Design: Case control study.
Setting: CAST Centres.
Sample Population: 4400 patients, who had attended various CAST centres and had suffered from myocardial infarction, had been analyzed through the Holter test. Furthermore, the patients were required to have experienced six or more premature depolarisations within an hour.
Inclusion Criteria
Case patients: persons who had suffered myocardial infarction and whose premature depolarisations in an hour exceeded six as evidenced by the Holter test. The patients would also receive Encainide and Flecaidine in recommended doses. Patients who had responded to the drugs were then further analyzed.
Control Subjects: patients who had suffered from myocardial infarction, whose premature depolarisations in an hour exceeded six and who responded to Encainide and Flecaidine. Unlike the case patients, these patients were given the placebo instead of the drugs.
Exclusion Criteria
Non responsiveness to Encainide and Flecaidine.
Intervention: No active intervention.
Outcome Measures
Primary: The relationship between mortality and active drugs was measured as a percentage of the total deaths observed within the whole population. The results were analyzed after ten months and presented at 95 percent confidence level.
Secondary: Correlation between death and reduction in quality of life, and the use of anti-arrhythmic drugs.
Titration
Patients were given Encainide and Flecaidine in relation to their ejection fraction measured by Holter in a 24 hour period for 4 to 10 days.
Randomization and Follow-up
Follow-up was only done to patients who were seen to be responding to the drugs and this was done over the telephone.
Statistical analysis
The study employed the traditional two-sided log rank was employed to establish the survival rate of patients who had received the active drug in comparison to the patients who had received the placebo. (The log rank test is a tool employed to confirm a null hypothesis, in this case that there was no variations in probability of death between patients who had taken the drug and the ones who had taken the placebo). The analysis employed a one-tailed test aimed at establishing whether the drug had positive medical effects or negative medical effects. The alpha level was 0.025 with a power of around 0.85. The nominal p value was adjusted for multiple groups. The objective was not aimed at establishing whether anti-arrhythmic drugs were harmful or not.
Results
Subjects
2309 patients had been successfully recruited. Suppression of anti-arrhythmia had been achieved in 1727 of the patients and these were assigned to blind study. 1455 were assigned to receive the medication. The findings were similar in both groups in terms of age, ejection fraction; time elapsed since myocardial infarction and the use of beta blockers. Patients with different ejection fraction exhibited different reactions to the drugs.
Outcomes
The results observed that death regardless of whether it was caused by arrhythmia or not increased in groups where the active drugs were administered. This was regardless of age, use of beta blockers or digitalis. The risk of death in patients given Encainide and Flecainide was 4.5 % as compared to 1.2 % for patients given the placebo. This was recorded at 95 % confidence level. When the two drugs were considered differently the results were not different as Encainide and Flecainide recorded risk of death of 3.4 and 4.4 percent respectively. The mortality rate for patients under Encainide and Flecainide was also observed to be higher at 7.7 % as compared to 3.0 percent for the placebo. When the Encainide and Flecainide were considered differently the results were not different at 2.7 and 2.2 percent respectively.
Discussion
The rate of risk had been significantly reduced in patients under the placebo and there was concern whether the anti-arrhythmic drugs actually worsened the situation.
Strengths Noted by Author
- The study considered the possibility of other parameters except reduction of ventricular premature polarizations as being significant in arrhythmia.
- The study concentrated on the overall quality of life.
- Only patients at risk of arrhythmia were included in the study.
- The period of study was long enough to allow for the realization of long term effects.
Weaknesses Noted by Author
- The doctors might have not chosen the sickest of their patients.
- The results could not be extrapolated and further research needed to be conducted in the area.
Author’s Explanation of the Results
Although Encainide and Flecaidine may have the outcome of reducing classic arrhythmic effects, they actually have negative effects on patients with structural heart disease and complex arrhythmia
Clinical Study Evaluation
Strengths of the Study
- The study was conducted by a number of centres under the umbrella name of CAST (Cardiac Arrhythmia Suppression Trial), mandated to look into the effectiveness of anti-arrhythmic drugs in the prevention of risk factors after myocardial infarction. The degree of objectiveness and accountability is optimized when several professional centres are involved. Furthermore, the knowledge of the chemistry of the drugs in use ensured that adverse reactions were avoided and only the desirable effects were realized. This was due to a pilot study that had been conducted and where the effects of the drugs were realized.
- The choosing criteria for patients eligible for the research were conducted in a manner as to ensure that only patients at risk of arrhythmia were under study. This further increased the likelihood of the results being true. The sample size was also arrived at after simulation of the study. The resultant size was large enough ensuring that a significant population had been covered and that the disparities would be evident.
- The essence of the study was founded on clinical grounds and the results would add knowledge and value to the medical fraternity. The study sought to establish the extent to which the drugs under study managed to reduce the risks of patients who have had myocardial infarction, to suffer from arrhythmia.
- The researchers were also transparent enough to point out that there would be inconsistencies when extrapolating the data findings to a larger group. This is because the research was only based on a sub-group. The researchers however pointed out that the basis of the research was to bring into perspective important medical variables following the use of drugs in question on the risk group.
Weaknesses of the Study
- The variables under study were not conclusive enough as to determine whether the use of the drugs would actually result to death. Furthermore, there was no consideration of other aspects that may affect the variables for instance the quality of life.
- The research was such that drawing strong correlations between the mechanism of action of the drugs and the condition of the patients would be superficial or totally impossible.
- Midway through the study the research procedures had to be altered due to the realization that some of the procedures would be harmful. The credibility of the results would be questioned as it implies that not all of the objectives would be arrived at conclusively.
- The extrapolation of the results to other study groups would be difficult since the parameters in question were limiting in terms of objectives.
Applicability to Practice
Patients who have had myocardial infarction are already at a risk of developing arrhythmia that may be fatal. Therefore the consideration of only one parameter in terms of reducing arrhythmia is erroneous. Several aspects should be put into consideration before qualifying a drug as being effective. Some drugs may actually have a short term positive effect and a long term negative effect.