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RESEARCH PAPER
Year : 2017  |  Volume : 8  |  Issue : 1  |  Page : 21-27  

Antianginal efficacy and tolerability of ranolazine as an add-on drug to concomitant medications primarily metoprolol in chronic stable angina patients: A prospective, open-label study


1 Department of Pharmacology, BLDEU's Shri B. M. Patil Medical College and RC, Vijayapura, Bengaluru, Karnataka, India
2 Department of Pharmacology, M. S. Ramaiah Medical College, Bengaluru, Karnataka, India
3 Department of Cardiology, M. S. Ramaiah Medical College, Bengaluru, Karnataka, India

Date of Submission28-Oct-2016
Date of Decision29-Dec-2016
Date of Acceptance20-Jan-2017
Date of Web Publication17-Mar-2017

Correspondence Address:
Anant Mahaveer Khot
Department of Pharmacology, BLDEU's Shri B. M. Patil Medical College and RC, Vijayapura - 586 103, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpp.JPP_168_16

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   Abstract 

Objective: To evaluate the efficacy and tolerability of ranolazine as an add-on drug in chronic stable angina patients and the impact of ranolazine on the quality of life in chronic stable angina patients receiving other antianginal medications. Materials and Methods: It was a prospective, open-label, hospital-based study involving 144 patients with chronic stable angina. First group received either metoprolol 12.5 or 25 mg/day or other antianginal medications; if the symptoms persist, the dose of metoprolol was increased to 50 mg/day, and to the second group, ranolazine 500 mg BD or 1 g OD was added along with metoprolol or others if the anginal attacks were not subsiding. The patients were followed up to 6 months with electrocardiography, treadmill test, and quality of life questionnaire. Adverse events were recorded at each visit during the study. Results: There was a statistically significant reduction in weekly anginal frequency (P < 0.001) and improvement in an exercise tolerance in both the groups, but more in the ranolazine group. Adverse events reported were mild, infrequent. Conclusion: Ranolazine is could be used as an add-on drug in chronic angina patients not improved with metoprolol or antianginal medications.

Keywords: Coronary artery disease, exercise tolerance, percutaneous intervention, quality of life, ranolazine


How to cite this article:
Khot AM, Anuradha H V, Prakash V S, Shivamurathy M C. Antianginal efficacy and tolerability of ranolazine as an add-on drug to concomitant medications primarily metoprolol in chronic stable angina patients: A prospective, open-label study. J Pharmacol Pharmacother 2017;8:21-7

How to cite this URL:
Khot AM, Anuradha H V, Prakash V S, Shivamurathy M C. Antianginal efficacy and tolerability of ranolazine as an add-on drug to concomitant medications primarily metoprolol in chronic stable angina patients: A prospective, open-label study. J Pharmacol Pharmacother [serial online] 2017 [cited 2017 Oct 21];8:21-7. Available from: http://www.jpharmacol.com/text.asp?2017/8/1/21/202393


   Introduction Top


Coronary heart disease (CHD) is the leading cause of death in India and worldwide. The Global Burden of Disease study estimate of age-standardized cardiovascular disease (CVD) death rate of 272/100,000 population in India is higher than the global average of 235/100,000 population. Premature mortality in terms of years of life lost because of CVD in India increased by 59%, from 23.2 million (1990) to 37 million (2010).[1]

Chronic stable angina is the major symptomatic presentation in about 50% of CHD patients. There is a growing prevalence of chronic ischemia and angina due to residual coronary artery disease after percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG). Despite optimal revascularization, nearly 80% of the patients in the PCI group and 60% in the CABG group continued to experience angina and require antianginal medications.[2]

Ranolazine, a piperazine derivative, is relatively new antianginal drug.[3] It exhibits its antianginal effect without eliciting any change in the heart rate, blood pressure, or rate pressure product, as compared to beta-blockers and calcium channel blockers. A post hoc analysis of diabetic patients in the CARISA trial reported not only a reduction in the mean number of anginal episodes per week but also a reduction in the glycated hemoglobin levels by 0.72 from the baseline.[4] Despite all these peculiarities, studies relating to its use as an antianginal drug (both monotherapy or in combination)[5] among Indian patients were only a few; hence, this study was undertaken with the following objectives:

  1. To evaluate the efficacy and tolerability of ranolazine as an add-on drug in chronic stable angina patients
  2. To study the impact of ranolazine on the quality of life in chronic stable angina patients receiving other antianginal medications.



   Materials and Methods Top


It was a prospective, open-label, hospital-based study involving 144 patients (both ranolazine and metoprolol group) with chronic stable angina, who attended the Cardiology Department at M. S. Ramaiah Medical College Hospital after November 2010.

The study participants were recruited based on following inclusion and exclusion criteria; written informed consent was obtained from all the patients and Institutional Ethics Committee approval was sought before performing the study.

Inclusion criteria

  1. Patients of either sex with age ≥18 years, diagnosed to be having chronic stable angina
  2. Chronic stable angina of ≥3 months and ≥2–3 episodes of angina per week during a ≥2-week qualification period despite treatment treatment with metoprolol 25 mg OD/BD.


