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......................m......................... Specific guide to this web site for:
Additional Topics: Large Randomized Clinical Trials
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This is the initial letter written to trial investigators bringing to their
attention the multiple problems with the trial protocol and suggestions for
improvement. This letter was sent to the directors of the study and some other
leaders in the field of cardiology.
Dear Dr.
Braunwald, I am writing because of my concern about the
ongoing TIMI IIIB trial. As you know the TIMI IIIB trial is designed to evaluate
the comprehensive management of patients with unstable angina and non-Q-wave
myocardial infarction. An invasive revascularization strategy is compared to a
conservative management strategy. Both treatment strategies have a protocol arm
with and without TPA. The TIMI IIIB trial appears to have
potential limitations in protocol design that may negatively impact the value of
the trial. results. One problem is that many of the patients undergoing
angioplasty in the invasive group will not have received adequate pretreatment
with aspirin. Another potential limitation in protocol design is that the
endpoints of the trial are analyzed earlier (at six weeks and one year) than may
be ideal for a comparison of a revascularization strategy with a medical
management strategy. Though this time frame may be adequate for evaluating the
effects of TPA, it may not be sufficient for evaluating a surgical intervention.
Finally, the TIMI IIIB trial data will be used to help evaluate the appropriate
role of coronary angiography in patients presenting with unstable angina and
non-Q-wave myocardial infarction. The protocol should include plans to report
the percentage of patients undergoing cardiac catheterization in the
conservative strategy at six weeks, one year, and all subsequent planned follow
up endpoints, I. Inadequate Pretreatment with Aspirin
Prior to Angioplasty in TIMI IIIB Trial There is a major potential problem with the
TIMI IIIB protocol which may have a substantial negative impact on the outcome
of the patients treated with the invasive strategy. The patients in the invasive
strategy by protocol design will in large numbers not be pretreated with aspirin
for adequate periods of time prior to undergoing angioplasty. The protocol
states that aspirin will not be administered during the first 24 hours after
randomization and will be started on day two at a 80mg. dose.
The protocol also calls for the patients in the invasive strategy to
undergo angiography 24 to 48 hours after randomization. Percutaneous
transluminal angioplasty, if indicated, will be performed at the same time as
the cardiac catheterization. This results in many patients in the
invasive treatment strategy not be pretreated with aspirin for an acceptable
period of time prior to undergoing angioplasty. As an example, a patient who is
randomized to the invasive strategy and undergoes cardiac catheterization and
percutaneous transluminal angioplasty 24 hours after randomization will not have
received aspirin. At the far end of the spectrum, patients with unstable angina
in the invasive strategy needing percutaneous transluminal angioplasty at the
most will have received 80 mg. of aspirin 24 hours prior to the procedure. All
the patients in this group fall somewhere between these two extremes. This differs from the current standard of
optimal care which is the treatment with aspirin and heparin prior to performing
percutaneous transluminal angioplasty after a patient presents with unstable
angina. In addition, the low dose of 80 mg. of aspirin may conceivably not be
adequate given the short duration between the time it is given to the patient
and the time the angioplasty is performed. Though an 80 mg. aspirin dose has
positive clinical benefits in patients with unstable angina, this smaller dose
of aspirin may possibly take a longer time period to produce clinically reliable
antiplatelet effects needed to reduce the acute reocclusion rate occurring with
angioplasty. Modification of the TIMI IIIB trial needs to be evaluated and
addressed before it progresses further from its current stages of patient
enrollment. II. Premature Evaluation of "points at
Six Weeks when Comparing Invasive and Noninvasive Strategies for Unstable Angina
and Non-Q-wave MI in TIMI IIIB The TIMI IIIB trial is currently designed to
