Special Article
Do the Results of Randomized Clinical Trials of Cardiovascular Drugs Influence Medical Practice?
N Engl J Med 1992; 327:241-247July 23, 1992
- Abstract
- Abstract
Background.
Medical practice patterns change in response to a variety of stimuli, one of which may be the publication of the results of randomized clinical trials. We assessed the temporal association between the publication of clinical trials on myocardial infarction and changes in treatment practices for this disorder.
Methods.
We analyzed the use of aspirin before and after myocardial infarction and that of calcium antagonists after myocardial infarction in 2231 survivors of myocardial infarction enrolled in the Survival and Ventricular Enlargement (SAVE) study over a three-year period (from January 1987 through January 1990). The proportion of patients using these treatments was analyzed before and after the publication dates of three clinical trials: the Physicians' Health Study, published in January 1988, which supported the use of aspirin to prevent a first myocardial infarction; the Second International Study of Infarct Survival (ISIS-2), published in August 1988, which supported the use of aspirin after myocardial infarction; and the Multicenter Diltiazem Postinfarction Trial, published in August 1988, which reported a deleterious effect of diltiazem in some patients after myocardial infarction.
Results.
The use of aspirin before myocardial infarction increased from 16.2 percent to 23.9 percent between January 1987 and January 1990 (P<0.001 ). Enrollment in the study after the publication of the Physicians' Health Study independently predicted aspirin use before myocardial Infarction (odds ratio, 1.43; 95 percent confidence interval, 1.11 to 1.85). The use of aspirin after myocardial infarction increased from 38.8 percent to 71.9 percent (P<0.001) during the three-year study period. Enrollment in the study after the publication of ISIS-2 independently predicted the use of aspirin after myocardial infarction (odds ratio, 2.28; 95 percent confidence interval, 1.89 to 2.76). The use of calcium antagonists after myocardial infarction decreased from 57.1 percent to 33.1 percent (P<0.001) during the study period. Enrollment in the study after the publication of the Multicenter Diltiazem Postinfarction Trial independently predicted the use of calcium antagonists after myocardial infarction (odds ratio, 0.47; 95 percent confidence interval, 0.39 to 0.57).
Conclusions.
These observations suggest that randomized clinical trials have a measurable influence on medical practice patterns. (N Engl J Med 1992;327: 241–7.)
Media in This Article
Figure 1
Aspirin Use before the Index Infarction in Selected Groups of Patients, According to the Time of Randomization into the Study.Figure 2
Aspirin Use after the Index Infarction in Selected Groups of Patients, According to the Time of Randomization into the Study.Article Activity
- Article
THE randomized clinical trial is the primary tool used to evaluate the clinical usefulness of technological procedures and treatments. Decisions to conduct such trials are based on the expectation that the results, whether positive or negative, will influence the future treatment of patients. However, there are divergent views about the direct effect of clinical trials on patient care. Chalmers1 has provided several examples of clear-cut results that did not alter practice patterns: despite the publication of trials that showed a lack of benefit, diethylstilbestrol continued to be used in pregnant women throughout the 1950s, strict bed rest continued to be prescribed for hepatitis long after controlled studies indicated that it did not improve clinical outcome, and a bland diet was prescribed for peptic ulcer disease even after trials demonstrated its ineffectiveness in promoting the healing of ulcers. In contrast, both Fineberg2 and Furberg3 have reviewed data showing that more recent randomized, controlled trials have influenced clinical practice patterns.
The purpose of the present study was to determine whether well-executed randomized, controlled trials related directly to the care of patients with heart disease could be associated with measurable changes in clinical practice, as observed during the three-year enrollment period of the Survival and Ventricular Enlargement (SAVE) study.
