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      Pharmacovigilance analysis of adverse event reports for aliskiren hemifumarate, a first-in-class direct renin inhibitor

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          Abstract

          Background

          The purpose of this study was to examine the postmarketing safety profile of aliskiren hemifumarate, a first-in-class direct renin inhibitor.

          Methods

          The US Adverse Event Reporting System (AERS) was utilized to conduct a retrospective pharmacovigilance analysis by applying the Multi-item Gamma Poisson Shrinker data mining algorithm to calculate empiric Bayes geometric mean (EBGM) values of aliskiren-related adverse event reports. Reports received from January 2007 through December 2008 are included in this analysis.

          Results

          In total, 1592 reports for aliskiren are identified in the AERS. Aliskiren was associated with reports of angioedema (EBGM 3.9, 95% confidence interval [CI] 3.2–4.7) and renal dysfunction (EBGM 3.4, 95% CI 2.6–4.5). Reports of hyperkalemia, dry cough, and diarrhea were also linked to aliskiren (EBGM 7.4, 95% CI 3.4–13.0, EBGM 11.0, 95% CI 7.8–14.2, EBGM 4.3, 95% CI 3.2–5.8, respectively).

          Conclusion

          Angioedema and renal dysfunction are potential adverse events associated with exposure to aliskiren. Patients with signs and symptoms of angioedema should stop aliskiren and seek urgent medical help. Aliskiren should not be used by patients with a risk of renal impairment. Additional studies are warranted to quantify further the risk of these events in patients with hypertension.

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          Most cited references 31

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          Use of screening algorithms and computer systems to efficiently signal higher-than-expected combinations of drugs and events in the US FDA's spontaneous reports database.

          Since 1998, the US Food and Drug Administration (FDA) has been exploring new automated and rapid Bayesian data mining techniques. These techniques have been used to systematically screen the FDA's huge MedWatch database of voluntary reports of adverse drug events for possible events of concern. The data mining method currently being used is the Multi-Item Gamma Poisson Shrinker (MGPS) program that replaced the Gamma Poisson Shrinker (GPS) program we originally used with the legacy database. The MGPS algorithm, the technical aspects of which are summarised in this paper, computes signal scores for pairs, and for higher-order (e.g. triplet, quadruplet) combinations of drugs and events that are significantly more frequent than their pair-wise associations would predict. MGPS generates consistent, redundant, and replicable signals while minimising random patterns. Signals are generated without using external exposure data, adverse event background information, or medical information on adverse drug reactions. The MGPS interface streamlines multiple input-output processes that previously had been manually integrated. The system, however, cannot distinguish between already-known associations and new associations, so the reviewers must filter these events. In addition to detecting possible serious single-drug adverse event problems, MGPS is currently being evaluated to detect possible synergistic interactions between drugs (drug interactions) and adverse events (syndromes), and to detect differences among subgroups defined by gender and by age, such as paediatrics and geriatrics. In the current data, only 3.4% of all 1.2 million drug-event pairs ever reported (with frequencies > or = 1) generate signals [lower 95% confidence interval limit of the adjusted ratios of the observed counts over expected (O/E) counts (denoted EB05) of > or = 2]. The total frequency count that contributed to signals comprised 23% (2.4 million) of the total number, 10.4 million of drug-event pairs reported, greatly facilitating a more focused follow-up and evaluation. The algorithm provides an objective, systematic view of the data alerting reviewers to critically important, new safety signals. The study of signals detected by current methods, signals stored in the Center for Drug Evaluation and Research's Monitoring Adverse Reports Tracking System, and the signals regarding cerivastatin, a cholesterol-lowering drug voluntarily withdrawn from the market in August 2001, exemplify the potential of data mining to improve early signal detection. The operating characteristics of data mining in detecting early safety signals, exemplified by studying a drug recently well characterised by large clinical trials confirms our experience that the signals generated by data mining have high enough specificity to deserve further investigation. The application of these tools may ultimately improve usage recommendations.
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            Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial.

