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Eudipharm Case Studies Series, 1/2001, Jean-Pierre Boissel, v1.0, 26/09/2011 11:55:00, 02/05/17
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Eudipharm Case studies
Deadly medicine1: the story of class I antiarrhythmic agents
Code number = EUDI CS 1/2001 SU CT
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Author
Jean-Pierre Boissel, Professor, Department of Clinical Pharmacology, Claude Bernard University. Has chaired the European
Co-ordinating Centre of IMPACT [2, 3]. Has wrote several articles on surrogacy [4, 5].
Key points
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Consequences of a wrong choice of a surrogate outcome.
Reasons for such a wrong choice.
All available evidence and how to weight it.
Limitations of the surrogacy approach in new drug development.
Interplay between companies, faculties, medicine agencies.
Roles of biomarkers.
Role of a public body promoting and financing clinical trials.
The “closeness” lemma in side-effect detection.
Mismanagement of science and mismanaged commercial interests are not good for pharmaceutical companies.
Key words
Suurogacy; clinical outcome; intermediary outcome; surrogate outcome; severe side-effect.
Covered educational objectives
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Define the quality of a trial (BM)
Understand the clinical trial methodology (BM)
Choose primary and secondary outcomes (BM)
Define the intermediate, clinical and surrogate outcomes (BM)
Explain the role and operational principles of safety and efficacy monitoring in clinical trials (EM)
Understand the impact of multiple statistical testing in monitoring efficacy and safety in clinical trials (EM)
Propose a rule to tackle the multiple statistical issue to decision making in monitoring safety and efficacy in a clinical
trial (EM)
Explain the meaning of the “closeness lemma” (EM)
Use meta-analysis in drug development (EM)
Difficulties in identifying proper data for a meta-analysis
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Description
Introduction
The modern history of medicine (i.e. for the last 2 or 3 centuries) is marked with milestones, that were sources (or indicators)
of tremendous speeding up of medical progress. They were either sad stories (e.g. Semmelweiss’ ) or bright ones (e.g.
Pasteur’s). The class I antiarrhythmic agent story is a terrible example of the former category, with thousands of undue
deaths caused by both a lack of proper thoughts and understandings of what medical science is from all players (but one), and
a total failure in managing a public health issue by both drug companies and regulatory agencies.
Setting
Progress in acute myocardial infarction management
In the middle of the 60s, coronary care units began to be established in leading hospitals in developed countries. Several
controlled trials carried on in the UK suggested that special cares might improve the prognosis of acute myocaridal infarction
(AMI). In parallel, engineers designed the first cardiac monitors that could record continuously EKG and pick up abnormal
beatings (or lack of beating).
The players
 Companies
Companies were the major players in the story. In the 70s and early 80s, 3M (lorcainide), Boerhinger-Ingelheim
(mexiletine), Bristol Myers Squibb (encainide), DuPont (moricizine) were interested in developing drugs against cardiac
arrhythmia. Usually, a company decides to launch a clinical trial with clinical outcome with their drugs either before they are
on the market (phase III) or after (phase IV). Companies proceed this way because of regulation or marketing purposes.
They put millions of $ in clinical trials. A phase III clinical trials costs between 10 to 100 M$.
 Experts
Companies rely on experts from medical school research centres for developing their new drugs. These experts also play a
major role as opinion leaders in persuading other doctors to use them. Little happens in the world of pharmaceuticals without
them. In the present story, with few exceptions, their full name will not be given. As it will be clearly established, they are
the culprits, together with the medicine agencies officers. Because they are the experts, those who are supposed to know the
proper things to do.
 Doctors
The medical community as a group tackles improperly with issues such as what is the type of evidence that proves the
efficacy of a treatment and what is or is not ethical when treating patients. A few days after the decision was made to stop
CAST I because an overwhelming excess death rate in the treated groups as compared to placebo, one CAST Steering
Committee member (who was not allowed to release the data at this time) was publicly criticised by cardiologists as
“immoral” because he said CAST randomised patients with ventricular arrhythmia to placebo!
