European Journal of Internal Medicine 25 (2014) 843–846
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Understanding adverse drug reactions in older adults through drug– drug interactions A. Marengoni a,⁎, L. Pasina b, C. Concoreggi c, G. Martini d, F. Brognoli d, A. Nobili b, G. Onder e, D. Bettoni f a
Geriatric Unit, Department of Clinical and Experimental Sciences, University of Brescia, Italy Department of Neuroscience, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy Intensive Brief Observation Unit, Emergency Room, Spedali Civili, Brescia, Italy d Haemostasis Centre Laboratory, Spedali Civili, Brescia, Italy e Centro Medicina dell'Invecchiamento, Policlinico A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy f Pharmacovigilance, Spedali Civili Pharmacy, Brescia, Italy b c
a r t i c l e
i n f o
Article history: Received 28 August 2014 Received in revised form 29 September 2014 Accepted 1 October 2014 Available online 11 October 2014 Keywords: Adverse drug reaction Drug–drug interaction Elderly
a b s t r a c t Aims: The aims of this study are to evaluate prevalence and characteristics of adverse drug reactions (ADRs) and to evaluate the potential contribution of specific medications, therapeutic categories and drug–drug interactions (DDIs) in older adults. Methods: All ADR reporting forms of persons aged 65+ years collected by the pharmacovigilance of one of the main hospitals in Italy during 2013 were evaluated. DDIs were analysed by a computerized prescription system (INTERCheck) and based on the interactions' database managed by the Istituto di Ricerche Farmacologiche Mario Negri. DDIs were classified according to their clinical relevance as contraindicated, major, and moderate. Results: Amongst all the ADR reporting forms (n = 1014) collected during 2013, 343 affected older adults. The most frequent ADRs were: haemorrhages (n = 122, 35.5%), allergic reactions (n = 56, 16.3%), and elevated International Normalized Ratio (INR N 6, n = 54, 15.7%). The specific medications that contributed to ADRs were warfarin (42.5%), acenocumarol (9%), and allopurinol (8.5%); while the therapeutic categories were haematological agents (67%) and proton pump inhibitors (13%). A total of 912 DDIs were found; one third of them were contraindicated or major and 31.5% of them potentially contributed to ADRs; of these, the most frequent were: warfarin and heparin (contraindicated, n = 5); warfarin and a statin (major, n = 38); warfarin and a proton pump inhibitor (moderate, n = 40). At least one DDI contributed to 66 haemorrhages out of 122 (54%) and to 41 elevated INR out of 54 (76%). Conclusion: DDIs significantly contribute to the onset of ADRs in older adults and intervention programmes, e.g., the employment of a computerized system, may reduce the burden of iatrogenic illnesses in the elderly. © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Due to the persistent exclusion of older persons from clinical trials, data on benefit–risk balance of several drugs in this section of the population are unknown. Research literature showed that adverse drug reactions (ADRs) are frequent and severe, and are responsible for considerable morbidity and mortality in older persons, leading to multiple admissions to the emergency room and acute hospitalizations [1,2]. This means that ADRs have a significant and detrimental impact on the healthcare system's economy.
⁎ Corresponding author at: Department of Clinical and Experimental Sciences, University of Brescia, Geriatric Unit, Spedali Civili, Piazzale Spedali Civili 1, 25123 Brescia, Italy. Tel.: +39 030 2528554/478; fax: +39 030 2528476. E-mail address: [email protected] (A. Marengoni).
In a recent editorial, the European Medicines Agency defined a strategy to overcome several key issues in the pharmacological treatment of older persons. The Agency suggested that ‘spontaneous reports of adverse events can be used to identify patterns of drug-disease and drug–drug interactions (DDIs) that were not apparent before authorization’ [3], with DDI being the ability of a drug to modify the action or effect of another drug administered successively or simultaneously. These interactions have rarely been considered to cause ADRs in geriatric persons compared to single pharmacologic agents, although they increase with increasing age and the number of drugs consumed. In particular, amongst hospitalized older adults, the overlap of acute and chronic diseases may increase the susceptibility to ADRs and their severity. This study aimed to evaluate the occurrence and characteristics of ADRs in persons aged 65 + years attending one of the inpatient units and/or to the anticoagulant outpatient unit of one of the main hospitals in Italy during 2013. The contribution of specific medications, therapeutic
http://dx.doi.org/10.1016/j.ejim.2014.10.001 0953-6205/© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
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A. Marengoni et al. / European Journal of Internal Medicine 25 (2014) 843–846
