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KORA Myocardial Infarction Registry
EJINME-03639; No of Pages 7 European Journal of Internal Medicine xxx (2017) xxx–xxx
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Medication use in long-term survivors from the MONICA/KORA Myocardial Infarction Registry☆ Ute Amann a,b,e,⁎, Inge Kirchberger a,b, Margit Heier a,b, Christian Thilo c, Bernhard Kuch c,d, Christa Meisinger e a
MONICA/KORA Myocardial Infarction Registry, Central Hospital of Augsburg, Augsburg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany Department of Internal Medicine I - Cardiology, Central Hospital of Augsburg, Augsburg, Germany d Department of Internal Medicine/Cardiology, Hospital of Nördlingen, Nördlingen, Germany e Chair of Epidemiology, Ludwig-Maximilians-Universität München, UNIKA-T, Augsburg, Germany b c
a r t i c l e
i n f o
Article history: Received 18 April 2017 Received in revised form 11 July 2017 Accepted 10 August 2017 Available online xxxx Keywords: Myocardial infarction Secondary prevention Drug use
a b s t r a c t Background: Prior studies reported high guideline adherence for secondary prevention medications (SPM) at hospital discharge in patients with acute myocardial infarction (AMI). Less is known about medication use in longterm AMI survivors. Methods: Of the 2077 registered persons with an AMI between 2000 and 2008 who responded to a postal followup survey in 2011, 1311 men and 356 women, aged between 34.4 and 84.9 years, reported medication intake 7 days prior to the survey. These study participants also had their current health condition and comorbidities assessed. Information regarding index AMI was selected from the population-based MONICA/KORA MI registry. Multivariable logistic regression models were conducted to identify factors associated with SPM use (all 4 drug classes). Results: The median time between index AMI and the follow-up survey was 6.1 years (IQR: 3.9). At follow-up, a total of 10,422 medications were reported and polypharmacy was observed in 73.8%. Regarding SPM, the proportion of patients taking antiplatelet agents, beta-blockers, statins, and renin-angiotensin-aldosteron system blockers were 90.9%, 86.7%, 85.4%, and 79.3% respectively. Factors associated with SPM use were hypertension (odds ratio [OR] 1.48, p = 0.006), SPM prescription at hospital discharge (OR 2.68, p b 0.0001), revascularization therapy at index AMI (OR 2.46, p N 0.0001), number of medications taken at follow-up (OR 1.48, p b 0.0001), and several comorbidities such as lung disorders (OR 0.17; p b 0.0001), depression (OR 0.53, p = 0.001), neurological disorders (without stroke) (OR 0.34, p = 0.002), and cancer (OR 0.45, p = 0.005). Conclusion: SPM use several years after AMI was high and associated with treatment at index AMI and patients' comorbidities. © 2017 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
1. Introduction Besides lifestyle changes and control of cardiovascular (CV) risk factors, the following drugs are recommended by the international guidelines for long-term management of patients after an acute coronary syndrome (ACS) to reduce the risk of a further cardiac event or other manifestations of vascular disease: antiplatelet agents, beta-blockers, statins and renin-angiotensin-aldosteron system (RAAS) blockers, especially angiotensin-converting enzyme (ACE) inhibitors or angiotensin-
☆ Conflicts of interest of all authors: none, except for CT, see COI statements.Funding: none.Authorship: All authors had access to the data and played a role in writing the manuscript. ⁎ Correspondence to: U. Amann, MONICA/KORA Myocardial Infarction Registry/Central Hospital of Augsburg, Stenglinstr. 2, 86156 Augsburg, Germany. E-mail address: [email protected] (U. Amann).
receptor blockers (ARB) [1–3]. A combined therapy of these drugs is known as secondary prevention medication (SPM). Clinical evidence for short-term use of SPM in patients with ACS is very well established, whereas routine use longer than 1 year has less evidence [4–6] and furthermore, use beyond 5 to 10 years after acute myocardial infarction (AMI) is considered without any evidence from clinical trials [6]. After decades aimed at improving SPM use after an ACS, several studies showed high guideline adherence for SPM prescription at the time of hospital discharge [4,5,7,8]. Due to limited research on long-term drug use in general, less information exists about how many patients are receiving SPM several years after ACS. In addition, little is known about the health condition (e.g., health status, disability, comorbidities, and polypharmacy) of this high-risk population. The aim of this study was to first provide a comprehensive description of total medication use 3 or more years after an AMI and then to analyze factors associated with SPM use in long-term AMI survivors.
