Dabigatran – a case history demonstrating the need for comprehensive approaches to optimize the use of new drugs

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Abstract

Background: There are potential conflicts between authorities and companies to fund new premium priced drugs especially where there are safety and/or budget concerns. Dabigatran, a new oral anticoagulant for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), exemplifies this issue. Whilst new effective treatments are needed, there are issues in the elderly with dabigatran due to variable drug concentrations, no known antidote and dependence on renal elimination. Published studies have shown dabigatran to be cost-effective but there are budget concerns given the prevalence of AF. There are also issues with potentially re-designing anticoagulant services. This has resulted in activities across countries to better manage its use.

Objective: To (i) review authority activities in over 30 countries and regions, (ii) use the findings to develop new models to better manage the entry of new drugs, and (iii) review the implications for all major stakeholder groups.

Methodology: Descriptive review and appraisal of activities regarding dabigatran and the development of guidance for groups through an iterative process.

Results: There has been a plethora of activities among authorities to manage the prescribing of dabigatran including extensive pre-launch activities, risk sharing arrangements, prescribing restrictions, and monitoring of prescribing post-launch. Reimbursement has been denied in some countries due to concerns with its budget impact and/or excessive bleeding. Development of a new model and future guidance is proposed to better manage the entry of new drugs, centering on three pillars of pre-, peri-, and post-launch activities.

Conclusion: Models for introducing new drugs are essential to optimize their prescribing especially where there are concerns. Without such models, new drugs may be withdrawn prematurely and/or struggle for funding.

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Most cited references 95

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Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.

A S Go, E Hylek, K. Phillips … (2001)

Atrial fibrillation is the most common arrhythmia in elderly persons and a potent risk factor for stroke. However, recent prevalence and projected future numbers of persons with atrial fibrillation are not well described. To estimate prevalence of atrial fibrillation and US national projections of the numbers of persons with atrial fibrillation through the year 2050. Cross-sectional study of adults aged 20 years or older who were enrolled in a large health maintenance organization in California and who had atrial fibrillation diagnosed between July 1, 1996, and December 31, 1997. Prevalence of atrial fibrillation in the study population of 1.89 million; projected number of persons in the United States with atrial fibrillation between 1995-2050. A total of 17 974 adults with diagnosed atrial fibrillation were identified during the study period; 45% were aged 75 years or older. The prevalence of atrial fibrillation was 0.95% (95% confidence interval, 0.94%-0.96%). Atrial fibrillation was more common in men than in women (1.1% vs 0.8%; P<.001). Prevalence increased from 0.1% among adults younger than 55 years to 9.0% in persons aged 80 years or older. Among persons aged 50 years or older, prevalence of atrial fibrillation was higher in whites than in blacks (2.2% vs 1.5%; P<.001). We estimate approximately 2.3 million US adults currently have atrial fibrillation. We project that this will increase to more than 5.6 million (lower bound, 5.0; upper bound, 6.3) by the year 2050, with more than 50% of affected individuals aged 80 years or older. Our study confirms that atrial fibrillation is common among older adults and provides a contemporary basis for estimates of prevalence in the United States. The number of patients with atrial fibrillation is likely to increase 2.5-fold during the next 50 years, reflecting the growing proportion of elderly individuals. Coordinated efforts are needed to face the increasing challenge of optimal stroke prevention and rhythm management in patients with atrial fibrillation.

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Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group.

C Bombardier, L Laine, A Reicin … (2000)

Each year, clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We assessed whether rofecoxib, a selective inhibitor of cyclooxygenase-2, would be associated with a lower incidence of clinically important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis. We randomly assigned 8076 patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) and who had rheumatoid arthritis to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily. The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers). Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib, as compared with 4.5 per 100 patient-years with naproxen (relative risk, 0.5; 95 percent confidence interval, 0.3 to 0.6; P<0.001). The respective rates of complicated confirmed events (perforation, obstruction, and severe upper gastrointestinal bleeding) were 0.6 per 100 patient-years and 1.4 per 100 patient-years (relative risk, 0.4; 95 percent confidence interval, 0.2 to 0.8; P=0.005). The incidence of myocardial infarction was lower among patients in the naproxen group than among those in the rofecoxib group (0.1 percent vs. 0.4 percent; relative risk, 0.2; 95 percent confidence interval, 0.1 to 0.7); the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups. In patients with rheumatoid arthritis, treatment with rofecoxib, a selective inhibitor of cyclooxygenase-2, is associated with significantly fewer clinically important upper gastrointestinal events than treatment with naproxen, a nonselective inhibitor.

