No abstract

Seventy-one "negative" randomized control trials were re-examined to determine if the investigators had studied large enough samples to give a high probability (greater than 0.90) of detecting a 25 per cent and 50 per cent therapeutic improvement in the response. Sixty-seven of the trials had a greater than 10 per cent risk of missing a true 25 per cent therapeutic improvement, and with the same risk, 50 of the trials could have missed a 50 per cent improvement. Estimates of 90 per cent confidence intervals for the true improvement in each trial showed that in 57 of these "negative" trials, a potential 25 per cent improvement was possible, and 34 of the trials showed a potential 50 per cent improvement. Many of the therapies labeled as "no different from control" in trials using inadequate samples have not received a fair test. Concern for the probability of missing an important therapeutic improvement because of small sample sizes deserves more attention in the planning of clinical trials.

No abstract

Controlled clinical trials of the treatment of acute myocardial infarction offer a unique opportunity for the study of the potential influence on outcome of bias in treatment assignment. A group of 145 papers was divided into those in which the randomization process was blinded (57 papers), those in which it may have been unblinded (45 papers), and those in which the controls were selected by a nonrandom process (43 papers). At least one prognostic variable was maldistributed (P less than 0.05) in 14.0 per cent of the blinded-randomization studies, in 26.7 per cent of the unblinded-randomization studies, and in 58.1 per cent of the nonrandomized studies. Differences in case-fatality rates between treatment and control groups (P less than 0.05) were found in 8.8 per cent of the blinded-randomization studies, 24.4 per cent of the unblinded-randomization studies, and 58.1 per cent of the nonrandomized studies. These data emphasize the importance of keeping those who recruit patients for clinical trials from suspecting which treatment will be assigned to the patient under consideration.

No abstract

We reexamined the association between corticosteroid therapy and subsequent peptic ulceration or gastrointestinal hemorrhage by pooling data from 71 controlled clinical trials in which patients were randomized to systemic corticosteroids (or ACTH) or to nonsteroid therapy. Of 3064 steroid-treated patients evaluated for peptic ulcer, 55 (1.8 per cent) had ulcers, as compared with 23 of 2897 controls (0.8 per cent) (relative risk, 2.3; 95 per cent confidence interval, 1.4 to 3.7). Of 3135 steroid-treated patients evaluated for gastrointestinal hemorrhage, 78 (2.5 per cent) had bleeding, as compared with 48 of 2976 controls (1.6 per cent) (relative risk, 1.5; 95 per cent confidence interval, 1.1 to 2.2). The incidence of ulcers varied directly with the dosage of steroids. When separate analyses were performed for studies that were double-blind, used only oral steroids, used only parenteral steroids, or excluded patients with a history of ulcer, the trend remained consistent but did not always reach statistical significance. This study strongly suggests that corticosteroids do increase the risk of peptic ulcers and gastrointestinal hemorrhage.

To evaluate the use of antibiotics given prophylactically of colon surgery, we examined 26 trials published from 1965 to 1980 in which patients given various antibiotic regiments were compared with controls given no antibiotic treatment. In 22 (85 per cent of these trials) antibiotics reduced postoperative wound infection (p less than 0.05 in 14). Combining the results of the trials published from 1965 to 1975 reveals a 95 per cent confidence interval from the true difference in infection rates of 14 +/- 6 per cent (36 per cent for control group vs. 22 per cent for treatment group) and the true difference in death rates of 6.7 +/- 4.4 per cent (11.2 per cent for control group vs 4.5 per cent for treatment group). Yet trials employing control groups given no treatment continue to be reported. Since the use of such controls is justified only when no effective alternative therapy exists, we believe that any further trials of antibiotic prophylaxis in colon surgery should employ a previously proved standard. However, steadily increasing efficacy of treatment means that comparisons of new therapies with standard therapies will become prohibitively expensive because of the large number of patients required.

Since the last comprehensive review of anticoagulation in acute myocardial infarction four additional randomized control trials have been reported. The overwhelming majority of all trials favored anticoagulation. Rates of thromboembolism were higher in the control, and hemorrhagic complications in the anticoagulated group. Pooling of all randomized control trials gives mean case fatality rates of 19.6% for the control and 15.4% for the anticoagulated group, a relative reduction of 21% (P less than 0.05 or less than 0.001, depending on the analytic method). Five of six randomized control trials reported "no effect" because the difference favoring anticoagulation was not statistically significant. However, sample sizes in these "negative" papers were too small to protect against missing a 21% reduction in true case fatality rate due to anticoagulation (beta greater than 0.10). All patients who present no specific contraindication should receive anticoagulants during hospitalization for infarction.