Colleagues,
I do think studies such as these (CAST, hormone replacement, others) are
good lessons. And they do suggest we should have known better. On the other
hand, the rationale for a study such as CAST is pathophysiology, and
pathophysiology is certainly a reasonable clue as to what treatments should
be pursued. Perhaps more pilot studies should have been done prior to a
large RCT (and perhaps they were, I do not know), but arrhythmias were
observed to precede death, and since they were often associated with
ineffective heart beats, patients who had them certainly wanted to be
relieved of them. A medication that could eliminate them seemed a
reasonable idea. In the end it turned out to be bad, thus the value of the
RCT....
Best
Rich
-----Original Message-----
From: Evidence based health (EBH)
[mailto:[log in to unmask]] On Behalf Of Jean Levasseur
Sent: Friday, March 04, 2011 8:44 AM
To: [log in to unmask]
Subject: Re: observational studies of antiarrthmic drugs
I believe the study was based on a survey of practicing cardiologists and,
at the time, it was initially designed as a one-sided study as it was
believed there could not be any harm... CAST was also thought to be
unethical because there was a placebo arm!!
You can access the study at NEJM.org, it is free :
http://www.nejm.org/doi/pdf/10.1056/NEJM199103213241201
Regards,
Jean Levasseur MD, MSc
Joliette, QC, Canada
Le 2011-03-04 à 08:25, Stephen Senn a écrit :
> Dear Jeremy,
> My recollection is that the background was that
> 1. Arhythmia was known to be a symptom that had a very adverse prognosis
> 2. The drugs had been shown in controlled studies to be highly effective
in eliminating the symptom
> However, I thought that there had been no observational studies showing
the treatments to be beneficial.
>
> Have you looked at the New England Journal paper (abstract below) or at
Thomas Moore's book, Deadly Medicine?
> Regards
> Stephen
>
> (1989). "Preliminary report: effect of encainide and flecainide on
mortality in a randomized trial of arrhythmia suppression after myocardial
infarction. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators."
N Engl J Med 321(6): 406-412.
> The occurrence of ventricular premature depolarizations in survivors
of myocardial infarction is a risk factor for subsequent sudden death, but
whether antiarrhythmic therapy reduces the risk is not known. The Cardiac
Arrhythmia Suppression Trial (CAST) is evaluating the effect of
antiarrhythmic therapy (encainide, flecainide, or moricizine) in patients
with asymptomatic or mildly symptomatic ventricular arrhythmia (six or more
ventricular premature beats per hour) after myocardial infarction. As of
March 30, 1989, 2309 patients had been recruited for the initial
drug-titration phase of the study: 1727 (75 percent) had initial suppression
of their arrhythmia (as assessed by Holter recording) through the use of one
of the three study drugs and had been randomly assigned to receive active
drug or placebo. During an average of 10 months of follow-up, the patients
treated with active drug had a higher rate of death from arrhythmia than the
patients assigned to placebo. Encainide and flecainide accounted for the
excess of deaths from arrhythmia and nonfatal cardiac arrests (33 of 730
patients taking encainide or flecainide [4.5 percent]; 9 of 725 taking
placebo [1.2 percent]; relative risk, 3.6; 95 percent confidence interval,
1.7 to 8.5). They also accounted for the higher total mortality (56 of 730
[7.7 percent] and 22 of 725 [3.0 percent], respectively; relative risk, 2.5;
95 percent confidence interval, 1.6 to 4.5). Because of these results, the
part of the trial involving encainide and flecainide has been discontinued.
We conclude that neither encainide nor flecainide should be used in the
treatment of patients with asymptomatic or minimally symptomatic ventricular
arrhythmia after myocardial infarction, even though these drugs may be
effective initially in suppressing ventricular arrhythmia. Whether these
results apply to other patients who might be candidates for antiarrhythmic
therapy is unknown.
>
>
>
>
>
> Stephen Senn
>
> Professor of Statistics
> School of Mathematics and Statistics
> Direct line: +44 (0)141 330 5141
> Fax: +44 (0)141 330 4814
> Private Webpage: http://www.senns.demon.co.uk/home.html
>
> University of Glasgow
> 15 University Gardens
> Glasgow G12 8QW
>
> The University of Glasgow, charity number SC004401
> ________________________________________
> From: Evidence based health (EBH) [[log in to unmask]]
On Behalf Of Jeremy Howick [[log in to unmask]]
> Sent: 04 March 2011 12:07
> To: [log in to unmask]
> Subject: observational studies of antiarrthmic drugs
>
>> Dear All,
>>
>> The CAST (randomized) trial revealed that treatments introduced solely on
>> the basis of 'pathophysiologic rationale' (mechanisms) can be deadly.
Does
>> anyone know whether there was any OBSERVATIONAL evidence supporting the
>> effectiveness of antiarrhythmic drugs for reducing mortality (obviously
>> before CAST)?
>>
>> Thank you!
>>
>> Jeremy
>>
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