Methods
The SAVE study was a randomized, multicenter trial that attempted to determine whether the angiotensin-converting—enzyme inhibitor captopril prolonged survival after myocardial infarction. Patients were eligible for enrollment if they were 21 to 79 years old and had had a myocardial infarction 3 to 16 days earlier, with a resulting left ventricular ejection fraction of 40 percent or less.4
The study involved 45 principal centers and their affiliated hospitals. The data on medical practice patterns reported here were collected from the overall group of 10 Canadian and 35 U.S. centers that enrolled patients, comprising 106 hospitals where randomization took place. The study investigator was the primary cardiologist for the study participants in only a minority of centers. Coronary care unit protocols regulating aspirin use after myocardial infarction were in effect in less than 30 percent of the centers; protocols regulating the use of calcium antagonists after myocardial infarction were not used in any center.
Cardiovascular treatments were selected that had been studied in well-known randomized, controlled trials published during the enrollment period (January 1987 through January 1990), the findings of which were clearly applicable to the study population. The enrollment period was then divided into six periods of six months each, and the use of the selected medications was monitored throughout the three-year period.
Clinical Trials of Aspirin Use
The Physicians' Health Study of the prevention of a first myocardial infarction with prophylactic aspirin therapy was published as a preliminary report in January 19885 and in final form in July 1989.6 This study reported that aspirin was an effective therapy for the primary prevention of acute myocardial infarction in normal, middle-aged men. No survival benefit was evident, however. We expected that practitioners would respond to this study by increasing the prophylactic use of aspirin. In contrast, the British Physicians' Study,7 published in January 1988, reported that aspirin did not reduce rates of myocardial infarction.
The administration of aspirin during and after acute myocardial infarction was the subject of two 1988 reports8 , 9 on the results of the Second International Study of Infarct Survival (ISIS-2). This large (17,187 patient) randomized, controlled trial found that survival five weeks after infarction was better among patients treated with aspirin than among patients not so treated. The investigators generally expected that practitioners would respond to the publication of this study by increasing the proportion of patients who took aspirin after a myocardial infarction.
Trials of the Use of Calcium Antagonists after Myocardial Infarction
Several long-term studies published during the enrollment period addressed the use of calcium antagonists after acute myocardial infarction. The SPRINT study,10 published in April 1988, was a double-blind clinical trial of 2276 patients randomly assigned to receive nifedipine or placebo after myocardial infarction. No survival benefit was demonstrated. The results of the Multicenter Diltiazem Postinfarction Trial were first reported at a meeting of the American College of Cardiology in March 198811 and then published in August of that year.12 This study reported that the calcium antagonist diltiazem had no overall effect on mortality after myocardial infarction. However, the subgroup of patients with left ventricular ejection fractions of 40 percent or less had excess mortality when treated with diltiazem — a clear message to physicians in the SAVE study to avoid using diltiazem, since all the study patients had ejection fractions of 40 percent or less. Finally, a meta-analysis published in November 1989 concluded convincingly that calcium antagonists administered routinely after myocardial infarction were not beneficial.13 Thus, diminished use of calcium antagonists appeared likely, particularly after the publication of the Multicenter Diltiazem Postinfarction Trial.12
Beta-Adrenoceptor Blockade after Myocardial Infarction
Beta-adrenoceptor blockade has long been established as a beneficial therapy after myocardial infarction.14 15 16 No new major randomized, controlled trials recommending the long-term use of beta-blocker therapy were published during the enrollment period. Consequently, the use of beta-blockers after myocardial infarction was analyzed as a control therapy.
Statistical Analysis
Differences between groups were evaluated for statistical significance by the chi-square statistic in the case of discrete variables17 and by the z score in the case of continuous variables.18 We used multiple logistic regression to determine the likelihood that a patient would use specific medications (i.e., aspirin or calcium-channel blockers) as a function of the date of randomization, while controlling simultaneously for all other variables that might influence the use of these medications.19 Ninety-five percent confidence limits for the odds ratios were computed. All P values are two-tailed.
