Refractory angina

Graham Jackson
Consultant Cardiologist, Guy’s and St Thomas’ Hospitals NHS Trust,
Cardiothoracic Centre, St Thomas’ Hospital, London, UK

Correspondence: Dr Graham Jackson, Guy’s and St Thomas’ Hospitals NHS Trust,
Cardiothoracic Centre, 6th Floor East Wing, St Thomas’ Hospital, Lambeth Palace Road,
London SE1 7EH, UK. Tel: +44 20 7928 9292, fax: +44 20 7960 5680,
e-mail: lilian.crossley@gstt.sthames.nhs.uk

Abstract
Refractory angina implies that optimal use of all treatment modalities have been rigorously applied. This case study illustrates the importance of combining a metabolic approach to treatment with conventional hemodynamic agents enabling a satisfactory quality of life to be restored. n Heart Metabol. 2002;16:26–29.

Keywords: Refractory angina, trimetazidine

A 70-year-old woman was referred because of angina on minimal activity. She had undergone CABG surgery 10 years previously and had been well until 3 months prior to her clinic visit when her angina had returned. She was being treated with aspirin 75 mg daily, simvastatin 20 mg daily, bisoprolol 10 mg daily, nifedipine retard 20 mg twice daily, isosorbide mononitrate in a long-acting preparation 40 mg daily, and glyceryl trinitrate spray.
Clinical evaluation revealed normal sinus rhythm, blood pressure 135/80 mm Hg, no evidence of anemia, and no murmurs to suggest aortic valve disease. She was a non-insulin-dependent diabetic, well controlled on gliclazide 80 mg daily. Routine blood tests ruled out anemia (Hb 12 g/dL) and her lipids were reasonably well controlled (cholesterol 5.9 mmol/L, HDL 1.18 mmol/L, LDL 3.51 mmol/L, triglycerides 1.55 mmol/L). Her fasting glucose was 5.8 mmol/L and HbA1c 6%. Her ECG revealed anterolateral ischemia (Figure 1) and her echocardiogram ruled out valvular heart disease but suggested reduced left ventricular function with an ejection fraction of 35% to 40%.


Figure 1. ECG showing extensive antero-lateral ischaemia.

Because her symptoms were severe on conventional medical therapy she underwent coronary angiography. Unfortunately, extensive coronary artery disease was documented and none of her bypass grafts were patent (Figure 2).

Figure 2. Extensive CAD - not suitable for percutaneaous intervention or surgery.

 

Discussion with the surgeons and interventional cardiologists identified no possibility of further surgery or coronary angioplasty.
It was therefore decided to continue medical therapy. Simvastatin was increased to 40 mg daily to try to achieve an LDL cholesterol <3.0 mmol/L. She was continued on bisoprolol because of the evidence of both symptomatic and prognostic benefit, but, as it was in the optimum hemodynamic dose, oral nifedipine and isosorbide mononitrate were discontinued and trimetazidine 20 mg three times daily substituted [1]. The combined strategy of a hemodynamic and a metabolic agent led to symptomatic improvement. Once stable, perindopril was added to her therapy for prognostic reasons as her ejection fraction was less than 40% [2]. Though still limited by angina, her quality of life has improved and she continues to be stable, living contentedly with her restrictions. Her current LDL cholesterol is 2.6 mmol/L.

