aliskiren and Angioedema

It is increasingly necessary to analyze data from multiple sources when conducting public health safety surveillance or comparative effectiveness research. However, security, privacy, proprietary, and legal concerns often reduce data holders' willingness to share highly granular information. We describe and compare two approaches that do not require sharing of patient-level information to adjust for confounding in multi-site studies.. We estimated the risks of angioedema associated with angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and aliskiren in comparison with beta-blockers within Mini-Sentinel, which has created a distributed data system of 18 health plans. To obtain the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs), we performed (i) a propensity score-stratified case-centered logistic regression analysis, a method identical to a stratified Cox regression analysis but needing only aggregated risk set data, and (ii) an inverse variance-weighted meta-analysis, which requires only the site-specific HR and variance. We also performed simulations to further compare the two methods.. Compared with beta-blockers, the adjusted HR was 3.04 (95% CI: 2.81, 3.27) for ACEIs, 1.16 (1.00, 1.34) for ARBs, and 2.85 (1.34, 6.04) for aliskiren in the case-centered analysis. The corresponding HRs were 2.98 (2.76, 3.21), 1.15 (1.00, 1.33), and 2.86 (1.35, 6.04) in the meta-analysis. Simulations suggested that the two methods may produce different results under certain analytic scenarios.. The case-centered analysis and the meta-analysis produced similar results without the need to share patient-level data across sites in our empirical study, but may provide different results in other study settings.

Topics: Adrenergic beta-Antagonists; Amides; Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Comparative Effectiveness Research; Computer Simulation; Confounding Factors, Epidemiologic; Databases, Factual; Fumarates; Humans; Logistic Models; Multivariate Analysis; Pharmacoepidemiology; Propensity Score

Angio-oedema is a rare, but potentially life-threatening side effect to medication that interferes with the renin-angiotensin-aldosterone system. Clinically controlled trials were reviewed and the incidence assessed. We conclude, that treatment with an angiotensin receptor blocker can be tried after angiotensin-converting enzyme inhibitor (ACE-I) induced angio-oedema. The assessment should be individually based and take the severity of the previous attack and the weight of the indication into account. The risk on ACE-I might be greater in persons that have had angio-oedema for other reasons.

Topics: Amides; Angioedema; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Fumarates; Humans; Renin-Angiotensin System; Risk Factors

We conducted a systematic review and meta-analysis of double-blind randomized controlled trials to quantify the dose-related systolic (SBP) and diastolic blood pressure (DBP) lowering efficacy of renin inhibitors vs placebo in the treatment of adults with primary hypertension. Databases searched were Medline (1966-March 2008), EMBASE (1988-March 2008) and Cochrane Central Register of Controlled Trials (CENTRAL). Six trials in 3694 patients met the inclusion criteria. All examined aliskiren, the only renin inhibitor licensed for marketing in Canada and the United States. Aliskiren caused a dose-related SBP/DBP lowering effect compared to placebo: weighted mean difference with 95% CI: aliskiren 75 mg, -2.9 (-4.6, -1.3)/-2.3 (-3.3, -1.3) mm Hg; aliskiren 150 mg, -5.5 (-6.5, -4.4)/-3.0 (-3.7, -2.3) mm Hg; aliskiren 300 mg, -8.7 (-9.7,-7.6)/-5.0 (-5.6, -4.3) and aliskiren 600 mg, -11.4 (-13.5, -9.2)/-6.6 (-7.9, -5.2) mm Hg. Aliskiren 300 mg significantly lowered both SBP -3.0 (-4.0, -2.0) and DBP -1.7 (-2.3, -1.0) as compared to aliskiren 150 mg. Aliskiren has no effect on blood pressure variability. No data were available to assess the effect of aliskiren on heart rate or pulse pressure. This review found weak evidence that during 4- to 8-week use, aliskiren did not increase withdrawals due to adverse effects as compared to placebo. We concluded that aliskiren has a dose-related blood pressure lowering effect better than placebo and magnitude of effect is similar to that determined for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Topics: Adult; Amides; Angioedema; Antihypertensive Agents; Blood Pressure; Cough; Dose-Response Relationship, Drug; Fumarates; Heart Rate; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Treatment Outcome; Young Adult

