Landmark Trials In Cardiovascular Medicine Biology Essay

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Cardiac arrhythmias are one of the many forms of CVD. They can be harmless and the individual affected can live a normal life or they can be fatal. It is estimated that a total of 15 million Americans have cardiac arrhythmias.1 Below I have evaluated the significance of 3 important clinical trials related to antiarrhythmic drugs. All the trials evaluated are large scale trials that statistically represent the general population.

These trials demonstrated that antiarrhythmic drugs were not always the best method of treatment and some very important clinical findings were revealed.


'Heart and circulatory disease is the UK's biggest killer'2. Statistics show that in 2007, cardiovascular disease (CVD) was responsible for 34% of deaths across the UK killing over 193,000 people.1 This was also the trend seen in most developed and some developing countries. Cardiovascular disease (CVD) is a major killer and hence it is an important target area for pharmaceutical intervention. Drugs developed for CVD need to be effective and have as few side effects as possible. They also have to have a positive effect on quality of life.

Due to the rapid advancement in technology coupled with our ever improving understanding of mechanisms of diseases, the pharmaceutical industry has been able to develop revolutionary treatments that were not even feasible only decades ago. Unfortunately these 'revolutionary treatments' do not always result in the best clinical outcome. AS a result, clinical trials have become an absolute necessity in order to evaluate the efficacy of drugs. Clinical trials can be tailored in a number of ways in order to obtain the desired information.

Trial 1 Cardiac Arrhythmia Suppression Trial (CAST) 3

The aim of this randomized clinical trial was to test the hypothesis that suppression of premature ventricular depolarisations in people who have survived a myocardial infarction would improve their survival without any fatal arrhythmic event occurring.3 Ventricular arrhythmias have been deemed to be the major arrhythmic event leading to sudden death in these patients. This trial used antiarrhythmic drugs to prevent ventricular arrhythmias from occurring and this effect was compared to the use of a placebo. The types of antiarrhythmic drugs used in the trial were selected by a Drug Selection Committee (DSC).3 The DSC considered drugs from all four Vaughan Williams classes of antiarrhythmic drugs but due to the effective findings of the Cardiac Arrhythmia Pilot Study (CAPS) 4 they decided to use ecainide, flecainide and moricizine in the trial. These agents are all Class I antiarrhythmic drugs and were shown to have good patient tolerance and arrhythmia suppression.4 The trial took place in two stages CAST I and CAST II. CAST I involved the use of ecainide and flecainide while CAST II involved moricizine.

A total of 3549 patients were enrolled on to the trial. Strict selection parameters were set for both legs of the trial. Patients were only eligible for the trial if they had suffered from a myocardial infarction (MI). In CAST I patients were randomized to encainide, flecainide, moricizine or the placebo the entry parameters were as follows:

Only screened patients between six days and two years of having an MI3

Have 6 or more ventricular premature depolarisations per hour on an ECG with a minimum of eight hours of recording time3

To enrol potentially high risk patients a left ventricular ejection fraction of less than 0.55 if the MI was between 6-90 days and less than 0.44 if the MI was between 90 days and 2 years was required3

Patients were ineligible for the trial if they suffered from very severe symptomatic ventricular arrhythmias or if 15 or more consecutive ventricular premature depolarisations were recorded.3

In the case of CAST II where patients were assigned to either moricizine or the placebo, the entry parameters were tighter and were as follows:

Only screened between 4-90 days of having an MI3

Have a left ventricular ejection fraction of less than 0.43

Patients with ventricular tachycardia that was symptomatic or lasted greater than 30 seconds at a rate of 120 beats per minute were excluded from the trail3

Patients were randomised to the respective drug but initially the trial was not blinded. This was in order to determine the correct dosage in each patient for arrhythmia suppression. The criteria for arrhythmia suppression was defined as a 24 hour ECG recording period whereby there was 'a greater than 80% reduction in the number of ventricular premature depolarisations and a greater than 90% reduction in episodes of unsustained ventricular tachycardia without intolerable adverse effects.'3 After determining the correct drug dosages the trial was then blinded and the patients were randomized to the placebo or the active treatment. This was the initiation point of the trial and the point at which scheduled follow ups began. Follow ups were scheduled at 4 month intervals. The end point for both legs of the trials was death from a cardiac arrhythmia or cardiac arrest.

