Department of Internal Medicine, Cardiovascular Unit, Chiang Mai University, Chiang Mai, Thailand
Received Date: April 12, 2017; Accepted Date: April 20, 2017; Published Date: April 27, 2017
Citation: Chanchai R, Kanjanavanit R, Leemasawat K, Amarittakomol A, Topaiboon P, et al. (2017) Clinical Tolerability of Generic vs. Brand Beta Blockers in Heart Failure with Reduced Left Ventricular Ejection Fraction: A Retrospective Cohort from Heart Failure Clinic. Cardiovasc Pharm Open Access 6:208. doi: 10.4172/2329-6607.1000208
Copyright: © 2017 Chanchai R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Background: Beta blockers have been shown to decrease mortality and morbidity in Heart Failure Reduced Ejection Fraction (HFrEF) patients. However, the side effects are also dose-related leading to the underdosing. Cost constraint may be one of limitations of appropriate beta blocker used which can be improved with generic drug. However, the effects in real life practice have not been investigated.
Methods and results: This study aimed to compare the efficacy and safety of generic and brand beta blockers in HFrEF patients. We performed a retrospective cohort analysis in HFrEF patients who received either generic or brand beta blocker in Chiang Mai Heart Failure Clinic. The primary endpoint was the proportions of patients received at least 50% target dose of beta blocker between generic and brand beta blockers. Adverse events were secondary endpoints. 217 patients (119 and 98 patients receiving generic and brand beta blocker respectively) were enrolled. There were no differences between groups regarding age, gender, etiology of heart failure, NYHA class, LVEF, rate of receiving ACEI, ARB or spironolactone. Patients receiving brand beta blocker had less resting heart rate at baseline (74.9 and 84.2 bpm, p=0.001). Rate of achieved 50% target dose and target daily dose did not differ between groups (40.4 vs. 44.5% and 48.0 vs. 55.0%, p>0.05 respectively). Rate of side effects was not different between groups (32.3 vs. 29.5%, p>0.05) and most common side effect was hypotension.
Conclusion: This study demonstrated that beta blocker tolerability was comparable between brands and generic. Generic or brand beta blockers should be prescribed to HFrEF patients without contraindication.
• Beta blocker tolerability was comparable between brands and generic.
• Generic beta blocker may improve accessibility in HFrEF patient.
• Brand or generic beta blocker should be prescribed in HFrEF patients who do not have contraindications.
Heart Failure (HF) is a major public health problem with increasing prevalence in worldwide and Thailand, it is associated with high mortality, mobility, and cost of care [1-7]. Neurohormonal activation such as Renin-Angiotensin-Aldosterone System (RAAS) and sympathetic system has been shown to be associated with adverse outcome in HF [8-10]. Treatments with neurohormonal blockage have shown to reduce mortality and morbidity in heart failure with reduced left ventricular ejection fraction (HFrEF) [11-30]. Beta blocker is well established in benefit of morbidity and mortality reduction in HFrEF. It has been studied in chronic symptomatic HF as well as left ventricular systolic dysfunction associated with Acute Myocardial Infarction (AMI) . However, there are heterogeneous effects among beta blockers in HFrEF. Some beta blockers including carvedilol, bisoprolol and metoprolol succinate have shown the beneficial effects [21-24], while bucinodol does not show benefits in HFrEF . In addition, head to head study which compared the effects of carvedilol and metoprolol tartate in chronic HFrEF showed the benefits of carvedilol over metoprolol tartrate . Therefore, guidelines recommended only clinical trial proven beta blockers [4,32]. Dose titration to target recommendation dose is also essential for the higher magnitude of benefits of beta blocker. Although beta blockers have been recommended by guidelines, several cohorts have shown the limited use of beta blocker [33-37]. The factors limiting beta blocker use including physician’s attitude, tolerability, and adverse effects of beta blocker as well as cost constrain.
HF management is costly due to high cost of medications, device therapy and cost of patient care. Due to multiple co-morbidities such as coronary artery disease, hypertension, diabetes, the cost of total medications used is high  and burden for health care system and household. Nevertheless, the majority of guideline recommended medications for HF such as angiotensin converting enzyme inhibitors, beta blockers have lost their patent protection and are available at relatively low cost. The generic drugs can provide better access to medications for HF patients. However, there are some concerns over manufacturing process leading to concerns of safety and tolerability of these generic drugs [38,39]. However, There is no report compare tolerability between generic and brand beta blocker in HFrEF patient.
The study compared pharmaceutical quality between brand and generic beta blocker reported that at least 48% generic beta blocker worsen than brand beta blocker . Therefore, we aim to study the safety and tolerability of generic beta blockers in HFrEF patients in real life practice. The primary objective was to compare the proportion of patients receiving at least 50% target dose of beta blocker between generic and brand beta blocker. The secondary objective was to compare the proportion of patients with adverse event and the reasons of not achieve target dose between generic and brand beta blocker.
This is retrospective analysis of the HF cohort from Chiang Mai University HF clinic. This clinic has been established since 2004. The HFrEF patients with high risk such as history of frequent hospitalization, having multiple co-morbidities or poor compliance were invited to participate in HF clinic. Their information including symptoms, physical examination and laboratory data were prospectively collected and recorded.
