European Journal of Cardiovascular Medicine

Chronic stable angina is the most prevalent manifestation of ischemic heart disease and its management is a priority. Stable angina pectoris is caused by a mismatch between the demand and supply of oxygen to myocardium due to obstruction in epicardial coronary arteries [1]. Major risk factors for angina include cigarette smoking, diabetes, high cholesterol, high blood pressure, sedentary lifestyle, and family history of ischemic heart disease. During periods of angina, depression or elevation of the ST segment may be observed [2]. To elicit these changes, an exercise ECG test (Treadmill test) may be performed, during which the patient exercises to his/her maximum ability before fatigue, breathlessness, or chest pain intervenes. More than 1 mm of flat or down-sloping ST depression in the ECG is considered diagnostic for ischemic etiology of chest pain. The 2013 European Society of Cardiology guidelines on the management of stable coronary artery disease proposed the use of β-blockers, Calcium-channel blockers and short-acting Nitrates as first-line treatment. If angina persist, then long-acting Nitrates, Ivabradine, Trimetazidine, Ranolazine and Nicorandil are recommended.

Trimetazidine inhibits the oxidation of fatty acids by selectively blocking 3-ketoacyl-CoA thiolase enzyme. This enzyme is involved in the β-oxidation of fatty acids in myocardial cells, and enhances glucose oxidation. Glucose oxidation requires less oxygen consumption in ischemic myocardial cells. Thus, Trimetazidine optimizes the energy utilization of myocardial cells, and maintains a proper energy supply during ischemia. Other possible effects have also been proposed to explain Trimetazidine’s anti-anginal mechanism such as- decreased production of superoxide free radicals; reduced neutrophil-mediated cardiac reperfusion injury; a direct effect on cardiac fast sodium current; decreased cardiac levels of malondialdehyde (a biomarker for oxidative stress), leading to an improvement in endothelial function [3-9].

Ranolazine is a late inward sodium channel inhibitor. Myocardial oxygen supply and demand mismatch is thought to result in increase in late sodium current with subsequent increase in intracytoplasmic calcium content which results in diastolic dysfunction. By inhibiting this ischemic cascade induced by late sodium current, Ranolazine has been shown to be effective in the treatment of anginal symptom in patients with coronary artery disease [10].

The Seattle Angina Questionnaire-7 (SAQ-7) is a commonly used instrument for measuring health status in patients with CAD. SAQ-7 has 3 domains that directly measure patient’s current health status: Physical Limitation, Angina Frequency and Quality of Life. Scores are generated for each domain and are scaled 0 to 100, with 0 denoting the worst and 100 the best possible status. The SAQ Angina Frequency score of 0 to 30 translate to daily angina, 31 to 60 to weekly angina, 61 to 99 to monthly angina and 100 to no angina[11]. The SAQ Quality of life domain score of 0 to 24 represents poor health status, 25 to 49 as fair, 50 to 74 as good, and 75 to 100 as excellent [12].

Trimetazidine and Ranolazine are the most commonly used add-on drugs in patients with stable angina. But there are no specific guidelines as to which drug- Trimetazidine or Ranolazine - should be preferred as add-on therapy in patients with stable angina. Also, there is lack of study in the present scenario comparing the 2 drugs. So, we did this study to compare Trimetazidine and Ranolazine to see which drug is better in terms of increasing exercise duration and quality of life in patients with uncontrolled stable angina.

AIM & OBJECTIVES

Aim

To compare Trimetazidine and Ranolazine as add-on therapy in patients with stable angina

Objectives

Primary objective of the study was to compare total duration of tolerable exercise (in seconds) in patients with stable angina who are taking Trimetazidine as add-on therapy with that of those taking Ranolazine as add-on therapy using Treadmill test (TMT). Secondary objective was to compare the quality of life in patients with stable angina who are taking Trimetazidine as add-on therapy with those who are taking Ranolazine as add-on therapy using Seattle Angina Questionnaire-7 (SAQ-7)

It was a comparative, 2 group, single center, observational study. The patients were recruited from Cardiology out-patient department of Dr. RMLIMS, Lucknow while TMT was done in Department of Pharmacology of Dr. RMLIMS. The study was done from December 2022 to May 2024. Based on intensive literature review and taking Koylan et al [13] as a reference study, at 95% confidence interval and 80% power, the final sample size was calculated as 70 participants in each group. The study was conducted after getting approval from the Institutional Ethics Committee (IEC No. 116/22).