categories, and all possible contraindicated, major, and moderate DDIs were assessed. 2. Methods In Italy, spontaneous ADRs are collected through the National Network of Pharmacovigilance, an extensive linkage that includes the Regional Centers of Pharmacovigilance, the Local Health Authorities, about one hundred hospitals, research institutes, and pharmaceutical companies, as well as the Italian Agency of Medicine. The system also operates in connection with the European network for pharmacovigilance, EudraVigilance, which collects all data provided by the EU countries at national level in a single database. Data analysed in this study were all spontaneous ADR reporting forms collected by the pharmacovigilance of the Spedali Civili, Brescia. The Spedali Civili is one of the main hospitals in Italy: in 2013, 72,132 persons were admitted to the hospital and 1868 were examined in the anticoagulant outpatient unit. Of these, 27,700 and 1444 were aged 65 + years, respectively. Usually, all the physicians are required to complete specific reporting forms and to submit them to the hospital pharmacy if an ADR is suspected. ADRs were here defined as a noxious and unintended response to a medicinal product that occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy of disease or for the restoration, correction, or modification of physiological function as well as harm caused by medication errors (in prescription, administration, or monitoring of drug therapy) or patient non-adherence (adherence defined as ‘the extent to which patients take the medications as prescribed by their health care providers’) [4]. Severity of ADRs was classified as i) mild-moderate, ii) severe with hospitalization, iii) severe with clinical condition not requiring hospitalization, iv) life-threatening, and v) leading to permanent invalidity and to death. Potential DDIs were analysed by a computerized prescription support system, i.e., INTERCheck, which was based on an Italian interactions' database managed by the Istituto di Ricerche Farmacologiche Mario Negri, which has been already validated and described in detail [5,6]. We classified all drug interactions in terms of clinical relevance, considering potential health outcomes, type, quality, and relevance of supporting clinical and pharmacological documentation. Coherently with other computerized support systems [7], each potential DDI was classified by clinical relevance as follows: contraindicated (drug combination should be avoided or may potentially lead to serious clinical consequences), major (the combination can be handled e.g. by dose adjustments or temporal separation, close monitoring is required), moderate (clinical outcome of the interaction is uncertain and/or may vary) and minor (drug combination probably has no clinical relevance or has not been completely assessed). Spontaneous ADRs reporting forms were collected by the hospital pharmacy and stored in a database including age, sex, medications possibly implicated in the ADR, concomitant medications, and narrative description of the adverse reaction as well as its severity and outcome. Number and prevalence per 100 of ADRs were calculated for different age groups; specific medications and therapeutic categories potentially contributing to ADRs were evaluated. The whole drug regimen of all the subjects was analysed using INTERCheck for the calculation of DDIs potentially contributing or not to ADRs. In this study, only contraindicated, major, and moderate interactions were analysed. The Ethical Committee of the Spedali Civili approved the study. 3. Results Amongst all the spontaneous ADR reporting forms (n = 1014) collected by the hospital pharmacovigilance from January 1st to December 31st 2013, 343 (34%) affected people aged 65 years or older (Fig. 1). The mean age of the patients was 76.4 years. The average number of drugs per patient was 8.5. ADRs were equally distributed in
men (n = 165) and women (n = 178), whereas a lower prevalence was found in the 60 very old (85 + years) persons compared to the younger age group (17.5 versus 82.5%). Prevalence of ADRs in the total number of patients admitted during 2013 was 1.3%; prevalence of ADRs in patients aged 65 + years was 1.2%. Spontaneous ADR reporting forms were mostly sent by the emergency room (n = 152) and the anticoagulant drug outpatient unit (n = 120), followed by the clinical inpatient wards (20 cases by haematology, 10 cases by dermatology, 7 cases by oncology, 7 cases by neurology, 26 cases by other units). Amongst all the ADRs, 194 (56.5%) were mild-moderate, 123 (35.9%) were severe requiring hospitalization, 16 (4.6%) were severe but not requiring hospitalization, 5 (1.5%) were life-threatening, 4 (1.2%) led to death, and 1 (0.3%) led to permanent invalidity. The most frequent ADRs were haemorrhages (n = 122, 35.5%), allergic reactions (n = 56, 16.3%), elevated International Normalized Ratio (INR N 6, n = 54, 15.7%), and neuropsychiatric/neurological effects (n = 26, 7.5%) (Table 1). Table 1 also shows the most frequent medications contributing to ADRs, which were warfarin, acenocumarol, and allopurinol. Also shown are the most frequent therapeutic categories, which were haematologic agents and proton pump inhibitors (Table 1). Fig. 1 shows the number of the DDIs found in the pharmacological regimen of the patients that could have contributed to the corresponding ADRs (Fig. 1). Amongst the DDIs potentially contributing to ADRs (n = 288, 31.5%), the most frequent contraindicated DDIs were warfarin and heparin (5 cases). The most frequent major DDIs were warfarin and a statin (38 cases), warfarin and allopurinol (27 cases), and warfarin and amiodarone (22 cases) (Table 2). The most frequent moderate DDI was warfarin and a proton pump inhibitor (41 cases). Forty-eight out of 123 (39%) ADRs that were classified as ‘severe requiring hospitalization’ were potentially caused by DDIs, but none led to death or were life-threatening. The analysis of the association between DDIs and the most frequent ADRs showed that at least one DDI contributed to 66 haemorrhages out of 122 (54%) and to 41 elevated INR out of 54 (76%).