http://dx.doi.org/10.1016/j.ejim.2017.08.011 0953-6205/© 2017 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
Please cite this article as: Amann U, et al, Medication use in long-term survivors from the MONICA/KORA Myocardial Infarction Registry, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.011
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U. Amann et al. / European Journal of Internal Medicine xxx (2017) xxx–xxx
2. Material and methods 2.1. Study design and data source The present observational study is based on data from the population-based myocardial infarction (MI) registry in Augsburg, Germany, which was established in 1984 as part of the World Health Organization MONICA Project (MONItoring Trends and Determinants in CArdiovascular disease). After the termination of MONICA in 1995, the MI registry became part of the framework of KORA (Cooperative Health Research in the Region of Augsburg). Since 1984, all cases of coronary death and at least 24 h surviving AMI of the 25 to 74 year old study population in the city of Augsburg and the two adjacent counties (defined as the study area with about 650,000 inhabitants) have been continuously registered. Data sources for hospitalized patients were collected from the 8 participating hospitals. About 80% of all AMI cases of the study region were treated in the region's major hospital Klinikum Augsburg, a tertiary care center offering 24/7 interventional CV procedures as well as heart surgery facilities. The methods of case identification, diagnostic classification of events, and data quality control have been described in detail elsewhere [9,10]. To summarize briefly, diagnostic criteria according to the European Society of Cardiology and American College of Cardiology are used for case identification [11]. Patients are interviewed during their hospital stay by trained nurses using a standardized questionnaire to collect sociodemographic characteristics, CV risk factors, and comorbidities. Additional information on clinical data, comorbidities, type of AMI, acute management (e.g., percutaneous coronary intervention (PCI)), and medication use are collected by review of medical chart and discharge report. Data collection at index AMI and at the follow-up survey has been approved by the ethics committee of the Bavarian Medical Association (Bayerische Landesärztekammer) and all study participants gave their written informed consent. 2.2. Study population and follow-up data collection The present study included all 2077 registered persons with an AMI between 2000 and 2008 (index AMI), who were alive on July 1, 2011, did not previously decline further participation, and responded to a follow-up survey mailed to them in September 2011 (response rate 84%) [12]. The postal survey included questions on sociodemographic characteristics (age, sex, employment, living environment), a wide range of self-reported comorbidities, the current health status (assessed by a single response with: “very good”, “good”, “fair”, “poor”, or “very poor”), health care, disability (assessed with the German version of the 12item World Health Organization Disability Schedule (WHODAS) 2.0 [13]), and medication intake. Patient-reported information on type 2 diabetes mellitus (diabetes) was confirmed by the treating physician. Persons were also asked to provide the following details about each medication used within 7 days prior to the survey: medication name, central pharmaceutical number (a national standard identification code for pharmaceutical products in Germany), pharmaceutical form, number of single dosage used per day (e.g., 1 tablet), and whether the medication was prescribed by physician or self-medication. All medications were recorded and classified in the registry according to the German Anatomical Therapeutic Chemical (ATC)-classification system, which was established in 2004, based on the international ATC-classification of the WHO Collaborating Centre for Drug Statistics Methodology and to the specifics of the current heath care situation in Germany (http://www.dimdi.de/static/en/klassi/atcddd/index.htm). Only pharmaceutical products with a valid German ATC code were counted. To obtain the study population of drug users, of the 2077 responding persons, we excluded 392 individuals who reported either no medication intake (n = 60; 2.9%) or who did not answer the question at all (n = 332; 16.0%). In addition, 18 individuals with missing information on general health status or disability were excluded since information
on health condition was considered relevant. Thus, the final study population covered 1667 persons that survived AMI who reported medication intake. The study population had a comparable distribution of sexes (women: 21.4% versus 25.6%, p = 0.06), but a slightly higher median age (68.3 versus 65.6 years, p = 0.001) compared with the excluded persons (n = 410). 2.3. Statistical analysis Categorical variables were expressed as absolute numbers and percentages (%), and continuous variables were expressed as mean and standard deviation or median with interquartile range (IQR) depending on distribution patterns. For descriptive purposes, SPM use at discharge (index AMI) and at follow-up (survey) were reported for the total study population and separated by gender. The total medication use at followup was analyzed according to the ATC main group (1st level). Pharmaceutical products, e.g. nutritional supplements with an ATC code starting with “V” (various), were excluded for this analysis to maintain the focus on medications. To determine the most frequently used drugs and the number of different medications taken by each person, the 5th level of the ATC code was used, which indicates the chemical substance. Definition of the 4 SPM drug classes (4 SPM) for this analysis was the following: antiplatelet agents (ATC: B01AC), beta-blockers (ATC: C07), statins (ATC: C10AA, C10BA) and RAAS blockers (ATC: C09). Polypharmacy was defined as the intake of 5 or more different medications by a person. Patients' characteristics were cross-tabulated with SPM use status (4 SPM vs. 3 or less SPM) at follow-up using the Chi2-test or Fisher's exact test for categorical variables and the Kruskal-Wallis test (Wilcoxon Analysis) for continuous variables. To identify factors associated with 4 SPM use at follow-up, multivariable logistic regression analyses were performed. Variables analyzed were sex (men/women), and the following characteristics assessed at follow-up: age (continuous), employed (yes/no), living alone (yes/no/missing), follow-up time in years between index AMI and survey (continuous), general health status (response options “very poor” and “poor” were collapsed resulting in a 4-categorial variable), WHODAS 2.0 score (dichotomized variable with the median value of the study population as cut point) (N4/≤ 4), number of medications used at follow-up (continuous), and several comorbidities (yes/no/missing). The following characteristics were assessed at index AMI: type of AMI (ST-elevation or non-ST-elevation MI/bundle branch block/missing), any revascularization therapy defined as PCI with or without stenting and/or coronary artery bypass grafting (yes/no), medical history of hypertension and hyperlipidemia (yes/no), obesity defined as body mass index ≥30 kg/m2 (yes/no), and SPM use at time of discharge (yes/no). As criterion for entry into the models, the explanatory variables had to meet the 0.2 significance level in the bivariate analysis with 4 SPM use at follow-up. Except for sex and age, which were a priori determined to be forced-in, the final model included only factors which significantly (p b 0.05) contributed to the model using backward selection technique. All analyses were performed using SAS version 9.2 (SAS Institute Inc., Cary, North Carolina). 3. Results 3.1. Study population The study population consisted of 1667 participants (1311 men and 356 women) aged between 34.4 and 84.9 years who reported medication use within 7 days prior the survey. The median time between index AMI and follow-up survey was 6.1 years (IQR: 3.9), and did not differ between men and women (6.1 vs. 6.0 years respectively, p = 0.85). The median age at follow-up was 67.5 years (IQR: 13.4) in men and 70.4 years (IQR: 13.0) in women (p b 0.0001). Table 1 shows the characteristics of the study population by SPM use status at follow-up.