The results of this trial were clinically significant. After 1 year, 95% of the placebo treated patients stayed alive compared to 90% of the drug treated patients.3 Also after 1 year, 96% of placebo treated patients stayed free of 'cardiac arrest or arrhythmic death'3 compared to 93% of the drug treated patients.3 This data clearly showed that the use of the antiarrhythmic drugs moricizine, encainide and flecainide reduced the survival of patients in comparison to the placebo.

From these results, it was concluded that patients suffering from symptom less ventricular arrhythmias after a MI event should not be treated with class I antiarrhythmic drugs (ecainide, flecainide and moricizine) despite the fact that these drugs may well be initially useful in suppressing ventricular arrhythmias. 3 This trial was significant because even though antiarrhythmic drugs are effective it showed that their use in this particular scenario had the completely opposite and undesired effect.

There were a couple of limitations to this trail:

The trial did not demonstrate the effect of other classes of antiarrhythmic drugs. This could be further investigated in other studies

No mechanisms were studied as to why class I drugs increased the mortality rate

Trial 2 Antiarrhythmics Versus Implantable Defibrillators (AVID) 5, 6

This Trial was sponsored by the National Heart, Lung, and Blood Institute (NHLBI). The main aim of this study was to compare two treatments for cardiac arrhythmias (in particular survivors of 'near fatal ventricular fibrillation and ventricular tachycardias'6). The two treatments available were antiarrhythmic drugs (the class III drugs amiodarone and sotalol) and state of the art implantable cardioverter defibrillators (ICDs). The Secondary objective of this study was to assess the economic and the quality of life effects.5 The study was a non-blinded randomised control trial with no control group.6 A variety of different models of ICDs were used in the trial but it was agreed amongst the investigators that no comparisons would be made between them.6 It was decided that the end point of the trial was to be mortality of the patients.6 This trial began in June 1993 and was terminated by the responsible board in April 1997.

To be eligible for this trial, patients had to meet the following entry criteria:

Patients had to suffer from 'ventricular fibrillation, sustained ventricular tachycardia with syncope or sustained ventricular tachycardia without syncope with an ejection fraction of 0.40'.5 All the patients that met this criteria were all followed until mortality through the National Death Index (NDI).

Patients that were randomised to either antiarrhythmic drugs or ICD treatment had to meet the above criteria but also be at a high risk and show potential long benefit from treatment5

Patients entered in to the trial had to be eligible for treatment with either of the two treatment options5

Patients were excluded if they were exposed to amiodarone in the past 6 months or had previously had an attempted ICD implantation5

Once the eligible patients were selected, they were randomized to treatment by antiarrhythmic drugs or implantation of an ICD. Patients randomised to the ICD group were installed with a 'state of the art' approved ICD5. In the antiarrhythmic drug group two drug options were available to patients. These were amiodarone or sotalol (both class III antiarrhythmic drugs). Patients that were eligible for treatment with both amiodarone and sotalol were again re-randomised to one of the two options. 5 The reasons why patients were excluded from sotalol treatment included having 'a history of asthma, a low left ventricular ejection fraction or a history of congestive heart failure'6 If either of the above two drugs were not effective then other antiarrhythmic drugs could be used instead.5 The study permitted side by side use of other therapies such as beta blockers and angiotensin converter enzyme inhibitors as long as they were being used before randomization and were to be continued after the randomisation process.5 Crossover between the two treatments was not desired but was allowed if it was clearly deemed to be in the patients best interests.5

Follow ups were conducted every 3 months, where serious effects of the ICD and antiarrhythmic drugs were recorded.5 The treatment delivered by the ICD in the past 3 months was also recorded.5 A ECG recording was obtained every 6 months and patients that were assigned to amiodarone therapy had specific laboratory tests conducted on them at 6 and 18 months.5