4. Discussion Data for these analyses were gathered from 1-year ADR reporting forms of one of the main hospitals in Italy. Specific medications (i.e., warfarin, acenocumarol and allopurinol), as well as therapeutic categories (i.e., haematological agents and proton pump inhibitors) mostly contributed to ADRs. Furthermore, a considerable number of DDIs were found in the therapeutic regimens, potentially related or unrelated to the specific ADR and more importantly, about one third of them were contraindicated or major. Finally, at least one DDI explained almost 40% of the ADRs classified as ‘severe requiring hospitalization’ as well as the majority of the most frequent ADRs, i.e. more than half of haemorrhages and two-third of elevated INRs. We evaluated specific medications potentially contributing to ADRs, and our results highlighted the presence of drugs that typically cause ADRs in older persons, such as warfarin [8], but also medications that are less known, such as allopurinol and proton pump inhibitors. These drugs are often inappropriately prescribed and considered safe in the elderly. For instance, proton pump inhibitors are frequently used for non-evidence-based indications or in case of the use of a high number of concomitant drugs [9]. Allopurinol is often inappropriately used in asymptomatic hyperuricaemia [10], following some epidemiological and experimental studies that suggested a linkage between hyperuricaemia and hypertension [11,12], although there is poor evidence indicating a role of allopurinol in preventing cardiovascular diseases [13]. A rational use of these drugs is warranted as not only can they have serious short- and long-term consequences, such as hypersensitivity syndrome or Steven–Johnson syndrome (allopurinol) [14], and intestinal and pulmonary infections (proton pump inhibitors) [15], but they are also frequently involved in DDIs.
A. Marengoni et al. / European Journal of Internal Medicine 25 (2014) 843–846
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All ADR reporng forms in 2013 n=1014
ADR reporng forms in children (0-18 yrs) n=266
ADR reporng forms in older persons (65+ yrs) n=343
ADR reporng forms in adults (19-64 yrs) n=405
Total number of DDIs n=912
Number of DDIs potenally contribung to ADRs n=288
Number of DDIs potenally not contribung to ADRs n=624 Contraindicated n=43
Contraindicated n=8
Severe n=124
Severe n=133 Moderate n=457
Moderate n=147
Fig. 1. Number (N) of ADRs in the whole sample according to age and number of DDIs potentially contributing or not to ADRs in older persons.
Table 1 Number of ADRs according to specific medications and therapeutic categories. Number and proportion per 100 (on a total number of ADRs = 343). Number Most common ADRs All haemorrhages 122 Epistaxis 31 Skin or wound haemorrhage 29 Intracranial haemorrhage 25 Gastrointestinal haemorrhage 17 Genitourinary haemorrhage 14 Others 6 Allergic reactions 56 a INR N6 54 Neurologic or neuropsychiatric effects 26 Dizziness and syncope 16 Gastrointestinal effects 15 Hypoglycaemia or acidosis 8 Osteonecrosis 5 Most commonly implicated medications Warfarin 146 Acenocumarol 31 Allopurinol 29 Acetylsalicylic acid 26 Amiodarone 23 Simvastatin 19 Amoxicillin/clavulanic acid 18 Pantoprazole 16 Omeprazole 15 Atorvastatin 15 Most commonly implicated therapeutic categories Haematologic agents 230 Proton pump inhibitors 44 Statins 41 NSAIDs 24 Antibiotics 22 a
INR denotes International Normalized Ratio.
Proportion (%) 35.5 9.0 8.4 7.2 4.9 4.0 1.7 16.3 15.7 7.5 4.6 4.3 2.3 1.4 42.5 9.0 8.5 7.6 6.7 5.5 5.2 4.6 4.4 4.4 67.0 12.8 11.9 6.9 6.4
Epidemiological studies of DDIs and the related risk of adverse clinical outcomes in elderly patients are rare and the prevalence of DDIs responsible for ADRs is not well-defined [16–19]. The prevalence of potential DDIs in geriatric patients may vary according to the design of the study, the clinical setting, and the severity of DDIs. According to a large prospective observational study, 1% of all hospital admissions are due to DDIs [19], but adverse events can be serious in the elderly. A literature review indicated that in the elderly, DDIs were responsible for 4.8% of the admissions [16]. The high prevalence of DDIs in elderly patients was suggested by another review that showed a prevalence of DDIs between 15 and 45% in hospital, higher in patients with heart diseases and elderly people [20]. Our findings suggest that DDIs are an important risk factor for ADRs, which explain around 40% of the ADRs classified as severe requiring hospitalization, as well as the majority of the most frequent ADRs (i.e. haemorrhages and elevated INR). In line with previous studies in the elderly [21], the medications most frequently involved in DDIs were Table 2 Most frequent contraindicated and major DDIs potentially contributing to ADRs and potential adverse effect. N Contraindicated DDIs (all) Warfarin and heparin Dabigatran and dronedarone Acenocumarol and acetylsalicylic acid Itraconazole and vincristine Major DDIs (all) Warfarin and allopurinol Warfarin and amiodarone Warfarin and simvastatin Warfarin and acetylsalicylic acid Warfarin and atorvastatin Warfarin and rosuvastatin Warfarin and amoxicillin
8 5 1 1 1 133 27 22 17 16 14 6 4
Potential adverse reaction Increased bleeding risk Increased dabigatran effect Increased bleeding risk Increased vincristine toxicity Increased bleeding risk Increased bleeding risk Increased anticoagulant effect Increased bleeding risk Increased anticoagulant effect Increased bleeding risk Increased bleeding risk
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anticoagulants, warfarin above all. Indeed, DDIs between anticoagulants and another medication explained the majority of ADRs linked to the use of these drugs.