Please cite this article as: Amann U, et al, Medication use in long-term survivors from the MONICA/KORA Myocardial Infarction Registry, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.011
U. Amann et al. / European Journal of Internal Medicine xxx (2017) xxx–xxx
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Table 1 Study population by SPM use status at follow-up survey. AMI survivors taking 4 SPM at follow-up n = 1667 (unless otherwise noted) Sex Men Women Characteristics assessed at follow-up Age (median, IQR) Follow-up time between index AMI and follow-up survey, years (median, IQR) Employed (n = 1661) Living alone (n = 1659) General health status Very good Good Fair Poor Very poor Disability (WHODAS 2.0 scoreb) ≤4 N4 Comorbidities Diabetes Renal disorders (n = 1562) Liver disorders (n = 1539) Cancer (n = 1550) Depression (n = 1562) Stroke (n = 1556) Neurological disorders (n = 1532) Joint disorders (n = 1553) Vision disorders (n = 1561) Lung disorders (n = 1568) Digestive disorders (n = 1550) Blood disorders (n = 1542) Number of different medications (median/IQR) Polypharmacy (≥5 different drugs) Characteristics assessed at index AMI Type of AMI STEMI NSTEMI Bundle branch block Non-classifiable/missing data Risk factors/Comorbidities Hypertension Hyperlipidemia Obesity (n = 1655) Acute treatment Any revascularization therapy (e.g., PCI) 4 SPM use at discharge
p Value
yes (n = 975)
no (n = 692)
779 (79.1) 196 (20.1)
532 (76.9) 160 (23.1)
68.2 (12.9) 6.0 (3.7) 216 (22.2a) 176 (18.1a)
68.8 (14.4) 6.2 (3.9) 161 (23.4a) 129 (18.8a)
88 (9.0) 453 (46.5) 362 (37.1) 67 (6.9) 5 (0.5)
53 (7.7) 297 (42.9) 269 (38.9) 59 (8.5) 14 (2.0)
510 (52.3) 465 (47.7)
331 (47.8) 361 (52.2)
0.07
331 (34.0) 58 (6.3a) 15 (1.7a) 41 (4.5a) 122 (13.3a) 31 (3.4a) 28 (3.1a) 273 (30.0a) 259 (28.3a) 48 (5.2a) 68 (7.5a) 33 (3.6a) 6 (3) 842 (86.4)
195 (28.2) 53 (8.2a) 19 (3.0a) 42 (6.6a) 127 (19.8a) 32 (5.0a) 32 (5.1a) 218 (34.0a) 207 (32.0a) 74 (11.5a) 58 (9.1a) 26 (4.1a) 5 (4) 388 (56.1)
0.01 0.14 0.07 0.06 0.001 0.11 0.05 0.10 0.11 b0.0001 0.25 0.60 b0.0001 b0.0001
389 (39.9) 519 (53.2) 51 (5.2) 16 (1.6)
249 (36.0) 398 (57.1) 31 (4.5) 14 (2.0)
795 (81.5) 730 (74.8) 275 (28.4a)
502 (72.5) 503 (72.7) 155 (22.6a)
b0.0001 0.32 0.01
902 (92.5) 804 (82.5)
578 (83.5) 449 (64.9)
b0.0001 b0.0001
0.14
0.38 0.01 0.56 0.75 0.02
0.29
SPM secondary prevention medication (4 SPM was defined as combined use of antiplatelet agent, beta-blocker, statin and renin-angiotensin-aldosteron system blocker), AMI acute myocardial infarction, ATC anatomical therapeutic chemical, IQR interquartile range (25th and 75th percentiles), WHODAS World Health Organization Disability Schedule, STEMI ST-segment elevation myocardial infarction, NSTEMI Non-ST segment elevation myocardial infarction, PCI percutaneous coronary intervention. a Percentage value were calculated based on total available data for each variable. b Higher scores reflect more disability.
AMI survivors taking 4 SPM significantly (p b 0.05) differed from their counterparts with 3 or less SPM use by not only follow-up time but also general health status, median number of medications at followup, polypharmacy, diabetes, depression, lung disorders, hypertension, obesity, receiving of any revascularization therapy, and taking 4 SPM at hospital discharge. 3.2. SPM and total medication use At hospital discharge after the index AMI, the proportion of patients taking antiplatelet agents, beta-blockers, statins, and RAAS blockers were 97.5%, 96.2%, 92.7%, and 83.6% respectively. In the follow-up survey, the respective proportions of patients taking these drug classes were 90.9%, 86.7%, 85.4%, and 79.3%. In total, 975 (58.5%) study participants received 4 SPM and 1466 (86.7%) used at least 3 SPMs at followup. Differences by sex regarding follow-up SPM use were only observed
with regard to antiplatelet agents, but not for 4 SPM use (Table 2). 120 persons (7.2%) reported more than one antiplatelet agent at follow-up, and polypharmacy was observed in 73.8% of the study population. Altogether, 10,422 different medications were reported by the study population at follow-up. Fig. 1 provides an overview of medication use by ATC code. Within the CV system group, lipid modifying agents followed by beta-blockers and RAAS blockers were the most frequently taken. Regarding single drug use, the most frequently used chemical substances were acetylsalicylic acid (ASS) and clopidogrel for antiplatelet agents; simvastatin and combination products with ezetimibe and atorvastatin for statins; Ramipril and combination products with hydrochlorothiazide for RAAS blockers; and bisoprolol and metoprolol for beta-blockers. The most frequently used non-SPM was torasemide (diuretic agent), followed by amlodipine (calcium channel blocker), pantoprazole (proton pump inhibitor), and allopurinol (anti-gout agent) (Table 3).