In April 1997, the trial was cut short due to analysis of statistical evidence by the Data and Safety Monitoring Board.6 By that time, 1016 of the 6035 patients initially screened were randomized to either treatment group.6 507 were assigned to ICD treatment and 509 to antiarrhythmic drug therapy.6

On the whole it was recorded that survival was greater in patients treated with an ICD.6 Survival after one year was 89.3% in ICD treatment compared to 82.3% in antiarrhythmic drug therapy.6 After two and three years survival was 81.6% and 74.7% in the ICD treatment group and 74.7% and 64.1% in the antiarrhythmic drug therapy group respectively.6

From the above trial it was concluded that the ICD was better than antiarrhythmic drugs at increasing survival in patients with 'ventricular fibrillation, sustained ventricular tachycardia with syncope or sustained ventricular tachycardia without syncope with an ejection fraction of 0.40'5 and that it should be used as the primary treatment.6 This was a significant trial as it showed how effective the ICD was in comparison to the available antiarrhythmic drug therapy. It demonstrated how ICDs were an important prophylactic tool against sudden cardiac death from ventricular arrhythmias.

The limitations of this trial were:

No control group was included in the study. This was due to the fact that the investigators felt it would be unethical to withhold treatment from the patients6

Many different types of ICDs were used in the trial and were programmed differently. Despite this, there was no difference in the overall effect between any of the ICDs.6

Trial 3 The Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study7, 8

This was a study that was also sponsored by the National Heart, Lung, and Blood Institute (NHLBI). This study was conducted in order to determine which of the two strategies in treating atrial fibrillation was more effective in reducing mortality.7 The two strategies used were both carried out in the presence of anticoagulant drugs.7 The first strategy was antiarrhythmic drug therapy and cardioversion to control sinus rhythm and the second strategy was to control rate using rate controlling drugs.7 This was a randomized clinical trial with the intention to treat. The secondary objective of the trial was to assess the quality of life and the cost of treatment. Several other substudies were also conducted.

To be eligible for the trial patients had to meet the following entry criteria:

Patients had to be older than 65 years of age and have a high risk of stroke or be below the age of 65 and have at least more than one risk factor for stroke (e.g hypertension, congestive heart failure)7,8

They had an episode of recorded atrial fibrillation in the past 6 weeks7

The atrial fibrillation was likely to be recurrent and the atrial fibrillation was likely to cause illness or death in the patients8

They were eligible for long term treatment for atrial fibrillation8

They had no contraindication to anticoagulant therapy7

Eligible patients were then randomised to one of the two treatment strategies.

The rhythm control leg of the trial involved patients being given antiarrhythmic drugs by their doctor in order to control sinus rhythm.8 The following antiarrhythmic drugs were approved for use in the trial; amiodarone, disopyramide, flecainide, moricizine, procainamide, propafenone, quinidine, sotalol and dofetilide.7, 8 Doctors were allowed to use various combinations of the above drugs and cardioversion in order to maintain the patients sinus rhythm.7 Atrial fibrillation was thought to be under control if the patient had no more than one episode of atrial fibrillation in the past 6 months.7After all the treatments had been exhausted patients were eligible for a range of Step II therapies7 although implantable cardioverter defibrillators were not approved in the study.

In the heart rate control leg of the trial atrial fibrillation was allowed to persist and instead heart rate was controlled.7 The approved drugs for this part of the trial were; beta blockers, calcium channel blockers and digoxin.7 The control of heart rate during atrial fibrillation was monitored both at rest and during a six minute walk.7,8 Heart rate was said to be under control if it was less than 80 beats per minute and less than 110 beats per minute during the 6 minute walking exercise.7 When the above therapies no longer worked the approved Step II7 therapies could be administered.