Comment
The mechanism of action of conventional antianginal drugs (b-blockers, calcium antagonists, oral nitrates, nicorandil) is to reduce myocardial oxygen demand by acting hemodynamically [3]. b-Blockers slow the heart rate, lower blood pressure, and reduce the inotropic state. Calcium antagonists, nitrates, and potassium channel activators (nicorandil), by acting as peripheral arterial and venous dilators to a variable degree, also reduce oxygen demand. Diltiazem and verapamil in addition slow the heart rate and reduce the inotropic state in a similar manner to that of b-blockers. This mechanism of benefit (reducing demand) outweighs any benefit from increasing blood supply by dilating the coronary arteries. When the maximum hemodynamic benefit has been achieved, for example by using optimal doses of b-blockers (atenolol 100 mg, not 50 mg), the addition of agents which act in a similar manner is unlikely to confer any further advantage. Judging optimal b-blockade relies on evidence from clinical trials which invariably involve peak exercise heart rate suppression as the benchmark for full b-blockade [4]. The resting heart rate is not an accurate guide. If a patient cannot tolerate full b-blockade, then combination therapy may be effective because the full hemodynamic option has not been maximized by monotherapy.
In his review of b-blockers and calcium antagonists in combination in stable angina, Packer [5] concluded:
“Evidence gathered from careful pharmacolo-
gic studies and controlled clinical trials does not support the concept that combined therapy with a ‚-blocker and a calcium-entry blocker produces additive or synergistic clinical benefits in most patients with coronary artery disease.”
Ferguson and colleagues [6] found no benefit from adding either nifedipine retard 20 mg twice daily or amlodipine 5 mg once daily to bisoprolol 10 mg daily in patients with chronic stable angina. Once more, these authors used optimal-dose b-blockade, maximizing the hemodynamic approach with, as a consequence, little chance of further benefit from adding other hemodynamic-acting agents.
Reviewing the literature in 1997, Thadani [7] concluded:
“Combination therapy with two or three agents is not always superior to optimal monotherapy.”
This view is supported by the results of two major trials (IMAGE [8], comparing metoprolol with nifedipine and its combination, and TIBET [9], comparing atenolol with nifedipine and its combination) in which, again, no additional benefits were demonstrated (Table I).

Table I. Trials suggesting combination hemodynamic therapy is of questionable value.

Studies that have suggested a possible benefit may have underdosed the b-blocker (eg, atenolol 50 mg daily in CESAR, a trial comparing amlodipine with diltiazem in addition to atenolol [10], and atenolol 50 mg or 100 mg in a study evaluating the addition of amlodipine to atenolol [11]), because adequate b-blockade was not defined.

Metabolic agents
In contrast to the negative findings of the abovementioned hemodynamic studies are the positive findings with the use of trimetazidine in combination with conventional therapy [11]. Trimetazidine does not have any hemodynamic effects, thus it offers a unique alternative approach to conventional therapy [12]. Clinical benefit has been shown in the management of stable angina in comparison with propranolol [13] and in addition to
b-blockade (which we would expect because of the different modes of action). Trimetazidine is also reported to be more effective than isosorbide dinitrate when added to propranolol [14]. In combination with diltiazem, trimetazidine favorably affects time to onset of ischemia [15].
Trimetazidine has a logical role in combination with hemodynamic agents because of its different mode of action. By using hemodynamic and metabolic agents in combination, we can optimize symptom relief for our patients with stable angina pectoris. Trimetazidine should be considered for all patients refractory to conventional hemodynamic agents.

Conclusions
– Metabolic agents combined with hemodynamic agents can significantly benefit patients with poorly controlled angina.
– A careful evaluation of other correctable exacerbating factors is essential.

REFERENCES 

1: Int J Clin Pract 2000 Jul-Aug;54(6):351 Related Articles, Books, LinkOut

Comment on:


Stable angina: maximal medical therapy is not the same as optimal medical therapy.

Jackson G.

Publication Types:

  • Comment
  • Editorial


PMID: 11092105 [PubMed - indexed for MEDLINE]

 
2: N Engl J Med 1992 Sep 3;327(10):669-77 Related Articles, OMIM, Books, LinkOut

Comment in:


Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators.

Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, et al.

Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.

BACKGROUND. Left ventricular dilatation and dysfunction after myocardial infarction are major predictors of death. In experimental and clinical studies, longterm therapy with the angiotensin-converting--enzyme inhibitor captopril attenuated ventricular dilatation and remodeling. We investigated whether captopril could reduce morbidity and mortality in patients with left ventricular dysfunction after a myocardial infarction. METHODS. Within 3 to 16 days after myocardial infarction, 2231 patients with ejection fractions of 40 percent or less but without overt heart failure or symptoms of myocardial ischemia were randomly assigned to receive doubleblind treatment with either placebo (1116 patients) or captopril (1115 patients) and were followed for an average of 42 months. RESULTS. Mortality from all causes was significantly reduced in the captopril group (228 deaths, or 20 percent) as compared with the placebo group (275 deaths, or 25 percent); the reduction in risk was 19 percent (95 percent confidence interval, 3 to 32 percent; P = 0.019). In addition, the incidence of both fatal and nonfatal major cardiovascular events was consistently reduced in the captopril group. The reduction in risk was 21 percent (95 percent confidence interval, 5 to 35 percent; P = 0.014) for death from cardiovascular causes, 37 percent (95 percent confidence interval, 20 to 50 percent; P less than 0.001) for the development of severe heart failure, 22 percent (95 percent confidence interval, 4 to 37 percent; P = 0.019) for congestive heart failure requiring hospitalization, and 25 percent (95 percent confidence interval, 5 to 40 percent; P = 0.015) for recurrent myocardial infarction. CONCLUSIONS. In patients with asymptomatic left ventricular dysfunction after myocardial infarction, long-term administration of captopril was associated with an improvement in survival and reduced morbidity and mortality due to major cardiovascular events. These benefits were observed in patients who received thrombolytic therapy, aspirin, or beta-blockers, as well as those who did not, suggesting that treatment with captopril leads to additional improvement in outcome among selected survivors of myocardial infarction.

