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. 2016 Apr 8;2016(4):CD010656. doi: 10.1002/14651858.CD010656.pub2

Ivabradine as adjuvant treatment for chronic heart failure

Carolina Mizzaci 1,✉, André T Vilela 2, Rachel Riera 3
PMCID: PMC6483709

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effectiveness and safety of ivabradine in chronic heart failure.

Background

Description of the condition

Heart failure is a progressive disorder that is initiated after damage to the heart muscle, with consequent loss of functioning cardiac myocytes and abnormality of cardiac contraction, relaxation, or both. (Mann 2012a). This disease is a common, disabling, and serious condition, and its prevalence is rising throughout the world (Lang 2005; Schocken 2008). In the United States of America, acute heart failure syndromes are a common cause of hospitalization in patients older than 65 years, and approximately 3 million people are admitted each year with a diagnosis of heart failure (Gheorghiade 2009; Pang 2010). Direct and indirect costs associated with heart failure were estimated at more than $37 billion in 2009 in the United States and are mainly related to hospitalization. The number of admissions for heart failure has tripled during the past three decades and will continue to grow because of a convergence of several epidemiologic trends: the aging of the population; greatly improved survival after myocardial infarction; and a growing incidence of obesity, diabetes, and hypertension in many countries, resulting in more patients living with chronic heart failure (Wang 2007; Mann 2012b). Several studies have described a decreasing trend in coronary heart disease and cerebrovascular disease hospitalization rates and an increasing trend in heart failure separately (Centers for Disease Control and Prevention 1998; Haldeman 1999; Koelling 2004; Brown 2005). Increases in the prevalence of heart failure hospitalization have also been reported from several other regions, including Scotland, the Netherlands, Spain, Singapore, Hong Kong, and Sweden (McMurray 1993; Reitsma 1996; Rodríguez‐Artalejo 1997; Hung 2000; Cline 2002; Ng 2003). Although the burden of coronary heart disease and cerebrovascular disease remains the major public health problem, heart failure has emerged as a new challenge in cardiovascular disease control (Liu 2011).

Systolic heart failure is characterized by depressed left ventricular ejection fraction. Heart failure with preserved ejection fraction (HFpEF) is characterized by signs or symptoms of congestive heart failure in the presence of normal or only mildly abnormal left ventricular systolic function. It has many potential causes, including impaired relaxation or diastolic dysfunction and restrictive or constrictive cardiomyopathy, among others. Patients with HFpEF have preserved left ventricular ejection fraction ≥ 45% to 50% (European Study Group 1998; Dickstein 2008). The most common manifestations of heart failure are dyspnea and fatigue, which may limit exercise tolerance and increase fluid retention, possibly leading to pulmonary congestion and peripheral edema. Those typical symptoms impair the functional capacity and quality of life of affected individuals. The degree of limitation imposed by heart failure is quantified by the New York Heart Association (NYHA) functional classification. Patients are classified into one of four functional classes: those with symptoms of heart failure at rest (class IV), on less‐than‐ordinary exertion (class III), or on ordinary exertion (class II), or no symptoms attributable to heart disease (class I). Evaluation of the NYHA functional class also provides important prognostic information as a stepwise increase in morbidity and mortality risk has been noted with increasing functional class (Mulder 2004; Greenberg 2012). Another classification that emphasizes both the development and the progression of the disease is the American Heart Association (AHA) classification, which consists of four stages. Stage A and B patients are defined as those with risk factors that predispose toward the development of heart failure. Individuals who do not yet demonstrate impaired left ventricular function, hypertrophy, or geometric chamber distortion would be considered Stage A, whereas those who are asymptomatic but demonstrate left ventricular hypertrophy and impaired left ventricular function would be designated as Stage B. Stage C denotes patients with current or past symptoms of heart failure associated with underlying structural heart disease, and Stage D designates patients with refractory heart failure (Jessup 2009).

