Context Controversy and uncertainty ensue when the results of clinical research
on the effectiveness of interventions are subsequently contradicted. Controversies
are most prominent when high-impact research is involved.
Objectives To understand how frequently highly cited studies are contradicted or
find effects that are stronger than in other similar studies and to discern
whether specific characteristics are associated with such refutation over
time.
Design All original clinical research studies published in 3 major general
clinical journals or high-impact-factor specialty journals in 1990-2003 and
cited more than 1000 times in the literature were examined.
Main Outcome Measure The results of highly cited articles were compared against subsequent
studies of comparable or larger sample size and similar or better controlled
designs. The same analysis was also performed comparatively for matched studies
that were not so highly cited.
Results Of 49 highly cited original clinical research studies, 45 claimed that
the intervention was effective. Of these, 7 (16%) were contradicted by subsequent
studies, 7 others (16%) had found effects that were stronger than those of
subsequent studies, 20 (44%) were replicated, and 11 (24%) remained largely
unchallenged. Five of 6 highly-cited nonrandomized studies had been contradicted
or had found stronger effects vs 9 of 39 randomized controlled trials (P = .008). Among randomized trials, studies with
contradicted or stronger effects were smaller (P = .009)
than replicated or unchallenged studies although there was no statistically
significant difference in their early or overall citation impact. Matched
control studies did not have a significantly different share of refuted results
than highly cited studies, but they included more studies with “negative”
results.
Conclusions Contradiction and initially stronger effects are not unusual in highly
cited research of clinical interventions and their outcomes. The extent to
which high citations may provoke contradictions and vice versa needs more
study. Controversies are most common with highly cited nonrandomized studies,
but even the most highly cited randomized trials may be challenged and refuted
over time, especially small ones.
Clinical research on important questions about the efficacy of medical
interventions is sometimes followed by subsequent studies that either reach
opposite conclusions or suggest that the original claims were too strong.
Such disagreements may upset clinical practice and acquire publicity in both
scientific circles and in the lay press. Several empirical investigations
have tried to address whether specific types of studies are more likely to
be contradicted and to explain observed controversies. For example, evidence
exists that small studies may sometimes be refuted by larger ones.1,2
Similarly, there is some evidence on disagreements between epidemiological
studies and randomized trials.3- 5 Prior
investigations have focused on a variety of studies without any particular
attention to their relative importance and scientific impact. Yet, most research
publications have little impact while a small minority receives most attention
and dominates scientific thinking and clinical practice. Impact is difficult
to measure in all its dimensions. However, the number of citations received
by a publication is a surrogate of the attention it has received in the scientific
literature and its influence on scientific debate and progress. Citations
are readily and objectively counted in established databases.6 High
citation count does not necessarily mean that these studies are accepted;
citations may sometimes be critical of an article. Nevertheless, citation
count is a measure of how much a study has occupied the thinking of other
scientists and has drawn attention—for good or bad.
It is important to evaluate the replication of clinical research studies
that have the highest citation impact. How frequently are such studies eventually
contradicted by other research or are found to have too strong results compared
with subsequent evidence? Is this more common for specific types of studies?
Answering these questions would be useful for interpreting the results of
influential clinical research.
Eligible Original Studies
Eligible original studies for this analysis included all publications
that had received more than 1000 Institute for Scientific Information (ISI)–indexed6 citations; had been published between 1990 and 2003
in the 3 general medical journals with the current highest impact factor (New England Journal of Medicine, JAMA, Lancet) or in medical
specialty journals with impact factor exceeding 7.0 (according to the Journal
Citation Reports 2003) that are likely to publish clinical research (including
in decreasing impact factor, the Journal of the National
Cancer Institute, Gastroenterology, Annals of Internal Medicine, Circulation, Journal of Clinical Oncology, Archives of General Psychiatry, Blood, Hepatology, American Journal of Respiratory and Critical Care
Medicine, Diabetes, Brain, Annals of Neurology, Journal of the American College of Cardiology, Diabetes
Care, Journal of the American Society of Nephrology, Arthritis and Rheumatism, and the American Journal of Psychiatry); addressed the efficacy
of therapeutic or preventive interventions; and pertained to primary data
(excluding reviews and meta-analyses).