Exclusion criteria

  1. Patients will be excluded if they have New York Heart Association functional Class IV congestive heart failure
  2. An episode of myocardial infarction or unstable angina within the previous 2 months
  3. Active acute myocarditis, pericarditis, hypertrophic cardiomyopathy, uncontrolled hypertension
  4. Patients with history of torsades de pointes and those receiving agents that are known to prolong QTc interval
  5. Patients with creatinine clearance <30 ml/min or chronic illnesses those are likely to interfere with protocol compliance.


Sample size

Sample size was calculated using the formula for assessing the difference between the means by nMaster software (ranolazine group and metoprolol group) from the ERICA trial.[6] Required sample size in each group was 72 to have a power of 90%.

The first group received either metoprolol 12.5 mg OD/BD or other antianginal medications [Table 1]; if the symptoms persist, the dose of metoprolol was gradually increased to a maximum dose as 100 mg OD(50 mg BD), or similarly, the doses of other antianginal drugs were also increased.
Table 1: Distribution of different class of antianginal drugs in two groups of patients studied

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The second group received ranolazine 500 mg BD/1 g OD if chronic stable angina of ≥3 months and ≥2–3 episodes of angina per week during a ≥2-week qualification period despite treatment with metoprolol 25 mg OD/BD or recommended dose of other antianginal medications. The flow of study sequence was as shown in [Figure 1].
Figure 1: Flow of participants through the trial

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Study sequence

Parameters measured

  1. Weekly angina frequency
  2. Exercise tolerance by performing treadmill test (TMT).


Investigations performed

  1. Electrocardiography (ECG)
  2. TMT.


Results were interpreted by using both Bruce and modified Bruce protocol.[7]

Follow-up

Patients were followed up for 6 months. ECG, exercise tolerance test, and the administration of pretested structured questionnaire Seattle Angina Questionnaire (SAQ)[8] were performed at the baseline and at the end of 2 months. At the end of 6 months, a stress ECG by TMT and administration of SAQ were repeated. Results were tabulated and statistical analysis was done.

[Additional file 1]

Statistical analysis

It was done by using SPSS 23, IBM obtained from SPSS South Asia Private limited, Bangalore, India. Descriptive and inferential statistical analysis has been carried out in the present study. Results of continuous variables are presented as mean ± standard deviation and of categorical variables are expressed as percentages. Student's t-test (two-tailed, independent) has been used to find the significance of study parameters on a continuous scale between two groups. Chi-square test was used for qualitative data.


   Results Top


This study was started from November 2010 with an intent to know the efficacy of ranolazine as an add-on drug to concomitant antianginal medications, primarily metoprolol in Indian patients. A total of 144 patients were enrolled in the study and baseline characteristics of both groups are summarized in [Table 2].
Table 2: Baseline characteristics

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Mean anginal frequency per week in both the groups at baseline and at the end of 2 and 6 months is shown in [Figure 2]. In both the groups, there was statistically significant reduction in frequency of angina per week at the end of 2 months (P < 0.001). However, at the end of 6 months, reduction in anginal frequency was more significant in ranolazine group as compared to metoprolol group.
Figure 2: Mean anginal frequency of the study groups. #Statistically significant difference in both groups from baseline to 2 months (P < 0.001). ++ Significant reduction in ranolazine group at the end of 6 months (P < 0.001)

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Exercise tolerance by TMT was performed at baseline and at the end of 2 and 6 months. [Figure 3] depicts the mean duration of exercise performed by the patients in both the groups either using Bruce or modified Bruce protocol. At baseline and at the end of 2 months, mean duration of exercise performed in both the groups was different statistically (P < 0.002). At the end of 6 months, the difference was not significant (P < 0.062). When assessed for exercise tolerance at baseline and at the end of 2 and 6 months within metoprolol and ranolazine group separately (intragroup analysis), it was found statistically significant in both the groups (P < 0.001).
Figure 3: Exercise tolerance by treadmill test. * Statistically significant difference at baseline. #Statistical significant difference in exercise tolerance between 2 groups at the end of 2 months (P = 0.002). xExercise tolerance was not significant statistically at the end of 6 months (P = 0.062)

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Quality of life was assessed using SAQ, but the results which are not included in the analysis because of absence of follow-up data on quality of life in few patients in both the groups and complexity of analysis of data derived from it and the adverse events reported during the study are summarized in [Table 3].
Table 3: Adverse events reported during the study

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   Discussion Top


Our findings show that when compared ranolazine as add-on drug with metoprolol in patients with chronic stable angina who were not controlled on monotherapy has proven to be safe and effective option.

