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Coralan Experience (CORE) Survey – First Malaysian Experience of Ivabradine in Stable Angina

Annual incidence of angina is as high as 213 per 100,000 population in those above the age of 30 [1]. Despite its high prevalence, investigational data on stable coronary artery disease especially those with manifest angina is scarce. Local data on prevalence of stable angina pectoris is not available. Nevertheless, cardiovascular disease death is the most common cause of mortality in Ministry of Health hospitals in Malaysia [2].


Introduction
Stable angina pectoris is induced or aggravated when increased heart rate (HR) shifts the balance towards an oxygen deficit in the equilibrium between myocardial oxygen demand vs. supply.
Annual incidence of angina is as high as 213 per 100,000 population in those above the age of 30 [1]. Despite its high prevalence, investigational data on stable coronary artery disease especially those with manifest angina is scarce. Local data on prevalence of stable angina pectoris is not available. Nevertheless, cardiovascular disease death is the most common cause of mortality in Ministry of Health hospitals in Malaysia [2].
This study evaluates the early experiences with Ivabradine in Malaysia amongst physicians in the management of stable angina pectoris.
Ivabradine is a novel, first its kind agent that targets the I f -channel. This channel is almost exclusively found in the SA node [3]. Ivabradine selectively reduces HR (negative chronotropic effect) via its action on the SA node without significant adverse inotropic effects on the myocardium [4]. It has been shown to improve ischaemic thresholds, reduce anginal events and severity and also reduce ischaemic events in patients with stable coronary artery disease (CAD) [5][6][7][8][9][10][11].

Method
In the 4-month period between November 2008 and February 2009, a survey was initiated to assess the anti-anginal effects of Ivabradine.
Stable angina patients were recruited by 73 participating clinicians based on the following inclusion criterias: • Symptomatic CAD with resting HR 60 bpm and above • Age 18 and above Following the recruitment visit, patients were assessed in 2 further monthly study visits, i.e. Total of 3 clinic reviews at 0, 1 and 2 months.

Visit 1 Visit 2 Visit 3
BP and HR measurements were specified as the average of 2 readings taken after a period of rest for at least 5 minutes.
Following recruitment, Ivabradine 5 mg bid was prescribed at the initial visit and the dose up-titrated to 7.5 mg bid if the HR remained above 60 bpm at the 2 nd Clinic visit.
The primary endpoints of this study were the angina-related parameters i.e. number of angina episodes per week, frequency of short-acting nitroglycerin use and severity of reported angina based on Canadian Cardiovascular Society (CCS) Grading [12].
Subjective patient assessment of efficacy of newly introduced agent, Ivabradine were recorded at visits 2 and 3. Patients were asked the following questions: • How do you feel after getting Ivabradine prescription?options: better, the same or worse • How would you rate the efficacy of Ivabradine compared to existing therapies in improving your angina symptoms. Options: better, the same or worse Patient reported side-effects, withdrawal rates and reasons were also recorded.
Comparisons of continuous variables were made using the Student's t-test. Level of significance was 5%.
The CCS classification for angina severity was an ordinal categorical variable, but is coded as a quantitative variable to allow a numerical representation of its severity grade.

Baseline characteristics
A total of 304 patients were recruited. At the end of 2 months, 213 patients completed the 2 follow-up visits (30% drop-out rate).
The mean age of the patients was 63.3 ± 12.9 years. The cohort was predominantly male (64%).

Baseline therapies
Majority of these patients with angina pectoris were on standard of care therapy with anti-platelet and lipid lowering agents. About 60% of them were on a renin-angiotensin system blocker (equally distributed between ACE-inhibitors and angiotensin receptor blockers). About a third was already on therapies for symptom-relief with either nitrates, calcium-channel blockers or metabolic agents -either singly or in combinations (Table 1).
Ivabradine treatment produced no significant alteration of the systolic blood pressure. The diastolic blood pressure however was reduced significantly on follow-up.
All the indices of angina status improved with the introduction of ivabradine.

Heart rate
Heart rate(bpm)

Angina grade (CCS classification) changes
At study initiation about half of the patients (132 (48.7%)), were in class II angina (Figure 3). During follow-up, progressively greater proportion of patients improved in their angina status. By the last visit, half of the cohorts were in angina class I. There was a paradoxical increase in the number of patients who experienced class III angina after the first visit but this reduced remarkably to just 7.6% by the second month of follow-up.
Not only were the angina grades improved, the frequency of angina episodes and concomitant use of short acting nitrates were also less frequent. These improvements were seen within a month of initiating Ivabradine 5 mg bid. Escalation of dosage to 7.5 mg bid provided for a non-significant trend towards further improvements in angina-related parameters (Tables 4 and 5).

