Dataset Information

Biased safety reporting in blinded randomized clinical trials: meta-analysis of angiotensin receptor blocker trials.

ABSTRACT:

Background

Cough is listed as an adverse drug reaction (ADR) on the labels of angiotensin receptor blockers (ARB). However, a causal association with cough has also been reported for angiotensin converting enzyme inhibitors (ACEI), which have frequently been used as comparator drugs in the registration clinical trials of ARBs. This prompted us to examine the possible influence of using comparator drugs with well-known ADRs on the safety reporting of investigational drugs in blinded randomized clinical trials.

Methods and findings

The double-blinded, randomized clinical trials with comparator drugs were identified in the Japanese dossiers for the new drug applications of ARBs. The risk ratios (RR) of reporting cough and headache in ARB arms were calculated for each ARB by comparing trials using ACEIs and trials using non-ACEIs, were then combined with a meta-analysis. 23 trials with a total of 6643 patients were identified, consisting 6 trials using an ACEI comparator including 819 ARB patients and 17 trials using a non-ACEI comparator including 5824 ARB patients. The combined RR of cough reporting was significantly elevated (20.77; 95% confidence interval [CI], 7.47 to 57.76), indicating more frequent reporting of cough in clinical trials using an ACEI comparator. In contrast, the combined RR of headache, a negative control, was insignificant (1.45; 95% CI, 0.34 to 6.22).

Conclusion

The use of comparators with well-known ADRs in blinded randomized trials produces potential bias in the reporting frequency of ADRs for investigational drugs. The selection of appropriate comparator drugs should be critical in unbiased safety assessment in double-blinded, randomized clinical trials and thus have relevance in reviewing the safety results from a regulatory point of view.

SUBMITTER: Takabayashi N

PROVIDER: S-EPMC3781030 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Biased safety reporting in blinded randomized clinical trials: meta-analysis of angiotensin receptor blocker trials.

Takabayashi Nobuyoshi N Urushihara Hisashi H Kawakami Koji K

PloS one 20130923 9

<h4>Background</h4>Cough is listed as an adverse drug reaction (ADR) on the labels of angiotensin receptor blockers (ARB). However, a causal association with cough has also been reported for angiotensin converting enzyme inhibitors (ACEI), which have frequently been used as comparator drugs in the registration clinical trials of ARBs. This prompted us to examine the possible influence of using comparator drugs with well-known ADRs on the safety reporting of investigational drugs in blinded rando ...[more]

PMID: 24086427

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Project description:Background: The purpose of this meta-analysis was to evaluate the controversy of angiotensin-converting enzyme inhibitor (ACEI) in combination with angiotensin-receptor blocker (ARB) in the treatment of chronic kidney disease (CKD) based on dose. Methods: PubMed, EMBASE, and Cochrane Library were searched to identify randomized controlled trials (RCTs) from inception to March 2020. The random effects model was used to calculate the effect sizes. Potential sources of heterogeneity were detected using sensitivity analysis and meta-regression. Results: This meta-analysis of 53 RCTs with 6,375 patients demonstrated that in patients with CKD, ACEI in combination with ARB was superior to low-dose ACEI or ARB in reducing urine albumin excretion (SMD, -0.43; 95% CI, -0.67 to -0.19; p = 0.001), urine protein excretion (SMD, -0.22; 95% CI, -0.33 to -0.11; p < 0.001), and blood pressure (BP), including systolic BP (WMD, -2.89; 95% CI, -3.88 to -1.89; p < 0.001) and diastolic BP (WMD, -3.02; 95% CI, -4.46 to -1.58; p < 0.001). However, it was associated with decreased glomerular filtration rate (GFR) (SMD, -0.13; 95% CI, -0.24 to -0.02; p = 0.02) and increased rates of hyperkalemia (RR, 2.07; 95% CI, 1.55 to 2.76; p < 0.001) and hypotension (RR, 2.19; 95% CI, 1.35 to 3.54; p = 0.001). ACEI in combination with ARB was more effective than high-dose ACEI or ARB in reducing urine albumin excretion (SMD, -0.84; 95% CI, -1.26 to -0.43; p < 0.001) and urine protein excretion (SMD, -0.24; 95% CI, -0.39 to -0.09; p = 0.002), without decrease in GFR (SMD, 0.02; 95% CI, -0.12 to 0.15; p = 0.78) and increase in rate of hyperkalemia (RR, 0.94; 95% CI, 0.65 to 1.37; p = 0.76). Nonetheless, the combination did not decrease the BP and increased the rate of hypotension (RR, 3.95; 95% CI, 1.13 to 13.84; p = 0.03) compared with high-dose ACEI or ARB. Conclusion: ACEI in combination with ARB is superior in reducing urine albumin excretion and urine protein excretion. The combination is more effective than high-dose ACEI or ARB without decreasing GFR and increasing the incidence of hyperkalemia. Despite the risk of hypotension, ACEI in combination with ARB is a better choice for CKD patients who need to increase the dose of ACEI or ARB (PROSPERO CRD42020179398).

