cardiac devices (cardiac resynchronization therapy [1%] and implantable cardioverter defibrillator [3% to 4%]). These may limit the generalizability of the study findings to North American/Canadian practice settings.

Compared with the pre-treatment group, ivabradine reduced the heart rate by a mean of 15.5 bpm (standard deviation 10.7) at 28 days. When corrected for change in heart rate observed in the placebo group, ivabradine reduced the heart rate by 10.9 bpm (95% CI, 10.4 to 11.4). The reduction in heart rate was 9.1 bpm (95% CI, 8.5 to 9.7) at 12 months and 8.1 bpm (95% CI, 7.5 to 8.7) at the end of the study.⁶ With respect to CV outcomes, 29% of patients in the placebo group reached the primary end point compared with 24% of patients in the ivabradine group (HR 0.82; 95% CI, 0.75 to 0.90, P < 0.0001). This result was mainly driven by a reduction in the rate of hospital admissions for worsening HF, which occurred in 21% of patients on placebo and 16% of patients on ivabradine, respectively (HR 0.74; 95% CI, 0.66 to 0.83, P < 0.0001).⁶ Neither all-cause mortality (HR 0.90; 95% CI, 0.80 to 1.02, P = 0.092) or CV deaths (HR 0.91; 95% CI, 0.80 to 1.03, P = 0.1280) were significantly reduced in the ivabradine group; however, HF deaths were significantly reduced (HR 0.74; 95% CI, 0.58 to 0.94, P = 0.014).⁶ All-cause hospital admission (HR 0.89; 95% CI, 0.82 to 0.96, P = 0.003), hospital admission for worsening HF (HR 0.74; 95% CI, 0.66 to 0.83, P ≤ 0.0001), any CV hospital admission (HR 0.85; 95% CI, 0.78 to 0.92, P = 0.0002), and composite of CV death, hospital admission for worsening HF, or hospital admission for non-fatal MI (HR 0.82; 95% CI, 0.74 to 0.89), P < 0.0001) were significantly reduced.⁶ The primary composite end point was also consistently improved in all prespecified subgroups, except in patient subgroups analyzed by baseline heart rate.⁶ In the latter group, a statistically significant reduction in primary composite end point was seen only in the subgroup of patients with a baseline heart rate higher than the median 77 bpm treated with ivabradine, versus the placebo group (27.4% versus 34.2%; HR 0.75; 95% CI, 0.67 to 0.85) while no statistically significant difference was observed in patients with baseline heart rate of less than 77 bpm (21.4% versus 22.8%; HR 0.93; 95% CI, 0.80 to 1.08).⁶

The beta-blocker_50% subgroup's mean heart rate reduction at day 28 was 15.5 bpm (standard deviation 10.7); year 1 heart rate reduction was not reported.⁶ The primary composite end point of CV death or hospital admission for worsening HF was not statistically significant different with ivabradine (HR 0.90; 95% CI, 0.77 to 1.04; P = 0.155); individual mortality components were also not significantly reduced with ivabradine. When reported as a single end point, the hospital admission for worsening HF was statistically significantly reduced with ivabradine (HR 0.81; 95% CI, 0.67 to 0.97; P = 0.021).⁶ Of note, interpretation of the results for the beta-blocker_50% subgroup should be made with caution as findings are based on a smaller sample size (i.e., 56% of beta-blocker users in the SHIFT trial population), which may reduce the power of this analysis. Following are brief summaries of findings from various post-hoc analyses of the SHIFT trial. Given the post-hoc nature of these analyses, findings should also be interpreted with caution:

An analysis of the SHIFT trial stratified patients by quintiles of baseline heart rate. Analyses identified that the patients who had the largest heart rate reduction with ivabradine (change from baseline of −22.5 bpm [ivabradine] and −8.8 bpm [placebo]) were those with the highest baseline heart rate (≥ 87 bpm); in comparison heart rate reductions were −11.1 bpm (ivabradine) and −2.7 bpm (placebo) among patients with baseline heart rate between 70 bpm and 72 bpm. Patients on ivabradine with the largest heart rate reduction also had the greatest relative reduction in outcome events (primary composite end point, HR 0.69; 95% CI, 0.58 to 0.83), compared with placebo. Authors stated that these observations support the concept that ivabradine has a use dependence property.¹³
An analysis to assess whether there is a relationship between the dose of background beta-blocker therapy and ivabradine's treatment effect was also conducted. Although a numerical reduction in outcomes was observed with higher doses of beta-blockers, results could not establish a relationship, as no statistically significant differences were observed on the primary or the secondary outcomes (P = 0.135). Authors concluded that the magnitude of heart rate reduction achieved with ivabradine beyond what is achieved with beta-blocker therapy, rather than background beta-blocker dose, primarily determines subsequent outcome events.³⁶ That being said, upon approving ivabradine in the US, the FDA stated that patients using ivabradine should be taking beta-blockers at the highest dose they can tolerate.³⁷
A number of other post-hoc analyses of the SHIFT study were also conducted to examine effects of ivabradine in various subpopulations (e.g., patients with chronic obstructive pulmonary disease).¹⁶ Of note, while such post-hoc analyses may be intended to help better characterize target populations for ivabradine therapy, given inherent limitations of such analyses, confirmatory studies are required to validate their findings.