Patient-reported assessment of treatment effects
Majority of patients reported better sense of well-being after the prescription of ivabradine and had favourable perception of the efficacy of ivabradine in the control of angina compared to baseline therapies. This rough measure of improvement in patient's quality of life and satisfaction with the newly added therapy improved over the 2-month follow-up. Very few actually felt worse or had negative perception of the new treatment (Table 6).

Side-effects
In general, side-effects were few (23 reported events) and uncommon. General discomfort, being unwell and headache was reported in 6 patients. There were 4 reports of chest discomfort in association with shortness of breath, nausea and giddiness. Bradycardia with hypotension was encountered in 2 patients. Another 2 had decompensated heart failure with bradycardia. Complaints of leg swelling with numbness, lethargy were seen in 2 cases for each complaint. Single reports of phosphene phenomenon, asthma attack, dyspnoea, pruritic rash and dyspepsia were documented.

Conclusion
Ivabradine reduced HR significantly in patients with stable angina pectoris. All measures of angina severity -angina class, frequency of angina episodes and the need for short-acting nitrates improved after ivabradine addition to existing anti-ischaemic and anti-anginal therapies. Adverse drug reactions were uncommon and this agent was well tolerated and accepted by patients.
This study of early experience with ivabradine use in Malaysia showed efficacy and safety profile which was consistent with currently available evidence in other largely Caucasian populations.

Limitations
This was a small observational study. Inherent bias in such trial         design and small cohort need to be taken into account in the data interpretation.

Discussion
This paper was a non-randomised observational study evaluating the early experiences with Ivabradine in the management of stable angina pectoris.
This small study highlighted an increasingly recognized fact that these symptomatic patients were not well treated to lower targets of HR. The average HR at baseline was 81.7 ± 13.8 bpm. This was seen in spite of beta-blocker therapy in more than half (53.3%) of the cohort. It was recognized that there were many factors to account for this deficiency.
Not infrequently, issues of drug related side-effects e.g. Lethargy, depression, erectile dysfunction, etc. hampered the prescription of optimal dosages of beta-blockers. Beta-blockers were also contraindicated/not encouraged in stable coronary artery disease patients who had certain co-morbidities e.g. Peripheral vascular disease, erectile dysfunction, bronchial asthma, etc. Patient non-adherence in relation to these side-effects and physician inertia were other equally important factors.
Addition of ivabradine effectively reduced resting HR that would translate to improvements in angina-related symptoms and other ischaemic parameters. The concerns with beta-blocker-related adverse effects were largely avoided with Ivabradine use. Ivabradine would be an ideal alternative when beta-blockers could not be used e.g. in patients with bronchial asthma. It had been shown to be as good as atenolol for HR-lowering and in fact, for each beat of HR reduction, it was more efficient in improving exercise duration on the treadmill [13].
In situations when beta-blockers were strongly indicated e.g. Postmyocardial infarction and left ventricular dysfunction, combination therapy with ivabradine offered an interesting choice for optimization of angina symptoms and HR lowering. The results from SHIFT study further consolidated the role of ivabradine in patients with heart failure with reductions in heart failure deaths and re-admissions for heart failure [14].
It was difficult to explain the paradoxical increase in the number of patients in Class III angina (note that there was a concomitant increase of the number of patients in Class I angina) after the 1 st month of therapy. This however reduced to a remarkably low level at the end of study, whilst the number of patients in Class I angina continued to increase. This observation contradicted the progressive reduction in the number of angina episodes and need of short-acting nitrate over the trial period. This might be a spurious result or reporting bias in a small sampled study.
The reduction of diastolic BP during follow-up could not be explained by pharmacological properties of ivabradine. Antihypertensive agent use (number of agents, dosage or combination therapy) was not recorded during follow-up. Such reporting bias could account for the unexpected finding.
The low incidences of side-effects in our cohort coupled to the high level of tolerance and acceptance of ivabradine amongst Malaysian patients dismissed concerns that this new agent might behave differently in an Asian population.
This study and other real world experiences with Ivabradine in the management of stable angina pectoris patients confirmed the findings of randomized controlled trials [15].

Disclosure
Authors reported no conflict of interest pertaining to this trial. This trial was conducted with the assistance of an unrestricted grant from Les Laboratoires Servier.