 Medicine Agencies
A new drug cannot be put on the market and prescribed largely without the approval of several Medicine Agency
Committees. These Committees evaluate all the evidence available on the dossiers. Based on Committees’ reviews and
recommendations, the Medicine Agencies approve or disapprove new drugs. These Committees are composed of experts
(see above) and managed by officers who are distinguished scientists, with the same background as the experts. As for
experts, no name will be given. In the US, the Medicine Agency is called the Food and Drug Administration (FDA). By
law, it can only accept to release a new drug if, beside to be safe, it has be proven effective by objective clinical trials. The
key issue which is well illustrated by the class I antiarrhythmic case, is that the FDA (and other Regulation Agencies in
Europe or Japan as well) relies on experts to decide what effective means.
 Public research biomedical organisations
In the US, the National Institutes of Health support clinical trials even with patented drugs. In Europe, only the UK Medical
Research Council sponsor clinical trials, although at a much smaller scale. In France, the Ministry of Health funds clinical
trials with public health interest. In Europe, the European Commission supports (partially) a few clinical trials. The
European Science Foundation is being setting up a co-sponsorship system to help to conduct pan-European clinical trials in
domains and/or with interventions (treatments) the private sector is not interested in.
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The story
Chapter 1 (1965-1975): discovery of ventricular arrhythmia
Rise of rhythm disturbances in coronary heart disease
Thanks to new approaches to record EKG continuously, it came up in the last 60s and early 70s that patients with coronary
heart disease present frequently atrial or ventricular rhythm abnormalities. The later were soon seen as potentially lethal.
They can complicate the course of AMI, leading to early death following the onset of symptoms (most of the time chest
pain). They also can occur without alerting symptoms, and when they evolve to ventricular fibrillation, they lead to electrical
pump failure (cardiac arrest) which, if not treated within a few minutes, causes sudden death. The “lethal sequence” of
ventricular premature beats (VPB), frequent and complex (i.e. with different forms in a single record), followed by
ventricular tachycardia (VT), then moving up to ventricular fibrillation (VF) was frequently recorded in patients dying
suddenly, thanks to Holter EKG recording. In the mean time, two types of treatment of ventricular arrhythmia were
discovered: drugs that decrease the number of VPB, and electrical shock (“DC conversion”) that can stop VT or VF and
restore normal rhythm. DC conversion became a current procedure to treat VT and VF complicating AMI in the coronary
care units. Since the mid 80s, DC conversion facilities are available in mobile care unit and even in places were people used
to gather such as stadiums. More recently, small automatic DC converters are surgically implanted in patients at risk of
severe ventricular arrhythmia. Several randomised trials have documented the efficacy of these devices.
Sudden death as a leading cause of death after acute MI
Beside qualitative knowledge that is summarised above, a few cohort studies were published in the 70s that documented the
correlation between VPBs recorded prior to discharge in patients who have recovered from an AMI and events occurring
later. In the placebo group of the Coronary Drug Project, among 2,035 men who had experienced a myocardial infarction at
least 6 months before inclusion (average 36 months), 235 (11.5%) had VPB in their base line conventional resting EKG [6].
During the three year follow-up period, deaths were about twice as frequent in those with any type of VPB (21.7%) as in
those with none VPB (11.4%). The excess risk increased with the frequency of VPB, and with complex VPB, and was
independent of other factors. In the cohort by Ruberman [7], 1739 men with prior myocardial infarction (50% have
experienced their MI within the three months before the base line examination), were monitored for VPB for one hour and
followed for mortality for periods up to four years (average 24.4 months). The presence at base line of complex VPB (R on
T, runs of 2 or more, multiform or bigeminal premature beats) was associated with a risk of sudden death three times that of
the men free of complex VPB. Accounting for other factors did change marginally the relation. In another prospective study
of 759 patients aged less than 66 years who were discharged alive from the hospital where they were admitted for AMI, 42
patients died within 6 months and 62% of these deaths were attributed to arrhythmia [8].
