Journal of Clinical Epidemiology 53 (2000) 335–342

COMMENTARY
The classics: a tribute to the fiftieth anniversary of the
randomized clinical trial
Flávio D. Fuchsa,*,1, Michael J. Klag b, Paul K. Wheltonc
a
Divisions of Cardiology and Clinical Pharmacology, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul,
Porto Alegre, RS, Brazil
b
Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins University, Baltimore, MD
c
School of Public Health and Tropical Medicine, Tulane University Medical Center, New Orleans, LA
Received 29 April 1998; revised 9 September 1999; accepted 10 September 1999

In 1998 we celebrated the fiftieth anniversary of the first
randomized clinical trial (RCT) [1]. Describing the plan and
conduct of a controlled study on the effects of streptomycin
in patients with tuberculosis (see below) the authors stated:
“determination of whether a patient would be treated by
streptomycin and bed rest or by bed rest alone was made by
reference to a statistical series based on random sampling
numbers drawn up for each sex and each centre by Profes-
sor Bradford Hill.” This and other randomized controlled
clinical trials, some of them presented in this essay, gave
origin to a revolutionary transformation in the standards of
medical practice. This essay aims to honor the scientists
who pioneered the development of methods for randomized
clinical trials and the refinement of their application in
practice.
The second half of this century has seen a number of
striking discoveries and developments in the field of the
biomedical sciences. The emergence of new diagnostic de-
vices, drugs, organ transplants, as well as other interven-
tions, has markedly improved the delivery of care to pa-
tients. In addition to these achievements, we have entered
into the era of evidence-based medicine, which should also
be recognized as an outstanding advance in health care. The
RCT, a basic method for assessment of treatment efficacy,
is perhaps the finest example of this era of evidence-based
decision making in clinical practice.
This opinion is not universal, and some have even pre-
dicted the demise of the RCT [2]. The rationale for such
criticism is primarily based on a concern that patients in pla-
cebo-controlled studies are knowingly assigned to an inac-
tive treatment. Concern that the welfare of an individual
* Corresponding author. Hospital de Clinicas de Porto Alegre, Servico
de Cardiologia, Ramiro Barcelos, 2350, 90.035-003 Porto Alegre, RS, Bra-
zil. Tel.: ⫹55-51-316-8420, fax: ⫹55-51-333-1541.
E-mail address: ffuchs@hcpa.ufrgs.br (Flávio D. Fuchs)
1
Dr. Fuchs was, at the time of preparing this manuscript, a visiting pro-
fessor at the Welch Center for Prevention, Epidemiology and Clinical
Research, The Johns Hopkins University, Baltimore, MD.
0895-4356/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved.
PII: S0895-4356(99)00 1 8 5 - 7
should prevail over the interest of science and society does
not, however, preclude participation in clinical trials, be-
cause a new therapy may result in harmful as opposed to the
hoped-for beneficial outcome. In fact, the placebo interven-
tion is sometimes superior to the new treatment. While we
must continue to explore alternative options for evaluating
the efficacy of new treatments, there is no obvious substi-
tute for the RCT at the present time.
Challenges such as difficulties in modeling complex hu-
man behavior, concern about generability, limitations in the
capacity to recognize a small treatment effect size, and an
inability to conduct trials of sufficient length to mimic treat-
ment of chronic disorders in clinical practice are still press-
ing concerns. Observational studies are often necessary to
complement the observations of a RCT, or in some cases
provide answers that cannot be answered by means of a
RCT. Other concerns about the intrinsic weaknesses of clin-
ical trials relate to misconduct and misinterpretation of re-
sults, rather than to the method itself [2].
Some of the greatest progress in drug treatment has ema-
nated from experience in case series, in which patients man-
aged with old therapies served as the comparison group.
The use of chlorpromazine in patients with schizophrenia,
for example, was initially supported by results from a single
study with just 38 patients [3]. Clinical trials, however, were
subsequently conducted to confirm the efficacy of chlorpro-
mazine compared to placebo [4], to delineate its effects in
different circumstances, and to evaluate the possible superi-
ority of new antipsychotic drugs in schizophrenia [5,6]. The
powerful effect of antibiotics in bacterial endocarditis pro-
vided another context in which it was feasible to demon-
strate therapeutic effectiveness in nonrandomized trials [7].
However, the benefit of antimicrobials in many other infec-
tious diseases is still debated [8], and will only be resolved
when the scientific underpinning of therapeutic recommen-
dations is strengthened by knowledge from RCTs.