Project description:IntroductionThis meta-analysis aimed to summarize the available evidence to compare angiotensin-converting enzyme (ACE) inhibitors with angiotensin II receptor blockers (ARBs) on improving insulin sensitivity in hypertensive patients.MethodsRandomized controlled trials (RCTs) comparing ACE inhibitors versus ARBs published with outcomes on homeostasis model assessment of IR (HOMA-IR), glucose infusion rate (GIR), the quantitative insulin sensitivity check index (QUICKI), insulin sensitivity index (ISI) composite, fasting plasma glucose (FPG), fasting plasma insulin (FPI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were searched through 5 databases. Data were searched from their inception to July 5, 2020. Stata 14.0 was used to perform the meta-analysis.ResultsEleven RCTs (n = 1015) were included in this meta-analysis. Pooled analysis of studies showed no significant difference in HOMA-IR between ARBs and ACE inhibitors (WMD = -0.09, 95% CI: -0.69 to 0.50, P = 0.755); however, subgroup analysis of therapeutic duration showed a significant difference in HOMA-IR between ARBs and ACE inhibitors among the long-term intervention subgroup (>12 weeks) (WMD = 0.41, 95% CI: 0.06 to 0.76, P = 0.022) and hypertensive patients with diabetes mellitus subgroup (WMD = 0.55, 95% CI: 0.49 to 0.61, P < 0.001); results showed no significant difference between ARBs and ACE inhibitors on QUICKI score (WMD = -0.00, 95% CI: -0.03 to 0.03, P = 0.953) in hypertensive patients; however, the efficacy of ACE inhibitors on improving GIR and ISI composite was significantly better than that of ARBs (WMD = -1.09, 95% CI: -1.34 to -0.85, P < 0.001; WMD = -0.80, 95% CI: -1.24 to -0.36, P < 0.001, respectively). Furthermore, no significant differences were noted on FPG (WMD = 0.72, 95% CI: -1.39 to 2.83, P = 0.505), FPI (WMD = -0.48, 95% CI: -1.60 to 0.64, P = 0.398), SBP (WMD = -0.65, 95% CI: -1.76 to 0.46, P = 0.254), and DBP (WMD = -0.30, 95% CI: -1.70 to 1.10, P = 0.675) between ARBs and ACE inhibitors.ConclusionResults from this meta-analysis showed that ACE inhibitors resulted in more effective improvement of HOMA-IR compared with ARBs among the long-term intervention and hypertensive patients with DM subgroup; furthermore, the efficacy of ACE inhibitors on improving GIR and ISI composite was significantly better than that of ARBs in hypertensive patients. However, ARBs had no significant difference in QUICKI score, FPG, FPI, SBP, and DBP compared with ACE inhibitors. Larger and better-designed studies are needed to further verify this conclusion.

Dataset Information

Biased safety reporting in blinded randomized clinical trials: meta-analysis of angiotensin receptor blocker trials.

Background

Methods and findings

Conclusion

Publications

Biased safety reporting in blinded randomized clinical trials: meta-analysis of angiotensin receptor blocker trials.

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