Please cite this article as: Amann U, et al, Medication use in long-term survivors from the MONICA/KORA Myocardial Infarction Registry, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.011
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U. Amann et al. / European Journal of Internal Medicine xxx (2017) xxx–xxx
Table 2 SPM use at index AMI (hospital discharge) and at follow-up survey. Drug class/SPM combination
Antiplatelet agents Beta-blockers Statins RAAS blockers 4 SPM At least 3 of the drug classes
All (n = 1667)
Men (n = 1311)
p Valuea
Women (n = 356)
Discharge
Follow-up
Discharge
Follow-up
Discharge
Follow-up
1625 (97.5) 1604 (96.2) 1545 (92.7) 1393 (83.6) 1253 (75.2) 1590 (95.4)
1515 (90.9) 1445 (86.7) 1424 (85.4) 1322 (79.3) 975 (58.5) 1466 (87.9)
1281 (97.7) 1268 (96.7) 1225 (93.4) 1089 (83.1) 991 (75.6) 1257 (96.0)
1202 (91.7) 1143 (87.2) 1126 (85.9) 1043 (79.6) 779 (59.4) 1162 (88.6)
344 (96.6) 336 (94.4) 320 (89.9) 304 (85.4) 262 (73.6) 333 (93.5)
313 (87.9) 302 (84.8) 298 (83.7) 279 (78.4) 196 (55.1) 304 (85.4)
0.03 0.25 0.30 0.62 0.14 0.10
SPM secondary prevention medication (4 SPM was defined as combined use of antiplatelet agent, beta-blocker, statin and renin-angiotensin-aldosteron system blocker), AMI acute myocardial infarction, RAAS renin-angiotensin-aldosteron system. a p Value calculated to assess differences between men and women regarding follow-up SPM use.
3.3. Factors associated with SPM use at follow-up
4. Discussion
In the multivariable logistic regression analysis, we found that the following factors were associated with use of all 4 SPM at follow-up: any revascularization therapy at index AMI, 4 SPM prescription at hospital discharge, history of hypertension, and the number of medications taken at follow-up. In contrast, persons suffering from lung disorders, neurological disorders (without stroke), cancer, depression, joint disorders, or diabetes at follow-up were less likely to take 4 SPM at followup (Table 4).
In the present, registry-based study of 1667 participants with a survived AMI between 2000 and 2008who responded to a postal follow-up survey in September 2011 and reported medication intake within 7 days prior to the survey, we found that almost 60% of these post-AMI patients were taking all 4 SPM. SPM use at follow-up was associated with SPM prescription at hospital discharge, receiving invasive treatment strategy, hypertension, number of medications used at follow-up, and absence of lung disorders, neurological disorders, cancer,
Fig. 1. Total medication use in % of total count and count of medications of the cardiovascular system taken by AMI survivors at follow-up.
Please cite this article as: Amann U, et al, Medication use in long-term survivors from the MONICA/KORA Myocardial Infarction Registry, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.011
U. Amann et al. / European Journal of Internal Medicine xxx (2017) xxx–xxx Table 3 Top 20 most frequently used drugs in AMI survivors (n = 1667) at follow-up. ATC code
Chemical substance(s)
Count (%)a
SPM yes (drug class)/no
B01AC06 C10AA01 C09AA05 C07AB07 C07AB02 C09BA25 C03CA04 C08CA01 A02BC02 M04AA01 B01AC04 A10BA02 H03AA01 C10BA02 B01AA04 A02BC01 G04CA02 C10AA05 A10BB12 M01AB05 Total top 20
Acetylsalicylic acid Simvastatin Ramipril Bisoprolol Metoprolol Ramipril and HCT Torasemid Amlodipin Pantoprazole Allopurinol Clopidogrel Metformin Levothyroxine sodium Simvastatin and Ezetimibe Phenprocoumon Omeprazol Tamsulosin Atorvastatin Glimepiride Diclofenac
1393 (13.4) 1018 (9.8) 671 (6.4) 645 (6.2) 640 (6.1) 353 (3.4) 279 (2.7) 253 (2.4) 240 (2.3) 221 (2.1) 217 (2.1) 213 (2.0) 191 (1.8) 187 (1.8) 124 (1.2) 121 (1.2) 92 (0.9) 85 (0.8) 76 (0.7) 74 (0.7) 7093 (68.1)
yes (antiplatelet agent) yes (statin) yes (RAAS blocker) yes (beta-blocker) yes (beta-blocker) yes (RAAS blocker) no no no no yes (antiplatelet agent) no no yes (statin) no no no yes (statin) no no
SPM secondary prevention medication, AMI acute myocardial infarction, ATC anatomical therapeutic chemical, HCT hydrochlorothiazide, RAAS renin-angiotensin-aldosteron system. a Count and percentage of all reported medications (n = 10,422) with specified ATC code within the study sample.
depression, joint disorders, and/or diabetes. To our knowledge, previous studies have not analyzed total medication use in AMI survivors. The present study showed a high frequency of polypharmacy and identified frequently used drugs. Our finding about high SPM use several years after AMI demonstrates that quality improvement interventions to maximize guideline-recommended therapies after AMI have worked sufficiently. Our results are in agreement with a recent German follow-up study in STelevation MI survivors with available information on drug use which reported similar rates after a median follow-up period of 3 years of 90.8%, 87.5%, 88.2% and 79.2% for ASS, beta-blockers, statins and ACE-inhibitors or ARB, respectively [14]. However, Reuter et al. [14] reported lower adherence to beta-blockers in women compared to men, while in our study which included all types of AMI differences in SPM use by sex, a lower adherence was only observed for antiplatelet agents. When comparing results of different studies on long-term adherence to SPM after AMI it is mandatory to consider drug prescription at the time of hospital discharge, because discharge after a survived AMI is a critical time in Table 4 Factors associated with 4 SPM use at follow-up in AMI survivors (n = 1468a).