In 1979, Lown published a review [9] untitled “Sudden cardiac death: the major challenge confronting contemporary
cardiology”. He wrote in the article introduction: “The enormity of this problem demands attention. In the United States,
sudden cardiac death claims about 1,200 lives daily, or approximately one victim every minutes”. Morganroth said at a
conference in 1980: "The solution of the problem of sudden cardiac death is the leading challenge to cardiology today". He
added: "The larger purpose…was providing to the American public effective and safe antiarrhythmic agents which can
eventually be used to prevent or decrease the epidemic of sudden cardiac death". An attendant at the conference he was
speaking in questioned the validity of the still-unproven theory that suppressing premature beats would prevent sudden death.
Morganroth answered that obtaining drugs that suppress ventricular arrhythmia and are well tolerated was the first objective.
Chapter 2 (1975-1989)
Summary of empirical data
Antiarrhythmic drugs decrease the incidence of ventricular arrhythmia (ventricular tachycardia or fibrillation) which are
thought to be responsible for sudden death in adults recovering from MI. Premature ventricular beats are thought to precede
ventricular tachyarrhythmias, which are the most frequently recorded cause of sudden death. Class I antiarrhythmic drugs
have been assessed in post-MI patients in various randomised clinical trials [2, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
22], and have demonstrated to have a rather marked effect on preventing arrhythmia. However, with the exception of the
Cardiac Arrhythmia Suppression Trial (CAST I [23]), no conclusions was obtained on sudden death and all cause mortality
because not enough patients were included to enable the effect on the incidence of death to be assessed. The results from
CAST I for the drugs flecainide and encainide appear to disprove the commonly accepted hypothesis that these drugs reduce
the incidence of sudden death in post-MI patients. Mortality at ten months was 7.7% for the treated group compared with
3.0% for the corresponding control group, giving a relative risk of 2.53 [23].
Twelve arrhythmia trials
The results from twelve randomised clinical trials aimed at assessing the effect of class I antiarrhythmic drugs on ventricular
arrhythmia in post-MI patients are summarized in Table 1. Overall, they showed an improvement of ventricular arrhythmia,
whatever the marker used (as compared to control: a between group difference in average decreases of mean or median
number of VPB, or in numbers [rates] of patients who reach X% reduction in the number of VPB). The results from CAPS
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are not included because the experimental plan does not enable the mortality to be analysed [24]. It is useful to note a few
points here which might of interest because they illustrate the variety in design:
 IMPACT was the preliminary phase of an ambitious study which aimed to assess the effects of mexiletine on total
mortality in post-MI patients. This preliminary phase was to document the effect of mexiletine on VPB, run of VPB,
complex VPB. The full-scale study was never started because of the higher observed incidence of mortality in the treated
group compared with the control group.
 In the Collaborative Group study recruitment of patients into the trial was stopped when it was found that the incidence
of mortality was similar in the two groups. The mortality monitoring process was not described in the publication.
 Patients in the control group for the Collaborative Group study received a daily dose of 3 or 4 mg of phenytoin which
was deemed ineffective.
 The GRAP study results have been reported in various publications but the final results have not been published. The
data used for this analysis were taken from the review by Furberg [22]. The mortality rate for the Bastian and the Rydén
trials were also taken from this review.
 In some of the trials (GRAP, Gottlieb, Nielsen), patients were selected on the basis of the presence of ventricular
arrhythmias and in one (Chamberlain) the selection was based on predicted risk.
 In three trials inclusion occurred during the acute phase of MI, either before hospital admission (Bell) or after (Rydén,
Smyllie), with treatment being started under the same conditions.
 The dose of the test drug administered was titrated in some trials, using plasma concentration (Peter), tolerance
(Collaborative Group), suppression of arrhythmia (GRAP) or all three (Gottlieb).
 In four trials the analysis was not on an intention-to-treat basis. For one of these studies data for the follow-up of
patients excluded from the analysis were available in the publication (Nielsen), and in another trial (Rydén) only patients
with a documented infarction were included in the analysis. For the remaining two the data shown on Table 1 were those
given in the publications.
 In one trial patients presenting with ventricular arrhythmia classified as severe who were, therefore, "high-risk" patients,
were excluded (Gottlieb), and in another patients who were thought to need antiarrhythmic treatment were excluded
(Collaborative Group). In the IMPACT study, the target population consisted of moderate-risk patients because those
requiring antiarrhythmic treatment were not eligible .