In many circumstances, the size of the benefit or risk as-
sociated with a proposed treatment of substantial potential
therapeutic importance has been small enough that its effi-
336 F. Fuchs et al. / Journal of Clinical Epidemiology 53 (2000) 335–342
cacy could only be convincingly demonstrated in a con-
trolled clinical trial. As a result of these trials, it has been
possible to prevent or alleviate the suffering of many per-
sons. The exposure of clinical trial participants to the poten-
tial risk of a harmful or ineffective treatment, with voluntary
consent, appears to be largely compensated by the subse-
quent ability to apply the trial findings in clinical practice.
Despite the limitations of clinical trials, contemporary med-
icine rests on the results of these studies, as is illustrated by
the following examples, which represent classic case studies
in the conduct of RCTs. Comparing the results of these
studies with the practice of medicine at the time the trials
were conducted underscores the substantial work that needs
to be done to provide a rational basis to various areas of
therapeutics.
The criteria for inclusion of a randomized trial in this ar-
ticle were somewhat arbitrary. Trials were chosen on the ba-
sis of on their innovation in design characteristics under the
prevailing state of knowledge at the time they were per-
formed, and the consequence of their results on medical
practice. Most importantly, they were chosen because in
their absence patients would have been denied access to
beneficial treatments or would have been exposed to delete-
rious or ineffective approaches to treatment. The list also re-
flects our subjective judgments. Our original plan was to in-
clude only 10 studies. It was so difficult, however, to limit
the list to 10 studies that we finally included 11 trials. Read-
ers may well consider additions, deletions, or a completely
different list of trials. Despite this, we hope that everyone
agrees that this or an alternative list supports the notion that
the results of clinical trials have proven to be of great bene-
fit in the care of patients. The 11 trials we have chosen are
presented in chronological order.
Marshall G, Blacklock JW, Cameron C, et al.
Streptomycin treatment of pulmonary tuberculosis.
Br Med J 1948;2:769–82
The benefits of antibiotics were first realized in the
fourth decade of the 20th century, but their role in the man-
agement of chronic infectious diseases was uncertain. Uni-
lateral pulmonary tuberculosis was treated by means of col-
lapse therapy (i.e., therapeutic pneumothorax). The only
treatment considered suitable for patients with bilateral dis-
ease was bed rest. Based on the in vitro effect of streptomy-
cin, the results of animal experiments, and preliminary find-
ings in humans, the Medical Research Council (England)
decided to evaluate the effects of streptomycin in patients
with pulmonary tuberculosis in a controlled clinical trial.
The major criterion for enrollment was the presence of
acute bilateral pulmonary disease that was bacteriologically
proven to be tuberculosis. Patients with unilateral disease
were treated with collapse therapy, which at that time was
assumed to be an effective method of treatment. For the first
time, the allocation of patients to the active treatment (strep-
tomycin and bed rest) or to control (bed rest alone) was
Table 1
Comparison of streptomycin and bed rest with bed rest alone in the
management of patients with bilateral pulmonary tuberculosis (adapted
from Marshal et al., Br Med J 1948;2:769–82)
Assignment Improved Same Worse Died
Streptomycin (55) 31 (56%) 4 (7%) 8 (15%) 12 (22%)
Control (52) 16 (31%) 5 (10%) 7 (13%) 24 (46%)
based on random sampling using a table of random num-
bers. No a priori estimate of the sample size necessary to an-
swer the question was presented, but after 6 months of fol-
low-up the benefit of the active treatment was large enough
to convincingly demonstrate the efficacy of streptomycin
(Table 1). The attributable benefit (deaths in the control group
minus deaths in the streptomycin group) corresponded to
the additional survival of 24 patients for every 100 who
were treated with streptomycin. A nonspecified statistical
test showed that the probability that this difference occurred
by chance alone was less than 1 in 100. The drift from in-
patient hospital treatment to outpatient-based care of patients
with tuberculosis, with a mass closing of wards and hospi-
tals exclusively dedicated to the care of patients with tuber-
culosis, is testimony to the effectiveness of streptomycin
and other drugs in the medical management of tuberculosis.
