Therapeutic Interchange of Carvedilol to Bisoprolol for Chronic Heart Failure: The Singapore Experience

In 2008, Singapore spent only 3.3% of gross domestic product on healthcare.¹ Carvedilol and bisoprolol are chronic medications which are not completely subsidized by the healthcare fi nancing system in Singapore. To a patient with chronic disease who has to rely on long-term medications, out-of-pocket healthcare expenditure can become a heavy burden, especially in old age. Generic substitutions of branded drugs can save costs for both the patient and the healthcare system. In the period of years from 2002 to 2005, generic substitutions across the National Healthcare Group cluster helped save a total of S$300,000 and S$350,000 for Alexandra Hospital and its patients, respectively. Examples of branded drugs for which generics have been substituted are Adalat LA, Augmentin, Humulin, and Neurontin.

Therapeutic substitution has been described by the American College of Clinical Pharmacy (ACCP) as “dispensing of a drug that is therapeutically equivalent to, but chemically different from, the drug originally prescribed by a physician or other authorized prescriber.” The difference between therapeutic substitution and therapeutic interchange was addressed by the American College of Cardiology/American Heart Association (ACC/AHA) Clinical Quality Committee in 2011. Therapeutic interchange is carried out with the physician or prescriber aware of the switch, whereas in the case of therapeutic substitution, the switch is carried out without prior authorization of the initial prescriber. Therapeutic substitution should never be accepted unless reviewed and approved by the healthcare team based on the science available.² The aim of a therapeutic interchange program is to achieve more affordable healthcare. Drug classes that have been most often used in therapeutic interchange include anti-secretory agents (eg, H₂-receptor antagonists, proton pump inhibitors), anti-infective agents (eg, fluoroquinolones, cephalosporins), cardiovascular drugs (eg, HMG-CoA reductase inhibitors, angiotensin-converting enzyme inhibitors), and analgesics (eg, COX-2 inhibitors and non-steroidal antiinflammatory drugs).Chronic heart failure (HF) is a condition requiring many medications which confer long-term mortality and morbidity benefi ts. Not only is the expenditure on medications high, the pill burden is also high. Three beta-blockers—carvedilol, bisoprolol, and metoprolol XL—have demonstrated improved survival rates, reduced hospital admissions, and improved New York Heart Failure Association functional class (NYHA FC).^3,4

In our institution, carvedilol was used for HF patients based on the fi ndings of the US Carvedilol Trials.5 However, in 2009, generic bisoprolol entered the Singapore market, leading to this initiative. As carvedilol is still proprietary, the cost savings to a subsidized-class patient could be as much as S$1197.20 (approximately US$958) per year per patient. Healthcare costs are paid out of pocket by the patients in the Singaporean healthcare system. The inability to afford medications may lead to poor compliance or adherence. This is an important issue to deal with, especially since both these beta-blockers have convincingly shown improved mortality and morbidity outcomes in HF, and are regarded by international experts and healthcare bodies as mandatory agents to prescribe to all HF patients unless absolute contraindications exist.^6-9

The once-daily dosing for bisoprolol, a selective beta-1 blocker, compared with a twice-daily dosing of carvedilol, a mixed beta- and alpha-blocker, is likely to confer a higher likelihood of adherence to medications. Additionally, it is believed that the alpha-blockade effect is more likely to cause hypotension and/or dizziness,¹ further discouraging adherence to carvedilol.

It is important that clinical equivalence can be established before therapeutic interchange is carried out.^2,10 The ACC/AHA 2011 statement further asserts that patients should be involved in the decision making of switching medications. Considering the various studies using carvedilol and bisoprolol,^1,11 the mortality reduction rates were regarded as acceptable for bisoprolol in NYHA FC I-IIIa patients. However, taking into consideration the COPERNICUS¹² study, it was decided that while for the NYHA FC I-III patients, this interchange will be highly encouraged, for Class IIIb-IV patients, the physicians may consider leaving the carvedilol unswitched.

METHODS

A total of 161 subsidized patients aged from 21 to 100 years were on carvedilol from June 2006 to January 2007. We excluded paying-class patients, those no longer on follow-up with Alexandra Hospital, those lost to follow-up, pregnant and breast-feeding patients, and patients who were deemed unable to selffi ll questionnaires.