In the management of patients with systolic heart failure whether symptomatic or asymptomatic, the main goals of treatment are to reduce symptoms, prolong survival, improve quality of life, and prevent disease progression. For those who have developed structural heart disease (stages B to D), the choice of therapy depends on their NYHA functional classification. For patients who have developed left ventricular systolic dysfunction but who remain asymptomatic (Class I), the goal should be to slow disease progression by blocking neurohormonal systems that lead to cardiac remodeling. For patients who have developed symptoms (Classes II to IV), the primary goals should be to alleviate fluid retention, lessen disability, and reduce the risk of further disease progression and death. Standard therapy for patients with heart failure who have a depressed left ventricular ejection fraction should consist of angiotensin‐converting enzyme inhibitors plus a beta blocker. Additional pharmacologic therapy should be considered in patients who have persistent symptoms or show progressive worsening despite optimized therapy. Agents that may be considered as part of additional therapy include angiotensin receptor blockers (NYHA Classes II to IV), spironolactone (NYHA Classes III and IV), the combination of hydralazine and isosorbide dinitrate (NYHA Classes III and IV), and digitalis (Mann 2012b). Another recommended treatment for selected patients with systolic heart failure is ivabradine. This drug inhibits the If channel in the sinus node; studies have shown benefit in terms of symptom reduction, heart failure hospitalization, or both, and this agent serves as a useful alternative or additional treatment for patients with heart failure (McMurray 2012).

Description of the intervention

Ivabradine (S16257‐7,8‐dimethoxy 3‐{3‐([(lS)‐(4,5‐dimethoxybenzocyclobutan‐l‐yl) methyl] methylamino)propyl) 1,3,4,5‐tetrahydro‐2H‐benzazepin 2‐one) is a new heart rate–lowering agent that selectively and specifically inhibits the depolarizing cardiac pacemaker If current in the sinus node, thus decreasing the diastolic depolarization rate of phase 4 of the action potential (Thollon 1994; Thollon 1997; DiFrancessco 2007). Its activity provides pure heart rate reduction at rest and during exercise, which improves myocardial oxygen balance and increases coronary perfusion, with no relevant influence on conduction, contractility, ventricular repolarization, or blood pressure. The metabolic clearance of ivabradine accounts for about 80% of its total clearance; the other 20% corresponds to renal clearance. Only CYP3A4 is involved in the metabolism of ivabradine, so numerous potential interactions can arise with CYP3A4 inhibitors and inducers. (DiFrancesco 2006). Randomized controlled trials (RCTs) show that ivabradine, when added to standard treatment, may reduce major risks associated with heart failure, such as incidence of cardiovascular death or hospitalization for worsening heart failure. The recommended starting dose of Ivabradine is 5 mg twice daily followed by uptitration to 7.5 mg (Fox 2006; Borer 2012). Results of studies in healthy hearts suggest that, at concentrations achieved during therapeutic use, ivabradine has no action on other channels in the heart or vascular system. Unlike beta blockers, ivabradine does not modify myocardial contractility and intracardiac conduction, even in patients with impaired systolic function (Savelieva 2008). The negative inotropic action of atenolol leads to prolonged ejection time and, consequently, a smaller increase in diastolic time for the same reduction in heart rate compared with ivabradine (Colin 2003). Ivabradine, unlike atenolol, does not depress the physiological exercise‐induced acceleration of left ventricular relaxation, so ivabradine does not show the negative lusitropic effects associated with beta blockade (Colin 2002).

How the intervention might work

Heart rate is related to risk of cardiovascular death or admission to hospital in patients with heart failure, and heart rate reduction is associated with improved outcomes (Opasich 2001; Cook 2006; Pocock 2006; Dickstein 2008). Heart rate remains increased in most patients treated with beta blockers, and this constitutes a reason to develop new therapeutic strategies (Komajda 2003). Several studies show that ivabradine may reduce mortality and produce cardiovascular outcomes such as reduced heart rate and improved quality of life in people with heart failure (Fox 2006; Fox 2008;Bohm 2010;;Borer 2012,Riccioni 2013). Rationale and design of a randomized, double‐blind, placebo‐controlled trial of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction: the morBidity‐mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) Study provided an opportunity to test the cardiac safety of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction. The BEAUTIFUL population consisted of 10,917 participants recruited in 33 countries (Fox 2006; Fox 2008). The Rationale and design of a randomized, double‐blind, placebo‐controlled outcome trial of ivabradine in chronic heart failure: the Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trial (SHIFT) showed the importance of heart‐rate reduction with ivabradine for improvement of clinical outcomes in heart failure and confirm the important role of heart rate in the pathophysiology of this disorder.