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Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.

Robert Bresalier, Robert Sandler, Hui Quan … (2005)

Selective inhibition of cyclooxygenase-2 (COX-2) may be associated with an increased risk of thrombotic events, but only limited long-term data have been available for analysis. We report on the cardiovascular outcomes associated with the use of the selective COX-2 inhibitor rofecoxib in a long-term, multicenter, randomized, placebo-controlled, double-blind trial designed to determine the effect of three years of treatment with rofecoxib on the risk of recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas. A total of 2586 patients with a history of colorectal adenomas underwent randomization: 1287 were assigned to receive 25 mg of rofecoxib daily, and 1299 to receive placebo. All investigator-reported serious adverse events that represented potential thrombotic cardiovascular events were adjudicated in a blinded fashion by an external committee. A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up (1.50 events per 100 patient-years), as compared with 26 patients in the placebo group during 3327 patient-years of follow-up (0.78 event per 100 patient-years); the corresponding relative risk was 1.92 (95 percent confidence interval, 1.19 to 3.11; P=0.008). The increased relative risk became apparent after 18 months of treatment; during the first 18 months, the event rates were similar in the two groups. The results primarily reflect a greater number of myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group. There was earlier separation (at approximately five months) between groups in the incidence of nonadjudicated investigator-reported congestive heart failure, pulmonary edema, or cardiac failure (hazard ratio for the comparison of the rofecoxib group with the placebo group, 4.61; 95 percent confidence interval, 1.50 to 18.83). Overall and cardiovascular mortality was similar in the two groups. Among patients with a history of colorectal adenomas, the use of rofecoxib was associated with an increased cardiovascular risk. Copyright 2005 Massachusetts Medical Society.

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Author and article information

Journal

Journal ID (nlm-ta): Front Pharmacol

Journal ID (iso-abbrev): Front Pharmacol

Journal ID (publisher-id): Front. Pharmacol.

Title: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-9812

Publication date (Electronic): 14 May 2013

Publication date Collection: 2013

Volume: 4

Electronic Location Identifier: 39

Affiliations

[1] ¹Clinical Pharmacology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna Stockholm, Sweden

[2] ²Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge Stockholm, Sweden

[3] ³Liverpool Health Economics Centre, University of Liverpool Liverpool, UK

[4] ⁴Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde Glasgow, UK

[5] ⁵Unitat de Coordinació i Estratégia del Medicament, Direcció Adjunta d’Afers Assistencials, Catalan Institute of Health Barcelona, Spain

[6] ⁶Austrian Medicines and Medical Devices Agency Wien, Austria

[7] ⁷Information Services Division, NHS National Services Scotland Edinburgh, UK

[8] ⁸Agency for Health Technology Assessment Warsaw, Poland

[9] ⁹Hauptverband der Österreichischen Sozialversicherungsträger Wien, Austria

[10] ¹⁰Centre for Primary Care, Institute of Population Health, University of Manchester Manchester, UK

[11] ¹¹London School of Economics and Political Sciences, LSE Health London, UK

[12] ¹²King’s Centre for Global Health, Global Health Offices, Weston Education Centre London, UK

[13] ¹³Health Insurance Institute Ljubljana, Slovenia

[14] ¹⁴Medicines Reimbursement Department, National Health Insurance Fund Vilnius, Lithuania

[15] ¹⁵Instituto Nacional da Farmácia e do Medicamento Lisboa, Portugal

[16] ¹⁶Osteba Basque Office for Health Technology Assessment, Ministry of Health of the Basque Country Donostia-San Sebastian, Vitoria-Gasteiz, Basque Country, Spain

[17] ¹⁷Norwegian Medicines Agency Oslo, Norway

[18] ¹⁸Kassenärztliche Vereinigung Hessen Frankfurt am Main, Germany

[19] ¹⁹Nätverk för läkemedelsepidemiologi, Department of Health Analysis, University Hospital Linköping, Sweden

[20] ²⁰Clinical Programs, Pharmacy Management, Horizon Blue Cross Blue Shield of New Jersey Newark, USA