The authors of this study referred to a previously con-
ducted controlled but not randomized trial that deserves
mention. The study conducted in the 1920s by Amberson,
McMahon, and Pinner [9] was designed to investigate
whether gold salts, which were being commonly prescribed
for treatment of patients with tuberculosis, had a beneficial
or adverse effect. This study was not included in our list be-
cause it is not strictly a randomized trial of patients. On the
basis of clinical, X-ray, and laboratory findings, two groups
of 12 patients were individually matched. Then, by the flip
of a coin, the groups were allocated to receive or not receive
sanocrysin, the compound with the highest amount of gold.
Patients were not aware of the difference in their treatment.
During the trial, five of the 12 patients allocated to sano-
crysin experienced a deterioration in their clinical status. In
contrast, only one experienced a deterioration in the control
group. Four patients treated with sanocrysin developed se-
vere adverse effects and one died. In contrast, no one died in
the control group. Besides contributing to the demise of
therapy with gold salts (unfortunately over a fairly long du-
ration of time), this splendid study inspired the second com-
parative study of anti-tuberculosis treatments, the first to
employ random allocation of patients, per se.
Cobb LA, Thomas GI, Dillard DH, Merendino KA,
Bruce RA. An evaluation of internal-mammary-artery
ligation by a double-blind technic. N Engl J Med 1959;
260:1115–18
The clear benefit of several surgical approaches, such as
the alignment of broken bones, excision of gangrenous ex-
 F. Fuchs et al. / Journal of Clinical Epidemiology 53 (2000) 335–342
tremities, and hemostasis of traumatic wounds, built an his-
torical a priori belief in the efficacy of surgery. This study
was, apparently, the first randomized surgical trial to show
the powerful placebo effect of surgery. Its conduct was in-
spired by prior experience in a comparative but nonrandom-
ized trial [10], and by the results from the first crossover
trial of drug therapy in patients with angina pectoris [11], a
syndrome in which many sufferers respond to placebo.
After its introduction by Italian surgeons, an operative
procedure in which both mammary arteries were ligated
was one among several proposed to treat angina. It was en-
thusiastically accepted by some American surgeons in the
1950s. It was thought that blood from the mammary arteries
would be diverted to the coronary circulation through col-
lateral channels proximal to the site of ligation. In a pioneer-
ing clinical trial, Cobb and collaborators randomized 17 pa-
tients with severe angina pectoris to internal mammary
bypass or to a sham surgical procedure. The investigators
limited enrollment to patients with severe angina, based ex-
clusively on the presence of angina induced by effort. In
each patient, surgery was conducted under local anesthesia,
and was identical until both internal mammary arteries were
isolated. At this point, the surgeon opened a sealed envelope
that contained instructions regarding whether the internal
mammary arteries should or should not be ligated. The in-
vestigators took special care to maintain blinding of the pa-
tients to the choice of their surgery. They were told that they
were participating in an evaluation of the new internal
mammary artery ligation procedure, which had already been
acclaimed as a success in the Reader’s Digest. Likewise, the
physicians who evaluated the patient’s postoperative expe-
rience were not informed as to the surgery that was actually
performed in the operating room. The results showed that
the number of nitroglycerin tablets used was reduced by
42% in those whose internal mammary arteries were not li-
gated and by 34% in their counterparts whose internal mam-
mary arteries were ligated. In each group, five patients re-
ported a significant improvement after their surgery. One
patient, whose arteries were not ligated, claimed complete
relief to the extent that he was able to return to work.
This trial radically influenced the evaluation of surgical
procedures proposed to treat coronary artery disease, leading
to the execution of large and well-designed trials [12–14].
Barrit DW, Jordon SC. Anticoagulant drugs in the
treatment of pulmonary embolism. A controlled trial.
Lancet 1960;1:1309–12
By the end of the 1950s, heparin and oral anticoagulants
had been used in the treatment of thromboembolic diseases
for almost a quarter of a century, but uncertainty about the
balance between the risks (bleeding) and benefits of these
agents still prevailed. Based on a case series of 1135 pa-
tients with venous thrombosis it was generally concluded
that the use of anticoagulants had not influenced the inci-
dence of massive pulmonary embolism, despite the absence
337
of a control group [15]. The results of a much smaller, but
controlled, study by Barrit and Jordan supported the oppo-
site view. They studied patients with a clinical diagnosis of
pulmonary embolism based on the presence of acute right-
sided heart failure (faintness, central chest pain, a fall in
blood pressure, and a rise in jugular venous pressure to-
gether with changes in the electrocardiogram) or the pres-
ence of pulmonary infarction (pleuritic pain, haemoptysis,
fever, pleural friction, loss of resonance at the lung base,
rales, and changes in the bedside chest radiograph). The
principal outcome, death attributable to recurrence of embo-
lism demonstrated on necropsy, would be recognized as a
very hard outcome event today. Allocation to the active
treatment or control group was based on written instructions
contained in a sealed envelope with an equal number of as-
signments to each arm. As such, treatment allocation was
not strictly random. Given the other strengths of this study,
and the assumption that any bias in allocation would merely
have diminished the treatment effect size, we decided to in-
clude it in our series.