HF patients who met inclusion criteria were enrolled in this analysis. Inclusion criteria consisted of heart failure patients with left ventricular ejection fraction less than 0.4 who received at least 1 dose of generic or brand beta blockers (carvedilol or bisoprolol). Patients with absolute contraindication for beta blockers were excluded from the analysis.
The data including symptoms, signs, dose titration, maximum dose, adverse effects and management of adverse effect were recorded at 3 points including the starting day (day with first dose of beta blocker), 1 ± 1 months and 6 ± 3 months after starting point.
Target dose of beta blocker was determined according to standard recommendation guideline as following: Carvedilol 50 mg/day and bisoprolol 10 mg/day at 6 months after start beta blocker.
Brand beta blockers in this study referred to Dilatrend (Roche, Switzerland) and Concor (MERCK, Germany).
Generic carvedilol referred to Caraten (Berlin Pharm, Thailand) and generic bisoprolol referred to Hypercor (Sriprasit Pharma, Thailand) and Bisloc (Unison, Thailand).
Sample size was calculated on the basis of proportion of patient received at least 50% target dose brand beta blocker around 80% [21-23,26,41]. Estimated patient received at least 50% target dose generic beta blocker around 40% . At type I error=0.05, type II error=0.10 this study aim to compare proportion of two independence sample, calculated sample size for each group=30, estimated incomplete data around 50%, so need total sample size at least 90 patients.
Continuous variables are presented as mean ± SD or median (IQR) where appropriate. Categorical variables are presented as number and percentage. Comparisons between groups of continuous variable were performed using student t or Mann-Whitney U test where appropriate. Comparisons of categorical variables were performed using Chi-square or Fisher exact test where appropriate. A probability values <0.05 (2- tailed) was considered statistically significant. Statistical analyses were performed using SPSS 18 (IBM, NY, USA).
From 500 patients in HF clinic, 217 patients met inclusion criteria and were enrolled in this analysis. Ninety-eight patients received brand beta blocker and 119 patients received generic beta blocker.
At baseline, there were no difference in age (59.4 ± 14.3 vs. 57.5 ± 14.9 years old, p=0.45), gender (male 53.1% vs. 61.3%, p=0.27), New York Heart Association (NYHA) functional class (FC) (2.9 ± 0.8 vs. 2.6 ± 0.8, p=0.14). Patients were in NYHA FC II 34% vs. 43%, FC III 43.6% vs. 42.4%, p=0.14. There were no difference in concomitant diseases including atrial fibrillation 26.0% vs. 27.7%, p=0.49, chronic obstructive pulmonary disease 10.5% vs. 7.6%, p=0.45, diabetes 37.4% vs. 28.6%, p=0.38, Chronic Kidney Disease (CKD) 48.4% vs. 36.1%, p=01. The proportion of left ventricular systolic dysfunction from ischemic cause was not significant difference between group (22.7% vs. 31.1%, p=0.06 in brand and generic beta blocker, respectively). There was no difference in LVEF (27.0 ± 10.3% vs. 25.4 ± 7.9%, p=0.49%) in brand and generic beta blocker, respectively.
The proportions of patients receiving recommendation treatment for HFrEF were not different between groups: Angiotensin Converting Enzyme Inhibitor (ACEi) or Angiotensin Receptor Blocker (ARB) (79.1% vs. 76.1%, p=0.64), spironolactone (65.7% vs.73.5%, p=0.31), digoxin (14.9% vs.25.66%, p=0.09) and device therapy including automatic implantable cardioverter-defibrillator (AICD) and cardiac resynchronization therapy (CRT) (7.3% vs.13.4%, p=0.28) in brand and generic beta blocker, respectively. There were no difference in systolic blood pressure and diastolic blood pressure: 115.9 ± 21.3 vs. 111.9 ± 16.8 mmHg, p=0.11 and 67.4 ± 13.9 vs. 67.4 ± 14.2, p=1.00 for brand and generic beta blocker, respectively. But patients in brand beta blocker had lower mean heart rate than generic beta blocker (74.8 ± 16.7 vs. 84.2 ± 16.2 bpm, p=0.00) (Table 1).
|Character||Brand beta blocker (n=98)||Generic beta blocker
|Age (Year)||59 ± 14.30||57.53 ± 14.92||0.45|
|SBP (mmHg)||115.9 ± 21.27||111.95 ± 16.77||0.11|
|HR (bpm)||74.86 ± 16.69||84.17 ± 16.15||0|
|LVEF (%)||27.04 ± 10.34||25.39 ± 7.98||0.49|
|Ischemic cause (%)||22.68||31.09||0.06|
|ACEi/ARB usaged (%)||79.1||76.1||0.64|
|Aldactone usaged (%)||65.67||73.45||0.31|
|Digoxin usage (%)||14.92||25.66||0.09|
|Device usage (%)||7.29||13.44||0.28|
Table 1: Proportion of patient receiving beta blockers.
