The benefits offered to coronary patients by FLAVEDON have been shown by double-blind trials, versus placebo and versus reference drugs, both as monotherapy and in combination.

FLAVEDON is the only antianginal agent which simultaneously offers 4 major advantages for the treatment of coronary patients.

• Its antianginal efficacy, not only fast (less than two hours)(20) but marked, equivalent to that of a ß-blocker(19) and that of a calcium antagonist:(21)
  
  
  • reduced frequency and severity of angina attacks,
    
  • parallel decrease in fast-acting trinitroglycerin consumption,
    
  • prolongation of time to onset of ST-segment depression,
    
  • gain of one or more exercise levels by virtue of:
    - increased coronary reserves,
    - improved myocardial adaptation to exercise,
    
  • increased exercise duration,
    
  • increased total work productivity during exercise test without myocardial injury.
    

Even at the final stage of coronary heart disease, in ischemic cardiomyopathy with severe heart failure, when used in combination with classical treatment for heart failure, FLAVEDON enables the conservation of cardiac function. Classical treatment alone is insufficient to prevent progression of the disease.

• This efficacy combines in its entirety with that of hemodynamic antianginal drugs, since its metabolic mechanism of action eliminates any possibility of overlap.In coronary patients inadequately controlled by other antianginal treatment, the addition of FLAVEDON results in added efficacy to a similar extent to that obtained with FLAVEDON used as monotherapy.

As a result, FLAVEDON offers the possibility of reducing the dose of certain combined drugs such as long-acting nitrates and calcium antagonists, or even of eliminating them altogether, thereby decreasing or eliminating their adverse effects, with the assurance of at least equal effectiveness.

• Its very good safety/acceptability: FLAVEDON is free of adverse effects.
  In addition, FLAVEDON is extremely safe:
  
  
  • FLAVEDON has no contraindications, and can therefore be prescribed even when other antianginal agents are contraindicated.
    
  • No drug interaction has been reported. FLAVEDON can be used in polymedicated patients, and in the context of any treatment regimen whatsoever.
    
    
• FLAVEDON is the only cytoprotective antianginal agent and thus provides constant myocardial protection against ischemia, regardless of the cause and even in situations of extreme ischemia.

In summary, FLAVEDON is a first line metabolic treatment of angina pectoris which:

• increases the exercise and physical activity capacities of the coronary artery disease patient,
  
• without myocardial injury,
  
• never overlapping with hemodynamic agents used in combination,
  
• with an excellent tolerability,
  
• and is the only cytoprotective antianginal agent. In other words, it is the only antianginal agent to have a powerful protective effect on the myocardium of coronary patients, regardless of the cause of ischemia.

FLAVEDON was compared with a ß-blocker in a double-blind European multicenter versus propranolol.(19)

• Protocol:
  This trial (TEMS: Trimetazidine European Multicenter Study)(19) was undertaken by 19 major European cardiology centers, involving 149 patients with severe coronary disease and treated, after one week of treatment washout and 2 weeks of placebo, with either FLAVEDON or propranolol for 3 months. Initial doses were FLAVEDON and propranolol 40 mg tid, with the possibility of treatment adjustment (decrease or increase by one tablet per day) after 2 weeks on the basis of clinical criteria.
  
  
• Results:
  FLAVEDON proved to be as effective as the ß-blocker, both in terms of angina attacks as well as exercise test parameters (total work, exercise duration, degree of ST-segment depression at maximum exercise, time to onset of 1 mm ST-segment depression). There were no statistically significant differences between the two groups for any of the parameters studied.
  This trial thus clearly confirmed that FLAVEDON has the efficacy of a first-line antianginal agent.

It also confirmed the myocardial protection provided by FLAVEDON against ischemic episodes detected by Holter. Patients were assessed by 24-hour Holter records, the computerized reading of which was centralized and blinded.

Patients with a positive Holter were analyzed, and showed no significant difference in the number and duration of ischemic episodes detected by Holter.

There was a significant decrease of a quarter in the number of ischemic episodes in the FLAVEDON group, while there was no difference in the propranolol group.
This study also confirmed the very good acceptability of FLAVEDON .

All classical antianginal hemodynamic agents aim to prevent the onset of ischemia, either by decreasing cardiac work (decreased oxygen and substrate consumption) or by increasing myocardial oxygen and substrates supplies (vasodilation enabling a theoretical increase in oxygen and substrates supplies).

FLAVEDON offers a completely different approach to ischemic disease. Due to its specific, purely metabolic, mechanism of action, FLAVEDON prevents and protects the myocardial cell from ischemia-related metabolic changes.

This difference in mode of action from all hemodynamic antianginals raises the question of the value of combining FLAVEDON with one of these antianginals.

This is all the more pertinent, since the usefulness of a combination of two antianginals with a hemodynamic action was long questioned because of the accumulation of their hemodynamic and cardiac depressant effects, is now in doubt concerning the actual addition of their respective efficacy on angina:

• As early as 1989, Milton Packer cast doubt on the habit of prescribing two (or more) antianginals with a hemodynamic action in view of:
  - the absence of individual therapeutic benefit demonstrated on the basis of current and exacting criteria,
  - the lack of clinical evidence on the efficacy of such combinations,
  - the accumulation of harmful depressant effects.
  