If the patients had follow-up appointments with cardiologists, we worked with their cardiologist-in-charge to carry out the interchange. However, for patients without cardiologist follow-up appointments, the therapeutic interchange was made in collaboration with their respective physicians instead. Road shows to all the medical doctors and geriatricians were carried out to explain the rationale and to share available evidence to reassure physicians.

The patients’ upcoming consultation dates were traced via a patient management module. On the day of their respective appointments, a text message of the patient’s name and identifi cation card number, appointment time, and a brief reminder to consider the switch was sent to the primary physician’s mobile phone.

Based on recommended initial starting and target doses of these 2 beta-blockers in the various clinical trials CIBIS II,¹³ US Carvedilol Studies,¹² and COPERNICUS,¹¹ and the Clinical Pharmacy Practice Guidelines for HF patients developed by Singapore Ministry of Health,⁷ we decided on a 5:1 dose conversion (eg, carvedilol 12.5 mg BD to bisoprolol 5 mg OM). We did not make it mandatory for all physicians to adopt this conversion, giving the physicians the freedom to decide on an optimal bisoprolol dose for each patient based on the clinical status of the patients during the consult. Small, laminated cards bearing the new dose of bisoprolol that corresponds to the original dose of carvedilol were placed in all consult rooms in the outpatient clinics (

Table 1

) for ease of reference. Patient information leafl ets were developed to aid the physicians and the pharmacy staff in explaining the switch.

To ensure that our patients were safely and effectively switched to bisoprolol, the Minnesota Living with Heart Failure (MLHF) Quality-of-Life (QoL) Questionnaire was used at the point of interchange (T0) and at an interval of approximately 2 months (T1) later, with permission from the University of Minnesota. This questionnaire was designed in 1984 to measure the effects of HF-associated treatments on an individual’s quality of life. It consists of 21 questions representing each of the 21 facets of activities of daily living. By ranking on a 6-point (0 to 5) Likert scale, the patients are asked to indicate how their condition has prevented them from living as desired in the past month. The total score is added up and taken as the best measure of how HF and treatments impact an individual’s QoL. We have also translated the questionnaire, with permission from the developers, into Mandarin and Malay versions to facilitate understanding among our patients who do not read or write English.

On the day of interchange, the patient’s consent was obtained and baseline QoL score was obtained face-toface using the MLHF questionnaire when they collected their medicines at the pharmacy. If they were missed at the pharmacy, the MLHF questionnaire was sent to their home address after getting their consent over the phone. The informed consent, together with the completed questionnaire, was mailed back to the pharmacy department. At T1, these patients would be contacted again to repeat the same set of questions. The difference in their T0 and T1 scores was computed and analyzed using the paired Student t test.

Readmission rates related to HF were also tracked longitudinally 6 months before and after interchange, using a national online database that keeps records of a patient’s admissions in all restructured hospitals nationwide.

Cost savings were computed based on direct drug costs only.

The study design was approved by the National Healthcare Groups Domain Specifi c Review Board (DSRB) Domain Board C. All subjects participating in this study signed an informed consent approved by the DSRB.

RESULTS

Out of the 161 patients retrieved from the database, 85 (65%) were switched to bisoprolol and 50 (37%) were left on carvedilol. Twenty-four were lost to follow-up; 6 (7%) in the switched group and 18 (36%) in the unswitched group (

Figure 1

). Patients’ average age was 69 and 73 years in the bisoprolol and carvedilol groups, respectively. Male patients made up 56.4% and 60% of the bisoprolol and carvedilol groups, respectively. About 73% of subjects had HF of ischemic origin.

At the end of the study period, 76 patients remained in the switched group and 15 remained in the carvedilol group. The successful switch to bisoprolol for the 85 subjects led to a total direct drug cost savings of S$12,321 (US$8730) for these patients.

This translates to about S$145 (US$103) per patient-year.

The numbers of readmissions for converted patients (n = 5) were lower in the 6 months after conversion compared with the 6-month period before conversion (n =10). The readmission rates before and after conversion were not signifi cantly different (P = .332, paired sample t test). There were 15 readmissions over 1 year for the 50 unconverted (carvedilol) patients (

Table 2

).