At 6 months, both of beta blocker were similar in percent of heart rate reduction (5.6 ± 2.0 vs. 7.4 ± 2.6 bpm, p=0.61, in brand and generic beta blocker, respectively).
Both beta blockers had similar proportion of patients achieving at least 50% target dose (40.4% vs. 44.5%, p=0.25) in brand and generic beta blocker group, respectively). The daily dose achievement as a percentage of target dose was not different between brand and generic beta blocker groups (48% vs. 55% of target dose, p=0.27) (Figure 1).
There were also similar proportion in achieved at least 50% maximum dose (34.7 ± 19.7% vs. 44.3 ± 24.1%, p=0.27) and percent mean daily dose achievement (42.0 ± 49.7% vs. 56.7 ± 49.9%, p=0.09) between brand and generic bisoprolol. There were also similar proportion in achieved at least 50% maximum dose (56.5 ± 34.4% vs. 45.3 ± 30.4%, p=0.14) and percent maximum target daily dose (68.0 ± 47.6% vs. 52.4 ± 50.3%, p=0.18) between brand and generic carvedilol. The titrations of beta blocker dose during 6 months of treatment were not different between brand and generic beta blocker including increased dose (46.9% vs. 66.8%), stable dose (39.8% vs. 26.3%) and decreased dose (13.3 vs. 6.8%), p=0.39 (Figure 2).
The reasons of not achieving target beta blocker dose including target heart rate achievement, postural hypotension, reactive airway disease, acute decompensated HF, bradycardia, unspecified reason in 51.1% vs. 43.4%, 27.8% vs. 16.8%, 2.22% vs. 5.3%, 3.3% vs. 2.65%, 10.0% vs. 23.8% in brand and generic beta blocker respectively.
There were 5 patients (2.3%) of both groups had discontinued beta blocker at 6 months. Three patients in brand beta blocker group discontinued due to ADHF, bradycardia, and unknown cause while 2 patients in generic beta blocker group discontinued due to reactive airway and bradycardia. Eight patients (2 vs. 6) in brand vs. generic beta blocker) were loss to follow up.
The side effects were not significant different between brand and generic beta blocker (32.3% vs. 29.5%, p=0.75). Acute decompensated HF, bradycardia, hypotension, dizziness and reactive airway disease were presented in 4.1% vs. 3.4 %, 3.1% vs. 3.4 %, 10.2% vs. 10.9 %, 1.0% vs. 1.7% and 0.8% vs. 0%, in brand and generic beta blocker, respectively (Table 2).
|Side effect||Brand beta blocker
|Generic beta blocker (n=23)|
|Heart Failure (%)||4.08||3.36|
|Reactive airway (%)||0.85||0|
Table 2: Side effect.
This study showed similar tolerability of brand and generic beta blocker either in term of proportion achieved 50% maximum target daily dose and percent maximum daily dose. This study showed lower at least 50% maximum target daily dose achieved than clinical trial [21-24,26] and community survey reported [33-36,41,42].
There are possible reasons for the disparity including patients’ body size, disease severity, comorbidities and heart rate response to beta blocker. The patients in our study have more disease severity, in terms of higher proportion of patients in NYHA FC III and IV and lower LVEF. Target heart rate response was achieved in more than haft of our patients which may preclude the physician from dose up-titration. Previous studies also showed causes of drug discontinuation or not achieved target daily dose are hypotension, bradycardia, worsen heart failure symptoms and reactive airway diseases [43-45]. However, our studied ensured that both brand and generic beta blocker were well tolerate, and almost HFrEF patients can tolerate low to moderate dose of beta blocker.
Generic medications have been used in clinical practice to improve patient’s access to treatment and cost effectiveness. The studies in China demonstrated that generic, low cost or free of charge anti-hypertensive drugs had enhanced medication adherence in hypertensive patient leading to prevent cardiovascular outcome, reduced total medical costs and cost effectiveness [46,47]. However, the efficacy and safety of generic medications are important to achieve the benefits of treatment.
Heart failure is the major health economic burden due to high cost of medications, device and hospitalization. Generic neurohormonal blockage can improve patient access to treatment, improve outcomes and reduce cost of care. This study demonstrated that generic beta blocker was not different to brand beta blocker in it tolerability and safety. Although this study did not investigate clinical outcomes, beta blocker dose and heart rate have been shown too associated with clinical outcome. Therefore, brand or generic carvedilol and bisoprolol in our study should be prescribed in HFrEF patients who do not have contraindications.
Regarding to retrospective study in nature, there were some limitations such as uncontrolled factors, incomplete data recorded.
This studied showed data only on beta blocker tolerability and side effects but, didn’t compared clinical efficacy of brand and generic beta blockers, Further investigation should performed for declared similarity in its clinical efficacy.
The proportion of patients achieving 50% target dose and maximum target dose was comparable between generic and brand beta blockers. Clinical tolerability was also not different. This data ensured that evidence-based beta blocker should be prescribe to HFrEF who has no contra-indication regardless either brand or generic.
This study is supported by Foundation of Support Research of Faculty of Medicine, Chiang Mai University, and Chiang Mai, Thailand.
The authors declare that there are no conflicts of interest.