Ranolazine has reduced mean anginal frequency, but the exercise tolerance as assessed by mean duration of exercise on TMT has shown statistically significant difference at baseline and at the end of 2 months and shown comparable result at the end of 6 months. One reason why it was significant at the end of 2 months but not at the end of 6 months could be due to the difference in exercise tolerance at the baseline (P < 0.002) and the adverse events reported during study period were infrequent and minor once.[9] No serious adverse events [10] were reported during the study period. It was really difficult to assess for the causality [11] as patients in both the groups were taking ≥2 medications. Findings of this study are consistent with ERICA trial which was conducted to know the efficacy of ranolazine as an add-on drug to calcium channel blockers.

In our study, we had nine patients in metoprolol group and 14 patients in ranolazine group who underwent PCI previously. Few patients underwent PCI during the follow-up visit and they received ranolazine perioperatively.

Strength of the study

Large sample size and long duration of follow-up are the strengths of the study.

Limitations of the study

Hospital-based study – sample what we get is not representative of whole Indian population.

Effect of ranolazine on quality of life was not assessed.

Another important problem with our patients was lack of compliance to therapy (on polypharmacy usually) and had multiple risk factors for CHD. Hence, the treating cardiologists preferred PCI (patients had multiple government schemes and insurances) over the trial of multiple medications and follow it for their efficacy and safety as it was concluded in the study conducted by Wijeysundera et al.[12] and opposite of COURAGE trial which states that there is no difference in survival between an initial strategy of PCI plus medical therapy and medical therapy alone in patients with stable ischemic heart disease.[13] Further well-designed randomized trials with meta-analysis are required to prove the efficacy of ranolazine.


   Conclusion Top


According to our study, ranolazine was justified for use as an augmenting agent [14] in combination with other antianginal drugs primarily metoprolol in chronic stable angina patients but not as monotherapy as it was concluded in MARISA trial.[15]

Acknowledgment

We would like to thank Dr. Sathyendra Kashyp, Dr. Mukunda N R and Dr. Niveditha for support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
Prabhakaran D, Jeemon P, Roy A. Global burden of cardiovascular disease cardiovascular diseases in India. Circulation 2016 Apr 18;133(16):1605.  Back to cited text no. 1
    
2.
Boden, WE. Medical management of stable coronary artery disease. In: Cairns JA, Gersh BJ, editors. Evidence-Based Cardiology. 3rd ed. London: John Wiley and Sons; 2011. p. 345-53.  Back to cited text no. 2
    
3.
Antman EM, Selwyn AP, Loscalzo J. Ischemic heart disease. In: Long DL, Kasper DL Jameson JL, Fauci AS, Hauser SL, Loscalzo J, editors. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012. p. 2000-13.  Back to cited text no. 3
    
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Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: A randomized controlled trial. JAMA 2004; 291:309-16.  Back to cited text no. 4
    
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Klein WW, Jackson G, Tavazzi L. Efficacy of monotherapy compared with combined antianginal drugs in the treatment of chronic stable angina pectoris: A meta-analysis. Coron Artery Dis 2002;13:427-36.  Back to cited text no. 5
    
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Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L; ERICA Investigators. Antianginal efficacy of ranolazine when added to treatment with amlodipine: The ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol 2006;48:566-75.  Back to cited text no. 6
    
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Henzlova MJ, Duvall WL, Einstein AJ, Travin MI, Verberne HJ. ASNC imaging guidelines for SPECT nuclear cardiology procedures: Stress, protocols, and tracers. J Nucl Cardiol 2016;23:606-39.  Back to cited text no. 7
    
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Spertus JA, Winder JA, Dewhurst TA, Deyo RA, Prodzinski J, McDonell M, et al. Development and evaluation of the Seattle Angina Questionnaire: A new functional status measure for coronary artery disease. J Am Coll Cardiol 1995;25:333-41.  Back to cited text no. 8
    
9.
Morrow DA, Boden WE. Stable ischemic heart disease. In: Mann DL, Zipes DP, Libby P, Bonow RO, editors. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia: Saunders; 2015. p. 1196-9.  Back to cited text no. 9
    
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Edwards IR, Aronson JK. Adverse drug reactions: Definitions, diagnosis, and management. Lancet 2000;356:1255-9.  Back to cited text no. 10
    
11.
Tripathi KD. Adverse drug effects. Essentials of Medical Pharmacology. 7th ed. New Delhi: Jaypee Brothers Medical Publishers; 2013. p. 82-3.  Back to cited text no. 11
    
12.
Wijeysundera HC, Nallamothu BK, Krumholz HM, Tu JV, Ko DT. Meta-analysis: Effects of percutaneous coronary intervention versus medical therapy on angina relief. Ann Intern Med 2010;152:370-9.  Back to cited text no. 12
    
13.
Sedlis SP, Hartigan PM, Teo KK, Maron DJ, Spertus JA, Mancini GB, et al. Effect of PCI on long-term survival in patients with stable ischemic heart disease. N Engl J Med 2015; 373:1937-46.  Back to cited text no. 13
    
14.
Cairns JA. Ranolazine: Augmenting the antianginal armamentarium. J Am Coll Cardiol 2006; 48:576-8.  Back to cited text no. 14
    
15.
Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol 2004;43:1375-82.  Back to cited text no. 15
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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