  
• In 1996, the TIBET study(32) also concluded that no therapeutic benefit was derived from the combination of a ß-blocker and calcium antagonist, whether on the basis of clinical or exercise parameters.
  
  The authors also state: "There would not appear to be any significant benefit, in terms of exercise test performance (treadmill or bicycle) nor in terms of reduced ischemic threshold, to be gained by combining two antianginals (with a hemodynamic action) as compared with treatment using either one as monotherapy."
  
  A review of the literature shows that, up to now, few studies have succeeded in confirming, on the basis of current efficacy criteria, the advantage of prescribing combinations of antianginals with a hemodynamic action for stable angina.
  
  
• In 1997, the IMAGE study(33) also concluded on the absence of cumulative efficacy of several antianginals with a hemodynamic action. In another clinical study designed to evaluate whether the claimed efficacy of antianginal combinations with the same hemodynamic mode of action, eg, a ß-blocker and a calcium antagonist, actually occurred individually in each treated coronary artery disease patient. The results showed not only that 80% of patients on a ß-blocker-calcium antagonist combination derived no additional clinical nor exercise performance benefit from that evaluated on monotherapy with either drug, but also that most who appeared to derive benefit were actually patients who were not responders to initial monotherapy.
  
  All these studies are in agreement in concluding that the combination of antianginals with a hemodynamic action has no additive clinical or exercise performance effect and that, when a beneficial effect is seen, it can be attributed to nonresponse to the first treatment.
  
  In contrast, the combination of two antianginals with totally different, and hence pharmacologically complementary, mechanisms of action, ie, an antianginal with a hemodynamic mechanism of action and an antianginal with a metabolic mechanism of action, is the most effective therapeutic approach, and most beneficial clinically and regarding exercise capacity.

In patients still developing ST-segment depression despite treatment with diltiazem 180 mg/day, the addition of FLAVEDON led to a gain of one exercise test increment (30 watts) and delayed latent time to ischemic threshold by 2 min 41 sec.(22)
In a study comparing the combination of FLAVEDON or isosorbide dinitrate with a ß-blocker,(23) the superiority of the combination FLAVEDON ß-blocker over that of the two antianginals with a hemodynamic action (ß-blocker/ISDN) was confirmed. FLAVEDON brought about a clinical and exercise performance improvement in patients whose angina was resistant to ß-blocker monotherapy:

• by significantly reducing the number of angina attacks,
  
• by significantly reducing nitroglycerin consumption,
  
• by delaying the time to onset of ST-segment depression,
  
• by delaying the time to onset of anginal pain,
  
• by increasing total exercise duration.
  
  this occurred to a significantly greater extent than with isosorbide dinitrate.

This study also confirmed the small benefit in terms of exercise performance derived from the combination of the two antianginals with a hemodynamic action.

The Trimpol II 2000 study(24) proved the fully additive efficacy of FLAVEDON in patients not controlled by metoprolol.

Hence the full efficacy of FLAVEDON , demonstrated in monotherapy, is totally added to that of any hemodynamic antianginal drug.

By virtue of their bradycardic and negative inotropic properties, ß-blockers act on angina by decreasing the working capacities of the heart and hence decreasing its oxygen consumption.

The physical exercise possibilities of the "ß-blocked" coronary disease patient are therefore reduced.

• When patients still have a positive exercise test despite ß-blocker treatment, FLAVEDON , by decreasing the myocardial cost of physical effort in coronary disease patients, enables them to perform more physical effort for the same amount of cardiac work (same rate-pressure product). FLAVEDON thus enables "ß-blocked" coronary disease patients to increase their physical activity possibilities despite the limitations on cardiac work imposed by ß-blockade.(25,26)
  Addition of FLAVEDON to ß-blocker resulted, in 2 months:(25)
  
  • in the disappearance of residual pain in almost all patients;
    
  • and a 72% gain in the level of effort possible without ST-segment depression on exercise test, despite a maximum heart rate limited to 120/min.

A clinical study comparing the combination ß-blocker/FLAVEDON with the combination ß-blocker/ISDN also confirmed the clinical and exercise performance benefits provided by the combination of FLAVEDON and a ß-blocker.(23)

The Trimpol II study confirmed the efficacy of FLAVEDON on clinical and exercise test parameters. Patients with stable angina not controlled by metoprolol were included and treated with FLAVEDON or placebo for 3 months. This broad-based study shows that the efficacy of FLAVEDON is fully added to that of a ß-blocker when used in combination.

Finally, the risk of ischemia is never totally excluded, even in a coronary disease patient apparently controlled by ß-blocker.
This emphasizes the need to use FLAVEDON to provide true myocardial protection against ischemia, the risk of which is never totally eliminated.

1. Manchanda SC, Krishnaswami S. Combination treatment with trimetazidine and diltiazem in stable angina pectoris. Heart 1997; 78(4): 353-357.
2. Manchanda SC. Treatment of stable angina with low dose diltiazem in combination with the metabolic agent trimetazidine. International Journal of Cardiology 2003; 88: 83-89.