Citation counts for articles published between January 1, 1990, and
December 31, 2003, in these journals were downloaded from ISI. Citation counts
are censored on August 20, 2004. All articles with more than 1000 citations
were screened further. Studies with group authorship may be cited in various
ways; therefore, I summed up citations cataloged under different entries for
the same article (using the first author name, group abbreviations, and anonymous
entries).7 The total citation count does not
capture the few citations for which wrong name, journal, volume, or page might
have been cited. Since citations depend on the time interval since publication,
a separate citation count was limited to the first 3 years after the publication
year.
Other Clinical Research on the Same Questions
For each eligible original study, a search was performed to identify
whether there had been any other concurrently or subsequently published clinical
research addressing the same question. Other research was considered eligible,
only if the sample size was close to or larger than that of the highly cited
original study or if it used a theoretically better controlled design. Thus,
for highly cited randomized trials, I perused all randomized trials having
at least 30% of the sample size of the eligible highly cited original study.
Whenever available, quantitative meta-analyses of trials were used as summaries
of trial results. Whenever several pertinent meta-analyses were available,
the one including the largest number of studies was preferred. For highly
cited nonrandomized studies, subsequently published pertinent randomized trials
and meta-analyses thereof were eligible regardless of sample size; nonrandomized
evidence was also considered, if randomized trials were not available.
Concurrently or subsequently published evidence was identified in PubMed
using searches that combined terms pertaining to the tested interventions,
disease and outcome, and terms pertinent to the search of randomized trials
and meta-analyses. Searches followed the Cochrane algorithms for finding meta-analyses
and randomized trials.8
Data Extraction and Classification of Studies
For each eligible original study, I recorded the study name, intervention,
disease and outcomes of interest, study design, sample size, main conclusions,
and citation counts. For the articles presenting or summarizing other relevant
research, I recorded the study design, total sample size, and the findings
as compared with those of the original highly cited study.
Highly cited studies were classified as negative (when they claimed
the tested experimental intervention was ineffective, harmful, or no better
from the control intervention), unchallenged (when no other clinical research
of eligible design and sample size was available to validate the claimed efficacy),
contradicted, initially stronger effects, or replicated effects. The classification
of studies in these categories was based on the final interpretation of the
results by the authors in the “Abstract” and “Discussion”
sections of their original publications. Highly cited articles were classified
according to whether their authors suggested that an intervention was overall
effective or ineffective. When both benefits and harms or caveats were presented,
I focused on the net conclusion of whether the experimental intervention merits
consideration for use in clinical practice. Subsequent research was classified
in the same manner. Contradiction was declared when the original highly cited
study claimed the intervention to be effective, while subsequent research
showed it to be ineffective. When both original and subsequent research claimed
the intervention was effective, studies were compared further regarding the
effect size for the major clinical outcome, the durability of the treatment
effect, and the generalizability and applicability to various settings. Initially
stronger effects were defined when the relative risk reduction for the main
outcome in the subsequent research was half or less compared with what had
been proposed by the original highly cited study (regardless of whether confidence
intervals might overlap or not), or when the subsequent research showed that
the originally proposed benefit was of short duration or its applicability
and generalizability was limited. Classification of the studies independently
by another investigator yielded a highly similar profile (weighted Cohen κ = 0.92).
Correlates of Contradicted or Initially Stronger Effects
Among original highly cited studies with efficacy claims, analyses examined
whether those with contradicted or initially stronger effects differed from
the replicated and unchallenged ones in study design, publication year, sample
size, type of disease (heart disease vs other), journal of publication, citation
count, early citation count, and average citations per year after publication.
Comparisons used the Mann-Whitney U test for continuous
variables and Fisher exact test for binary variables.