Acknowledgements The authors gratefully thank Dr. Simona Ghibelli and Leonardo Peroni for their valuable contribution in analyzing drug–drug interactions.
4.1. Limitations and strengths References The reported prevalence of ADRs in older persons varies in the literature. Previous studies have found a higher effect than in our study [22]. However, it is worth noting that in our sample the prevalence of ADRs is significantly lower in the oldest old than in the younger elderly. In the oldest old, the presentation of ADRs may be unusual and they can be difficult to recognize, especially by physicians who are not specialized in geriatrics. For example, the onset of geriatric syndromes, such as falls, delirium, and incontinence, may be wrongly attributed to diseases rather than to ADRs. Secondly, despite the fact that all drug prescriptions of patients were collected, we did not have any information on comorbidities. Furthermore, we did not have information on the time in target therapeutic range of warfarin and so we could not adjust the risk of haemorrhage for this variable. 5. Conclusions Older adults are the main users of drugs. Therefore, the number of ADRs and DDIs is the highest in the population. Recent findings, including ours, might have relevant implications to plan appropriate prevention programmes aimed at reducing the rate of iatrogenic illness in the old population. Given valuable information that can be obtained by already existing instruments, e.g., computerized prescription systems, our work suggests to use these systems more in clinical settings and integrate them in a global approach capable of targeting all potential factors involved in the onset of ADRs. In addition to a computer-based prescribing system, a global approach in complex elderly may include medication review so that potentially inappropriate medications can be avoided and a comprehensive geriatric assessment can be achieved. Learning points • Specific medications (i.e., warfarin, acenocumarol and allopurinol), as well as specific therapeutic categories (i.e., haematological agents and proton pump inhibitors) mostly contribute to ADRs in older adults. • A large number of DDIs were found in the therapeutic regimens of the patients and about one third of them were contraindicated or major. • At least one DDI explained almost 40% of the ADRs classified as ‘severe requiring hospitalization’ as well as the majority of the most frequent ADRs, i.e. more than half of haemorrhages and two-third of elevated INR.
Conflict of interest The authors do not have any conflict of interest to disclose.
[1] Atkin PA, Veitch PC, Veitch EM, Ogle SJ. The epidemiology of serious adverse drug reactions among the elderly. Drugs Aging 1999;14(2):141–52. [2] Onder G, van der Cammen TJ, Petrovic M, Somers A, Rajkumar C. Strategies to reduce the risk of iatrogenic illness in complex older adults. Age Ageing 2013;42(3):284–91. [3] Cerreta F, Eichler HG, Rasi G. Drug policy for an aging population—the European Medicines Agency's geriatric medicines strategy. N Engl J Med 2012;367(21):1972–4. [4] Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353(5): 487–97. [5] Garattini S, Nobili A. Interazioni tra farmaci: una valutazione della loro rilevanza clinica. Pavia: Selecta Medica Eds.; 2001. [6] Ghibelli S, Marengoni A, Djade CD, Nobili A, Tettamanti M, Franchi C. Prevention of inappropriate prescribing in hospitalized older patients using a computerized prescription support system (INTERcheck(®)). Drugs Aging 2013;30(10):821–8. [7] Vonbach P, Dubied A, Krahenbuhl S, Beer JH, et al. Prevalence of drug–drug interactions at hospital entry and during hospital stay of patients in internal medicine. Eur J Intern Med 2008;19:413–20. [8] Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011;365:2002–12. [9] Pasina L, Nobili A, Tettamanti M, Salerno F, Corrao S, Marengoni A, et al. REPOSI investigators. Prevalence and appropriateness of drug prescriptions for peptic ulcer and gastro-esophageal reflux disease in a cohort of hospitalized elderly. Eur J Intern Med 2011;22(2):205–10. [10] Mikuls TR, Farrar JT, Bilker WB, Fernandes S, Saag KG. Suboptimal physician adherence to quality indicators for the management of gout and asymptomatic hyperuricaemia: results from the UK General Practice Research Database (GPRD). Rheumatology 2005;44(8):1038–42. [11] Luk AJ, Levin GP, Moore EE, et al. Allopurinol and mortality in hyperuricaemic patients. Rheumatology 2009;48(7):804–6. [12] Thanassoulis G, Brophy JM, Richard H, et al. Gout, allopurinol use, and heart failure outcomes. Arch Intern Med 2010;170(15):1358–64. [13] Gois PH, Souza ER. Pharmacotherapy for hyperuricemia in hypertensive patients. Cochrane Database Syst Rev Jan 31 2013;1:CD008652. [14] Calogiuri G, Nettis E, Di Leo E, Foti C, Ferrannini A, Butani L. Allopurinol hypersensitivity reactions: desensitization strategies and new therapeutic alternative molecules. Inflamm