Sex (men vs. women) Characteristics assessed at follow-up Age (cont.) Lung disorders (yes vs. no) Neurological disorders (yes vs. no) Cancer (yes vs. no) Depression (yes vs. no) Joint disorders (yes vs. no) Diabetes (yes vs. no) Number of medications (cont.) Characteristics assessed at index AMI 4 SPM prescription at discharge (yes vs. no) Hypertension (yes vs. no) Any revascularization therapy (yes vs. no)
OR [95% CI]
p Value
1.30 [0.97–1.74]
0.076
0.99 [0.98–1.00] 0.17 [0.10–0.30] 0.34 [0.18–0.67] 0.45 [0.25–0.79] 0.53 [0.37–0.75] 0.75 [0.57–0.97] 0.75 [0.57–0.99] 1.48 [1.38–1.58]
0.073 b0.0001 0.002 0.005 0.001 0.029 0.042 b0.0001
2.68 [2.05–3.52] 1.48 [1.12–1.95] 2.46 [1.66–3.65]
b0.0001 0.006 b0.0001
SPM secondary prevention medication (4 SPM was defined as combined use of antiplatelet agent, beta-blocker, statin and renin-angiotensin-aldosteron system blocker), AMI acute myocardial infarction, OR odds ratio, CI confidence interval. a Note: 199 observations were deleted due to missing values for the explanatory variables.
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which use and prescription of SPM is very important for optimal longterm management [4]. For example, in a prior US study which reported low 3-year medication continuation rates with b50% for statins, betablockers and ACE-inhibitors/ARB, the medication use at discharge was not as high as observed in our study [15]. A Dutch primary care study within diabetes patients with a previous MI evaluated repeat prescriptions of SPM (anti-thrombotic agent, beta-blocker and statin) at 6 months, 1 year, 2 years and 5 years and found that prescription rates of each single drug and all 3 medications remained quite stable over the observed follow-up time up after AMI [16]. The high frequency of polypharmacy we observed was obviously caused by SPM and other CV medications (e.g. diuretics and calcium channel blockers), however diabetes drugs (e.g. metformin and glimepiride) and other medications may also be contributing to polypharmacy in AMI survivors. It has been demonstrated in prior studies that CV drugs are the most commonly used drugs in polypharmacy cohorts [6]. Our study adds the finding that AMI survivors may receive drugs with potential risks, especially when used in multimorbid patients and/or in combination with CV drugs. Within the most frequently used drugs, we observed that diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), and phenprocoumon, a vitamin K antagonist, both chemical substances prone to pharmacodynamic and pharmacokinetic drug interactions may cause gastrointestinal bleeding in patients with concomitant use of both drugs [17]. Furthermore, combined use of a NSAID with a diuretic and/or a RAAS blocker was associated with an increased risk of acute kidney injury by 60% [18]. In addition, we observed that 7% of long-term AMI survivors were using more than one antiplatelet agent. We did not know the current ischaemic risk of these participants. However, an extended dual antiplatelet therapy beyond the recommended 12 months (up to 24 or 30 months) after a PCI was found to be associated with more major bleeding and possible with increased all-cause mortality in a recent meta-analysis [19], and thus, should be prescribed deliberately. Our results with regard to factors associated with SPM use are in concordance with earlier studies of a shorter follow-up period which reported that patients' comorbidities such as depression [7,20,21], cancer [7,21] and neurological disorders [7,21] were associated with nonadherence. Conversely, SPM use at discharge [22,23] and hypertension [7,14,20] were strongly associated with long-term adherence. In contrast to earlier studies, we did not observe that the female sex [21] and being of older age [16,21,23] determined non-use. This finding emphasizes that sex and age did not influence physicians prescribing in our study region. In addition to earlier studies, we observed that patients receiving any revascularization therapy at index AMI were 2.5 times more likely to use 4 SPM at follow-up. One explanation might be that the hospital treatment strategy, including invasive and medication treatment following AMI, has worked very successful, showing that these patients had a strong belief in the efficacy of continuous SPM use. However, one should keep in mind that adherence is a multidimensional issue and may change over time as medical conditions alter. For example, it could be possible that some persons in our study received additional cardiac interventions after discharge or prior to the index AMI, and were therefore more prone to take all SPM regardless of other influencing variables analyzed in this study. Previous studies have shown that discharge prescriptions for secondary prevention treatments after ACS are associated with improved outcomes [4–6]. Additionally, it has been reported that special populations (e.g., women, elderly and frail patients) or patients with a potential worse prognosis after ACS (e.g., patients with chronic kidney disease or heart failure) were less likely to receive evidence-based treatments [1] even though they would have profited. Considering most of the drug efficacy trials were conducted in the pre-reperfusion era and the fact that acute treatment after AMI has changed tremendously since then, with PCI and stent implantation considered the standards of care, questions arose about the long-term (N3 years) benefit impact of SPM, especially in persons without any symptoms of angina pectoris
Please cite this article as: Amann U, et al, Medication use in long-term survivors from the MONICA/KORA Myocardial Infarction Registry, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.011
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U. Amann et al. / European Journal of Internal Medicine xxx (2017) xxx–xxx
or with preserved cardiac ejection fraction [6,24]. In 2011, “recommendations on secondary prevention therapy for beta-blocker therapy have been clarified to reflect the fact that evidence supporting their efficacy is greatest among patients with recent myocardial infarction (b3 years) and/or left ventricular systolic dysfunction (left ventricular ejection fraction ≤ 40%)” [3]. In conclusion, we believe that further effectiveness studies are necessary to find out which patient groups will benefit from long-term SPM use. Also we would like to recommend to the prescribing physicians to consider potential side effects due to routine prescribing praxis, such as hypotension on exercise and bradycardia due to long-term beta-blocker use [25], risk of severe angioedema with ACEinhibitors [26], potential beta-blocker or statin-induced diabetes [27], or increased risk of statin-related adverse events in older adults, including cognitive impairment, falls, neuropathy, and muscle damage [6]. 