Results
The patients in the study were predominantly male (82.5 percent), with a mean (±SD) age of 59±11 years. Their myocardial infarctions had occurred 11± 3 days before randomization. Their left ventricular ejection fractions as measured by radionuclide angiography before randomization averaged 31±7 percent. There were no significant differences in base-line demographic or clinical characteristics, except hypertension (P = 0.048), between the six enrollment groups (Table 1Table 1
Base-Line Characteristics of the Study Patients, According to Six-Month Enrollment Period.*). The use of thrombolytic therapy during the acute infarction did, however, increase later in the period.20 Use of Aspirin before and after the Index Infarction
Overall, 21.2 percent of the randomized patients (474 of 2231) took aspirin during the 72 hours before the index infarction. These patients were somewhat older than those in the no-aspirin group (61 vs. 59 years; P<0.001), and more of them had a history of cardiovascular disease (53 percent had undergone cardiac catheterization, as compared with 18 percent in the no-aspirin group; P<0.001).
From January 1987 through January 1990, aspirin use before myocardial infarction increased from 16.2 percent to 23.9 percent (Fig. 1Figure 1
Aspirin Use before the Index Infarction in Selected Groups of Patients, According to the Time of Randomization into the Study.A). To determine whether patients expected to be at higher risk of myocardial infarction were more likely to have taken aspirin before their reference infarction, we identified 1674 of the 2231 patients (75.0 percent) who had a history of heart disease or a diagnosis of diabetes, hyperlipidemia, or hypertension. These patients had a significant increase in aspirin use over the three-year period, from 18.3 percent to 28.1 percent (Fig. 1B). In contrast, those without a history of cardiac events or a cardiac risk factor that had been identified by a physician (557 patients, or 25.0 percent) had a low prevalence of aspirin use that did not change significantly between January 1987 and January 1990 (Fig. 1C).A logistic-regression model was constructed to determine the independent significance of the date of the patient's randomization in relation to the use of aspirin before infarction. The randomization period was divided into two periods on the basis of the publication date (January 28, 1988) of the preliminary report of the Physicians' Health Study.5 Other variables included in the model were demographic data and type of hospital (academic or community). Logistic-regression analysis demonstrated that entry into the study after the publication of the preliminary report was an independent predictor of aspirin use before the index infarction (odds ratio, 1.43; 95 percent confidence interval, 1.11 to 1.85) (Table 2Table 2
Logistic-Regression Model to Predict Aspirin Therapy before Infarction.*).The use of aspirin after a myocardial infarction was analyzed according to whether a patient used this medication 24 hours before randomization. Overall, 58.7 percent of the patients were taking aspirin 10 days after their myocardial infarctions. In general, they had had a more complicated course after myocardial infarction than those who were not taking aspirin, with more frequent catheterization (aspirin vs. no aspirin, 61 percent vs. 47 percent; P<0.001), angioplasty (22 percent vs. 10 percent; P<0.001), and coronary-bypass grafting (11 percent vs. 6 percent; P<0.001). There was an increase in the use of aspirin after myocardial infarction between January 1987 and January 1990 (from 38.8 percent to 71.9 percent; P<0.001) (Fig. 2Figure 2
Aspirin Use after the Index Infarction in Selected Groups of Patients, According to the Time of Randomization into the Study.A). This progressive increase in aspirin use after myocardial infarction was also observed in the 1183 patients who were not treated with thrombolysis, coronary angioplasty, or coronary-artery bypass grafting at the time of the index infarction (Fig. 2B). A time-related increase in aspirin use was also evident in the 1048 patients who underwent thrombolysis, coronary angiography, or coronary-bypass grafting between the time of the index infarction and that of randomization (Fig. 2C).A logistic-regression model was constructed to determine the independent significance of the date of randomization with regard to the use of aspirin after infarction. The randomization period was divided into two parts on the basis of the publication date (August 13, 1988) of ISIS-2.8 The other variables in the model were the same as those for aspirin use before infarction, but they also included aspirin use before infarction, thrombolytic therapy for the index infarction, and cardiac procedures after infarction. Randomization after the publication date of ISIS-2 was found to be an independent predictor of aspirin use after infarction (odds ratio, 2.28; 95 percent confidence interval, 1.89 to 2.76) (Table 3Table 3
Logistic-Regression Model to Predict Aspirin Therapy after Infarction.*).Use of Calcium Antagonists after the Index Infarction