Mortality trials: Cast I
CAST stands for Cardiac Arrhythmia Suppression Trial. CAST I was designed in the mid 80s. Recruitment began in June
1987. The trial involved more than 300 researchers, 27 clinical sites, took 5 years to be completed, and cost about $40
million to the US Federal budget. In CAST I, 25% of the patients were eliminated in the drug titration phase, before
randomisation, because of the poor efficacy of the tested treatments on ventricular arrhythmia or for a variety of other
reasons including death [23, 25]. It should be noted that the mortality rate for the control group in CAST was 3.0% at ten
months (or 3.2% when extrapolated to a year) which is low compared with rates that have previously been observed, for
example, 17% in the EPSIM register and 14% in the APSI register [26, 27, 28]. The mortality rate of patients who
participated in the pre-randomisation titration period but who were not randomised in the CAST I study was 8.5% at 10
months, compared with 3.0% for the encainide-flecainide placebo group and 4.0% for the entire placebo group [23]. Trials
with other class I antiarrhythmic drugs carried out on the same target population give controversial results, but the results do
not show statistically significant differences between the groups because none was sized for mortality (Table I).
CAST I was stopped prematurely [29]. In April 1989 the Data and Safety Monitoring Board recommended that the use of
encainide and flecainide be discontinued because the data indicated it was unlikely that benefit could be demonstrated and it
was likely that the drugs were harmful. The analysis was based on 1455 patients recruited up to March 30, 1989, when the
data base was frozen for the interim analysis. There were 56 deaths in the treated groups and 22 in the placebo group. The
boundary z = - 3.11, and the observed z = -3.22. The final results were based on 1498 records and the numbers of death were
63 and 26, respectively.
CAST II [30] and SWORD [31] were also stopped prematurely. IMPACT second stage did not begin because the mortality
in the first stage was in the opposite of the expected direction.
With the results of CAST, cardiologists realised that the current practice of prescribing class I antiarrhythmic drugs in postMI patients was a total mess.
Chapter 3 (1989-1996 ): further trials
A second trial, CAST-II [30], which was the continuation of CAST, in which moricizine was compared with placebo after
certain changes were made to the original protocol so that patients more likely to experience severe arrhythmias were
enrolled. The study was terminated prematurely because of the higher incidence of cardiac mortality in the moricizine
groups. Results were published in 1992. CAST II had a rather complex design (see Table and the article), with, at the end,
three separate trials. Overall, at the final analysis, there was an increase in mortality and cardiac arrest in the moricizine
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groups. Interesting, in the long term sub-study on patients with adequate suppression of arrhythmias the trend of an excess
mortality in the test drug group was not statistically significant.
The same year, the results of a trial achieved 8 years before CAST I were finally published [32]. They illustrate the reality
and the danger of publication bias.
Finally, in 1996, a trial of d-sotalol was published. Although the drug does not belong to class I, it increased mortality as did
the tested class Is.
The three trials are shown at the bottom of Table.
Complete information extraction: meta-analysis and effect model
In 1990, a meta-analysis [33] of the available published evidence was published [34]. It did not include CAST I. In 1993, a
new meta-analysis with careful assessment of heterogeneity and an exploration of the effect model of class I antiarrhythmic
in post-MI patients was published [35]. CAST II data were not available at the time the work was done. Thus, they were not
included in the analysis.
Since the duration of treatment was heterogeneous across trials, one year was taken as standard and all observed death rates
were converted to 1-year rate. This was achieved by assuming a constant instantaneous probability of death within each
group. In such a case, mortality at time "t" is given by % = 1 - e-t where % is mortality and  is the instantaneous probability
of death.
Results and a few up-dated calculations are shown in Figures 1-4.
The end
A few days after the decision to stop CAST I was made, Claude Lenfant, the Director of the National Heart Lung and Blood
Institute which sponsored the trial, arranged a press conference to disclose the results and to warn patients taking the drugs.