4.1. Limitations One of the main limitations of the study was related to the study design of an observational study with data collection at index AMI and later at a follow-up survey. No information was available on clinical treatment, medication use, or further cardiac intervention during the period between the index AMI and the data collection at follow-up. In addition, the variable of interest (4 SPM use at follow-up) was collected at the same time as most of the other variables. Furthermore, as we do not have information on adherence rates, possible side effects and contraindications of SPM therapy in our survey, we were not able to analyze relevant potential determinants of long-term drug use. Therefore, the results of our analysis regarding factors associated with 4 SPM use should be interpreted carefully. Secondly, medication intake was selfreported by patients and might therefore have been susceptible to recall bias. However, as observed SPM use at follow-up was high and in concordance with another recent study in Germany [14], we do not assume a relevant medication underreporting, especially for CV drugs. 5. Conclusions As recent studies with a prolonged follow-up period are rare, our study provides interesting results of medication use in long-term AMI survivors. SPM use was high after a median period of 6 years post AMI and was strongly associated with the following factors: any revascularization therapy at index AMI, SPM prescription at discharge, and patient's comorbidities. Further research seems necessary to assess the risk-benefit ratio of SPM use beyond 3 years, particularly in polypharmacy cohorts and in multimorbid patients. Authors' contributions UA and CM conceived the study. UA performed the statistical analyses and drafted the manuscript. CM, IK, MH, CT, and BK contributed to data acquisition and to the design of the study. CM, IK, MH, CT, and BK critically revised the manuscript. All authors have read and approved the final manuscript. Acknowledgements The KORA research platform and the MONICA Augsburg studies were initiated and financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education, Science, Research and Technology and by the State of Bavaria. Since the year 2000, the collection of MI data has been co-financed by the German Federal Ministry of Health to provide population-based MI morbidity data for the official German Health Report (see www.gbe-bund.de). Steering partners of the MONICA/KORA Infarction Registry, Augsburg, include the KORA research platform, Helmholtz Zentrum München and the Department of Internal Medicine I, Cardiology, Central Hospital of Augsburg.
We would like to thank all the members of the Helmholtz Zentrum München, Institute of Epidemiology II and the field staff in Augsburg who were involved in the planning and conduct of the study. We wish to thank the local health departments, the office-based physicians, and the clinicians of the hospitals within the study area for their support. Finally, we express our deep appreciation to all study participants. References [1] Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37:267–315. http://dx.doi.org/10.1093/eurheartj/ehv320. 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Long-term medication adherence in patients with ST-elevation myocardial infarction and primary percutaneous coronary intervention. Eur J Prev Cardiol 2015;22:890–9. http://dx. doi.org/10.1177/2047487314540385. [15] Shah ND, Dunlay SM, Ting HH, Montori VM, Thomas RJ, Wagie AE, et al. Long-term medication adherence after myocardial infarction: experience of a community. Am J Med 2009;122:961.e7-13. http://dx.doi.org/10.1016/j.amjmed.2008.12.021. [16] Kasteleyn MJ, Wezendonk A, Vos RC, Numans ME, Jansen H, Rutten GE. Repeat prescriptions of guideline-based secondary prevention medication in patients with type 2 diabetes and previous myocardial infarction in Dutch primary care. Fam Pract 2014;31:688–93. http://dx.doi.org/10.1093/fampra/cmu042. [17] Schmiedl S, Rottenkolber M, Hasford J, Rottenkolber D, Farker K, Drewelow B, et al. 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Please cite this article as: Amann U, et al, Medication use in long-term survivors from the MONICA/KORA Myocardial Infarction Registry, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.011
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Medication use in long-term survivors from the MONICA/KORA Myocardial Infarction Registry☆ Ute Amann a,b,e,⁎, Inge Kirchberger a,b, Margit Heier a,b, Christian Thilo c, Bernhard Kuch c,d, Christa Meisinger e a
MONICA/KORA Myocardial Infarction Registry, Central Hospital of Augsburg, Augsburg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany Department of Internal Medicine I - Cardiology, Central Hospital of Augsburg, Augsburg, Germany d Department of Internal Medicine/Cardiology, Hospital of Nördlingen, Nördlingen, Germany e Chair of Epidemiology, Ludwig-Maximilians-Universität München, UNIKA-T, Augsburg, Germany b c
a r t i c l e
i n f o
Article history: Received 18 April 2017 Received in revised form 11 July 2017 Accepted 10 August 2017 Available online xxxx Keywords: Myocardial infarction Secondary prevention Drug use
a b s t r a c t Background: Prior studies reported high guideline adherence for secondary prevention medications (SPM) at hospital discharge in patients with acute myocardial infarction (AMI). Less is known about medication use in longterm AMI survivors. Methods: Of the 2077 registered persons with an AMI between 2000 and 2008 who responded to a postal followup survey in 2011, 1311 men and 356 women, aged between 34.4 and 84.9 years, reported medication intake 7 days prior to the survey. These study participants also had their current health condition and comorbidities assessed. Information regarding index AMI was selected from the population-based MONICA/KORA MI registry. Multivariable logistic regression models were conducted to identify factors associated with SPM use (all 4 drug classes). Results: The median time between index AMI and the follow-up survey was 6.1 years (IQR: 3.9). At follow-up, a total of 10,422 medications were reported and polypharmacy was observed in 73.8%. Regarding SPM, the proportion of patients taking antiplatelet agents, beta-blockers, statins, and renin-angiotensin-aldosteron system blockers were 90.9%, 86.7%, 85.4%, and 79.3% respectively. Factors associated with SPM use were hypertension (odds ratio [OR] 1.48, p = 0.006), SPM prescription at hospital discharge (OR 2.68, p b 0.0001), revascularization therapy at index AMI (OR 2.46, p N 0.0001), number of medications taken at follow-up (OR 1.48, p b 0.0001), and several comorbidities such as lung disorders (OR 0.17; p b 0.0001), depression (OR 0.53, p = 0.001), neurological disorders (without stroke) (OR 0.34, p = 0.002), and cancer (OR 0.45, p = 0.005). Conclusion: SPM use several years after AMI was high and associated with treatment at index AMI and patients' comorbidities. © 2017 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
1. Introduction Besides lifestyle changes and control of cardiovascular (CV) risk factors, the following drugs are recommended by the international guidelines for long-term management of patients after an acute coronary syndrome (ACS) to reduce the risk of a further cardiac event or other manifestations of vascular disease: antiplatelet agents, beta-blockers, statins and renin-angiotensin-aldosteron system (RAAS) blockers, especially angiotensin-converting enzyme (ACE) inhibitors or angiotensin-
☆ Conflicts of interest of all authors: none, except for CT, see COI statements.Funding: none.Authorship: All authors had access to the data and played a role in writing the manuscript. ⁎ Correspondence to: U. Amann, MONICA/KORA Myocardial Infarction Registry/Central Hospital of Augsburg, Stenglinstr. 2, 86156 Augsburg, Germany. E-mail address: [email protected] (U. Amann).