Publication Types:

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 1386652 [PubMed - indexed for MEDLINE]

 
3: Br Heart J 1978 Sep;40(9):998-1004 Related Articles, Books, LinkOut

Comparison of atenolol with propranolol in the treatment of angina pectoris with special reference to once daily administration of atenolol.

Jackson G, Harry JD, Robinson C, Kitson D, Jewitt DE.

Fourteen patients with angina pectoris completed a double blind trial of atenolol 25 mg, 50 mg, and 100 mg twice daily and propranolol 80 mg thrice daily. In comparison with placebo, all active treatments significantly reduced anginal attacks, consumption of glyceryl trinitrate, resting and exercise heart rate, resting and exercise systolic blood pressure, and significantly prolonged exercise time. There was no significant difference between the effects of propranolol and atenolol. Nine patients completed a further trial comparing atenolol given once or twice daily. Both regimens were effective and there was no significant difference between the reductions in anginal attacks, glyceryl trinitrate consumption, systolic blood pressure, or heart rate. Twenty-four-hour ambulatory electrocardiograms showed that atenolol consistently reduced heart rate throughout the 24-hour period whether given once or twice daily. Atenolol is a potent antianginal agent which, in most patients, is likely to be effective once daily.

Publication Types:
  • Clinical Trial
  • Controlled Clinical Trial


PMID: 101223 [PubMed - indexed for MEDLINE]

 
4: Lancet 1991 Oct 26;338(8774):1036-9 Related Articles, Books, LinkOut

Comment in:


Efficacy of nifedipine and isosorbide mononitrate in combination with atenolol in stable angina.

Akhras F, Jackson G.

Cardiac Department, Guy's Hospital, London, UK.

Many patients with angina pectoris whose symptoms are not completely controlled by beta-blockers are treated with several types of drugs, but it is not clear whether addition of a calcium-channel antagonist and/or a nitrate confers any advantage over beta-blockade alone. 18 patients receiving atenolol for stable angina pectoris completed a double-blind, randomised, crossover trial of atenolol treatment plus placebo, isosorbide mononitrate, nifedipine, and mononitrate and nifedipine (triple therapy). The patients were assessed subjectively and by treadmill exercise testing and 24 h ambulatory electrocardiographic recordings at the end of each 4-week treatment period. There were no significant differences among the treatment periods in angina attack rates, glyceryl trinitrate consumption, exercise duration to onset of angina or 1 mm ST depression, or duration of symptomless ischaemia. Total exercise duration was longer on atenolol plus mononitrate than on atenolol alone (mean difference 46 [95% confidence interval 18-88] s; p = 0.005), atenolol plus nifedipine (36 [2-71] s; p = 0.04), or triple therapy (28 [6-61] s; not significant). In 12 patients the exercise time was shorter on triple therapy than on atenolol plus mononitrate alone. Although "maximum" antianginal treatment with two or three drugs is commonly accepted, this approach confers no substantial advantage over optimum beta-blockade as monotherapy. If a second drug is needed, there is a slight advantage in favour of isosorbide mononitrate, but if this is not effective, treatment should be changed rather than added. Many patients with angina pectoris seem to be pharmacologically overtreated.

Publication Types:

  • Clinical Trial
  • Randomized Controlled Trial


PMID: 1681355 [PubMed - indexed for MEDLINE]

 5. Packer M. Combined beta-adrenergic and calcium-entry blockade in angina pectoris. N Engl J Med. 1989;320:708–718. 

6: Int J Clin Pract 2000 Jul-Aug;54(6):360-3 Related Articles, Books, LinkOut

Comment in:


Bisoprolol alone and in combination with amlodipine or nifedipine in the treatment of chronic stable angina.