(Bohm 2010; Swedberg 2010a; Swedberg 2010b).

Why it is important to do this review

Despite current intensive multidrug therapy, people with heart failure are frequently admitted to hospital because of exacerbation of their symptoms and later are often readmitted (Dunlay 2009). The reported 3‐month to 1‐year readmission rate has varied between 30% and 50% (Kruse 1991; Haldeman 1999). Indeed, worsening heart failure is the most common cause of hospitalization in people with heart failure and, when recurrent, presages death (Setoguchi 2007; Solomon 2007). Heart failure accounts for between 1% and 2% of the total health care expenditure, and the total economic burden of heart failure is increasing (Liao 2008). The greatest portion is attributable to heart failure－related hospitalization, which accounts for two‐thirds of the costs (Stewart 2002). Heart failure is a public health problem in progression that causes high mortality and increasing public spending on health. Because of this, it is extremely important that drugs are developed for the treatment of patients with heart failure with the goal of reducing hospitalizations, improving quality of life, and reducing mortality. When possible, a systematic review should be performed to examine the role of ivabradine in heart failure treatment, to gather available evidence to assess the methodological quality of relevant studies, and to carry out meta‐analyses.

Objectives

To assess the effectiveness and safety of ivabradine in chronic heart failure.

Methods

Criteria for considering studies for this review

Types of studies

We will select RCTs and will look at parallel trials.

Types of participants

  • Adults 18 years of age and older.

  • Both male and female individuals.

  • Adults with sinus rhythm of chronic heart failure diagnosed by clinical and echocardiographic criteria, including moderate to severe chronic heart failure (NYHA II to IV) (Table 1) and left ventricular systolic dysfunction (Table 2).
    Table 1.
    New York Heart Association functional classification based on severity of symptoms and physical activity
    Class I No limitation of physical activity. Ordinary physical activity does not cause undue breathlessness, fatigue, or palpitations.
    Class II Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in undue breathlessness, fatigue, or palpitations.
    Class III Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in undue breathlessness, fatigue, or palpitations
    Classe IV Unable to carry on any physical activity without discomfort. Symptoms can be present at rest. If any physical activity is undertaken, discomfort is increased.
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    Table 2.
    Reference limits of left ventricular function
    Reference range Mildly abnormal Moderately abnormal Severely abnormal
    Ejection fraction, % ≥ 55 45‐54 30‐44 < 30
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  • Persons with left ventricular systolic function ≤ 40% (Lang 2005).

Types of interventions

  • Intervention: Ivabradine should be initiated with dose of 2.5 mg twice daily  and  progressively increased  until 7.5 mg twice (unless the resting heart rate is lower than 60 b.p.m. or the patient is experiencing signs or symptoms related to bradycardia) plus standard treatment for chronic heart failure for at least 3 months, as recommended by the American Heart Association.

  • Comparison: placebo plus standard treatment for chronic heart failure, as recommended by the American Heart Association (Jessup 2009).

Types of outcome measures

Primary outcomes

  • Mortality from cardiovascular causes.

  • Safety (bradycardia, slowed conduction of electrical messages between chambers of the heart, such as first‐degree atrioventricular block, second‐ or third‐degree heart block, or sick sinus syndrome).

We will assess these outcomes at least every 3 months on the basis of available data.

Secondary outcomes

  • Mortality from all causes.

  • Hospitalization rate for worsening heart failure.

  • Hospitalization rate for all causes.

  • Quality of life (as assessed by questionnaires such as the 36‐Item Short‐Form Health Survey (SF‐36), the Minnesota Living With Heart Failure Questionnaire, and the Kansas City Cardiomyopathy Questionnaire) (Rector 1987; Ware 1992; Green 2000).

  • Change in NYHA functional class (Harvey 1974).

  • Frequency of mild, moderate, and severe adverse events as related to ivabradine (bradycardia, slowed conduction of electrical messages between chambers of the heart, such as first‐degree atrioventricular block, second‐ or third‐degree heart block, or sick sinus syndrome).