The incidence of fatal embolism among the 16 patients
treated with heparin followed by an oral anticoagulant was
zero, compared to an occurrence of five deaths from pulmo-
nary embolism among the 19 patients in the control group.
An additional five cases of recurrent nonfatal embolism oc-
curred in the control group while none was noted in the ac-
tive treatment group. One patient treated with anticoagu-
lants died as a consequence of pneumonia and complications
of gastrointestinal bleeding. Thus, the results suggested that
a total of 46 patients could be protected from recurrent pul-
monary embolism or death for every 100 who were treated
with anticoagulants. The number necessary to treat in order
to prevent one death or recurrence of nonfatal pulmonary
embolism was only two patients.
Because of the strong effect observed in the controlled
phase of the study, the authors subsequently began to pre-
scribe anticoagulants to all of their patients with pulmonary
embolism. Using this approach, they treated an additional
38 patients, all of whom were alive at the end of their study.
Recurrence of pulmonary embolism was noted in only one
instance. Since then, heparin and oral anticoagulants have
been standard treatment for venous thromboembolic dis-
eases, and they are the standard against which any new anti-
thrombotic therapy must be tested.
Various Authors. Rheumatic fever in children and
adolescents: a long-term epidemiologic study of
subsequent prophylaxis, streptococcal infections,
and clinical sequelae. Ann Intern Med 1964;
60(suppl. 5):1–129
This classic is, in fact, a series of seven papers published
as a supplement to the Annals of Internal Medicine, each of
them with different first authors from the Irvington House,
New York. The first authors are H. F. Wood, A. Taranta,
and A. R. Feinstein. The papers describe the rationale,
338 F. Fuchs et al. / Journal of Clinical Epidemiology 53 (2000) 335–342
methods, and results of an elegant randomized study, in
which the authors investigated the effect of three antibiotics
on the incidence of streptococcal infection and recurrence
of rheumatic fever. This study may have been one of the
first to employ stratified randomization to control for poten-
tially confounding covariables. Accordingly, before ran-
domization the participants were stratified into eight groups
according to the presence or absence of heart disease, age
(5–9 or 10–18 years), and duration of freedom from rheu-
matic activity (3–14 months or 15 or more). The three regi-
mens of antibiotics compared in the study were benzathine
penicillin G, 1,200,000 units IM every 4 weeks, buffered
potassium penicillin G, 200,000 units/day orally in a single
dose before breakfast, and sulfadiazine, 1 g/day orally in a
single dose. The attention to all details of the clinical inves-
tigation, including the precise criteria for selection of partic-
ipants and for diagnosis of streptococcal infection and re-
currence of rheumatic fever, as well as the investigators’
perseverance in following 431 children and adolescents for
a mean time of 3.6 years, make this trial a model for studies
of its time. The two groups treated with oral medication had
a lower degree of treatment adherence than the group
treated with the parenteral regimen. The authors recognized
the difficulties in maintaining and measuring compliance in
studies with this long follow-up, a problem that is still diffi-
cult to resolve in trials and in clinical practice.
The results were remarkable: 2 cases of recurrence of
rheumatic fever among 156 patients allocated to the
parenteral regimen versus 30 among 159 recipients of oral
penicillin, and 16 cases among the 156 participants treated
with oral sulfadiazine. The authors presented the incidence
rate per group, certainly an innovative approach at that time.
The corresponding numbers were 0.4, 5.5, and 2.8 cases per
100 patient-years, respectively. The beneficial effects of the
depot penicillin were evenly distributed among the various
clinical strata. The incidence of streptococcal infections was
also significantly reduced in the group treated with benza-
thine penicillin. In the remaining papers of the supplement
the authors presented a meticulous description of the clini-
cal, laboratory, radiological, and electrocardiographic
events that occurred in the trial. This information still con-
stitutes a rich a treasure trove of information on rheumatic
fever and its sequelae. The significance of this trial’s main
result, however, is best represented by the fact that, 35 years
later, it still forms the foundation for the guidelines to pre-
vent recurrence of acute rheumatic fever.