Ferguson JD, Ormerod O, Lenox-Smith AJ.

Department of Cardiology, John Radcliffe Hospital, Oxford, UK.

Beta-blockers and calcium antagonists are both effective monotherapy for stable angina. When symptoms persist, these two agents are commonly co-prescribed in the hope that this combination has added benefit compared with monotherapy alone. We investigated the additional efficacy of the calcium antagonists amlodipine and nifedipine when added to bisoprolol in patients with stable angina. Patients were randomised in a multicentre, single-blind study, with crossover of three treatments consisting of bisoprolol 10 mg once daily, bisoprolol plus nifedipine 20 mg twice daily, and bisoprolol plus amlodipine 5 mg once daily. Exercise tests were performed at the end of each four-week study period and the exercise time to onset of angina was assessed. A total of 198 patients from 17 centres were recruited of whom 147 were evaluable for efficacy. There were no statistically significant differences in exercise duration to onset of angina between any of the groups. The combination of bisoprolol plus nifedipine was least well tolerated. In summary, this study suggests there is little benefit in adding a calcium antagonist to bisoprolol in treating patients with stable angina.

Publication Types:

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 11092108 [PubMed - indexed for MEDLINE]

 
7: Am J Cardiol 1997 Jun 26;79(12B):24-30 Related Articles, Books, LinkOut

Management of patients with chronic stable angina at low risk for serious cardiac events.

Thadani U.

Cardiovascular Department, University of Oklahoma-HSC, Oklahoma City 73104, USA.

Successful management of the patient with chronic stable angina requires correct stratification by assessing the risk of future coronary events. Patients at low risk for such events have a relatively good prognosis; revascularization procedures (balloon angioplasty or surgery) offer no benefit over medical management. Such patients should be offered medical therapy as their first option. The goals in management of chronic stable angina are (1) treatment of other conditions that may worsen angina; (2) treatment with aspirin and modification of risk factors for coronary artery disease (CAD) to improve outcome; and (3) effective relief of anginal symptoms. Most patients with stable angina will have CAD. It is well established that treatment with aspirin and modification of risk factors for CAD are beneficial in reducing cardiovascular mortality and morbidity. Blood pressure reduction, lowering of blood cholesterol level, and smoking cessation are interventions of proven value and appear to correct defects (at least partially) in the endothelial function of the coronary blood vessels. Other interventions that are helpful are estrogen replacement treatment in postmenopausal women, and low-dose aspirin therapy-which is recommended for all patients who can tolerate it. For controlling symptoms and improving angina-free walking time, nitrates, beta blockers, and calcium channel antagonists are efficacious as first-line monotherapy for chronic stable angina in this group of patients. Nitrates may be of special use in patients with impaired left ventricular function, overt congestive heart failure, intermittent coronary vasoconstriction, or coronary artery spasm. In patients with concomitant hypertension or supraventricular tachycardia, beta blockers are helpful. Calcium channel antagonists may be useful in patients with chronic obstructive pulmonary disease, peripheral vascular disease, or hypertension. When optimal monotherapy with a given class of drug fails to control symptoms, alternative monotherapy with a different class of agent should be tried before combination therapy. Combination therapy with 2 or 3 agents is not always superior to optimal monotherapy. Patients who fail to respond to adequate medical therapy should be considered for a revascularization procedure.

Publication Types:
  • Review
  • Review Literature


PMID: 9223354 [PubMed - indexed for MEDLINE]

 8. Savonitto S, Ardissino D, Egstrup K, et al. Combination therapy with metoprolol and nifedipine versus monotherapy in patients with stable angina pectoris. J Am Coll Cardiol. 1996;27:311–316. 

9: Eur Heart J 1996 Jan;17(1):96-103 Related Articles, Books, LinkOut

The Total Ischaemic Burden European Trial (TIBET). Effects of atenolol, nifedipine SR and their combination on the exercise test and the total ischaemic burden in 608 patients with stable angina. The TIBET Study Group.

Fox KM, Mulcahy D, Findlay I, Ford I, Dargie HJ.

Royal Brompton Hospital, London, UK.