American doctors were angry about the procedure, and many said they would go on prescribing them! However, CAST I
(and II) killed the class I antiarrhythmics. It was though that class III might be different since there molecular mode of action
was different. However, the findings from SWORD that were issued 7 years after CAST I blunted these hopes. It remains
that amiodarone has been proven with fair evidence not to increase mortality and likely to reduce it. Nobody knows why
amiodarone behaves differently.
In 1991, the House Subcommittee on Human Resources and Intergovernmental Relations arranged a hearing of the
antiarrhythmic case. That was the first overt step of an investigation that started the very day the CAST I data have been
released at the press conference. The hearing identified the responsibilities from both the medical school experts who
advised the companies on the most appropriate way to assess the clinical efficacy of the drugs, as well as the FDA to release
them. The FDA was also criticised: it made a serious mistake when it approved loracainide and encainide for mild
arrhythmias because the agency did not know at the time the decision was made if the drugs safe for that use, said the SubCommittee.
The case for lorcainide and encainide was rather conspicuous. For the other class I, that was less clear and no decision was
made but to observe a 37% increase in mexiletine sells over pre-CAST levels.
A slow, steady decline in on the overall sales of antiarrhythmics that begun even before CAST results continued into the
early 1990s.
How many deaths?
Thomas Moore [1] tried to estimate the total death toll attributable by prescriptions of antiarrhythmic class I drugs in the US.
As he wrote, the main task of such estimates is limited to establish an order of magnitude. The limitations of the
documentation prevent from achieving a precise estimate. The uncertainty concerned all three elements of the calculation:
the size of the population at risk, the magnitude of the risk, the time period. The simplest approach made by Moore was the
following:
 During 1989-90, an average of 733,000 subjects were exposed because they were given one of the 6 best-seller class I
antiarrhythmic drugs in the US. This figure was obtained by dividing the total number of pills sold by the pharmacists and
drug stores for each drug by the drug recommended daily dose (DDD). The total number of pills was derived from
observations made in panels of pharmacists.
 In CAST I, the absolute increase in the risk of dying over one year of treatment was 5.88 %.
By applying the second valued parameter to the first, one comes up with 43,106 unnecessary deaths per year.
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The lessons
Understand the whereabouts
Development of new medicines is not just science. Culture plays a large role, leaving apart mismanaged commercial
interests. But the main lesson of this story comes from epistemology. As Karl Popper put it, science is a series of theoretical
statements on reality that must be confronted to reality trough appropriate experiments. For Popper, the definition of a
scientific statement is that it is refutable. The parallel with the antiarrhythmic case is clear. Beside not to account for all
available evidence at the time these drugs were submitted to clinical evaluation, the therapeutic model has not been properly
submitted to refutation. The key point in the statement was that by decreasing the rate of ventricular arrhythmias, these drugs
should decrease the rate of sudden death and consequently of total mortality in subjects in whom the way of dying was most
of the time sudden death. Thus appropriate clinical trials should have been mounted to test the point since the beginning.
Using the jargon of drug development, the phase III trials the companies did ith the aimed of proving the effect on arrhythmia
should have been sized to test the effect on mortality. That was not done and 40,000 Americans died each year for several
years because of this mismanagement of science.
The need of comprehensive and refutable therapeutic models
The therapeutic model all the development of the new generation drugs such as encainide and the trials mentioned above
were based on was quite simple. Since the drugs, both on animal models and on small scale clinical trials, were
demonstrated to decrease the rate of ventricular arrhythmias, they should be effective in decreasing mortality, and specially
sudden death, that cohort follow-up has shown to be more frequent in patients with such arrhythmias. In his review (9),
Lown wrote: “Any prophylactic program against sudden death must involve the use of antiarrhythmic drugs to subdue
ventricular premature complex”. Thus the model was endorsed and enforced in practice even before it has been submitted to
refutation.