Veterans Administration Cooperative Study Group on
Antihypertensive Agents. Effects of treatment on
morbidity in hypertension. Results in patients with
diastolic blood pressures averaging 115 through
129 mmHg. JAMA 1967;202:1028–34
The presumption that drug treatment of malignant and
severe arterial hypertension would reduce the incidence of
fatal and morbid events in patients with hypertension was
shared by most physicians in the 1960s. At lower levels of
blood pressure, however, it was not clear whether antihy-
pertensive medication would be beneficial. This uncertainty
was the basis for the conduct of this classic clinical trial.
The selection of participants was meticulous. All were hos-
pitalized for 6 days and only male patients whose diastolic
blood pressures averaged 90 through 129 mmHg without
treatment from the fourth through the sixth day of their hos-
pitalization were considered for admission to the preran-
domization period of the trial. Patients with a higher score
of severity, based on blood pressure and the degree of clini-
cally detectable end organ damage, were excluded. Follow-
ing their discharge from the hospital, potential trial partici-
pants entered a prerandomization trial period of 2–4 months
of duration, during which they received placebo treatment
with riboflavin, in order to select those who were the most
compliant pill takers (50% were excluded). The terminating
events defined by the investigators were death or class “A”
events (mainly hemorrhage of one or both optic fundi), or
treatment failure (primarily hospitalization with high blood
pressure or adverse effects of the study drugs). A second
group of events (class “B”) were nonterminating but in-
cluded serious outcomes, such as cerebrovascular accidents,
congestive heart failure, and myocardial infarction. After 2
years, a strong treatment benefit emerged in patients with a
baseline diastolic blood pressure equal to or greater than
115 mmHg. Classification of the author’s findings accord-
ing to a more current definition of “hard outcomes” yelds
the results presented in Table 2. The only class “A” termi-
nating event that is not included in the table was a patient
assigned to active drug therapy who developed hyperglyce-
mia and depression. Only one hard endpoint, a case of non-
fatal cerebrovascular thrombosis, occurred in the active
treatment group. Based on the results of this trial, one could
estimate that treatment of only three patients with severe hy-
pertension for 2 years would prevent a major adverse outcome.
A parallel trial in patients with an entry diastolic blood
pressure between 105 and 114 mmHg identified a smaller
Table 2
Number of events in patients with an initial diastolic blood pressure
averaging 115 through 129 mmHg who were randomly allocated to active
treatment with antihypertensive medications or to placebo (adapted from
Veterans Administration Cooperative Study Group on Antihypertensive
Agents. JAMA 1967;202:116–22)
Placebo Active
Events (n ⫽ 70) (n ⫽ 73)
Death 4 0
Cerebrovascular accident 5 1
Myocardial infarction 2 0
Congestive heart failure 4 0
Retinal hemorrhage 7 0
Elevation of creatinine or urea 2 0
Total 24 1
 F. Fuchs et al. / Journal of Clinical Epidemiology 53 (2000) 335–342
benefit of treatment [16]. A lack of statistical power pre-
cluded evaluation of treatment effects in patients with lower
blood pressure values. More than 30,000 patients were ran-
domized in subsequent trials in order to document the
smaller absolute benefit of antihypertensive drug therapy in
patients with less severe hypertension, first in younger pa-
tient [17], and subsequently in the elderly [18–20].
According to some critics of clinical trials, this study
should not have been performed, because the expectation of
benefit in severe hypertension was relatively high. How-
ever, this viewpoint is consistent with the opinion that all
new drugs capable of reducing blood pressure can be safely
used for treatment of hypertension without the need for their
formal comparison with older agents to determine if they re-
duce morbidity and mortality. The current controversy sur-
rounding use of calcium antagonists in hypertensive pa-
tients [21] demonstrated that clinical trials are still essential
requirement for determining the optimal approach to treat-
ment of such patients.
The EC/IC Bypass Group. Failure of extracranial–
intracranial arterial bypass surgery to reduce risk of
ischemic stroke. N Engl J Med 1985;313:1191–200
This rigorously conducted trial included 1377 patients
who had suffered one or more transient ischemic attacks or
a minor completed stroke in the carotid distribution area.