Inclusion and exclusion criteria:

Patients of either gender, aged between 18-70 years with stable angina symptoms for at least 3 months duration who were already on first line antianginal medications were started on either Trimetazidine or Ranolazine as add-on therapy by the treating physician within last 1 week, were eligible to participate in the study, if they provided a written informed consent.

Patients with chest pain at rest, recent MI, hemodynamic or electrical instability, severe aortic stenosis, symptomatic heart failure, significant lung disease, myocarditis or pericarditis, aortic dissection or history of allergy to any of the 2 medications were excluded from the study. Pregnant and lactating women, patients who are unable to walk on treadmill and those who were not available for follow-up at 1 month were also excluded from the study.

Flowchart of work:

Statistical Analysis:

All continuous values were summarized as Mean  SD. Risk factors and Treatment history were presented as percentages and compared using the Chi-square (χ²) or Fisher exact test. General characteristics, Treadmill test parameters of the Trimetazidine and Ranolazine group were compared by applying independent t test. A p-value < 0.05 was considered as statistically significant. Statistical analysis was performed using R statistical software (R-4.3.3 version).

A total of 140 patients were recruited in this study with 70 patients each in Group-A (Trimetazidine group) and Group-B (Ranolazine group). 6 patients lost-to-follow-up in both the groups and were excluded from the study. So final data analysis was performed with 64 patients each in Group-A (Trimetazidine group) and Group-B (Ranolazine group).

Fig-1: Flowchart showing distribution of patients in both the groups

Table-1: General characteristics of the patients

Demographic data of the study participants is shown in Table-1. General characteristics were well matched between the 2 groups. Out of 64 patients in Group-A (Trimetazidine group), 48 were males and 16 were females while in Group-B (Ranolazine group), 52 were males and 12 were females. Middle aged men were the most frequent group. No statistically significant difference was seen between Trimetazidine group and Ranolazine group in their age and BMI distribution.

Baseline antianginal medications were similar between the 2 groups, with 100% patients taking Nitrates, β-blockers, Aspirin and Statins. 12.5 % patients were taking calcium channel blockers (CCB) in Group-A and Group-B.  ACEI / ARB were prescribed in 37.5 % in Group-A and 53.1 % in Group-B.

Table-2: Risk factors and co-morbidities of the patients

* Fisher-exact test was used

Table-2 shows that Dyslipidemia was the most common risk factor (93.7 % in Group-A and 84.4 % in Group-B) followed by Hypertension (71.8 % in both Group-A and Group-B) and Diabetes (50 % in Group-A and 40.6 % in Group-B). Risk factors were well matched in Group-A and Group-B.

Table-3: Treadmill Test (TMT) parameters of the patients

Figure-2: Bar diagram showing mean exercise duration in TMT at baseline a and after 1 month in Trimetazidine and Ranolazine group

Table-3 and Figure-2 shows that at baseline, the mean exercise duration in TMT was well matched in Group-A and Group-B and there was no statistically significant difference between both the groups (p=0.716). After 1 month of therapy, the mean exercise duration in TMT was significantly higher in Group-B as compared to Group-A (p < 0.001). Exercise capacity as measured in METs in TMT was well matched in Group-A and Group-B at baseline, but after 1 month of therapy, a significantly higher Mets were achieved in Group-B as compared to Group-A (p=0.009).

Table-4: SAQ7-AF & SAQ7-QoL score of the patients

Table-4 and Figure-3 show that at baseline, mean SAQ7-AF score was well matched in Group-A and Group-B and there was no statistically significant difference between both the groups (p=0.108). After 1 month of therapy, the mean SAQ7-AF score was significantly higher in Group-B as compared to Group-A (p < 0.001). Secondary end point of mean SAQ7-QoL score was well matched in Group-A and Group-B at baseline (p=0.073). After 1 month of therapy, the mean SAQ7-QoL score was significantly higher in Group-B as compared to Group-A           (p < 0.001)

Figure-3: Bar diagram showing mean SAQ7-QoL score at baseline and after 1 month I in Trimetazidine and Ranolazine group