The negative results of CAST and other trials were explained by the pro-arrhythmogenic and negative inotropic effects of the
study drugs. The former effect, which has been observed in animals and is thought to occur in humans, can induce
ventricular fibrillation leading to death [36]. This has been observed with old class I antiarrhythmic agents. With the new
generation, it was suspected by some doctors even before the CAST I publication. Roger Winckle collected 11 cases severe
ventricular arrhythmias, some being fatal despite repeated electrical shock, that occurred soon after the first dosing of
encainide in a series of 140 cases at Stanford teaching hospital. He submitted a paper in 1980 to warn cardiologists. His
article was rejected by three leading American medical journals.
The negative inotropic effects have been well documented in humans although heart failure objectively caused by the use of
these drugs is rare [37]. Nonetheless, in CAST II long term therapy in patients with adequate suppression of ectopic beats,
there were 17.6% of patients with new or worsened congestive heart failure in the moricizine group and 13.2% in the placebo
group (p = 0.04). Negative inotropic effect of some class I agents has been also demonstrated in healthy volunteers [38].
One may wonder why these evidence were not integrated in the therapeutic model. They should have motivated
investigators for mortality trials since the beginning of the story.
The model had another potential flaw. The very arrhythmic nature of sudden death was not at all certain. First, sudden death
is difficult to identify unless their is a witness who can describe the circumstances. But what about a man living alone found
died in is bed in the morning? Autopsy does not allow to diagnose sudden death. It can only identify the accompanying
pathologies. In a series of 238 men and 84 women, who had suffered “sudden cardiac death”, 59% had evidence of
significant ischaemic heart disease, 8% had another cardiac condition (including left ventricular hypertrophy, valvular
disease or congenital abnormalities), 30% had extracardiac diseases (most commonly pulmonary embolism and subarachnoid haemorrhage) and 3% had no obvious lesions [39]. Further, the definition of sudden death varied largely across
studies and over time, from the WHO definition (death within 24 hours after onset of symptoms) to more stringent definition
(instantaneous death).
Theoretical basis for surrogacy
A few key definitions
In many instances assessment of the benefit of new therapies is based on intermediate outcomes rather than on the events or
conditions they are supposed to cure or prevent. The former are called surrogate outcomes (SO) whereas the latter are called
clinical outcomes (CO) [40]. A clinical outcome is any clinical event (E), caused by a disease, that impairs duration or
quality of life, such as premature death, disabling conditions or symptoms which limit physical autonomy or intellectual
faculties. The goal of health care is to prevent or cure clinical events. An intermediate outcome (IO) is any sign or symptom
which is statistically correlated with the disease state and the clinical event. An intermediate outcome qualifies as a surrogate
outcome (SO) if it can be used as an appropriate alternative to a clinical outcome (CO) for the sake of assessing the efficacy
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of an intervention on the clinical event. Surrogate means that these outcomes are used instead of the relevant clinical
outcomes. For decades assessment of new medical technologies, especially drugs, have been based on surrogate outcomes.
Such a substitution spares time and money of pharmaceutical firms. However, questions as to whether the currently used
surrogate outcomes are appropriate substitutes for clinical outcomes have recently arisen and the story of antiarrhythmic
agents was one of the empirical facts that brought up concerns [41].
This definition of surrogate outcomes is somewhat more restrictive than some proposed by others [42, 43, 44]. Ellenberg and
Hamilton gave as examples of surrogate outcomes the amount of analgesic received or requested by cancer patients as a
substitute for pain, and the skinfold thickness as a substitute for nitrogen, potassium and water measurement for the
assessment of muscle mass [4]. In the former case, the reduction in analgesic consumption may be by itself a clinical
outcome and not merely a substitute for pain. In the latter case, muscle mass as well potassium, nitrogen and water body
contents are not clinical outcomes.
Provisos that a SO should meet
In order to use a IO as a convenient substitute for a CO, the IO should meet a series of three provisos:
Proviso (1): convenience
A SO should be easier to assess than its corresponding E in terms of delay before occurrence and requirements for validation.
However the most salient feature of a SO compared to its E is its frequency of occurrence: it should occur more frequently
than E. Thus:
P(I) > P(E)
Proviso (2): correspondence
The relationship between the IO and the CO should be well established, both qualitatively and quantitatively, through reliable
epidemiological studies. Hence:
P(I) <====> P(E)
Proviso (3): estimate
An estimate of the size of the benefit in terms of E, i.e. the clinical benefit that the patients are waiting for, should be derived
from the estimate of the reduction of the incidence of IO obtained from the RCT data. Thus one should know the function F:
dt(E) = F{dt(I)}
Proviso (4): permanence
The link between I and E should not be altered by the treatment, or at least should be affected in the same way and the
proportion by all types of treatment.