  • Exercise capacity (assessed by peak VO2 or the 6‐minute walk test).

  • Left ventricular remodeling and function (as analyzed by echocardiogram: left ventricular ejection fraction, left ventricular end‐systolic volume index, and left ventricular end‐diastolic volume index) (Lang 2005).

Search methods for identification of studies

Electronic searches

We will search the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, LILACS, ISI Web of Science With Conference Proceedings, and CINAHL. The search strategy that will be used to search MEDLINE can be found in Appendix 1. The terms used to search MEDLINE will be modified where necessary for search of the other databases listed.

No restrictions regarding language or date of publication will be applied. In cases of incomplete reports, we will search further to identify connected papers, or we will contact trial authors to retrieve missing information.

Searching other resources

We will search trials that are registered in the World Health Organization International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/) and in the Current Controlled Trials Register (www.controlled‐trials.com/).

We will check the reference lists of relevant papers to find RCTs not identified by the electronic searches. Grey literature will be searched in OpenGrey (System for Information on Grey Literature in Europe) (http://www.opengrey.eu/) and in material from the international congresses of the European Society of Cardiology (www.escardio.org), the American Heart Association (AHA) (www.heart.org), and the American College of Cardiology (ACC) (www.acc.org).

We will contact laboratories that market ivabradine to ask about the existence of apparently relevant clinical trials that may be included in this review.

Data collection and analysis

Selection of studies

Two review authors (CM, ATV) will independently check identified studies and will examine abstracts of studies retrieved from the search. These two review authors will identify potentially eligible studies by reading all titles and abstracts of articles found. In the absence of consensus between the two review authors regarding the selection of studies, the matter will be resolved by a third review author (RR).

Data extraction and management

At least two review authors will independently extract data (CM, ATV), and disagreements will be resolved by consensus involving a third review author (RR). We will extract information about methods used in the trial reports as well as details of risk of bias, participants (inclusion criteria, age, gender, stage of disease, exclusion criteria, number enrolled in each group, numbers of losses and withdrawals), interventions (standard treatment, ivabradine, dosage, placebo), results (outcome measures, adverse events), and duration of follow‐up. We may contact study authors if the data extracted are insufficient or unclear (Higgins 2011). When possible, extracted data will be summarized in a meta‐analysis using Review Manager 5 (RevMan) software (Copenhagen, Denmark: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011) (RevMan 2011).

Assessment of risk of bias in included studies

Two review authors (CM, ATV) will assess the risk of bias of each included study, in accordance with the criteria of The Cochrane Collaboration tool for assessing risk of bias (Higgins 2011). We will consider the following domains.

  • Random sequence generation (selection bias).

  • Allocation concealment (selection bias).

  • Blinding of participants and personnel (performance bias).

  • Blinding of outcome assessment (detection bias).

  • Incomplete outcome data as addressed (attrition bias).

  • Selective reporting (reporting bias).

Each of these criteria, according to our analysis, will be classified as Yes (low risk of bias), No (high risk of bias), or Inconclusive, according to the criteria of The Cochrane Collaboration. Two independent review authors (CM, ATV) will assess the risk of bias by applying The Cochrane Collaboration risk of bias tool (Higgins 2011). Disagreements will be resolved by discussion and consensus and, if necessary, with the involvement of a third review author. Those trials deemed to be inconclusive or to have a high risk of bias or low methodological quality will be excluded. We will consider only high‐quality studies with a low risk of bias.

Measures of treatment effect

We will perform the analyses using Review Manager 5 (RevMan 2011). Measures of treatment effect will vary with the types of data presented in the individual studies. For continuous outcomes, the weighted mean difference (WMD) with 95% confidence interval (CIs) will be used to summarize the pooled effect. Where only a single study is included in a subgroup, the mean difference (MD) will be presented. We will calculate the number needed to treat for an additional harmful outcome (NNTH) and the number needed to treat for an additional beneficial outcome (NNTB), and, if possible, the P value will be calculated for all comparisons. For dichotomous data, we will use the risk ratio (RR) with 95% CIs (Higgins 2011).

Unit of analysis issues

The unit of analysis is the individual.