On average, carvedilol was converted to bisoprolol at a dosage ratio of 4.15 to 1.

The MLHF QoL scores were compared for 9 patients who completed the study (

Figure 2

). A paired t test analysis of these scores showed that there was no statistical difference (P = .826) in the patients’ QoL scores pre- and post-conversion. The average QoL scores pre- and postconversion were 24 and 26, respectively.

DISCUSSION

To our knowledge, this is the first beta-blocker therapeutic interchange program in chronic heart failure NYHA FC I-IIIa patients. It is also likely the first therapeutic interchange program to be attempted and measured in Singapore. Singapore is in the unique position of having experience with both carvedilol, a primarily American-studied beta-blocker, and bisoprolol, a primarily European-studied beta-blocker. Not only did we use QoL as a surrogate end point, outcomes like readmission and mortality rates were also reported. There have been studies showing better outcomes with more expensive proprietary medications published in the literature.⁹ It is important that while trying to cut down on healthcare costs, outcomes like mortality and morbidity do not suffer.^2,10 Further, we had sought patient consent before switching beta-blockers. All effort was made to reassure patients of the effi cacy of bisoprolol through a previously prepared patient information leafl et and price information. We had also made every effort to inform the primary physician in charge of each patient through road shows detailing evidence from published clinical trials and our rationale and recommendations for switching carvedilol to bisoprolol, while leaving the fi nal decision to them. What we have done is completely in line with the ACC/AHA 2011 recommendations to involve patients in decision making when interchanging medications.

As evidenced by the lack of statistically signifi cant change in QoL scores and readmission rates, we were able to demonstrate that our HF patients were not worse off after switching to bisoprolol. Readmission rate in the carvedilol group was assessed only as a reference and we did not compare between the 2 groups because we think that it is possible that the carvedilol group consists of a greater proportion of the sicker NYHA FC IIIb-IV patients. Although readmission and mortality rates were much higher in the carvedilol group, we cannot conclude that patients remaining on carvedilol did worse than the bisoprolol population.

The dose conversion ratio of carvedilol to bisoprolol was 4.15 to 1 on average. This indicates that on average, the doctors switched carvedilol to a higher-than-recommended dose of bisoprolol. This was possibly because of dose optimizations to the highest tolerated beta-blocker dose after carvedilol was switched to bisoprolol.

One of the limitations of our study was the small number of patients who were successfully surveyed using the MLHF QoL questionnaire. One of the most commonly encountered issues was the sentiment that fi lling out the questionnaire was arduous, and patients tended to misunderstand some questions. However, it is the authors’ opinion that since the readmission rates and mortality rates did not demonstrate poorer outcomes, this initiative was a successful one.

The second limitation was the fact that patients’ compliance was ascertained by a simple yes/no answer and not by pill count or refill information. We were thus unable to measure if compliance rates had improved after switching, or any factors that might have been associated with change in compliance. The authors feel that since these were “real-world” measurements, they would accurately reflect actual patients who are placed on long-term beta-blockers for chronic HF. Therefore, our study would serve to reassure practitioners that, outside of a clinical trial setting, interchange programs are safe and effective.

The other limitations include the lack of control for dietary salt and fluid intake, and the possibility that there were confounders like patients entering specialized HF programs and receiving additional counseling, leading to lowered readmission rates. However, the authors feel that since the patients’ fl ight through the system has been constant and their physicians have not changed with time, it is unlikely that such factors have a large infl uence over the outcomes.

Our study comprised only a small percentage of all the HF patients on follow-up with Alexandra Hospital, and only direct drug cost savings were measured. Greater cost savings could potentially be conferred if extrapolated to the total number of HF patients in the whole country, or if costs accrued due to hospitalizations were included as well.

We conclude that the Carvedilol-Bisoprolol Therapeutic Interchange Programme has effectively reduced healthcare costs both for the patients and the healthcare system without compromising the outcomes of these patients. Using these fi ndings, we have been advocating a hospitalwide interchange to the generic bisoprolol for all NYHC FC I-IIIa HF patients.