Anticoagulation therapy was required in both legs of the trail. Warfarin was used to maintain an International Normalized Ratio (INR) of between 2.0 to 3.0.7, 8 In the rhythm control leg of the trial, anticoagulation therapy was promoted but could be stopped or lowered if sinus rhythm had been maintained for 12 weeks with antiarrhythmic drug therapy.7,8 Aspirin was administered instead. In the rate control group anticoagulation therapy was mandatory.7, 8

It was decided that all patients would be followed until 2 years after the randomization of the last patient enrolled onto the trial.7 Patients were followed after 2 months, 4 months and every 4 months thereafter.7 At these follow ups rhythm, angina and congestive heart failure status were measured.7 A selection of randomly selected patients were also followed up independently in order to assess cognitive function and quality of life.7 In order to assess the cost of treatment side, various details regarding costly treatments were to be recorded.7

At the end of the trial, 7401 patients were eligible to be enrolled in to the trail and 4060 of these were randomized.8 2027 patients were randomised to the rate control group and 2033 patients were randomised to the rhythm control group.

There were 356 deaths recorded in the rhythm control group and 310 deaths in the rate control group.8 It was also noticed that more patients in the rhythm control group were hospitalized and suffered more serious drug side effects.8 This data showed that there was no significant difference between rate control and rhythm control.8

From these results it was concluded that, treatment of atrial fibrillation with rhythm control offers no benefit on survival over rate control.8 Although rate control does have the benefit of a lower risk of serious side effects.8 It was decided that in clinical practice rate control should be used as the primary option for atrial fibrillation treatment and rhythm control should be stopped early if it is not succesfful.8 Also anticoagulation therapy should be used in all atrial fibrillation patients with a high risk of stroke.8 The significance of this trial is that it demonstrated the better method of treating atrial fibrillation using antiarrhythmic drug therapy.

Some of the limitations of this study were:

Patients used in this trial were above the age of 65. Although this data obtained was said to be representative of most people with atrial fibrillation8, this data may not apply to younger patients

There was no blinding in the trial which may have led to possible bias

There was no control group used. Although this would have been seen to be unethical


The above trials were all large scale clinical trials that showed the efficacy of antiarrhythmic therapy. All 3 trials displayed that antiarrhythmic drugs were not the most successful treatment options. Currently there are quite a few treatment and management options available to clinicians for cardiac arrhythmias.

Antiarrhythmic drugs are still used as the first line of therapy to manage heart rhythm in patients with atrial fibrillation9. The downside of these drugs is their proarrhythmic side effects10 which is a problem related to all antiarrhythmic drugs. If this treatment with antiarrhythmic drugs is unsuccessful then other non pharmacological therepies are considered. Currently there are a number of different antiarrhythmic drugs in development. 9 One of these drugs that has been recently approved (2008) was dronedarone an amiodarone analogue.9 This drug has the same mode of action as amiodarone but with an alteration that enables fewer systemic side effects.9 New antiarrhythmic drugs in development still need to be run through rigorous clinical trials in order to assess their effect on patients.

The other important pharmacological therapy in patients with cardiac arrhythmias is anticoagulation therapy. This is in order to reduce the risks of blood clots and stroke.11

Non Pharmacological therapies include:

Cardioversion for atrial fibrillation where an electrical current is sent to the heart through a defibrillator in order to normal rhythm.12

Pacemakers for heart block or atrial fibrillation where electrical currents are sent to the heart from an implanted device in order to control heart rate.12

Catheter ablation therapy for atrial fibrillation, supraventricular arrhythmias and ventricular tachycardias where abnormal areas in the electrical conduction system of the heart are found and destroyed in order to eliminate abnormal heart rhythms.12

Implantable cardioverter defibrillators (ICD) used for ventricular arrhythmias and ventricular fibrillation where the ICD is used to monitor the heart beat and is able to deliver an electric shock to restore the beat to normal if it detects an anomaly.12

Overall, the future of arrhythmia therapy looks very promising as cardiovascular disease is one of the leading killers word wide and a lot of research is being devoted in order to further improve current cinical therapies.