All had to have radiological evidence of severe atheroscle-
rotic lesions in the trunk of major branches before the mid-
dle cerebral artery or in the internal carotid artery at a loca-
tion that was inaccessible to carotid endarterectomy. The
participants were randomly assigned to the best medical
care or to the same treatment with the addition of bypass
surgery intended to join the superficial temporal artery and
the middle cerebral artery. The surgical patients fared worse
than their counterparts assigned to the nonsurgical control
group. Most of the difference in treatment effect occurred
during a 39-day perioperative period. During this phase of
the study, 4.5% of the surgical patients experienced a fatal
or nonfatal stroke, compared to a corresponding incidence
of 1.3% in those allocated to medical therapy. A less dra-
matic difference persisted during the remaining 55.8 months
of the follow-up. Another important feature of this study
was the fact that it involved the cooperation of a large num-
ber of surgeons in several countries, an example that will
have to emulate if we are to obtain unambiguous and exter-
nally validated answers for many of the complex therapeu-
tic questions that face us in clinical practice.
As a consequence of this study, other surgical ap-
proaches to the treatment of cerebral ischemia resulting
from carotid artery disease have been evaluated in random-
ized controlled studies before being accepted as efficacious
in patients with various degrees of carotid artery obstruction
[22]. Medical therapies for acute cerebrovascular events
have also been tested in rigorous RCTs, but a consensus re-
339
garding the use of medications and the timing of their ad-
ministration has yet to be reached [23].
With the inclusion of the EC/IC bypass study and the
trial of Cobb et al. (see above), we honor those surgeons
who have employed the clinical trial as a gold standard for
evaluating the efficacy of their treatments, often performing
their investigations under challenging conditions.
We also owe a debt of gratitude to the physicians who
have used randomized clinical trials to investigate the use-
fulness of other nondrug therapies. Evaluation of the effects
of photocoagulation in diabetic retinopathy by The Diabetic
Retinopathy Study Research Group is a good example of
such a trial [24]. Enrolling more than 1700 patients in a
multicenter cooperative study, and taking special care to
control for multiple comparisons, the investigators in this study
showed that photocoagulation reduced the incidence of signifi-
cant acuity loss by 57%. Contemporaneous interventions, such
as angioplasty and other revascularization techniques, are now
under close scrutiny in randomized clinical trials.
Fischl MA, Richman DD, Grieco MH, et al. The efficacy
of azidothymidine (AZT) in the treatment of patients
with AIDS and AIDS-related complex. A double-blind
placebo-controlled trial. N Engl J Med 1987;317:185–91
This and the remaining classical trials that we have cho-
sen for inclusion in our review were planned and conducted
with the implicit belief that the randomized trial is an almost
indispensable element in evaluating the efficacy of a new
treatment, and with the knowledge that national agencies,
such as the Food and Drug Administration, would require
clinical trial experience before granting approval for use of
such treatments in clinical practice. This particular trial
dealt with a very sensitive area, a new infectious disease
with a poor prognosis at the time that the study was initi-
ated. Instead of submitting a large number of patients to un-
controlled and dubious observations, this trial established
with great accuracy and precision the size of benefit af-
forded by the first active drug against HIV.
In this double-blind, placebo-controlled trial, 282 pa-
tients with the Acquired Immunodeficiency Syndrome
(AIDS), as manifested by Pneumocystis carinii pneumonia,
alone or as a component of the AIDS-related complex, were
randomly assigned to receive zidovudine (Azidotimidine or
AZT at that time) or placebo. Nineteen persons who re-
ceived placebo and one zidovudine recipient died during 24
weeks of observation (P ⬍ 0.001). Opportunistic infections
developed in 45 participants who received placebo, com-
pared with 24 of those who were treated with zidovudine.
Serious adverse effects of the treatment, particularly bone
marrow suppression, were observed but they did not nullify
the benefits of zidovudine therapy [25].
Based on the results of this trial, zidovudine became the
standard against the efficacy of new treatments have been
tested.
340 F. Fuchs et al. / Journal of Clinical Epidemiology 53 (2000) 335–342
Bone RC, Fisher CJ, Clemmer TP, et al. A controlled
clinical trial of high-dose methilprednisolone in the
treatment of severe sepsis and septic shock. N Engl J
Med 1987;317:653–8. The Veterans Administration
Systemic Sepsis Cooperative Study Group. Effect of
high dose glucocorticoid therapy on mortality in
patients with clinical signs of systemic sepsis.
N Engl J Med 1987;317:659–65
Neither of these papers had the primacy to be nominated
alone, because they are complementary and were published
in the same issue of New England Journal of Medicine.