Comparison of Highly Cited Articles Against Less Cited Articles
To evaluate whether highly cited studies differ from other studies that
are not so highly cited in their findings and potential for contradiction,
a control group of articles pertaining to the assessment of interventions
was also assembled. Control-group articles were 1:1 matched for journal, year
of publication, and design (randomized vs nonrandomized) against each of the
highly cited articles. Control articles were selected by screening chronologically
the contents of the pertinent journals for each pertinent year starting July
1 (to ensure approximately similar follow-up for citations with the highly
cited articles against which they were matched). Other research was searched
and the control articles were categorized in a similar fashion as described
for the highly cited articles above. Differences between highly cited and
control articles were examined with conditional logistic regression to account
for matching.
Analyses were performed in SPSS version 12.0 (SPSS Inc, Chicago, Ill)
and StatXact (Cytel Corp, Boston, Mass). P values
are 2-tailed, and P<.05 was considered statistically
significant.
One hundred fifteen articles published between 1990 and 2003 had received
more than 1000 citations (major general clinical journals, n = 91;
specialty journals, n = 24). Of those, 66 were excluded (nonsystematic
reviews or editorials, n = 20; meta-analyses, n = 7; case-control
studies of risk factors, n = 12; prevalence or incidence studies,
n = 8; cohort studies of risk factors, n = 3; recommendations,
n = 3; prognostic models, n = 4; time-trend analysis,
n = 1; case series, n = 1; presentations of interviews,
instruments, or assays n = 3, classification criteria n = 4).
The remaining 49 articles were eligible (Table
1)9- 57 of
which 47 had appeared in major general medical journals. They included 43
randomized trials, 4 prospective cohorts, and 2 case series. In recent years
(1998 through 2003), the 3 general journals have published an almost equal
number of highly cited articles (New England Journal of
Medicine, n = 4; JAMA, n = 3; Lancet, n = 3). A smaller proportion of highly
cited articles published in specialty journals than those published in general
journals were eligible for the analysis (2/24 vs 47/91, P<.001), because highly cited articles in specialized journals were
mostly nonsystematic reviews or editorials (10/24); classification criteria
(4/24); or descriptions of standardized interviews, instruments, and assays
(3/24). Many diverse disciplines were represented, but the most common topic
was heart disease (n = 27).
Four eligible highly cited studies showed no efficacy for the tested
interventions. They contradicted prior claims for potential efficacy of vitamin
E, beta carotene, and retinol for lung cancer and/or coronary artery disease;
and showed an increased risk of coronary artery disease with hormone therapy
in postmenopausal women (Table 2).
Of the 45 eligible highly cited studies with efficacy claims (Table 2), 7 (16%) were contradicted by subsequent
research, and another 7 (16%) were found to have initially stronger effects.
In all these 14 cases (Box 1),
subsequent studies were either larger or better controlled (randomized vs
a nonrandomized original study). The findings of 20 highly cited articles
(44%) were replicated (also with a larger sample size in subsequent research
compared with the original highly cited study) and 11 (24%) had remained largely
unchallenged.58- 78
Box Section Ref IDBox 1. Contradicted and Initially Stronger Effects in Highly Cited
Studies
Contradicted Findings
The Nurses’ Health Study,13 a prospective
cohort, found a 44% relative risk reduction in coronary artery disease events
in women receiving hormone therapy. A small randomized trial42 found
major beneficial effects of this intervention on surrogate markers of coronary
artery disease (lipoprotein and fibrinogen levels) claiming that this should
translate to a major clinical benefit. Although the latter trial was not refuted
at the level of surrogate outcomes, inferences for the anticipated effects
on clinical outcomes were contradicted. The Women’s Health Initiative,46 a large randomized trial, found that estrogen and
progestin significantly increased the relative risk of coronary events by
29% among postmenopausal women, and refuting results were also seen in another
large randomized trial, the Heart and Estrogen/progestin Replacement Study
(HERS).44
Two large prospective cohort studies, the Health Professionals Follow-Up
study20 and the Nurses’ Health Study,21 found that vitamin E was significantly associated
with a decreased risk of coronary artery disease and a trial of 2002 patients
also suggested a 47% relative risk reduction for cardiovascular deaths or
nonfatal myocardial infarction with vitamin E.51 However,
an even larger randomized trial66 subsequently
showed absolutely no beneficial effect for vitamin E on coronary artery disease
(relative risk 1.05 for cardiovascular deaths and 1.02 for myocardial infarction).