receptor blockers (ARB) [1–3]. A combined therapy of these drugs is known as secondary prevention medication (SPM). Clinical evidence for short-term use of SPM in patients with ACS is very well established, whereas routine use longer than 1 year has less evidence [4–6] and furthermore, use beyond 5 to 10 years after acute myocardial infarction (AMI) is considered without any evidence from clinical trials [6]. After decades aimed at improving SPM use after an ACS, several studies showed high guideline adherence for SPM prescription at the time of hospital discharge [4,5,7,8]. Due to limited research on long-term drug use in general, less information exists about how many patients are receiving SPM several years after ACS. In addition, little is known about the health condition (e.g., health status, disability, comorbidities, and polypharmacy) of this high-risk population. The aim of this study was to first provide a comprehensive description of total medication use 3 or more years after an AMI and then to analyze factors associated with SPM use in long-term AMI survivors.
http://dx.doi.org/10.1016/j.ejim.2017.08.011 0953-6205/© 2017 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
Please cite this article as: Amann U, et al, Medication use in long-term survivors from the MONICA/KORA Myocardial Infarction Registry, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.011
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U. Amann et al. / European Journal of Internal Medicine xxx (2017) xxx–xxx
2. Material and methods 2.1. Study design and data source The present observational study is based on data from the population-based myocardial infarction (MI) registry in Augsburg, Germany, which was established in 1984 as part of the World Health Organization MONICA Project (MONItoring Trends and Determinants in CArdiovascular disease). After the termination of MONICA in 1995, the MI registry became part of the framework of KORA (Cooperative Health Research in the Region of Augsburg). Since 1984, all cases of coronary death and at least 24 h surviving AMI of the 25 to 74 year old study population in the city of Augsburg and the two adjacent counties (defined as the study area with about 650,000 inhabitants) have been continuously registered. Data sources for hospitalized patients were collected from the 8 participating hospitals. About 80% of all AMI cases of the study region were treated in the region's major hospital Klinikum Augsburg, a tertiary care center offering 24/7 interventional CV procedures as well as heart surgery facilities. The methods of case identification, diagnostic classification of events, and data quality control have been described in detail elsewhere [9,10]. To summarize briefly, diagnostic criteria according to the European Society of Cardiology and American College of Cardiology are used for case identification [11]. Patients are interviewed during their hospital stay by trained nurses using a standardized questionnaire to collect sociodemographic characteristics, CV risk factors, and comorbidities. Additional information on clinical data, comorbidities, type of AMI, acute management (e.g., percutaneous coronary intervention (PCI)), and medication use are collected by review of medical chart and discharge report. Data collection at index AMI and at the follow-up survey has been approved by the ethics committee of the Bavarian Medical Association (Bayerische Landesärztekammer) and all study participants gave their written informed consent. 2.2. Study population and follow-up data collection The present study included all 2077 registered persons with an AMI between 2000 and 2008 (index AMI), who were alive on July 1, 2011, did not previously decline further participation, and responded to a follow-up survey mailed to them in September 2011 (response rate 84%) [12]. The postal survey included questions on sociodemographic characteristics (age, sex, employment, living environment), a wide range of self-reported comorbidities, the current health status (assessed by a single response with: “very good”, “good”, “fair”, “poor”, or “very poor”), health care, disability (assessed with the German version of the 12item World Health Organization Disability Schedule (WHODAS) 2.0 [13]), and medication intake. Patient-reported information on type 2 diabetes mellitus (diabetes) was confirmed by the treating physician. Persons were also asked to provide the following details about each medication used within 7 days prior to the survey: medication name, central pharmaceutical number (a national standard identification code for pharmaceutical products in Germany), pharmaceutical form, number of single dosage used per day (e.g., 1 tablet), and whether the medication was prescribed by physician or self-medication. All medications were recorded and classified in the registry according to the German Anatomical Therapeutic Chemical (ATC)-classification system, which was established in 2004, based on the international ATC-classification of the WHO Collaborating Centre for Drug Statistics Methodology and to the specifics of the current heath care situation in Germany (http://www.dimdi.de/static/en/klassi/atcddd/index.htm). Only pharmaceutical products with a valid German ATC code were counted. To obtain the study population of drug users, of the 2077 responding persons, we excluded 392 individuals who reported either no medication intake (n = 60; 2.9%) or who did not answer the question at all (n = 332; 16.0%). In addition, 18 individuals with missing information on general health status or disability were excluded since information