Allergy Drug Targets 2013;12(1):19–28. [15] Tleyjeh IM, Bin Abdulhak AA, Riaz M, Alasmari FA, Garbati MA, AlGhamdi M, et al. Association between proton pump inhibitor therapy and clostridium difficile infection: a contemporary systematic review and meta-analysis. PLoS One 2012;7(12): e50836. [16] Becker ML, Kallewaard M, Caspers PW, Visser LE, Leufkens HG, Stricker BH. Hospitalisations and emergency department visits due to drug–drug interactions: a literature review. Pharmacoepidemiol Drug Saf 2007;16:641–51. [17] Hines LE, Murphy JE. Potentially harmful drug–drug interactions in the elderly: a review. Am J Geriatr Pharmacother 2011;9(6):364–77. [18] Nobili A, Pasina L, Tettamanti M, Lucca U, Riva E, Marzona I, et al. Potentially severe drug interactions in elderly outpatients: results of an observational study of an administrative prescription database. J Clin Pharm Ther 2009;34(4):377–86. [19] Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 2004;329(7456):15–9. [20] Espinosa-Bosch M, Santos-Ramos B, Gil-Navarro MV, Santos-Rubio MD, Marín-Gil R, Villacorta-Linaza P. Prevalence of drug interactions in hospital healthcare. Int J Clin Pharmacol 2012;34(6):807–17. [21] Obreli-Neto PR, Nobili A, de Oliveira Baldoni A, Guidoni CM, de Lyra Júnior DP, Pilger D, et al. Adverse drug reactions caused by drug–drug interactions in elderly outpatients: a prospective cohort study. Eur J Clin Pharmacol 2012;68(12):1667–76. [22] Petrovic M, van der Cammen T, Onder G. Adverse drug reactions in older people: detection and prevention. Drugs Aging 2012;29(6):453–62.
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Understanding adverse drug reactions in older adults through drug– drug interactions A. Marengoni a,⁎, L. Pasina b, C. Concoreggi c, G. Martini d, F. Brognoli d, A. Nobili b, G. Onder e, D. Bettoni f a
Geriatric Unit, Department of Clinical and Experimental Sciences, University of Brescia, Italy Department of Neuroscience, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy Intensive Brief Observation Unit, Emergency Room, Spedali Civili, Brescia, Italy d Haemostasis Centre Laboratory, Spedali Civili, Brescia, Italy e Centro Medicina dell'Invecchiamento, Policlinico A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy f Pharmacovigilance, Spedali Civili Pharmacy, Brescia, Italy b c
a r t i c l e
i n f o
Article history: Received 28 August 2014 Received in revised form 29 September 2014 Accepted 1 October 2014 Available online 11 October 2014 Keywords: Adverse drug reaction Drug–drug interaction Elderly
a b s t r a c t Aims: The aims of this study are to evaluate prevalence and characteristics of adverse drug reactions (ADRs) and to evaluate the potential contribution of specific medications, therapeutic categories and drug–drug interactions (DDIs) in older adults. Methods: All ADR reporting forms of persons aged 65+ years collected by the pharmacovigilance of one of the main hospitals in Italy during 2013 were evaluated. DDIs were analysed by a computerized prescription system (INTERCheck) and based on the interactions' database managed by the Istituto di Ricerche Farmacologiche Mario Negri. DDIs were classified according to their clinical relevance as contraindicated, major, and moderate. Results: Amongst all the ADR reporting forms (n = 1014) collected during 2013, 343 affected older adults. The most frequent ADRs were: haemorrhages (n = 122, 35.5%), allergic reactions (n = 56, 16.3%), and elevated International Normalized Ratio (INR N 6, n = 54, 15.7%). The specific medications that contributed to ADRs were warfarin (42.5%), acenocumarol (9%), and allopurinol (8.5%); while the therapeutic categories were haematological agents (67%) and proton pump inhibitors (13%). A total of 912 DDIs were found; one third of them were contraindicated or major and 31.5% of them potentially contributed to ADRs; of these, the most frequent were: warfarin and heparin (contraindicated, n = 5); warfarin and a statin (major, n = 38); warfarin and a proton pump inhibitor (moderate, n = 40). At least one DDI contributed to 66 haemorrhages out of 122 (54%) and to 41 elevated INR out of 54 (76%). Conclusion: DDIs significantly contribute to the onset of ADRs in older adults and intervention programmes, e.g., the employment of a computerized system, may reduce the burden of iatrogenic illnesses in the elderly. © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Due to the persistent exclusion of older persons from clinical trials, data on benefit–risk balance of several drugs in this section of the population are unknown. Research literature showed that adverse drug reactions (ADRs) are frequent and severe, and are responsible for considerable morbidity and mortality in older persons, leading to multiple admissions to the emergency room and acute hospitalizations [1,2]. This means that ADRs have a significant and detrimental impact on the healthcare system's economy.