Overall, the SHIFT trial demonstrated that when ivabradine is added on to guidelines-based background therapy, there is a statistically significant decrease of 18% in the rate of primary end point achieved, compared with placebo.⁶ The treatment effect was established within three months and was maintained throughout the duration of the study.⁶ Secondary end points were also statistically significantly decreased for patients in the ivabradine group, except for the two single mortality end points (i.e., all-cause death and CV death).⁶ This study also demonstrated that patients with a high heart rate (i.e., above the median value of 77 bpm) were at an increased risk for a CV event; these patients were also the ones to receive the most benefit from the ivabradine treatment in terms of reducing events compared with patient groups with lower baseline heart rates. Of note, there was evidence of a significant treatment effect only in the prespecified subgroup of patients with a baseline heart rate greater than 77 bpm.⁶ This finding may be important for selecting best candidates for therapy with ivabradine.⁶ However, there are also limitations in the study worth noting, as they could have an impact on the generalizability of the results. The following are the limitations presented by the SHIFT trial investigators:⁶

All eligible patients in the SHIFT trial had a heart rate of 70 bpm or higher (average heart rate was 79.9 bpm), and had a stable HF for at least four weeks.
There was a low number of patients who underwent cardiac resynchronization therapy or received an implantable cardioverter defibrillator.
The proportion of elderly patients was low (average age was 60.4 years).
Most patients treated with beta-blockers as part of the background therapy were dosed below the guidelines target dose (due to tolerance, contraindications to beta-blockers, or other issues).

These limitations may represent HF populations that differ from the general HF demographics. In consequence, it may narrow the actual number of eligible HF patients for ivabradine treatment and also restrict ivabradine's place in therapy to a subpopulation of patients with HF. Hence, based on this study, it can be interpreted that ivabradine may have a role in the treatment for symptomatic HFrEF (EF ≤ 35%) patients who are in sinus rhythm with heart rate of 70 bpm or higher and who are unable to tolerate optimal beta-blocker dosing. HFrEF patients with heart rate greater than 77 bpm may be the ones deriving the most benefit from initiating ivabradine therapy.⁶ Of note, the effect of ivabradine on patients with HFpEF is currently unknown.⁸

Adverse Events

Withdrawals due to adverse events was more common with ivabradine than with placebo (21% versus 19%, P = 0.017); however, more serious adverse events occurred in the placebo group (45% versus 48%, P = 0.025).⁶ Table 2 describes selected adverse events observed in the ivabradine group versus the placebo group.¹ ^, ⁶ ^, ¹⁰

Table 2

Ivabradine Selected Adverse Events

Withdrawal due to bradycardia (both symptomatic and asymptomatic) was the only adverse event found to be significant in both the ivabradine and placebo groups, affecting about 1% of the study population.⁶

Ivabradine is metabolized in the liver by cytochrome CYP3A4 enzyme; therefore, its use may pose a risk to patients when CYP3A4 inducers and/or inhibitors are administered concomitantly.¹ ^, ¹⁰

Strong CYP3A4 inhibitors are contraindicated with the use of ivabradine (e.g., ketoconazole increases ivabradine's plasma concentration by 7-fold). Also, non-dihydropyridine calcium channel blockers verapamil and diltiazem should not be used with ivabradine as they increase ivabradine concentrations through moderate CYP3A4 inhibition and can enhance bradycardia.¹
Strong CYP3A4 inducers (e.g., St. John's wort, rifampicin, and phenytoin) decrease ivabradine plasma concentration, and are also contraindicated.¹

In May 2014, following the release of preliminary findings from the SIGNIFY study (which compared the effect of ivabradine with placebo on the rate of CV events in patients with CAD); the EMA initiated a safety review of ivabradine. This was prompted by findings in patients receiving up to 10 mg twice daily, a higher dose than in the SHIFT trial (maximum of 7.5 mg twice daily), which showed a small but significant increase in the combined risk of CV death or non-fatal MI in a subgroup of patients who had symptomatic angina (CCS guidelines Class II to Class IV).³⁸ EMA completed this review in November 2014 and concluded that the use of ivabradine is associated with a small but significant increase in the combined risk of CV death or non-fatal MI (3.4% versus 2.9% yearly incidence rates) as well as a higher risk of bradycardia (17.9% versus. 2.1%), compared with placebo. Through this evaluation, EMA also noted that ivabradine increases the risk of atrial fibrillation (4.86% versus 4.08%), compared with controls.²¹