            The aim of this study was to assess dual renin system intervention with the maximum recommended doses of aliskiren and valsartan, compared with each drug alone in patients with hypertension. In this double-blind study, 1797 patients with hypertension (mean sitting diastolic blood pressure 95-109 mm Hg and 8-h daytime ambulatory diastolic blood pressure > or =90 mm Hg) were randomly assigned to receive once-daily aliskiren 150 mg (n=437), valsartan 160 mg (455), a combination of aliskiren 150 mg and valsartan 160 mg (446), or placebo (459) for 4 weeks, followed by forced titration to double the dose to the maximum recommended dose for another 4 weeks. The primary endpoint was change in mean sitting diastolic blood pressure from baseline to week 8 endpoint. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov with the number NCT00219180. 196 (11%) patients discontinued study treatment before the end of the trial (63 in the placebo group, 53 in the aliskiren group, 43 in the valsartan group, and 37 in the aliskiren/valsartan group), mainly due to lack of therapeutic effect. At week 8 endpoint, the combination of aliskiren 300 mg and valsartan 320 mg lowered mean sitting diastolic blood pressure from baseline by 12.2 mm Hg, significantly more than either monotherapy (aliskiren 300 mg 9.0 mm Hg decrease, p<0.0001; valsartan 320 mg, 9.7 mm Hg decrease, p<0.0001), or with placebo (4.1 mm Hg decrease, p<0.0001). Rates of adverse events and laboratory abnormalities were similar in all groups. The combination of aliskiren and valsartan at maximum recommended doses provides significantly greater reductions in blood pressure than does monotherapy with either agent in patients with hypertension, with a tolerability profile similar to that with aliskiren and valsartan alone.
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              Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6-month, randomized, double-blind trial.

              This double-blind study compared long-term efficacy, safety and tolerability of the oral direct renin inhibitor aliskiren and the angiotensin-converting enzyme inhibitor ramipril alone and combined with hydrochlorothiazide in patients with hypertension. After a 2-4-week placebo run-in, 842 patients [mean sitting diastolic blood pressure (msDBP) 95-109 mmHg] were randomized to aliskiren 150 mg (n = 420) or ramipril 5 mg (n = 422). Dose titration (to aliskiren 300 mg/ramipril 10 mg) and subsequent hydrochlorothiazide addition (12.5 mg, titrated to 25 mg if required) were permitted at weeks 6, 12, 18 and 21 for inadequate blood pressure control. Patients completing the 26-week active-controlled treatment period were re-randomized to their existing regimen or placebo for a 4-week double-blind withdrawal phase. Six hundred and eighty-seven patients (81.6%) completed the active treatment period. At week 26, aliskiren-based therapy produced greater mean reductions in mean sitting systolic blood pressure (17.9 versus 15.2 mmHg, P = 0.0036) and msDBP (13.2 versus 12.0 mmHg, P = 0.025), and higher rates of systolic blood pressure control (< 140 mmHg; 72.5 versus 64.1%, P = 0.0075) compared with ramipril-based therapy. During withdrawal, blood pressure increased more rapidly after stopping ramipril than aliskiren-based therapy; median blood pressure reached 140/90 mmHg after 1 and 4 weeks, respectively. Blood pressure reductions were maintained with continued active treatment. Aliskiren therapy was well tolerated. Overall adverse event rates were similar with aliskiren (61.3%) and ramipril (60.4%); cough was more frequent with ramipril (9.5%) than aliskiren (4.1%). Aliskiren-based therapy was well tolerated and produced sustained blood pressure reductions in patients with hypertension over 6 months, greater than those with ramipril-based therapy.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2011
                2011
                09 August 2011
                : 7
                : 337-344
                Affiliations
                Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL, USA
                Author notes
                Correspondence: Ayad K Ali, Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, 101 S Newell Drive, PO Box 100496, Gainesville, FL 32610-0496, USA, Tel +1 352 273 6629, Fax +1 352 273 6270, Email ayadali@ 123456ufl.edu
                Article
                tcrm-7-337
                10.2147/TCRM.S23889
                3176166
                21941439
                © 2011 Ali, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Categories
                Original Research

                Medicine

                adverse event reporting system, postmarketing safety surveillance, aliskiren

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