⁎ Corresponding author at: Department of Clinical and Experimental Sciences, University of Brescia, Geriatric Unit, Spedali Civili, Piazzale Spedali Civili 1, 25123 Brescia, Italy. Tel.: +39 030 2528554/478; fax: +39 030 2528476. E-mail address: [email protected] (A. Marengoni).
In a recent editorial, the European Medicines Agency defined a strategy to overcome several key issues in the pharmacological treatment of older persons. The Agency suggested that ‘spontaneous reports of adverse events can be used to identify patterns of drug-disease and drug–drug interactions (DDIs) that were not apparent before authorization’ [3], with DDI being the ability of a drug to modify the action or effect of another drug administered successively or simultaneously. These interactions have rarely been considered to cause ADRs in geriatric persons compared to single pharmacologic agents, although they increase with increasing age and the number of drugs consumed. In particular, amongst hospitalized older adults, the overlap of acute and chronic diseases may increase the susceptibility to ADRs and their severity. This study aimed to evaluate the occurrence and characteristics of ADRs in persons aged 65 + years attending one of the inpatient units and/or to the anticoagulant outpatient unit of one of the main hospitals in Italy during 2013. The contribution of specific medications, therapeutic
http://dx.doi.org/10.1016/j.ejim.2014.10.001 0953-6205/© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
844
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categories, and all possible contraindicated, major, and moderate DDIs were assessed. 2. Methods In Italy, spontaneous ADRs are collected through the National Network of Pharmacovigilance, an extensive linkage that includes the Regional Centers of Pharmacovigilance, the Local Health Authorities, about one hundred hospitals, research institutes, and pharmaceutical companies, as well as the Italian Agency of Medicine. The system also operates in connection with the European network for pharmacovigilance, EudraVigilance, which collects all data provided by the EU countries at national level in a single database. Data analysed in this study were all spontaneous ADR reporting forms collected by the pharmacovigilance of the Spedali Civili, Brescia. The Spedali Civili is one of the main hospitals in Italy: in 2013, 72,132 persons were admitted to the hospital and 1868 were examined in the anticoagulant outpatient unit. Of these, 27,700 and 1444 were aged 65 + years, respectively. Usually, all the physicians are required to complete specific reporting forms and to submit them to the hospital pharmacy if an ADR is suspected. ADRs were here defined as a noxious and unintended response to a medicinal product that occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy of disease or for the restoration, correction, or modification of physiological function as well as harm caused by medication errors (in prescription, administration, or monitoring of drug therapy) or patient non-adherence (adherence defined as ‘the extent to which patients take the medications as prescribed by their health care providers’) [4]. Severity of ADRs was classified as i) mild-moderate, ii) severe with hospitalization, iii) severe with clinical condition not requiring hospitalization, iv) life-threatening, and v) leading to permanent invalidity and to death. Potential DDIs were analysed by a computerized prescription support system, i.e., INTERCheck, which was based on an Italian interactions' database managed by the Istituto di Ricerche Farmacologiche Mario Negri, which has been already validated and described in detail [5,6]. We classified all drug interactions in terms of clinical relevance, considering potential health outcomes, type, quality, and relevance of supporting clinical and pharmacological documentation. Coherently with other computerized support systems [7], each potential DDI was classified by clinical relevance as follows: contraindicated (drug combination should be avoided or may potentially lead to serious clinical consequences), major (the combination can be handled e.g. by dose adjustments or temporal separation, close monitoring is required), moderate (clinical outcome of the interaction is uncertain and/or may vary) and minor (drug combination probably has no clinical relevance or has not been completely assessed). Spontaneous ADRs reporting forms were collected by the hospital pharmacy and stored in a database including age, sex, medications possibly implicated in the ADR, concomitant medications, and narrative description of the adverse reaction as well as its severity and outcome. Number and prevalence per 100 of ADRs were calculated for different age groups; specific medications and therapeutic categories potentially contributing to ADRs were evaluated. The whole drug regimen of all the subjects was analysed using INTERCheck for the calculation of DDIs potentially contributing or not to ADRs. In this study, only contraindicated, major, and moderate interactions were analysed. The Ethical Committee of the Spedali Civili approved the study. 3. Results Amongst all the spontaneous ADR reporting forms (n = 1014) collected by the hospital pharmacovigilance from January 1st to December 31st 2013, 343 (34%) affected people aged 65 years or older (Fig. 1). The mean age of the patients was 76.4 years. The average number of drugs per patient was 8.5. ADRs were equally distributed in