Therefore, our list that was originally planned to have 10
classics has 12 papers! The two trials of steroid therapy in
sepsis were chosen to symbolize the importance of trials
with negative results. The criteria of inclusion were prima-
rily based on the presence of septic syndrome accompanied
by some degree of hypotension. In the study of Bone et al.,
34% of 191 patients randomized to high doses of methyl-
prednisolone died, compared to 25% of 190 patients who re-
ceived placebo (P ⫽ 0.06). In the study conducted by The
Veterans Administration Systemic Sepsis Cooperative
Study Group, 22% of 112 patients treated with methylpred-
nisolone died versus 21% of 111 patients who received pla-
cebo (P ⫽ 0.97).
Both of these trials were well-designed and addressed a
controversial topic. At the time of their execution, large
books could have been written about the results of animal
experiments and uncontrolled observations of the effects of
glucocorticoids in sepsis. Despite this, there was no cer-
tainty as to the effect of steroid therapy in patients with sep-
sis. These trials settled the controversy and redirected both
the clinical care of patients with sepsis and research aimed
at improvements in therapy of such patients.
ISIS-2 Collaborative Group. Randomized trial of
intravenous streptokinase, oral aspirin, both, or
neither among 17,187 cases of suspected acute
myocardial infarction: ISIS-2. Lancet 1988;2:349–60
A powerful effect of thrombolytics in acute myocardial
infarction was suggested by results from several small trials
and subsequently demonstrated in a convincing manner by
the GISSI trial [26]. In order to comply with our self-
imposed constraint on the number of trials to be presented
in this review, we chose to select the ISIS-2 trial from the
many evaluations of thrombolytic agents employed in the
treatment of acute myocardial infarction. We based this
choice on the investigator’s wisdom and creativity in testing
the effects of a very old and inexpensive treatment, aspirin.
Trial procedures in the ISIS-2 trial were intended to be as
simple as possible, involving randomization by telephone
call with no use of written study forms, and a follow-up
after discharge that was confined to monitoring for mortal-
ity. The fundamental criterion for inclusion was based on
the norms of clinical practice—a case of suspected myocar-
dial infarction for whom the responsible physician was un-
certain about the indication of streptokinase or aspirin. The
results showed that the protection conferred by 160 mg/day
of aspirin was equivalent to that provided by streptokinase
and that the effects of both drugs were cumulative. The ab-
solute benefit of treatment in terms of vascular mortality
was 24 patients per 1000 treated with aspirin, 28 per 1000
treated with streptokinase, and 52 per 1000 patients treated
with both drugs (a highly significant relative benefit of 42%
with both drugs). With the results of this trial and the GISSI
trial clinicians entered in the era of real treatment of myo-
cardial infarction.
Marshall BJ, Goodwin CS, Warren JR, et al.
Prospective double-blind trial of duodenal ulcer
relapse after eradication of Campylobacter pylori.
Lancet 1988;2:1437–42
Discovery of the infectious etiology of most cases of
peptic ulcer is mostly attributable to the perseverance of Dr.
Barry J. Marshall. He and other investigators identified
Campylobacter pylori bacillus in a series of patients with
ulcer and induced experimental ulcers in animals with the
inoculation of this bacillus. In an attempt to fulfill the re-
quirements of Koch’s postulates, he swallowed a flourish-
ing culture of the microorganism. A histologically docu-
mented gastritis was identified 10 days after the ingestion of
the culture [27]. This case report and various uncontrolled
studies demonstrating ulcer healing following treatment of
Campylobacter pylori were not sufficient to convince the
scientific community of the etiologic role of the bacteria in
peptic ulcer. The results of a randomized trial conducted by
Marshall and his collaborators (citation above) provided
more convincing documentation of the beneficial effects of
antimicrobial therapy in patients with duodenal ulcer. The
diagnosis of duodenal or pyloric ulcer both for enrollment
and efficacy evaluation was based on endoscopic findings.
The trial was relatively small (100 patients), various combi-
nations of bismuth, cimetidine, tinidazol (an antibiotic
known to be effective in the treatment of Campylobacter
pylori), and placebo were administered, and the analysis
was conditioned on eradication of the bacillus. Recognizing
these limitations, duodenal ulcer recurred after 1 year of fol-
low-up in 92% of 13 patients treated with cimetidine and
placebo compared to only 25% in 20 patients treated with
bismuth and tinidazol. Most of the Helycobacter pylori (the
new name for the bacillus)-free patients remained well 7
years after the active treatment [28]. Subsequent trials con-
ducted by Graham et al. [29] and others employed more rig-
orous techniques to demonstrate the efficacy of Helyco-
bacter pylori treatment in the prevention of recurrent peptic
ulceration.
