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The risks associated with short-term placebo-controlled antihypertensive clinical trials: a descriptive meta-analysis

Abstract

Short-term (4–8 weeks) placebo-controlled trials are used to evaluate new antihypertensive drug treatment. To evaluate the consequences of such practice, a descriptive meta-analysis was conducted, consisting of blinded review of original case report forms for all patients who died or left a study before its completion for all short-term, placebo-controlled hypertension trials submitted to the Food and Drug Administration from 1973 through 2001. There were 93 marketing applications or supplements involving 590 individual trials that involved 86 137 randomized patients (64 438 randomized to experimental drug and 21 699 randomized to placebo) with 12 658 patient years of observation. There were 9636 dropouts (mean time to dropout was 28 days) and relative risk (RR (placebo/drug))=1.33 (95% confidence limits, 1.28, 1.39; P<10−16). As expected, lack of blood pressure (BP) control was far more common in patients randomized to placebo; therapeutic failure, RR=2.53 (2.35, 2.73; P<10−15) and hypertensive emergency, RR=2.75 (2.19, 3.57; P<10−15). When administrative dropouts and dropouts resulting from inadequate BP control were excluded, the remaining 38% of dropouts were disproportionately more from drug (2810 drug, 816 placebo), RR=0.80 (0.74, 0.86; P<10−8). There were 43 deaths, RR=0.72 (0.33, 1.45; P=0.37); 40 strokes, RR=1.43 (0.68, 2.81; P=0.33) and 77 myocardial infarctions, RR=1.06 (0.62, 1.75; P=0.82). Irreversible harm (a combination of death, stroke and myocardial infarction, 160 total events) was equally distributed between the drug and placebo groups, RR=1.03 (0.71, 1.47; P=0.86).

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Acknowledgements

This study was enabled by, and could not have been completed without, support (by two primary reviewers and data entry personnel) from The Ischemia Research Foundation (IREF), Dennis Mangano, MD, Director who was also a co-principal investigator. We appreciate the permission (by signed letter) from each pharmaceutical company (too numerous to list) for us to use the data they had submitted to NDAs. The original idea for the study came from Stephen P Glasser MD, who had generated a previous publication related to anti-angina trials.35 The entire staff and document control support of the Division of Cardio-Renal Drug Products (DCRDP), FDA worked long hours to make the study possible. Albert DeFelice, PhD and Jim Willard, PhD (DCRDP) undertook major supervisory tasks in addition to their regular regulatory workload. James Hung, PhD and John Lawrence, PhD (Division of Biostatistics, FDA) provided the initial statistical analysis plan and performed the maximum likelihood and Mantel Haenszel analyses. Douglas C Throckmorton, MD, prepared the original protocol and negotiated the IREF support. The paper was originally drafted by Raymond J Lipicky and Robert Fenichel, MD, PhD and Stephen Glasser, MD made major revisions and final suggestions were made by Robert Temple, MD (Director of the Office of Medical Policy—CDER FDA). The results were initially reported in abstract form36 shortly after the original analysis.

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Correspondence to R J Lipicky.

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There are no conflict of interest to declare. Robert Fenichel, MD, PhD and Raymond J Lipicky, MD, were employees of FDA at the time of the study; each has now left the FDA and is functioning as a paid consultant to many pharmaceutical companies. Stephen Glasser, MD, has been involved with hypertension drug intervention trials, including some of those analysed in PHARM. IREF as a personnel source did not conceive the project, nor was it involved in any supervisory capacity or any original analyses.

Supplementary Information accompanies the paper on the Journal of Human Hypertension website (http://www.nature.com/jhh)

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DeFelice, A., Willard, J., Lawrence, J. et al. The risks associated with short-term placebo-controlled antihypertensive clinical trials: a descriptive meta-analysis. J Hum Hypertens 22, 659–668 (2008). https://doi.org/10.1038/jhh.2008.51

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