Comments
1) The preceding conditions are sufficient as well as requisite properties in order to accept an IO as an appropriate surrogate
outcome. Provisos (2) and (3) reflect [I-E]. They can be approached either mathematically or pathophysiologically. Proviso
(1) depends purely on the intermediate outcome; it pertains only to practical considerations.
2) Proviso (3) represents the key condition, because d t(E) is required for assessing the risk/benefit ratio, and thus should
be derived from the observed effect on the SO. It is also called the prediction criterion.
3) The capture criterion [45, 46] is different. It is a statistical approach, which presents the same limitations as every
attempts to prove the null hypothesis.
4) Proviso (4) is the most difficult since it should be questioned each time a new therapeutic class is invented.
5) The advantages of using IO instead of CO are conspicuous. Blood cholesterol and blood pressure are quantitative
variables; therefore the sample size required is much smaller than with the corresponding clinical outcomes which are
binary variables. DVT is much more common than symptomatic pulmonary embolism, hence, although phlebography is a
binary variable, the sample size required is much smaller. Trials where the fall of blood lipids or blood pressure are the
outcomes can be terminated more quickly, i.e. within a couple of days or weeks, whereas the corresponding clinical
outcomes need years to manifest themselves. Consequently the cost of trials and the total cost of new drug development
are substantially reduced. In addition, assessment of IOs is thought to be easier to standardise, e.g. phlebography for deep
venous thrombosis. However, none of the IO commonly used as surrogate has been unequivocally demonstrated as true SO
[47].
The antiarrhythmic story put in the perspective of surrogacy
In the introduction section, we pointed that, because of the recent results of CAST [48], ventricular arrhythmias, i.e.
ventricular ectopic beats (VEB) and ventricular tachycardia (VT), cannot longer be considered as a surrogate for sudden
death or total mortality. However, the antiarrhythmic drugs have been released for years on their efficacy on VPB. Hence,
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the data available prior to CAST are still useful to illustrate the theory. The reasons were that: 1) sudden cardiac death
(SCD) is very often caused by ventricular fibrillation, the mechanism of which is supposed to be closely related to VEB and
VT; and 2) the occurrence of VEB and/or VT on an ambulatory EKG record in patients with clinical evidence of coronary
heart disease identifies a group of patients with an increased risk of subsequent sudden death. Post myocardial infarction
patients with ventricular arrhythmia are at higher risk of death, especially of sudden death. This has been documented by
several prospective surveys [29, 49]. A series of placebo controlled RCTs with VEB and VT as outcomes have documented
the efficacy of several antiarrhythmic agents. However, none of these trials was large enough to test the effect of the
treatments on the clinical event, i.e. SCD, until the Cardiac Arrhythmia Suppression Trial (CAST) was especially designed
for this purpose. Twelve randomized clinical trials of antiarrhythmic agents in post myocardial infarction patients have been
published prior CAST was launched. Among them, seven provided efficacy data for both arrhythmia and mortality. In all,
the effect on arrhythmia was observed over a much shorter period of time. Although there was a marked reduction in the
incidence of ventricular arrhythmia in treated patients, as compared to control, whatever was the definition of arrhythmia, the
death rate was not altered. The published data do not permit to check precisely the effect of T on [I-E] because Pt(E/nI) is
not given. However, it is likely from the observation in patients with previous myocardial infarction who died suddenly
while long term EKG was recorded that sudden coronary deaths are due to either a primary ventricular fibrillation or a
ventricular fibrillation secondary to a ventricular tachycardia. Hence we can assume that the antiarrhythmic agents modify
[I-E] in some extent. Clearly, proviso (3) is not met.