have as the primary endpoint an assessment at six weeks of the differences
between the treatment groups for myocardial infarction, death, and exercise
treadmill test response. Follow up at one year is planned as well. This may not
be an adequate time frame to compare the clinical outcome of a revascularization
strategy to a conservative strategy particularly in this type of patient. Unstable angina is associated with a high
frequency of subsequent cardiac events for the first six to twelve months after
the initial presentation. Dr. Robert Califf presented the Duke experience (ACCEL
December 1989) which indicated that the risk of dying from unstable angina did
not return to the baseline of a patient with stable angina for six to twelve
months. The VA Cooperative Study of Unstable Angina documented a high frequency
of crossover from medical management to surgical therapy during the first
sixteen months following the initial randomization for unstable angina. Non-Q-wave myocardial infarctions have a
significant subsequent event rate occurring the first two years after the
initial event. Though the initial mortality is lower than a Q-wave myocardial
infarction, the overall mortality and morbidity for a non-Q-wave myocardial
infarction becomes similar to a Q-wave infarction two years after the initial
infarction because of a higher rate of subsequent cardiac events. Hence, both
unstable angina and non-Q-wave myocardial infarction continue to have a
relatively high frequency of events after presentation that persists beyond six
weeks and extends up to one year if not two years. The TIMI IIIB trial should
have as its primary endpoint a comparison of cardiac events at one year with
subsequent follow up at two years and three years. The study should continue
follow up through the time period when a high rate of subsequent cardiac events
and crossovers from medical to surgical treatment are expected. Comparing endpoints at six weeks clearly has
potential problems particularly when comparing a medical treatment strategy to a
revascularization strategy. Both coronary artery bypass surgery and angioplasty
have many of their untoward clinical events occurring early in tithe course of
treatment as perioperative myocardial infarctions and fatalities.
The
differences in outcome between medical treatment and surgical treatment can take
several years to develop. The CASS study as an example showed a
significant reduction in the mortality of patients undergoing surgery who had
decreased left ventricular function and triple vessel disease. This difference
in outcome was not present at one year, but developed in later subsequent follow
up. If longer follow up of the treatment groups had not been continued, this
important difference in treatment outcomes would not have been substantiated.
Though trials such as the VA Cooperative Study of Unstable Angina in patients
with abnormal left ventricular function have shown a difference between
treatment groups developing by one year , this does not provide a guarantee that
significant differences will be manifest within the initial first year. Analysis
at six weeks or even at one year of a trial comparing medical versus surgical
therapy may miss important differences in outcome. The publication of the TIMI II trial data at
one year does not provide reassuring information that a one year time period of
follow up is sufficient. One week after randomization, the invasive group had a
statistically significant higher incidence of death and myocardial infarction
than the noninvasive group (8.9% cardiac event rate invasive group vs. 6.3%
noninvasive group, p !5.05). However, after the initial first week of
randomization and treatment there has been a contrasting trend of lower cardiac
events in the invasive strategy group. Because of this trend, there was a
cumulative lower incidence of cardiac events in the invasively treated group
after one year of follow up (14.5% cardiac event rate invasive group vs. 15.1%
noninvasive group, NS). The subsequent lower cardiac event trend for
the invasively treated group persisted not only in the one week to six week
follow up time period, but continued as well in the six weeks to one year follow
up time frame. Does this trend of lower cardiac events in the invasive group
continue after one year? If such a trend did continue, it is conceivable
that a statistically significant difference may develop between the groups.