The treatment of stable angina has two major purposes. Firstly, to prevent myocardial infarction (MI) and death and, secondly, to reduce symptoms of angina. Conventional pharmacotherapy of myocardial ischemia targets both and covers three different approaches: decreasing oxygen demand by β-adrenergic blockade, improvement of myocardial flow and oxygen delivery by nitrates and calcium channel blockers and limitation of platelet-endothelium interaction [14]. A novel approach in this setting is the use of cellular anti-ischemic agents like Trimetazidine and Ranolazine which are used as add-on therapy in patients with stable angina [15]. In this study, our aim was to compare the effects of Trimetazidine with Ranolazine on exercise performance and quality of life in patients with stable angina. To the best of our knowledge, this is the first study in Indian set-up comparing Trimetazidine and Ranolazine as add-on therapy in patients with stable angina.

In a double-blind, parallel group, multi-centre, prospective study by Koylan et al[13], Trimetazidine was compared with Diltiazem in patients with stable angina. A total of 116 male patients with documented coronary artery disease at 11 center were randomized into Trimetazidine and Diltiazem groups. The study consisted of a two-week placebo washout period and a four-week active treatment phase. Clinical examinations and exercise tests were performed at the beginning (Day 0) and at the end (Day 28) of the active treatment. Both trimetazidine and diltiazem decreased the number of anginal attacks per week (p < 0.0001 for both drugs) and weekly nitrate consumption (p = 0.0008 and p < 0.0001, respectively). Both trimetazidine and diltiazem improved the recovery of anginal pain (p = 0.0188 and p = 0.0079, respectively) and maximal ST-segment depression (p = 0.0134 and p = 0.0214, respectively) but none of the drugs significantly changed the time to 1 mm ST-segment depression and ST recovery time on exercise test. This study suggested that Trimetazidine is an effective and safe alternative for Diltiazem in the treatment of patients with stable angina.

In a double-blind, parallel group, multi-centre, prospective study by Detry et al[16], Trimetazidine was compared with Propranolol in patients with stable angina. Reproducibility of exercise performance was verified during a 3 week run-in placebo washout period. After 3 months, similar anti-anginal efficacy was observed between Trimetazidine and Propranolol groups. No significant differences were observed between Trimetazidine and Propranolol groups in anginal attack rate per week and exercise duration or time to 1mm ST segment depression. Heart rate and rate-pressure product at rest and at peak exercise remained unchanged in the Trimetazidine group but significantly decreased with Propranolol (p < 0.001). With both drugs there was a decrease in anginal episode in 46% patients who experienced ambulatory ischaemia on Holter monitoring. The result of this study suggested that Trimetazidine and Propranolol have similar efficacy in patients with stable angina.

The strengths of this study were- It is the first study in Indian population comparing Trimetazidine and Ranolazine as add-on therapy in patients with stable angina. There was a head-to-head comparison between the 2 drugs. A validated questionnaire was used to compare the quality of life between the 2 drugs. Lastly, objective criteria of exercise duration in seconds was used.

Although it is the first study of its kind but there are few limitations. Our study was observational, single-centric study of short duration, so the results cannot be generalized to all populations. Therefore, a large, multicentric, prospective study of longer duration can be done to confirm the findings of this study.

Improvement in anginal symptoms is an important target in management of stable coronary artery disease. The present study compared role of Trimetazidine as compared to Ranolazine for symptom control in stable CAD patients. This study suggests that Ranolazine may be superior to Trimetazidine as add-on therapy in patients with stable angina in terms of improvement in exercise duration and quality of life.

Author Contributions

All authors have reviewed the final version to be published and agreed to be accountable for all aspects of the work

Concept and design: Siddhant Lohia, Atul Jain, Ashish Jha, Arpita Singh, Pooja Shukla, Bhuwan C Tiwari, Joonmoni Lahon

Acquisition, analysis or interpretation of data: Siddhant Lohia, Atul Jain, Ashish Jha, Arpita Singh, Pooja Shukla, Bhuwan C Tiwari, Joonmoni Lahon

Drafting of the manuscript: Siddhant Lohia, Atul Jain, Ashish Jha, Arpita Singh, Pooja Shukla, Bhuwan C Tiwari, Joonmoni Lahon