The closeness lemma
Another important lesson form this story, is an illustration of the “closeness lemma”. This lemma said that more a side-effect
is close to the therapeutic objective of a therapy, less it is easy to sort out. Take a 58 year old man, with a history of acute
myocardial infarction 10 months ago. He was watching Roland Garros tournament at TV with a couple of friends. After the
third set was won by Pit Sampras, he turned pale, and quickly collapsed. His friends know a little of cardiac reanimation and
went on to maintain a low blood flow until an emergency mobile care team (SAMU) came in, recorded a ventricular
fibrillation at the EKG and delivered him several cardiac electric shocks that restored normal beatings. The patient was
taking flecainide since his MI because he had frequent VPBs on his discharge EKG. What was the culprit of this cardiac
arrest? Was it the underlying coronary disease or the drug? Before CAST, the coronary disease would have been the single
suspect. Adding more cases, would not have made the issue clearer. In such a setting, the (potential) drug side effect mimics
quite closely, or even is indistinguishable from, one of the clinical outcomes of the disease, and even the one the drug is
supposed to prevent, as in the antiarrhythmic agent story. Traditional pharmacovigilance cannot be efficient in such
instances. Only randomised, placebo controlled trials could sort out the increase incidence of sudden death or cardiac arrest.
First year mortality rate in treated groups (%)
Figure 1
35
30
25
20
15
10
b
5
0
0
10
So
20
30
40
First year mortality rate in control groups (%)
50
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Figure 2
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Figure 3
Figure 4
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Figure 5
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Tableau 1
trials
test drug
Collaborative Group
phenytoin
Kosowsky
Nielsen
Peter
procainamide
procainamide
phenytoin
GRAP
Bastian
Rydén
Chamberlain
Bell
Smyllie
IMPACT
Gottlieb
CAST I
aprindine
tocainide
tocainide
mexiletine
mexiletine
mexiletine
mexiletine
aprindine
encainide flecainide
SWORD
Cowley
CAST II ST
CAST II LT ade
CAST II LT par
TOTAL
d-sotalol
lorcainide
moricizine
moricizine
moricizine
control
duration
year of control group
(m)
publication
RR
test group
low dose phenytoin
6
1971
N
283
deaths
26
%
9,2%
% 1 year
17,5%
N
285
deaths
23
%
8,1%
% 1 year
15,5%
87,8%
placebo
low dose phenytoin
24
6
24
1973
1978
1978
39
35
76
5
6
14
12,8%
17,1%
18,4%
6,6%
31,3%
9,7%
39
35
74
1
6
18
2,6%
17,1%
24,3%
1,3%
31,3%
13,0%
20,0%
100,0%
132,0%
placebo
placebo
placebo
placebo
placebo
placebo
placebo
placebo
5,5
6
4
1,5
1,5
9
12
10
1979
1980
1980
1980
1982
1984
1984
1987
1989
149
74
56
163
113
120
313
72
743
18
3
6
19
20
32
15
16
26
12,1% #DIV/0!
4,1%
8,6%
10,7% 20,3%
11,7% 31,1%
17,7% 79,0%
26,7% 91,6%
4,8%
6,3%
0,0%
3,5%
4,2%
151
72
56
181
103
120
317
71
755
11
4
6
24
12
23
24
13
63
7,3%
5,6%
10,7%
13,3%
11,7%
19,2%
7,6%
8,3%
#DIV/0!
11,7%
20,3%
34,7%
62,9%
81,8%
10,0%
0,0%
9,9%
60,3%
137,0%
100,0%
113,8%
65,8%
71,9%
158,0%
238,5%
placebo
placebo
placebo
placebo
placebo
5
1,5
0,5
18
18
1996
1993
1992
1992
1992
1572
47
660
574
109
2962
48
1
3
42
15
109
3,1%
2,1%
0,5%
7,3%
13,8%
1549
48
665
581
110
2953
78
9
17
49
10
163
5,0%
18,8%
2,6%
8,4%
9,1%
11,7%
81,0%
46,3%
5,7%
6,2%
164,9%
881,3%
562,4%
115,3%
66,1%
7,2%
15,8%
10,4%
4,9%
9,4%
p
0.006
0.015
0.02
0.40
0.38
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