[21] ²¹Ninewells Hospital, NHS Tayside Dundee, UK

[22] ²²Pharmaceutical Department, Local Health Unit of Verona Verona, Italy

[23] ²³Republic Institute for Health Insurance Belgrade, Serbia

[24] ²⁴State Agency of Medicines Tartu, Estonia

[25] ²⁵Wissenschaftliches Institut der AOK Berlin, Germany

[26] ²⁶Lancashire Commissioning Support Unit, Jubilee House Leyland, Lancashire, UK

[27] ²⁷Department of Healthcare Development, Stockholm County Council Stockholm, Sweden

[28] ²⁸HTA Consulting Cracow, Poland

[29] ²⁹Public Health School, The Medical Centre of Postgraduate Education Warsaw, Poland

[30] ³⁰National Centre for Pharmacoeconomics, St James’s Hospital Dublin, Ireland

[31] ³¹Scottish Medicines Consortium Glasgow, UK

[32] ³²Faculty of Medicine, University of Banja Luka Banja Luka, Bosnia and Herzegovina, Republic of Srpska

[33] ³³Ministry of Health and Social Welfare Banja Luka, Bosnia and Herzegovina, Republic of Srpska

[34] ³⁴NHS Bury Bury, UK

[35] ³⁵Institut de Recherche et Documentation en Économie de la Santé Paris, France

[36] ³⁶KU Leuven Department of Pharmaceutical and Pharmacological Sciences Leuven, Belgium

[37] ³⁷President of the Turkish Rational Drug Use Platform Ankara, Turkey

[38] ³⁸Faculty of Pharmacy, Comenius University Bratislava, Slovakia

[39] ³⁹Faculty of Medicine, Slovak Medical University Bratislava, Slovakia

[40] ⁴⁰Ministry of Health Zagreb, Republic of Croatia

[41] ⁴¹Unit for Clinical Pharmacology, University Hospital Rijeka Rijeka, Croatia

[42] ⁴²Independent Consumer Advocate Brunswick, VIC, Australia

[43] ⁴³Prescribing Support Unit, c/o Pharmacy Department, Royal Cornwall Hospitals NHS Trust Truro, Cornwall, UK

[44] ⁴⁴Dutch Institute for Rational Use of Medicine Utrecht, Netherlands

[45] ⁴⁵Barcelona Health Region, Catalan Health Service Barcelona, Spain

Author notes

Edited by: Dominique J. Dubois, Université Libre de Bruxelles, Belgium

Reviewed by: Mark J. C. Nuijten, Ars Accessus Medica BV, Netherlands; Zoltan Kalo, Health Economics Research Centre; Eötvös Loránd University, Hungary

*Correspondence: Brian B. Godman, Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, C1:68, Huddinge, SE-141 86 Stockholm, Sweden. e-mail: brian.godman@ki.se

^†Present address: Andrew Martin, NHS Greater Manchester Commissioning Support Unit, Salford, UK.

This article was submitted to Frontiers in Pharmaceutical Medicine and Outcomes Research, a specialty of Frontiers in Pharmacology.

Article

DOI: 10.3389/fphar.2013.00039

PMC ID: 3653065

PubMed ID: 23717279

SO-VID: a5c5a33b-7407-4dbd-ae98-724f6733a27c

Copyright © Copyright © Malmström, Godman, Diogene, Baumgärtel, Bennie, Bishop, Brzezinska, Bucsics, Campbell, Ferrario, Finlayson, Fürst, Garuoliene, Gomes, Gutiérrez-Ibarluzea, Haycox, Hviding, Herholz, Hoffmann, Jan, Jones, Joppi, Kalaba, Kvalheim, Laius, Langner, Lonsdale, Lööv, Malinowska, McCullagh, Paterson, Markovic-Pekovic, Martin, Piessnegger, Selke, Sermet, Simoens, Tulunay, Tomek, Vonèina, Vlahovic-Palcevski, Wale, Wilcock, Wladysiuk, van Woerkom, Zara and Gustafsson.

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

History

Date received : 04 January 2013

Date accepted : 20 March 2013

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Figures: 1, Tables: 5, Equations: 0, References: 187, Pages: 31, Words: 0

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Dabigatran – a case history demonstrating the need for comprehensive approaches to optimize the use of new drugs

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Most cited references 95

Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.

Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group.

Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.

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