A small randomized trial (n = 200) suggested that the human
IgM monoclonal antibody to endotoxin could almost halve mortality due to gram-negative
sepsis.15 A subsequent randomized trial of
more than 10-fold larger sample size62 found
a nonsignificant 11% relative risk increase for mortality.
Finally, a small series of 9 patients22 proposed
that nitric oxide inhalation is very effective in patients with respiratory
distress syndrome by improving oxygenation. However 5 randomized trials involving
535 patients67 failed to show any clinical
benefit.
Initially Stronger Effects
The early results of a trial on zidovudine monotherapy in asymptomatic
patients with human immunodeficiency virus infection9 showed
a significant 60% relative risk reduction against disease progression in the
first year. The short-term benefit was not exaggerated. Yet this effect was
short-lived and the benefit was lost after 18 months both in the same trial
and also as shown in a subsequent meta-analysis.58
A randomized trial of 395 patients18 showed
that immediate angioplasty was superior to thrombolysis with tissue plasminogen
activator in acute myocardial infarction, achieving a 58% relative risk reduction
for death or reinfarction. However, a subsequent meta-analysis with more than
2500 patients65 suggested that the benefit
is probably much smaller (relative risk reduction 30%) and the largest and
most recent trial that involved both specialized and nonspecialized centers
had not shown any sizeable benefit of angioplasty (nonsignificant 20% risk
reduction for death and nonsignificant 33% risk reduction for reinfarction).
Two randomized trials of 410 and 520 patients, respectively,26,27 showed that stents were superior
to balloon angioplasty for management of coronary artery disease with 31%
and 42% relative risk reductions, respectively, in the need for revasularization.
Current evidence, as summarized by a meta-analysis of almost 10 000 patients,
suggests that the benefit is probably much smaller that originally thought
(approximately 10% relative risk reduction), and unblinding may have led to
an increased effect on repeat angioplasty in these trials.69
Another trial suggested a prime role for tissue plasminogen activator
in acute ischemic stroke.29 However, subsequent
evidence has narrowed indications and the intervention is considered effective
mostly when given very early after symptom onset.70
Carotid endarterectomy was initially reported to achieve a 5.9% absolute
risk reduction for stroke or death, projected at 5 years,43 in
patients with asymptomatic stenosis of the carotid artery exceeding 60%. A
meta-analysis of several trials suggested a more modest benefit with 2% absolute
risk reduction at 3.1 years.75
Finally, a cohort study of 805 people found a 68% adjusted relative
risk reduction for coronary artery disease with flavonoids48 while
a meta-analysis of prospective cohorts with total sample size exceeding 100 000
suggests only a 20% relative risk reduction in the top vs bottom third of
flavonoid uptake.76
Comparison of Contradicted or Initially Stronger vs Replicated or Unchallenged
Findings
Five of 6 highly cited nonrandomized studies had been contradicted or
had initially stronger effects while this was seen in only 9 of 39 highly
cited randomized trials (P = .008). Table 3 shows that trials with contradicted or
initially stronger effects had significantly smaller sample sizes and tended
to be older than those with replicated or unchallenged findings. There were
no significant differences on the type of disease. The proportion of contradicted
or initially stronger effects did not differ significantly across journals
(P = .60). There was also no significant
difference in the number of citations received in the first 3 years between
these 2 groups or in the overall number of citations over time although the
citations per year tended to be nonsignificantly fewer in trials with contradicted
or initially stronger effects.