There is no way of knowing if this trend persists unless the TIMI II trial
publishes results at two years and three years of follow up. Judging from prior
trials comparing surgical versus medical therapy, differences may be seen after
the first year of randomization. Particularly with a sustained apparent
difference in cardiac event rates between treatment groups, it would seem
reasonable to continue follow up analysis past one year. Hence, the TIMI II
trial does not provide convincing evidence that six weeks or even one year of
follow up is definitely sufficient for assessing a revascularization versus a
medical treatment strategy even in the setting of a Q-wave myocardial infarction
(which has many of its subsequent cardiac events occurring relatively early
after initial presentation). III. Reporting the Percentage of Patients Undergoing Cardiac Catheterization in the Conservative Strategy Group Attempts to make recommendations for the appropriate use of cardiac catheterization in patients following thrombolytic therapy are being formulated on the basis of the TIMI II trial. Similarly, the results of the TIMI IIIB study are almost certain to be used in future discussions concerning the role of cardiac angiography in the setting of unstable angina and non-Q-wave myocardial infarction. A more complete reporting than was given in the TIMI II study of the percentage of patients undergoing cardiac catheterization in the conservative treatment strategy group will benefit the TIMI IIIB trial. Though the TIMI II results have
played prominently in discussions concerning the appropriate role of coronary
angiography after thrombolytic therapy, important information regarding this
issue from the TIMI II trial has not yet been released. What percentage of the
patients assigned to the initial conservative management approach underwent
cardiac catheterization? The only published data at this point indicates that
32.7% underwent cardiac catheterization after two weeks of randomization. What
percentage of these patients underwent cardiac catheterization after six weeks
of therapy and after completion of one year of follow up? If the number
requiring cardiac catheterization in the conservatively treated group by one
year is high in the 50 to 75% range, this has different implications for the
role of coronary arteriography in this study than if only a relatively limited
number of patients required cardiac catheterization by the end of twelve months. There is another important reason for making
known the data on the percentage of patients undergoing cardiac catheterization
at six weeks, twelve months, and all subsequent follow up endpoints. When a
study is analyzed to assess the impact of cardiac catheterization on morbidity
and mortality, what is actually being evaluated is a particular invasive
revascularization treatment strategy compared to a particular noninvasive
strategy. The particular conservative patient management strategy used in the
TIMI II trial is not fully described until the percentage of patients who
underwent coronary angiography is known. The percentage of patients undergoing
cardiac catheterization helps define the threshold for proceeding with
angiography used to obtain the excellent morbidity and mortality results that
were achieved in the TIMI II study. The TIMI IIIB trial would be similarly
benefited by reporting the percentage of patients undergoing cardiac angiography
at all planned follow up time intervals. SUMMARY The TIMI trials have yielded important
information regarding thrombolytic therapy. The TIMI IIIB trial addresses the
comprehensive management of unstable angina and non-Q-wave myocardial
infarction. The results of this trial will be used to help guide patient
management for this group of patients for years to come. Funding allotment for medical research and
clinical trials appears to be diminishing at a time when controlled clinical
trials will increasingly direct the way medicine in practiced in this country.
It becomes even more imperative that the trials which are undertaken address the
questions they attempt to answer in an optimum fashion, even if this requires
modification of a trial already in progress. Obviously, there will be more expense to the
TIMI IIIB trial if the primary cardiac endpoints are changed to one year and the
patient outcomes are followed for at least three years. However, the incremental
cost to follow and report the endpoints for a longer duration would be
relatively small compared to the total initial outlay of our national research
funds being used for this study. I know the time demands on basic and clinical
researchers are heavy, so please forgive the length of this letter. Thank you
for your patience and consideration in this matter. Sincerely
yours, Eric F. Roehm, M.D., cc: 1. TIMI IIIB protocol. Dec 7,1989. 2.
Califf, Robert. Unstable angina long-term
results. AHA 62nd Scientific Session: Plenary Session VIII, Nov 15, 1989. 3.
Mulcahy, et al. Natural history and
prognosis of unstable angina. Am Heart J 1985; 109:753-8. 4.
Wallentin, et al. Aspirin 75 mg. after an
episode of unstable coronary artery disease; effects on angina and need for
revascularization. Circulation 1989; 80 (Suppl II):II-419.5. Scott, et al.
Veterans Administration Cooperative Study for treatment of patients with
unstable angina; results in patients with abnormal left ventricular function.
Circulation 1988; 78 (Suppl I): 1-113-1-121. 6. Williams, et al. The TIMI Trial; outcome
at one year of patients randomized to either invasive or conservative
management. Circulation 1989; 80 (Suppl II);II-519. 7.
Passamani, et al. A randomized trial of
coronary artery bypass surgery: survival of patients with a low ejection
fraction. N Eng J Med 1985; 312:1665-71. 8. TIMI Study Group. Comparison of invasive
and conservative strategies after treatment with intravenous TPA in acute
myocardial infarction: results of the TIMI Phase II Trial. N Eng J Med 1989;
320:618-27. |