Before the index infarction, 22.8 percent of the patients studied were taking calcium antagonists. After the infarction, 42.1 percent of the patients received these agents. The patients taking calcium antagonists after a myocardial infarction were more likely to have a history of hypertension than those not taking calcium antagonists (47 percent vs. 40 percent, P = 0.002), more likely to have undergone coronary angioplasty (25 percent vs. 11 percent, P = 0.004), and more likely to have remained free of pulmonary congestion during the infarction (63 percent vs. 58 percent, P = 0.025). There was a significant decrease in the use of calcium-antagonist agents after the index infarction (from 57.1 percent of patients to 33.1 percent) (Fig. 3Figure 3
Use of Calcium Antagonists after the Index Infarction in Selected Groups of Patients, According to the Time of Randomization into the Study.A) between January 1987 and January 1990. When the 1852 patients (83.0 percent) who had not undergone coronary angioplasty after myocardial infarction were analyzed, the decreased use of calcium antagonists after myocardial infarction was more pronounced (from 56.8 percent of patients to 28.6 percent) (Fig. 3B). A less striking decrease was evident in the remaining 379 patients, who underwent angioplasty between the time of the index infarction and that of randomization (from 71.6 percent in the second six-month period to 54.2 percent in the final period).A logistic-regression model was constructed to determine whether the date of randomization had an independent influence on the use of calcium antagonists. The randomization period was divided into two parts on the basis of the publication date (August 18, 1988) of the Multicenter Diltiazem Postinfarction Trial.12 The other variables included in the model were the same as those described for aspirin use after myocardial infarction, except that calcium-antagonist use before myocardial infarction was substituted for aspirin use before myocardial infarction. Entry into the study after the publication of the Multicenter Diltiazem Postinfarction Trial was an independent predictor of the decline in calcium-antagonist use after myocardial infarction (odds ratio, 0.47; 95 percent confidence interval, 0.39 to 0.57) (Table 4Table 4
Logistic-Regression Model to Predict Calcium-Antagonist Therapy after Infarction.*).Beta-Blocker Use after the Index Infarction
The use of beta-adrenoceptor blockade after the index infarction served as a temporal control. Over the six periods of six months, the prevalence of therapy using beta-adrenoceptor blockade did not differ significantly between the time of the index infarction and that of randomization (Fig. 4Figure 4
Use of Beta-Adrenergic—Blocking Agents in all 2231 Study Patients after the Index Infarction.).Discussion
Large-scale randomized trials have emerged as the preferred means of evaluating new treatments in clinical research. Both proponents21 and opponents22 , 23 of randomized, controlled trials agree that it would be unethical to conduct a trial that had no chance of altering medical therapy. Consequently, it is important to demonstrate that clinical trials do, in fact, alter medical practice.
Furberg3 has identified five factors that may influence clinical practice: scientific findings, awareness or knowledge by physicians, marketing, public knowledge, and product features. The present analyses cannot differentiate among these factors in accounting for changes in practice patterns. Indeed, the observations presented here constitute the aggregate effect of many potential stimuli. By carefully analyzing the temporal relation of publication dates to changes in practice, however, we hoped to obtain an estimate of the influence that clinical trials may have in a selected population of patients and physicians.
Fineberg2 concluded that the results of trials change practice patterns, and he has developed strict criteria according to which analyses of such changes should be judged. Only 2 of 28 such studies reviewed found that the randomized, controlled trial in question had clear clinical implications, that practice data were gathered longitudinally instead of at a single time, and that the recommendations of the trial differed from standard clinical practice then in effect.
The present study fulfilled all these criteria. The use of aspirin and calcium antagonists after an infarction is relevant to clinical practice, and the trials we studied all had clear implications for patient care. The second criterion was also met, since all practice data were gathered longitudinally, rather than at one time. Finally, all the published studies analyzed made recommendations that differed from standard clinical practice in effect at the time of their publication. For example, during the first six-month period of observation, 16.2 percent of the study patients were taking aspirin at the time of the index infarction, 38.8 percent were taking aspirin after myocardial infarction, and 57.1 percent were taking calcium antagonists after myocardial infarction. The published studies supported the use of aspirin both before and after myocardial infarction but did not support the use of calcium antagonists. Thus, the publications selected and the method of analysis all conform to Fineberg's criteria.