Comparison of Highly Cited Articles Against Less-Cited Control Articles
Of the 49 articles in the control group79- 127 (with
median of 157 citations, range 38-815, until 2004), the findings of 2 articles91,119 were contradicted128,129 and
8 studies82,90,92,95,96,109,110,117 had
initially stronger effects130- 137 (Box 2); 20 articles79- 81,83,86- 89,101,103,104,106,108,111,112,118,123,125- 127 contained
“positive” findings that were replicated,68,138- 155 8
studies93,97,98,102,107,114,115,120 remained
unchallenged, and 11 studies84,85,94,99,100,105,113,114,119,120,122 did
not have any “positive” results; in 7 articles with some “positive”
finding,79,87,91,98,108,112,120 there
were also other interventions evaluated that had “negative” results
although this mixture of “positive” and “negative”
results had not been observed in any of the highly cited articles. The control
articles had a larger number of “negative” findings compared with
the highly cited articles (matched odds ratio [OR], 8; 95% confidence interval
[CI], 1.8-34; P = .006 for any “negative”
finding; and matched OR, 3.3; 95% CI, 0.92-12.0, P = .07
for exclusively “negative” findings). The highly cited articles
did not have a smaller proportion of contradicted or initially stronger effects
than the control articles if anything there was a trend for more contradicted
or initially stronger effects in the highly cited articles (matched OR, 1.6;
95% CI, 0.6-4.0; P = .35; matched OR, 6.0;
95% CI, 0.7-50; P = .10 when limited to
contradicted findings).
Contradicted Findings
In a prospective cohort,91 vitamin A
was inversely related to breast cancer (relative risk in the highest quintile,
0.84; 95% confidence interval [CI], 0.71-0.98) and vitamin A supplementation
was associated with a reduced risk (P = .03)
in women at the lowest quintile group; in a randomized trial128 exploring
further the retinoid-breast cancer hypothesis, fenretinide treatment of women
with breast cancer for 5 years had no effect on the incidence of second breast
malignancies.
A trial (n = 51) showed that cladribine significantly improved
the clinical scores of patients with chronic progressive multiple sclerosis.119 In a larger trial of 159 patients, no significant
treatment effects were found for cladribine in terms of changes in clinical
scores.129
Initially Stronger Effects
A trial (n = 28) of aerosolized ribavirin in infants receiving
mechanical ventilation for severe respiratory syncytial virus infection82 showed significant decreases in mechanical ventilation
(4.9 vs 9.9 days) and hospital stay (13.3 vs 15.0 days). A meta-analysis of
3 trials (n = 104) showed a decrease of only 1.8 days in the duration
of mechanical ventilation and a nonsignificant decrease of 1.9 days in duration
of hospitalization.130
A trial (n = 406) of intermittent diazepam administered during
fever to prevent recurrence of febrile seizures90 showed
a significant 44% relative risk reduction in seizures. The effect was smaller
in other trials and the overall risk reduction was no longer formally significant131; moreover, the safety profile of diazepam was deemed
unfavorable to recommend routine preventive use.
A case-control and cohort study evaluation92 showed
that the increased risk of sudden infant death syndrome among infants who
sleep prone is increased by use of natural-fiber mattresses, swaddling, and
heating in bedrooms. Several observational studies have been done since, and
they have provided inconsistent results on these interventions, in particular,
they disagree on the possible role of overheating.132
A trial of 54 children95 showed that
the steroid budenoside significantly reduced the croup score by 2 points at
4 hours, and significantly decreased readmissions by 86%. A meta-analysis
(n = 3736)133 showed a significant
improvement in the Westley score at 6 hours (1.2 points), and 12 hours (1.9
points), but not at 24 hours. Fewer return visits and/or (re)admissions occurred
in patients treated with glucocorticoids, but the relative risk reduction
was only 50% (95% CI, 24%-64%).
