Tools for Evaluating Health Technologies: Five Background Papers Page: 71
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Large and Simple Randomized Trials I 71
cipal thrombolytic drugs, so a head-to-head com-
parison of the agents was carried out.
All patients in ISIS-3 received thrombolytic
drugs, with one-third of the study participants ran-
domly assigned to each agent. To detect meaning-
ful differences among the treatments, all of which
were expected to confer roughly comparable
benefits, 1S1S-3 randomized more than 41,000 pa-
tients. The trial provided statistically conclusive
evidence that there were no significant differences
between the three thrombolytic drugs in reducing
mortality following acute MI. Moreover, in terms
of the most serious adverse effects associated with
thrombolytic drugs, tPA and APSAC were shown
in ISIS-3 to be associated with significantly more
cerebral hemorrhages than streptokinase. The
three drugs differ substantially in cost, which
ranges from roughly $300 per dose for streptoki-
nase to approximately $1,700 for APSAC and
$2,200 for tPA.
A subsequently reported trial, GUSTO (Global
Utilization of Streptokinase and Tissue Plasmino-
gen Activator for Occluded Coronary Arteries),
which included comparisons of streptokinase and
tPA, suggested that a newer method of administer-
ing tPA very rapidly conferred a slight advantage
in reducing mortality over streptokinase (26).
Again, however, tPA was associated with a higher
rate of cerebral hemorrhage. Considerable contro-
versy has surrounded specific issues in the inter-
pretation of the GUSTO findings (41).
An issue raised by the findings from GUSTO
and other trials of thrombolytic agents is the need
to distinguish between differences in treatment ef-
fects that are statistically significant, based on
comparisons of tens of thousands of patients, and
those that are clinically meaningful in treating pa-
tients. In the case of streptokinase and tPA, cur-
rently available evidence from large-scale trials
suggests that emphasizing the differences in
thrombolytic agents' efficacy and safety is far less
important than encouraging their wider use, since
all of them confer clear benefits in a large propor-
tion of acute MI patients (41).I Testing Widely Practicable Treatments
The need to test widely practicable treatments is
another principle of large and simple trials. From
a public policy standpoint, a treatment is likely to
have a greater effect on public health if it can be
readily administered at most community hospitals
than if it is very complicated or expensive (or re-
quires specialized training or resources available
only at tertiary care facilities), even if the two
treatments confer the same degree of benefit.
For example, three recent small randomized
trials of treatments for acute MI patients compared
the effects of a clot-dissolving thrombolytic agent
with those of coronary angioplasty, a procedure in
which a balloon-tipped catheter is guided into the
blocked coronary artery and briefly inflated to re-
open the occluded vessel (22,23,53). In two of the
three trials, patients receiving angioplasty experi-
enced lower rates of mortal it y or recurrent MI than
did those receiving thrombolytic therapy (23,53).
The third trial found no clear evidence of a differ-
ence in the effects of the two treatment strategies
(22).
These results suggest that the two approaches
may be equally effective, or perhaps even that an-
gioplasty has a short-term advantage. Of far more
significance from a public health perspective,
however, is the fact that only 18 percent of U.S.
hospitals are capable of performing angioplasty,
with even fewer equipped to conduct emergency
coronary bypass surgery (which is necessary in
the small number of cases where a vessel abruptly
closes following angioplasty). Many acute MI pa-
tients in the United States probably live reason-
ably near hospitals equipped to perform angio-
plasties as well as emergency coronary bypass
surgery, but the widespread use of angioplasty
instead of thrombolytic therapy would greatly in-
crease the demands on such facilities and would
have tremendous implications for the level of cor-
onary care services required in U.S. hospitals.
Consequently, the editorial accompanying the
three trial reports concluded that "the strategy of
immediate angioplasty for acute myocardial in-
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United States. Congress. Office of Technology Assessment. Tools for Evaluating Health Technologies: Five Background Papers, report, September 1994; [Washington D.C.]. (https://digital.library.unt.edu/ark:/67531/metadc39759/m1/80/: accessed April 19, 2024), University of North Texas Libraries, UNT Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.