The lag between the development of an idea or practice pattern, its testing in a randomized, controlled trial, and its adoption varies greatly and may occasionally be measured in decades.24 Among various other reasons, this lag may be due to the publication of results in journals with restricted circulations.25 26 27 28 The present study demonstrates rapid changes in practice patterns in response to the publication of studies in influential journals.
The present study allows us to compare the clinical effect of two trials with divergent results, the British Physicians' Study7 and the Physicians' Health Study.5 The use of aspirin to prevent myocardial infarction increased after the publication of these conflicting studies. A possible reason for the increase may be that in the British Physicians' Study7 (the results of which did not support the use of aspirin) there were unexpectedly low rates of cardiac events that may have adversely affected the study's ability to show a small benefit of aspirin therapy.
A subgroup analysis of the Multicenter Diltiazem Postinfarction Trial recommended against the use of calcium antagonists in patients such as those we studied. We observed a clear reduction in the use of calcium antagonists after the publication of that study.
The present study points out important inconsistencies in physicians' application of the results of clinical trials. For example, the ISIS-2 results supporting the use of aspirin after myocardial infarction were clear-cut,8 , 9 but 29 percent of the patients we studied were not taking aspirin after myocardial infarction at the end of the randomization period. The results of the Multicenter Diltiazem Postinfarction Trial were based on the analysis of a subgroup, a method that is traditionally suspect, but the use of calcium antagonists decreased.
The generalizability of this study may be challenged by the contention that the investigators were privy to specialized knowledge not available in the same form to the general medical community. For example, 9 of the 106 centers or affiliated hospitals participating in the study also took part in the Multicenter Diltiazem Postinfarction Trial, and the principal investigator of that trial advised the SAVE steering committee. This relationship may have led in part to the observed reduction in calcium-antagonist use, beginning at the time the results of the Multicenter Diltiazem Postinfarction Trial were presented at a national meeting, months before their full publication. However, there were no such relationships in the case of the aspirin studies analyzed.
Another important consideration arising from these observations concerns the identity of the patients' primary physicians. The study investigator was the patient's primary clinical provider during the index admission in a minority of cases, and the research protocol controlled only the use of angiotensin-converting—enzyme inhibitors, not therapy that was otherwise standard. Practice patterns did not differ according to whether the study patients were enrolled at an academic center or a community hospital; both were represented in the trial. Nevertheless, patients were enrolled in the study with at least the tacit approval of their personal physicians, and often the enthusiastic endorsement. This may have led to the selection of a group of providers more likely to follow the recommendations emerging from randomized, controlled trials, and it may potentially have led to our presentation of an ideal result for changes in practice patterns.
Despite its limitations, this study does support the hypothesis that well-executed, clinically relevant randomized trials published in highly visible clinical journals can have a measurable and prompt effect on patterns of medical practice.
Supported by a grant from Bristol-Myers Squibb, Princeton, N.J.
*A complete list of investigators and institutions can be found in the Appendix.
Source Information
From the Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, both in Boston (G.A.L., M.A.P., E.B.); the School of Public Health, University of Texas Health Science Center at Houston (P.H.); Centre Hospitalier de l'Université de Sherbrooke, Sherbrooke, Que. (J.-L.R.); and Albert Einstein Medical Center and Temple University School of Medicine, Philadelphia (J.W.). Address reprint requests to Dr. Lamas at the Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115.