Administration and Cost

Ivabradine is available in 5 mg and 7.5 mg film-coated tablets, which are administered orally twice daily.⁶ ^, ¹⁴ ^, ¹⁵ ^, ²⁰ ^, ³⁵ Ivabradine should be administered with food (to increase and maintain plasma concentration).¹

The recommended starting dose is 5 mg twice daily with meals. Dose can be titrated after two weeks to achieve a target heart rate of 50 bpm to 60 bpm. The dose can be decreased to 2.5 mg twice daily, or increased to 7.5 mg twice daily (maximum). Patients at risk of hemodynamic compromise secondary to conduction defects or bradycardia can begin with 2.5 mg twice daily instead of 5 mg twice daily.⁸ ^, ³⁵ Dose adjustment is not required for patients with renal impairment and a creatinine clearance above 15 mL/min.⁸ ^, ³⁵

In Canada, the price of ivabradine is projected to be around C$2.54 per day, or approximately C$928.83 per year (Frederic Fasano, CEO Servier Canada Inc., Laval, QC: personal communication, 2016 Aug 16).

Concurrent Developments

Clinical trials are currently ongoing for ivabradine as well as for valsartan/sacubitril (Entresto, Novartis), a recently approved drug for HFrEF, to determine their effect in patients with HFpEF. This research could potentially lead to the expansion in the use of these drugs to the wider HF population.³⁹ The EDIFY (Effect of Ivabradine versus Placebo on Cardiac Function and on Capacity to Perform Exercise in Patients Suffering from Diastolic Heart Failure) trial aims to study the effects of ivabradine on cardiac function, exercise capacity, and neuroendocrine activation in HFpEF patients compared with placebo;⁴⁰ the estimated completion date of this phase 2 proof-of-concept study is currently unknown. A multinational phase 3 study, the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial is currently in the recruitment process. It aims to evaluate the efficacy and safety of valsartan/sacubitril compared with valsartan alone on morbidity and mortality in HFpEF patients.⁴¹ The estimated study completion date is March 2019.⁴¹

There is also another If channel inhibitor, cilobradine, that has completed its phase 1 clinical development program.⁴² ^– ⁴⁴ These studies' primary outcome measures included incidence of visual phenomenon, change in heart rate at rest, change in heart rate during exercise, and change in flicker fusion frequency test. Results are not available at this time.

Following are short summaries about examples of HF drugs currently in phase 2 and 3 clinical trials.²² These molecules have the potential to reach clinical practice, should their respective clinical development programs continue and eventually lead to positive results:

Finerenone: The two currently existing steroidal MRAs used for HF (spironolactone and eplerenone) accumulate in the kidneys and increase the risk of hyperkalemia, limiting their use in patients with renal impairment. Animal studies found that finerenone is a highly selective nonsteroidal MRA that is equally distributed in the heart and the kidney. A phase 2 trial, ARTS (Miner Alocorticoid Receptor antagonist Tolerability Study), assessed the effects of finerenone in patients with HFrEF with a moderate renal impairment. Results showed finerenone to be comparable to spironolactone in terms of reducing an HF biomarker called NT-proBNP, except with lower incidence of hyperkalemia. A phase 2b trial (ARTS-HF) showed a reduction in NT-proBNP with finerenone (comparable with eplerenone) at day 90, compared with baseline. In addition, there were meaningful reductions in all-cause death and CV hospitalization with finerenone versus eplerenone, with the lowest incidence in the 10 mg/20 mg finerenone dose group. A phase 3 trial (FINESSE-HF) is ongoing and comparing finerenone with eplerenone in HFrEF patients.²² ^, ⁴⁵
Omecamtiv mecarbil: this molecule is a myosin activator that works to improve cardiac contractility independently from calcium cycling, and has been shown to increase LVEF and ejection time in animal studies and studies of healthy volunteers. A phase 2b trial evaluating omecamtiv mecarbil in patients with stable HFrEF showed similar results. There is a safety concern around increased risk of impaired coronary perfusion and cardiac ischemia at high doses.²²
Vericiguat: this drug is a soluble guanylate Cyclase (sGC) stimulator that increases nitrogen oxide sensitivity. In a phase 2 trial (SOCRATES [Soluble guanylate Cyclase stimulatoR in heart failure Studies]), vericiguat did not reduce the NT-proBNP level in HFrEF patients, but higher doses were associated with a significant trend toward a reduction in NT-proBNP level.²² A phase 2b clinical trial for HFpEF patients (SOCRATES-PRESERVED [Safety and Efficacy Study of Four Dose Regimens of BAY1021189 in Patients With Heart Failure and Preserved Ejection Fraction Suffering From Worsening Chronic Heart Failure]) was completed in 2015.⁴⁶ A phase 3 clinical trial for HFrEF is ongoing — the VerICguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA). The estimated completion date of this trial is January 2020.⁴⁷
Anakinra: this biological drug is an interleukin 1 receptor antagonist that has been shown to improve left ventricular function and remodelling in mice. In a phase 2 trial, it decreased the incidence of HF after an MI. Anakinra was also tested in HFpEF patients and showed an association with improved exercise capacity.²² There are an ongoing phase 2 and 3 trials evaluating anakinra in acute or chronic HF patients,²² ^, ⁴⁸ including a phase 2 trial in HFpEF patients (Interleukin-1 Blockade in Heart Failure With Preserved Ejection Fraction [HFpEF]: a Randomized Placebo-controlled Double Blinded Study [D-HART2]).⁴⁹