Failure to recognize the infectious nature of peptic ulcers
for such a long period after the introduction of effective an-
timicrobial therapy can be regarded as an astonishing pitfall
of scientific medicine. Confirmation of Marshall’s original
 F. Fuchs et al. / Journal of Clinical Epidemiology 53 (2000) 335–342
findings in many subsequent trials provides the basis for our
current understanding that peptic ulcer results from Helyco-
bacter pylory infection or the use of anti-inflammatory
drugs [30].
The Cardiac Arrhythmia Suppression Trial (CAST)
Investigators. Preliminary report: effect of encainide
and flecainide on mortality in a randomized trial of
arrhythmia suppression after myocardial infarction.
N Engl J Med 1989;321:406–12
This is probably the study that best demonstrates the lim-
itations of surrogate endpoints in evaluating the efficacy of
different treatments. Everything in the planning phase of
this carefully conceived and conducted clinical trial pointed
to an expectation that antiarrhythmic drugs would reduce
risk in patients with a history of myocardial infarction and
assymptomatic or mildly symptomatic ventricular prema-
ture depolarizations. The rationale was logical because ven-
tricular arrhythmias were known to be independent predic-
tors of cardiac mortality and the drugs used in the trial were
effective in decreasing the number of ventricular premature
depolarizations. Following a careful open-label titration pe-
riod to identify those who responded to one of the drugs
with at least 80% suppression of their ventricular premature
depolarizations and at least 90% suppression of runs of ven-
tricular tachycardia, the trial participants were randomly as-
signed to one of the three active drugs or placebo. Unex-
pectedly, the incidence of death or cardiac arrest was 2.4
times higher in those treated with flecainide or encainide
compared to their counterparts who received placebo (8.5%
among 755 patients in the active treatment group compared
to 3.5% among the 743 patients in the placebo arm, a highly
significant difference). As a consequence, the encainide and
flecainide treatment evaluation was terminated prematurely.
A moricizine treatment arm was also stopped prematurely
because moricizine treatment was associated with excess
mortality compared to placebo during the first 14 days after
a myocardial infarction [31]. In addition to initiating a com-
plete reorientation in the treatment of patients with arrhyth-
mias, this trial has had profound impact on the interpretation
of trials in which surrogate endpoints have been used to es-
timate the benefit of treatment.
Conclusion
These studies share the fundamental common thread for
conduct of an RCT, uncertainty regarding the usefulness or
superiority of different therapies. In our review we included
studies that compared presumably active treatments with no
treatment (or placebo in most instances) or a control treat-
ment, in the case of the study of rheumatic fever. This char-
acteristic, together with the fact that some presented posi-
tive results and others showed an absence of any effect or
even an harmful outcome, highlights their importance in the
development of rational therapeutics. Pioneering of the
341
technique in the earliest studies and refinement of the study
methods in the more recent trials demonstrates the manner
in which the technique has become a progressively more
useful tool for clinical decision making. But more than this,
the importance of the clinical trial may be contemplated by
considering where we would be in the absence of such stud-
ies. For how long would patients with pulmonary tuberculo-
sis, unilateral or bilateral, have been treated with ineffica-
cious or even harmful therapies? Would patients with
ventricular arrhythmias still be taking dangerous antiar-
rhythmic agents in the false belief that they are of benefit?
The results of the trials presented and others like them have
propelled therapeutic decision making into a new and more
efficacious stage. Recognizing this, much more must be ac-
complished in the area of medical therapeutics. Further, the
success of clinical trials in therapeutics underscored the
need for application of RCT methods in other areas of con-
troversy in patient care. The study of cost-effectiveness is a
good example of a complementary area of research that
could be strengthened substantially by application of RCT
methodology to choice of therapies for use in communities.
We hope that this essay is a fitting tribute not only to the
authors of the trials described but to all clinical investigators
who are responsible for the design and conduct of similar
studies and to the patients who have participated in the tri-
als. Their commitment to the scientific method has provided
a more rational basis for treatment decisions and produced
relief and comfort for many patients who would otherwise
have been assigned to treatments of unproven worth.
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