Appendix
The following investigators and institutions participated in the SAVE study: Policy Board: R. Gorlin, W.W. Parmley, J. Ware, and K.T. Weber; Data Coordinating Center: B.R. Davis, C.M. Hawkins, and L.A. Moyé; Radionuclide Ventriculography Quality Control: F.J.Th. Wackers; SAVE Study Centers: Albany Medical Center: T.L. Biddle and J. Sacco; Albert Einstein Medical Center—Northern Division: C. Strauss and S. Deron; Bowman Gray School of Medicine: H.S. Miller, Jr.; Brigham and Women's Hospital: L.H. Hartley, J.D. Rutherford, M. St. John Sutton, T. Plappert, B. Heller, R. Bevivino, R. Zickl, R. Rimmer, M. Hession, C. Gaughan, G. Mitchell, S. Gabbay, F.E. Hubbard, G. Gaughan, and P.E. Boinay; Iowa Heart Center: D. Gordon and W.J. Wickemeyer; Geisinger Medical Center: F.J. Menapace, Jr., R.J. Butcher, and T. Modesto; Hôpital du Sacre-Cœur: J.-L. Rouleau, M. Klein, and R. LeBeau; Hôpital Notre Dame: F. Sestier, D. Savard, P. Laramee, and J. Lenis; Hospital of the Medical College of Pennsylvania: P.R. Kowey, M. Crawford, S.J. Rials, R. Marinchak, M. Koslow, T. Friehling, and A. Belber; Howard University Hospital: O.S. Randall, J. Diggs, C. Curry, and P.P. Mehrotra; The Jackson Clinic Foundation: D.J. Farnham, J.H. Morledge, P.H. Hinderaker, G. Musser, D. Logan, and D. Danahy; Jewish General Hospital: J. McCans, D. Langleben, and C. Maranda; Kingston General Hospital: J.O. Parker; Laval Hospital—Quebec Heart Institute: G.R. Dagenais, J. Rouleau, C. Nadeau, and F. DeLage; Lutheran General Hospital: R. Sorkin; Maine Medical Center: C.T. Lambrew; Massachusetts General Hospital: R. Zusman; Mayo Clinic: D. Hayes, B.J. Gersh, and I. Clements; Memorial University of Newfoundland: B.A. Sussex, M. Furey, and B. Josephson; Mount Sinai Medical Center (Cleveland): D. Adler; Mount Sinai Medical Center (New York): M. Packer, R. Steingart, N. Kantrowitz, S. Katz, M.L. Kukin, Z. Neuwirth, R. Dharawat, G. Neuberg, D. Pinsky, M.H. Abittan, P. Wilson, W. Schwartz, J. Machac, and J. Skarzynski; Oregon Heart Institute: S. Lewis; Sacred Heart Hospital: K. Jacobson, L.C. Barlow, M.S. Heerema, and F.H. Littell; Sharp Hospital: S.C. Smith, Jr.; State University of New York: E.J. Brown, Jr., R. Joseph, F. Maxxucchi, and M. Zema; Tulsa Heart Center: L.L. Basta and A.D. Hagan; University of Arizona and Veterans Affairs Medical Center, Tucson: S. Goldman and H. Richter; University of Arkansas Medical School: H. Dinh, J. Bissett, B.J. Baker, M.L. Murphy, and M. Khan; University of British Columbia: V. Bernstein; University of California—Davis Medical Center: E. Amsterdam and R. Martschinske; University of Connecticut Health Center: W. D. Hager, A.L. Riba, M. Radford, and B. Clark; University of Louisville: J. Kupersmith; University of Manitoba: T.E. Cuddy, R. Hoeschen, and M. Frais; University of Maryland School of Medicine: S.S. Gottlieb and M. Effron; University of Massachusetts Medical School: J.S. Alpert; University of Missouri: G.C. Flaker and R. Webel; University of New Mexico: J. Abrams and B. Shively; University of South Florida: S.P. Glasser, D. Schocken, and U.R. Shettigar; University of Tennessee, Memphis: B. Hackman, E. Shick, Jr., J.M. Sullivan, and D. Mirvis; University of Texas at Galveston: J.M. Wallace; University of Toronto: P. McEwan, Z. Sasson, and P. Daly; University of Wisconsin—Madison: N. Bittar; Victoria Hospital: M. Arnold; Wads-worth Veterans Affairs Hospital: B.N. Singh; Washington University School of Medicine: E.M. Geltman, A.S. Jaffe, J.E. Perez, and D. Bauwens.
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