Rate of Technology of Diffusion

As observed in other countries where the drug has been available, and with the very recent approval of ivabradine for HF in Canada, its rate of diffusion into the market may depend on the diffusion of good quality guidance to prescribers, mainly cardiologists.³⁹ In Canada, CCS included guidance on the use of ivabradine in their 2016 Companion Guide to HF Treatment; as a consequence, a number of Canadian specialists may already or soon be aware of this new therapy. The CCS Companion Guide recommends ivabradine be used in patients with HFrEF (LVEF ≤ 40%) who are in sinus rhythm with a heart rate of 70 bpm or higher who continue to experience NYHA Class II to Class IV HF symptoms despite receiving triple therapy (ACEi [or ARB], beta-blocker, and MRA).²⁵ ^, ⁵⁰ Of note, the criteria of LVEF ≤ 40% from CCS appears to be more liberal than the criteria used in the SHIFT trial, which limited the enrolment of patients to those with a LVEF ≤ 35%. This could potentially increase the pool of candidates for ivabradine therapy in Canada. In the US, a Focused Update on the treatment of HF was released jointly by the American College of Cardiology and the American Heart Association in 2016. In this document, it is stated that ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA Class II to Class III), stable chronic HFrEF (LVEF ≤ 35%) who are receiving evidence-based background therapy (including a beta-blocker at maximum tolerated dose) and who are in sinus rhythm with a resting heart rate of 70 bpm or higher.⁵¹

Another factor that may influence the uptake of ivabradine is the availability of evidence to support its use in non-HF related conditions. As previously mentioned, ivabradine has been approved for use in patients with chronic stable angina by the EMA and TGA.¹⁴ ^, ¹⁵ Therefore, with the recent NOC granted in Canada for the treatment of patients with HFrEF, it is possible that Canadian cardiologists would also consider prescribing this drug to treat chronic stable angina, a condition for which no NOC has been granted. Although likely limited to small and specific populations, other potential (non-approved) uses for ivabradine that could impact the rate of its use in Canada include:¹¹

inappropriate sinus tachycardia
postural orthostatic tachycardia syndrome
heart rate reduction before computed tomography coronary angiography
prevention of atrial fibrillation following cardiac surgery
heart transplantation
mild to moderate mitral stenosis
acute decompensated HF requiring dobutamine
right ventricular pacing
exercise testing performance
acute decompensated HF.

Implementation Issues

With the very recent approval of ivabradine in Canada, three implementation issues to consider are:

Patient selection: based on the design of the SHIFT trial, which tested the use of ivabradine as adjunct therapy to standard treatment of HFrEF patients with LVEF ≤ 35%, health care providers must ensure eligible patients are appropriately selected (e.g., ensuring all standard treatments are titrated to their target dose or maximum evidence-based tolerated dose) before prescribing ivabradine. Patients will also have to be monitored regularly, given that they would be on multiple drugs.
Polypharmacy: in addition to the multiple drugs that patients with HF typically take, these patients also tend to be older persons who may have other comorbidities for which additional medications may have been prescribed. Polypharmacy increases the risk of drug interactions and non-compliance, which lead to suboptimal therapy and poorer health outcomes.
Cost: drug prices may impact access to treatment for patients without insurance coverage, particularly when these patients have to take several medications. As previously mentioned, it is expected that the annual cost of ivabradine will be close to C$1,000.00 (more precisely, ivabradine is expected to cost approximately C$928.83 per year per patient) (Frederic Fasano, CEO Servier Canada Inc., Laval, QC: personal communication, 2016 Aug 16).

Further studies are required to help better define patient groups and examine long-term efficacy and safety outcomes in patients with HF.

Acknowledgments

CADTH would like to acknowledge the contribution of James Brophy, MEng, MD, FRCP(c), FACC, PhD, Professor of Medicine and Epidemiology, McGill University, Montreal, Quebec, for his review of the draft version of this horizon scan report.

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