men (n = 165) and women (n = 178), whereas a lower prevalence was found in the 60 very old (85 + years) persons compared to the younger age group (17.5 versus 82.5%). Prevalence of ADRs in the total number of patients admitted during 2013 was 1.3%; prevalence of ADRs in patients aged 65 + years was 1.2%. Spontaneous ADR reporting forms were mostly sent by the emergency room (n = 152) and the anticoagulant drug outpatient unit (n = 120), followed by the clinical inpatient wards (20 cases by haematology, 10 cases by dermatology, 7 cases by oncology, 7 cases by neurology, 26 cases by other units). Amongst all the ADRs, 194 (56.5%) were mild-moderate, 123 (35.9%) were severe requiring hospitalization, 16 (4.6%) were severe but not requiring hospitalization, 5 (1.5%) were life-threatening, 4 (1.2%) led to death, and 1 (0.3%) led to permanent invalidity. The most frequent ADRs were haemorrhages (n = 122, 35.5%), allergic reactions (n = 56, 16.3%), elevated International Normalized Ratio (INR N 6, n = 54, 15.7%), and neuropsychiatric/neurological effects (n = 26, 7.5%) (Table 1). Table 1 also shows the most frequent medications contributing to ADRs, which were warfarin, acenocumarol, and allopurinol. Also shown are the most frequent therapeutic categories, which were haematologic agents and proton pump inhibitors (Table 1). Fig. 1 shows the number of the DDIs found in the pharmacological regimen of the patients that could have contributed to the corresponding ADRs (Fig. 1). Amongst the DDIs potentially contributing to ADRs (n = 288, 31.5%), the most frequent contraindicated DDIs were warfarin and heparin (5 cases). The most frequent major DDIs were warfarin and a statin (38 cases), warfarin and allopurinol (27 cases), and warfarin and amiodarone (22 cases) (Table 2). The most frequent moderate DDI was warfarin and a proton pump inhibitor (41 cases). Forty-eight out of 123 (39%) ADRs that were classified as ‘severe requiring hospitalization’ were potentially caused by DDIs, but none led to death or were life-threatening. The analysis of the association between DDIs and the most frequent ADRs showed that at least one DDI contributed to 66 haemorrhages out of 122 (54%) and to 41 elevated INR out of 54 (76%).
4. Discussion Data for these analyses were gathered from 1-year ADR reporting forms of one of the main hospitals in Italy. Specific medications (i.e., warfarin, acenocumarol and allopurinol), as well as therapeutic categories (i.e., haematological agents and proton pump inhibitors) mostly contributed to ADRs. Furthermore, a considerable number of DDIs were found in the therapeutic regimens, potentially related or unrelated to the specific ADR and more importantly, about one third of them were contraindicated or major. Finally, at least one DDI explained almost 40% of the ADRs classified as ‘severe requiring hospitalization’ as well as the majority of the most frequent ADRs, i.e. more than half of haemorrhages and two-third of elevated INRs. We evaluated specific medications potentially contributing to ADRs, and our results highlighted the presence of drugs that typically cause ADRs in older persons, such as warfarin [8], but also medications that are less known, such as allopurinol and proton pump inhibitors. These drugs are often inappropriately prescribed and considered safe in the elderly. For instance, proton pump inhibitors are frequently used for non-evidence-based indications or in case of the use of a high number of concomitant drugs [9]. Allopurinol is often inappropriately used in asymptomatic hyperuricaemia [10], following some epidemiological and experimental studies that suggested a linkage between hyperuricaemia and hypertension [11,12], although there is poor evidence indicating a role of allopurinol in preventing cardiovascular diseases [13]. A rational use of these drugs is warranted as not only can they have serious short- and long-term consequences, such as hypersensitivity syndrome or Steven–Johnson syndrome (allopurinol) [14], and intestinal and pulmonary infections (proton pump inhibitors) [15], but they are also frequently involved in DDIs.
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845
All ADR reporng forms in 2013 n=1014
ADR reporng forms in children (0-18 yrs) n=266
ADR reporng forms in older persons (65+ yrs) n=343
ADR reporng forms in adults (19-64 yrs) n=405
Total number of DDIs n=912
Number of DDIs potenally contribung to ADRs n=288
Number of DDIs potenally not contribung to ADRs n=624 Contraindicated n=43
Contraindicated n=8
Severe n=124
Severe n=133 Moderate n=457
Moderate n=147
Fig. 1. Number (N) of ADRs in the whole sample according to age and number of DDIs potentially contributing or not to ADRs in older persons.