Angioedema is a subcutaneous swelling typically affecting the face, larynx or pharynx. It is a known adverse drug reaction (ADR) of ACE inhibitors (ACEi), angiotensin-II-receptor blockers (ARBs) and aliskiren (renin inhibitor). Several studies have reported pathophysiological mechanisms and risk factors of ACEi-associated angioedemas, whereas little is known for ARBs and aliskiren. The aim of the study was to analyze comparatively ACEi versus ARBs and aliskiren angioedema reports contained in the European ADR database EudraVigilance with regard to reported risk factors and clinical phenotypes.. All spontaneous angioedema reports received between 01/2010-06/2017 reporting either an ACEi, ARB, or aliskiren as "suspected/interacting" drug were identified using the Standardized MedDRA Query "angioedema (narrow)". In order to perform a comparative analysis, odds ratios (ORs) were calculated for angioedema reports of ACEi (n = 3.194) versus ARBs (n = 687) and aliskiren (n = 162).. More patients with a history of allergy were included in angioedema reports of ARBs (6.8%) and aliskiren (13.6%) versus ACEi (4.3%). "Urticaria" as an ADR was reported more frequently in angioedema reports of ARBs (18.5%) and aliskiren (9.0%) versus ACEi (5.0%). ACEi-associated angioedemas were more often designated as "life-threatening" compared to ARBs (OR 2.2 [1.6-2.9]) and aliskiren-associated angioedemas (OR 14.2 (3.5-57.4). Concomitant therapy with mTOR inhibitors (OR 4.3 [1.0-17.9]) and fibrinolytics (OR 7.8 [1.1-57.2]) was reported more often in ACEi versus ARBs angioedema reports.. The reported clinical phenotypes differed between ACEi versus ARBs and aliskiren angioedema reports. Differences between the patient populations as observed in our study or differences with regard to underlying pathomechanisms could account for this finding. Due to the methodological limitations of spontaneous reporting systems, we cannot draw a firm conclusion in this regard. Hence, further research is necessary to confirm our observation and elucidate the underyling causes.

Topics: Aged; Amides; Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Databases, Factual; Drug Prescriptions; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Odds Ratio; Renin-Angiotensin System; Smoking

A non-interventional study suggested that use of angiotensin-converting enzyme inhibitors (ACEIs) or aliskiren was associated with an angioedema risk three times that of beta-blockers (BBs).. The aim was to assess angioedema incidence rates (IRs) and the relative angioedema risk of aliskiren compared to other antihypertensive drugs (AHDs).. A cohort study in hypertensive patients with an AHD prescription between 2007 and 2012 was conducted using data from the US PharMetrics Plus™ claims database. Angioedema was identified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM) code 995.1. Additionally, a nested case-control analysis was conducted to assess the relative angioedema risk of aliskiren or other AHDs versus BBs.. A total of 3,090,114 patients were included (aliskiren n = 30,720). There were 15,744 angioedema events (IR 2.28/1000 person-years; 95% confidence interval (CI) 2.24-2.32). Aliskiren IRs were: any aliskiren 2.58 (2.08-3.17), aliskiren monotherapy 1.71 (0.74-3.37), aliskiren fixed-dose combination (FDC) 1.27 (0.41-2.96), and aliskiren free-standing combination (FSC) 2.93 (2.31-3.66). The case-control analysis included 15,100 angioedema cases and 60,400 controls; the angioedema risk for both aliskiren monotherapy and FDC was not significantly different from BBs [adjusted odds ratio (adjOR) 0.99 (95% CI 0.45-2.20) and 1.06 (0.40-2.76)]; aliskiren FSC was associated with an increased angioedema risk [adjOR 3.29 (2.42-4.48)], mainly driven by concomitant ACEI use [adjOR 7.03 (4.10-12.05)].. The IR and risk of angioedema in patients with aliskiren monotherapy or FDC are comparable to BBs. The higher IR and risk of angioedema identified in the aliskiren FSC group may largely be driven by the concomitant use of ACEIs.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Aged; Amides; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Case-Control Studies; Cohort Studies; Databases, Factual; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Incidence; Male; Middle Aged; United States; Young Adult

Topics: Amides; Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Data Interpretation, Statistical; Databases, Factual; Epidemiologic Research Design; Fumarates; Humans; Multicenter Studies as Topic; Product Surveillance, Postmarketing; Research Support as Topic; United States

Topics: Amides; Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Fumarates; Humans; Renin

Topics: Amides; Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cough; Drug Interactions; Fumarates; Humans

Topics: Adult; Amides; Angioedema; Antihypertensive Agents; Female; Fumarates; Humans; Hypertension; Renin