Dealing with missing data

If data are missing, we will contact study authors for clarification and for possible recovery of data. Only assessable data will be considered in this review, and the impact of missing data will be addressed in the discussion sections.

Assessment of heterogeneity

We will analyze statistical heterogeneity between studies using the I2 statistic test. An I2 value > 50% in the analysis will be considered substantially heterogeneous (Higgins 2011). The following factors will be evaluated as potential causes of statistical heterogeneity: clinical heterogeneity (types of participants, types of outcomes, comorbidities, types of treatments) and methodological diversity (evaluation of the randomization method used, of study quality, of the analytical method used).

Assessment of reporting biases

We will assess publication bias on the basis of funnel plots. Asymmetry in the funnel plots may suggest publication bias. Other causes of asymmetry may be related to the clinical and methodological heterogeneity of the studies (Higgins 2011).

Data synthesis

We will try to combine outcome measures from individual trials in a meta‐analysis to provide a pooled effect estimate for each outcome only if the studies are clinically and methodologically comparable. For this purpose, we will use Review Manager 5 (RevMan 2011). However, if many heterogeneous studies are identified and a meta‐analysis is not possible, we will prepare a narrative synthesis of the data. We will use fixed‐effect and random‐effects models to measure the effect size of the results. We will use the fixed‐effect model if the studies do not show heterogeneity, but we will apply the random‐effects model if the studies are heterogeneous (Higgins 2011). We will present the effect size of included studies in forest plots, along with their respective confidence intervals.

Subgroup analysis and investigation of heterogeneity

If sufficient studies are identified, we will undertake the following subgroup analyses.

  • Moderate versus severe congestive heart failure (CHF) (NYHA functional classes II to IV).

  • Diastolic function.

  • Doses of ivabradine.

  • Schemes of treatment used in association with ivabradine.

  • Gender.

  • Participant age.

  • Comorbidities (eg, coronary heart disease, diabetes).

Sensitivity analysis

We will undertake sensitivity analyses that include or exclude studies of lower quality to assess the robustness of observed effects.

Acknowledgements

The authors would like to thank Nicole Martin, Trials Search Co‐ordinator, Cochrane Heart Group; Dr Fiona Taylor, Managing Editor, Cochrane Heart Group; and Dr Álvaro Nagib Atallah, Director of the Brazilian Cochrane Center. We also would like to thank the Cochrane Handbook for Systematic Reviews of Interventions study group from the Brazilian Cochrane Center.

Appendices

Appendix 1. 'MEDLINE (via Ovid) search strategy'

1. ivabradin*.tw.

2. coraxan.tw.

3. corlentor.tw.

4. procoralan.tw.

5. s 16257.tw.

6. s16257.tw.

7. s 16260.tw.

8. s16260.tw.

9. or/1‐8

10. exp Heart Failure/

11. ((heart or cardia* or myocard*) adj2 (fail* or insufficienc*)).tw.

12. (decompensat* adj2 (heart* or cardia*)).tw.

13. decompensatio cordis.tw.

14. insufficientia cardis.tw.

15. ((cardiac or heart) adj2 incompetenc*).tw.

16. cardiac stand still.tw.

17. Heart Rate/

18. heart rate*.tw.

19. pulse rate*.tw.

20. cardiac chronotrop*.tw.

21. or/10‐20

22. 9 and 21

23. randomized controlled trial.pt.

24. controlled clinical trial.pt.

25. randomized.ab.

26. placebo.ab.

27. drug therapy.fs.

28. randomly.ab.

29. trial.ab.

30. groups.ab.

31. 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30

32. exp animals/ not humans.sh.

33. 31 not 32

34. 22 and 33

 

What's new

Date Event Description
8 April 2016 Amended withdrawal of protocol
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Contributions of authors

Co‐ordinating the protocol: CM. Searching studies to write the background section: CM, RR. Planning the methods section, drafting the review, and approving the final version of the protocol: CM, ATV, RR.

Sources of support

Internal sources

  • None, Other.

External sources

  • No sources of support supplied

Declarations of interest

None known.

Notes

This protocol has been withdrawn as the author team is unable to progress to the final review stage. This title is now covered by a new protocol.

Withdrawn from publication for reasons stated in the review

References

Additional references

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