A trial (n = 55) showed that misprostol was as effective as
dinoprostone for termination of second-trimester pregnancy and was associated
with fewer adverse effects than dinoprostone.96 A
subsequent trial134 showed equal efficacy,
but a higher rate of adverse effects with misoprostol (74%) than with dinoprostone
(47%).
A trial (n = 50) comparing botulinum toxin vs glyceryl trinitrate
for chronic anal fissure concluded that both are effective alternatives to
surgery but botulinum toxin is the more effective nonsurgical treatment (1
failure vs 9 failures with nitroglycerin).109 In
a meta-analysis135 of 31 trials, botulinum
toxin compared with placebo showed no significant efficacy (relative risk
of failure, 0.75; 95% CI, 0.32-1.77), and was also no better than glyceryl
trinitrate (relative risk of failure, 0.48; 95% CI, 0.21-1.10); surgery was
more effective than medical therapy in curing fissure (relative risk of failure,
0.12; 95% CI, 0.07-0.22).
A trial of acetylcysteine (n = 83) showed that it was highly
effective in preventing contrast nephropathy (90% relative risk reduction).110 There have been many more trials and many meta-analyses
on this topic. The latest meta-analysis136 shows
a nonsignificant 27% relative risk reduction with acetylcysteine.
A trial of 129 stunted Jamaican children found that both nutritional
supplementation and psychosocial stimulation improved the mental development
of stunted children; children who got both interventions had additive benefits
and achieved scores close to those of nonstunted children.117 With
long-term follow-up, however, it was found that the benefits were small and
the 2 interventions no longer had additive effects.137
Original highly cited articles about medical interventions are published
almost exclusively in 3 general medical journals. Actually, there has been
an approximate equal share of very highly cited articles among these 3 journals
since 1998 as impact factor differences have diminished among these 3 journals.
Articles in specialty journals that reach such high numbers of citations are
usually review articles or articles describing tools useful to specific diseases
rather than original data. Contradicted and potentially exaggerated findings
are not uncommon in the most visible and most influential original clinical
research: 16% of the top-cited clinical research articles on postulated effective
medical interventions that have been published within the last 15 years have
been contradicted by subsequent clinical studies and another 16% have been
found to have initially stronger effects than subsequent research. Contradiction
or initially stronger effects have been encountered in 5 of 6 cases for which
nonrandomized designs were used, but even randomized trials have not escaped
controversy. More than a third of the top-cited randomized trials published
from 1990 through 1995 have already been affected, while for more recent trials,
the time frame is still early and more may be contradicted in the future.
Sample size seems to be important, with smaller sample sizes in trials that
have met controversy vs those that have not.
The classification of studies in this analysis involves many judgments
pertaining to the complexity of studying a given research question with somewhat
different populations, interventions, durations, and outcomes. However, these
studies are widely known for their inferences and this is also proven by the
high interrater agreement. Nevertheless, it should also be acknowledged that
although the classification was performed in duplicate, the searches were
performed by only 1 investigator. It is unavoidable that some other investigators
may feel differently about the categorization of specific studies, especially
for topics that may also have heavy debates surrounding them. However, this
is unlikely to change the aggregate picture about refutation rates.
The examination of contradictions and refutations offers a fascinating
look at the process of science. Four of the highly cited articles examined
herein were refuting investigations with “negative” results. However,
in a sense, even the other highly cited articles with “positive”
results refuted prior knowledge and practice by introducing new concepts and
proposing new interventions. We should acknowledge that there is no proof
that the subsequent studies and meta-analyses were necessarily correct. A
perfect gold standard is not possible in clinical research, so we can only
interpret results of studies relative to other studies. Whenever new research
fails to replicate early claims for efficacy or suggests that efficacy is
more limited than previously thought, it is not necessary that the original
studies were totally wrong and the newer ones are correct simply because they
are larger or better controlled. Alternative explanations for these discrepancies
may include differences in disease spectrum, eligibility criteria, or the
use of concomitant interventions.156 Different
studies on the same question are typically not replicas of each other. In
fact discrepancies may be interesting on their own because they require careful
scrutiny of the data and reappraisal of our beliefs. Thus, it is probably
not surprising that the citation rate of these refuted studies did not seem
to be much affected. Nevertheless, the controversy generates considerable
uncertainty for clinical practice and none of the contradicted interventions
is currently recommended by practice guidelines.