Critical review of the manuscript for important intellectual content: Siddhant Lohia, Atul Jain, Ashish Jha, Arpita Singh, Pooja Shukla, Bhuwan C Tiwari, Joonmoni Lahon

Supervision: Siddhant Lohia, Atul Jain, Ashish Jha, Arpita Singh, Pooja Shukla, Bhuwan C Tiwari, Joonmoni Lahon

Disclosures

Human subjects: Consent was obtained by all participants in this study

Animal subjects: All authors have confirmed that that this study did not involve animal subjects or tissue

Conflict of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:

Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.                                        

Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.                                                                                                                                      

Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

1. Fuchs RM, Becker LC. Pathogenesis of angina pectoris. Archives of Internal Medicine 1982; 142 (9): 1685-1692
2. Duprez DA. Angina in the elderly. European Heart Journal 1996; 17: 8-13
3. Guarnieri C, Muscari C. Beneficial effects of trimetazidine on mitochondrial function and superoxide production in the cardiac muscle. Cardiovascular Drugs and Therapy 1990; 4 (Suppl. 4): 814–815
4. Coetzee WA, Enous R, Opie LH. Trimetazidine: effects on delayed after depolarizations (DADs) and upstroke velocity of the action potential. Cardiovascular Drugs and Therapy 1990; 4 (Supple 4): 806–807
5. Guarnieri C, Muscari C. Effect of trimetazidine on mitochondrial function and oxidative damage during reperfusion of ischemic hypertrophied rat myocardium. Pharmacology 1993; 46 (6): 324–331
6. Tritto I, Wang P, Kuppusamy P, Giraldez R, Zweier JL, Ambrosio G. The anti-anginal drug trimetazidine reduces neutrophil-mediated cardiac reperfusion injury. Journal of Cardiovascular Pharmacology 2005; 46 (1): 89–98
7. Lavanchy N, Martin J, Rossi A. Anti-ischemic effects of trimetazidine: 31P-NMR spectroscopy in the isolated rat heart. Archives Internationales de Pharmacodynamie et de Therapie 1987; 286 (1): 97–110
8. Lagadic-Gossmann D, Le Prigent K, Feuvray D. Effects of trimetazidine on pH regulation in the rat isolated ventricular myocyte. British Journal of Pharmacology 1996; 117 (5): 831–838
9. Feener EP, King GL. Endothelial dysfunction in diabetes mellitus: role in cardiovascular disease. Heart Failure Monitor 2001; 1 (3): 74–82
10. Hasenfuss G, Maier LS. Mechanism of action of the new anti-ischemia drug ranolazine. Clinical Research in Cardiology 2008; 97 (4): 222-226
11. Arnold SV, Kosiborod M, Li Y, et al. Comparison of the Seattle Angina Questionnaire With Daily Angina Diary in the TERISA Clinical Trial. Circulation Cardiovascular Quality and Outcomes 2014; 7 (6): 844–850
12. Patel KK, Arnold SV, Chan PS, et al. Validation of the Seattle angina questionnaire in women with ischemic heart disease. American Heart Journal 2018; 201: 117–123
13. Koylan N, Bilge AK, Adalet K, Mercanoglu F, Buyukozturk K. Comparison of the effects of trimetazidine and diltiazem on exercise performance in patients with coronary heart disease. The Turkish trimetazidine study (TTS). Acta Cardiologica 2004; 59 (6): 644–650
14. Gibbons RJ, Chatterjee K, Levy D, Daley J, Douglas JS, Fihn SD, Gardin JM, Grunwald MA, Lytle BW, O’Rourke RA, Schafer WP, Williams SV, Ritchie JL, Cheitlin MD, Eagle KA, Gardner TJ, Garson A Jr, Russel RO, Ryan TJ, Smith SC Jr.                 Guidelines for the Management of Patients With Chronic Stable Angina. Journal of American College of Cardiology 1999; 33 (7): 2092-2097
15. Jackson G. The place of metabolic agents in the management of stable angina pectoris. Revista Portuguesa de Cardiologia 1999; 18 (4): 23-27
16. Detry JM, Sellier P, Pennaforte S, Cokkinos D, Dargie H, Mathes P. Trimetazidine: a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Trimetazidine European Multicenter Study Group. British Journal of Clinical Pharmacology 1994; 37: 279–288