OBJECTIVES: To determine the effects of atenolol, nifedipine and their combination on exercise parameters and ambulatory ischaemic activity in patients with mild chronic stable angina. SETTING: Multicentre, multinational study involving 608 patients from 69 centres in nine countries. DESIGN: Placebo washout followed by double-blind parallel-group study comparing atenolol 50 mg bd, nifedipine SR 20 mg bd, and their combination. Patients underwent maximal exercise testing using either a bicycle (n = 289) or treadmill (n = 319) and 48 h of ambulatory ST segment monitoring outside the hospital environment at the end of the placebo washout period and after 6 weeks of active therapy. RESULTS: Both medications alone and in combination caused significant improvements in exercise parameters and significant reductions in ischaemic activity during daily activities, when compared with placebo. There were, however, no significant differences between groups, for any of the measured ischaemic parameters although combination therapy resulted in a greater fall in resting systolic and diastolic blood pressure than either treatment alone. CONCLUSIONS: In the management of mild chronic stable angina there appears to be little advantage gained from using combination therapy for ischaemia reduction.

Publication Types:
  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 8682138 [PubMed - indexed for MEDLINE]

 
10: Am J Cardiol 1998 Jan 15;81(2):133-6 Related Articles, Books, LinkOut
Click here to read
Amlodipine versus diltiazem as additional antianginal treatment to atenolol. Centralised European Studies in Angina Research (CESAR) Investigators.

Knight CJ, Fox KM.

Royal Brompton Hospital, London, England.

The antianginal efficacy and tolerability of amlodipine and diltiazem were compared in a double-blind randomized trial of 97 patients with angina resistant to atenolol alone. Both amlodipine and diltiazem significantly reduced the frequency of angina attacks (p <0.001) and glyceryl trinitrate consumption (p <0.05 to p <0.01). During Holter monitoring, both treatments reduced the overall frequency of ambulatory myocardial ischemia, although changes did not reach statistical significance. Exercise test parameters (total exercise time, time to angina, time to ST depression, and maximum ST depression) tended to improve with both treatments, but changes did not achieve statistical significance relative to baseline or to each other. Both drugs were generally well tolerated. Adverse events occurred in 15 patients in the amlodipine group (30%) and in 17 patients in the diltiazem group (36%), but patients taking diltiazem reported almost twice as many adverse events (30) patients taking amlodipine (18). Quality of life, as assessed by total Nottingham Health Profile Scores, was not significantly different between treatments. The addition of either once-daily amlodipine or twice-daily sustained release diltiazem improved symptoms in patients with angina resistant to atenolol alone, but diltiazem was associated with more frequent and more serious adverse events.

Publication Types:
  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 9591893 [PubMed - indexed for MEDLINE]

 
11: Am J Cardiol 1998 Jan 15;81(2):128-32 Related Articles, Books, LinkOut
Click here to read
Value of the addition of amlodipine to atenolol in patients with angina pectoris despite adequate beta blockade.

Dunselman PH, van Kempen LH, Bouwens LH, Holwerda KJ, Herweijer AH, Bernink PJ.

Department of Clinical Pharmacology, University of Groningen, The Netherlands.

Anginal patients who remain symptomatic despite optimally dosed beta blockade may also be given dihydropyridine calcium antagonists. This treatment regimen was examined in a double-blind parallel, randomized, controlled study in 147 patients with angina and positive bicycle exercise tests despite optimal beta blockade with atenolol (heart rate at rest <60 beats/min). Patients were randomized to atenolol and/or placebo (control), and atenolol and/or amlodipine. The main outcome measurement was exercise tolerance after 8 weeks compared with baseline. After 8 weeks, no significant differences in time to 0.1-mV ST-segment depression, time to chest pain, and time to end of exercise were observed. The number of patients with chest pain during exercise decreased significantly in the amlodipine group (p = 0.04 vs controls). The subgroup of patients with an early (<6 minutes) onset of chest pain at baseline showed a significant increase in time to chest pain after amlodipine (p = 0.0001 vs controls). In the amlodipine group, ST depression and rate-pressure product at submaximum comparable workload decreased to 0.4 mm (0.56) (p = 0.03 vs controls) and 1.223 (2.652) beats/ min x mm Hg (p = 0.01 vs controls). The number of patients in each group with adverse events was not different. The addition of amlodipine to the treatment of patients with myocardial ischemia, despite optimal beta blockade, is well tolerated and may lead to improvement in symptomatic anginal patients, who have a rapid onset of exercise-induced ischemia.