The mere fact that a study is highly cited suggests that there is a
strong active interest in the questions addressed from a clinical or research
perspective. This may increase the chances that other, larger trials may eventually
be conducted. However, for most clinical questions of interest, no large trials
are ever conducted and evidence is based only on small trials or nonrandomized
studies.157 Small trials or meta-analyses thereof
may often be refuted subsequently by large trials1,2 when
such large trials are performed. Small studies using surrogate markers may
also sometimes lead to erroneous clinical inferences.158 There
were only 2 studies with typical surrogate markers among the highly cited
studies examined herein, but both were subsequently contradicted in their
clinical extrapolations about the efficacy of nitric oxide22 and
hormone therapy.42 In the case of initially
stronger effects, the differences in the effect sizes could often be within
the range of what would be expected based on chance variability. This reinforces
the notion that results from clinical studies, especially early ones, should
be interpreted using not only the point estimates but also the uncertainty
surrounding them. However, besides differences in effect sizes, most initially
stronger effects pertained also to issues of durability, generalizability,
or applicability of the proposed effects, as discussed above. Thus, clinicians
should be aware that these important aspects may not be fully settled when
an important treatment breakthrough is announced.
A third of the most-cited clinical research seems to have replication
problems, and this seems to be as large, if not larger, than the vast majority
of other, less-cited clinical research. The current analysis found that matched
studies that were not so highly cited had a greater proportion of “negative”
findings and similar or smaller proportions of contradicted results as the
highly cited ones. Publication bias159,160 and
time-lag bias161,162 favoring
the rapid and prominent publication of “positive” findings may
underlie some of the observed phenomena. Highly cited articles are already
a selected sample with underrepresentation of “negative” findings
compared with the average article on interventions published in major journals.
It is possible that high-profile journals may tend to publish occasionally
very striking findings and that this may lead to some difficulty in replicating
some of these findings.163 Poynard et al164 evaluated the conclusions of hepatology-related
articles published between 1945 and 1999 and found that, overall, 60% of these
conclusions were considered to be true in 2000 and that there was no difference
between randomized and nonrandomized studies or high- vs low-quality studies.
Allowing for somewhat different definitions, the higher rates of refutation
and the generally worse performance of nonrandomized studies in the present
analysis may stem from the fact that I focused on a selected sample of the
most noticed and influential clinical research. For such highly cited studies,
the turnaround of “truth” may be faster; in particular nonrandomized
studies may be more likely to be probed and challenged than nonrandomized
studies published in the general literature.
Finally, a certain proportion of highly cited trials may remain unchallenged.
Sometimes the evidence from the original study may seem so overwhelming that
further similar studies are deemed unethical to perform. The original study
may be widely considered as a milestone for clinical practice and may provide
the gold standard for testing new interventions. However, sometimes other,
validating research may be in the works. Clinical research is time-consuming
and challenging results may take several years to generate and publish. Therefore
evidence from recent trials, no matter how impressive, should be interpreted
with caution, when only one trial is available. It is important to know whether
other similar or larger trials are still ongoing or being planned. Therefore,
transparent and thorough trial registration is of paramount importance165 in order to limit premature claims for efficacy.
Corresponding Author: John P. A. Ioannidis,
MD, Department of Hygiene and Epidemiology, University of Ioannina School
of Medicine, Ioannina 45110, Greece (jioannid@cc.uoi.gr).
Author Contributions: Dr Ioannidis had full
access to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Financial Disclosures: None reported.
Acknowledgment: I thank Dr Tom Trikalinos for
classifying independently the status of the highly cited articles.
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