Table 1 Number of ADRs according to specific medications and therapeutic categories. Number and proportion per 100 (on a total number of ADRs = 343). Number Most common ADRs All haemorrhages 122 Epistaxis 31 Skin or wound haemorrhage 29 Intracranial haemorrhage 25 Gastrointestinal haemorrhage 17 Genitourinary haemorrhage 14 Others 6 Allergic reactions 56 a INR N6 54 Neurologic or neuropsychiatric effects 26 Dizziness and syncope 16 Gastrointestinal effects 15 Hypoglycaemia or acidosis 8 Osteonecrosis 5 Most commonly implicated medications Warfarin 146 Acenocumarol 31 Allopurinol 29 Acetylsalicylic acid 26 Amiodarone 23 Simvastatin 19 Amoxicillin/clavulanic acid 18 Pantoprazole 16 Omeprazole 15 Atorvastatin 15 Most commonly implicated therapeutic categories Haematologic agents 230 Proton pump inhibitors 44 Statins 41 NSAIDs 24 Antibiotics 22 a
INR denotes International Normalized Ratio.
Proportion (%) 35.5 9.0 8.4 7.2 4.9 4.0 1.7 16.3 15.7 7.5 4.6 4.3 2.3 1.4 42.5 9.0 8.5 7.6 6.7 5.5 5.2 4.6 4.4 4.4 67.0 12.8 11.9 6.9 6.4
Epidemiological studies of DDIs and the related risk of adverse clinical outcomes in elderly patients are rare and the prevalence of DDIs responsible for ADRs is not well-defined [16–19]. The prevalence of potential DDIs in geriatric patients may vary according to the design of the study, the clinical setting, and the severity of DDIs. According to a large prospective observational study, 1% of all hospital admissions are due to DDIs [19], but adverse events can be serious in the elderly. A literature review indicated that in the elderly, DDIs were responsible for 4.8% of the admissions [16]. The high prevalence of DDIs in elderly patients was suggested by another review that showed a prevalence of DDIs between 15 and 45% in hospital, higher in patients with heart diseases and elderly people [20]. Our findings suggest that DDIs are an important risk factor for ADRs, which explain around 40% of the ADRs classified as severe requiring hospitalization, as well as the majority of the most frequent ADRs (i.e. haemorrhages and elevated INR). In line with previous studies in the elderly [21], the medications most frequently involved in DDIs were Table 2 Most frequent contraindicated and major DDIs potentially contributing to ADRs and potential adverse effect. N Contraindicated DDIs (all) Warfarin and heparin Dabigatran and dronedarone Acenocumarol and acetylsalicylic acid Itraconazole and vincristine Major DDIs (all) Warfarin and allopurinol Warfarin and amiodarone Warfarin and simvastatin Warfarin and acetylsalicylic acid Warfarin and atorvastatin Warfarin and rosuvastatin Warfarin and amoxicillin
8 5 1 1 1 133 27 22 17 16 14 6 4
Potential adverse reaction Increased bleeding risk Increased dabigatran effect Increased bleeding risk Increased vincristine toxicity Increased bleeding risk Increased bleeding risk Increased anticoagulant effect Increased bleeding risk Increased anticoagulant effect Increased bleeding risk Increased bleeding risk
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anticoagulants, warfarin above all. Indeed, DDIs between anticoagulants and another medication explained the majority of ADRs linked to the use of these drugs.
Acknowledgements The authors gratefully thank Dr. Simona Ghibelli and Leonardo Peroni for their valuable contribution in analyzing drug–drug interactions.
4.1. Limitations and strengths References The reported prevalence of ADRs in older persons varies in the literature. Previous studies have found a higher effect than in our study [22]. However, it is worth noting that in our sample the prevalence of ADRs is significantly lower in the oldest old than in the younger elderly. In the oldest old, the presentation of ADRs may be unusual and they can be difficult to recognize, especially by physicians who are not specialized in geriatrics. For example, the onset of geriatric syndromes, such as falls, delirium, and incontinence, may be wrongly attributed to diseases rather than to ADRs. Secondly, despite the fact that all drug prescriptions of patients were collected, we did not have any information on comorbidities. Furthermore, we did not have information on the time in target therapeutic range of warfarin and so we could not adjust the risk of haemorrhage for this variable. 5. Conclusions Older adults are the main users of drugs. Therefore, the number of ADRs and DDIs is the highest in the population. Recent findings, including ours, might have relevant implications to plan appropriate prevention programmes aimed at reducing the rate of iatrogenic illness in the old population. Given valuable information that can be obtained by already existing instruments, e.g., computerized prescription systems, our work suggests to use these systems more in clinical settings and integrate them in a global approach capable of targeting all potential factors involved in the onset of ADRs. In addition to a computer-based prescribing system, a global approach in complex elderly may include medication review so that potentially inappropriate medications can be avoided and a comprehensive geriatric assessment can be achieved. Learning points • Specific medications (i.e., warfarin, acenocumarol and allopurinol), as well as specific therapeutic categories (i.e., haematological agents and proton pump inhibitors) mostly contribute to ADRs in older adults. • A large number of DDIs were found in the therapeutic regimens of the patients and about one third of them were contraindicated or major. • At least one DDI explained almost 40% of the ADRs classified as ‘severe requiring hospitalization’ as well as the majority of the most frequent ADRs, i.e. more than half of haemorrhages and two-third of elevated INR.
Conflict of interest The authors do not have any conflict of interest to disclose.
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