Publication Types:
  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 9591892 [PubMed - indexed for MEDLINE]

 
12: Br J Clin Pharmacol 1994 Mar;37(3):279-88 Related Articles, Books, LinkOut

Trimetazidine: a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Trimetazidine European Multicenter Study Group.

Detry JM, Sellier P, Pennaforte S, Cokkinos D, Dargie H, Mathes P.

Saint-Luc University Hospital, Brussels, Belgium.

1. Trimetazidine has a direct anti-ischaemic effect on the myocardium without altering the rate x pressure product or coronary blood flow. 2. The effects of trimetazidine (20 mg three times daily) were compared with those of propranolol (40 mg three times daily) in a double-blind parallel group multicentre study in 149 men with stable angina. 3. Reproducibility of exercise performance was verified during a 3 week run-in placebo washout period. All patients had > 1 mm ST-depression on exercise test. 4. After 3 months, similar anti-anginal efficacy was observed between the trimetazidine (n = 71) and propranolol (n = 78) groups. No significant differences were observed between trimetazidine and propranolol as regards anginal attack rate per week (mean difference P-TMZ: 2; 95% CI: -4.4, 0.5) and exercise duration (mean difference P-TMZ: 0 s; 95% CI: -33, 34) or time to 1 mm ST segment depression (mean difference P-TMZ: 13 s; 95% CI: -24, 51). Heart rate and rate x pressure product at rest and at peak exercise remained unchanged in the trimetazidine group but significantly decreased with propranolol (P < 0.001 in all cases). With both drugs there was a trend to decreased ischaemic episodes in the 46% patients who experienced ambulatory ischaemia on Holter monitoring. Six patients stopped trimetazidine and 12 propranolol. Of these, five in each group were withdrawn because of deterioration in cardiovascular status. 5. The results suggest that trimetazidine and propranolol at the doses studied have similar efficacy in patients with stable angina pectoris.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication Types:
  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 8198938 [PubMed - indexed for MEDLINE]

13. Michaelides AP, Vyssoulis GP, Bonoris PB. Beneficial effects of trimetazidine in men with stable angina under beta blocker treatment. Curr Ther Res. 1989;46:1179–1190.
14. Michaelides AP, Spiropoulos K, Dimopoulos K, et al. Trimetazidine-propranolol compared with isosorbide dinitrate-propranolol in patients with stable angina. Clin Drug Invest. 1997;13(1):8–14.

15: Am J Cardiol 1995 Aug 24;76(6):12B-16B Related Articles, Books, LinkOut

Combination therapy of trimetazidine with diltiazem in patients with coronary artery disease. Group of South of France Investigators.

Levy S.

Division of Cardiology, Hopital Nord, University of Marseille School of Medicine, France.

The efficacy of trimetazidine, an antianginal agent with a direct effect on ischemic myocardium, has been tested alone or in combination with beta blockers or nifedipine. The combination with diltiazem, a widely used calcium antagonist, has not been studied. The aim of this study was to evaluate the potential benefit of oral trimetazidine (20 mg 3 times daily) in combination with oral diltiazem (60 mg three times daily). This was a multicenter, placebo-controlled study with a follow-up period of 6 months. Patients with stable angina and a positive exercise electrocardiogram before and after 15 days of diltiazem therapy were included. The 67 patients were randomized to diltiazem plus placebo (group I, 35 patients) and diltiazem plus trimetazidine (group II, 32 patients). Follow-up included a bicycle ergometer maximal exercise test and a physical examination at inclusion and at 3 and 6 months. The 2 groups were similar in terms of ergometric parameters, except for the ischemic threshold, defined as the time to 1-mm ST-segment depression. The latter was shorter in group II. Comparison of exercise tests performed at inclusion and after 6 months of therapy in both groups showed that the ischemic threshold was significantly prolonged (2 minutes 41 seconds; p < 0.001) in group II. This was not the case for group I, which showed a 41-second prolongation only (difference not significant). The work (kPM) produced at 1-mm ST-segment depression was also significantly increased in group II (1,445.9 kPM; p < 0.001) compared with group I (563.7 kPM; p = 0.012).(ABSTRACT TRUNCATED AT 250 WORDS)

Publication Types:
  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 7645522 [PubMed - indexed for MEDLINE]

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