on health condition was considered relevant. Thus, the final study population covered 1667 persons that survived AMI who reported medication intake. The study population had a comparable distribution of sexes (women: 21.4% versus 25.6%, p = 0.06), but a slightly higher median age (68.3 versus 65.6 years, p = 0.001) compared with the excluded persons (n = 410). 2.3. Statistical analysis Categorical variables were expressed as absolute numbers and percentages (%), and continuous variables were expressed as mean and standard deviation or median with interquartile range (IQR) depending on distribution patterns. For descriptive purposes, SPM use at discharge (index AMI) and at follow-up (survey) were reported for the total study population and separated by gender. The total medication use at followup was analyzed according to the ATC main group (1st level). Pharmaceutical products, e.g. nutritional supplements with an ATC code starting with “V” (various), were excluded for this analysis to maintain the focus on medications. To determine the most frequently used drugs and the number of different medications taken by each person, the 5th level of the ATC code was used, which indicates the chemical substance. Definition of the 4 SPM drug classes (4 SPM) for this analysis was the following: antiplatelet agents (ATC: B01AC), beta-blockers (ATC: C07), statins (ATC: C10AA, C10BA) and RAAS blockers (ATC: C09). Polypharmacy was defined as the intake of 5 or more different medications by a person. Patients' characteristics were cross-tabulated with SPM use status (4 SPM vs. 3 or less SPM) at follow-up using the Chi2-test or Fisher's exact test for categorical variables and the Kruskal-Wallis test (Wilcoxon Analysis) for continuous variables. To identify factors associated with 4 SPM use at follow-up, multivariable logistic regression analyses were performed. Variables analyzed were sex (men/women), and the following characteristics assessed at follow-up: age (continuous), employed (yes/no), living alone (yes/no/missing), follow-up time in years between index AMI and survey (continuous), general health status (response options “very poor” and “poor” were collapsed resulting in a 4-categorial variable), WHODAS 2.0 score (dichotomized variable with the median value of the study population as cut point) (N4/≤ 4), number of medications used at follow-up (continuous), and several comorbidities (yes/no/missing). The following characteristics were assessed at index AMI: type of AMI (ST-elevation or non-ST-elevation MI/bundle branch block/missing), any revascularization therapy defined as PCI with or without stenting and/or coronary artery bypass grafting (yes/no), medical history of hypertension and hyperlipidemia (yes/no), obesity defined as body mass index ≥30 kg/m2 (yes/no), and SPM use at time of discharge (yes/no). As criterion for entry into the models, the explanatory variables had to meet the 0.2 significance level in the bivariate analysis with 4 SPM use at follow-up. Except for sex and age, which were a priori determined to be forced-in, the final model included only factors which significantly (p b 0.05) contributed to the model using backward selection technique. All analyses were performed using SAS version 9.2 (SAS Institute Inc., Cary, North Carolina). 3. Results 3.1. Study population The study population consisted of 1667 participants (1311 men and 356 women) aged between 34.4 and 84.9 years who reported medication use within 7 days prior the survey. The median time between index AMI and follow-up survey was 6.1 years (IQR: 3.9), and did not differ between men and women (6.1 vs. 6.0 years respectively, p = 0.85). The median age at follow-up was 67.5 years (IQR: 13.4) in men and 70.4 years (IQR: 13.0) in women (p b 0.0001). Table 1 shows the characteristics of the study population by SPM use status at follow-up.
Please cite this article as: Amann U, et al, Medication use in long-term survivors from the MONICA/KORA Myocardial Infarction Registry, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.011
U. Amann et al. / European Journal of Internal Medicine xxx (2017) xxx–xxx
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Table 1 Study population by SPM use status at follow-up survey. AMI survivors taking 4 SPM at follow-up n = 1667 (unless otherwise noted) Sex Men Women Characteristics assessed at follow-up Age (median, IQR) Follow-up time between index AMI and follow-up survey, years (median, IQR) Employed (n = 1661) Living alone (n = 1659) General health status Very good Good Fair Poor Very poor Disability (WHODAS 2.0 scoreb) ≤4 N4 Comorbidities Diabetes Renal disorders (n = 1562) Liver disorders (n = 1539) Cancer (n = 1550) Depression (n = 1562) Stroke (n = 1556) Neurological disorders (n = 1532) Joint disorders (n = 1553) Vision disorders (n = 1561) Lung disorders (n = 1568) Digestive disorders (n = 1550) Blood disorders (n = 1542) Number of different medications (median/IQR) Polypharmacy (≥5 different drugs) Characteristics assessed at index AMI Type of AMI STEMI NSTEMI Bundle branch block Non-classifiable/missing data Risk factors/Comorbidities Hypertension Hyperlipidemia Obesity (n = 1655) Acute treatment Any revascularization therapy (e.g., PCI) 4 SPM use at discharge
p Value
yes (n = 975)
no (n = 692)
779 (79.1) 196 (20.1)
532 (76.9) 160 (23.1)
68.2 (12.9) 6.0 (3.7) 216 (22.2a) 176 (18.1a)
68.8 (14.4) 6.2 (3.9) 161 (23.4a) 129 (18.8a)
88 (9.0) 453 (46.5) 362 (37.1) 67 (6.9) 5 (0.5)
53 (7.7) 297 (42.9) 269 (38.9) 59 (8.5) 14 (2.0)
510 (52.3) 465 (47.7)
331 (47.8) 361 (52.2)
0.07
331 (34.0) 58 (6.3a) 15 (1.7a) 41 (4.5a) 122 (13.3a) 31 (3.4a) 28 (3.1a) 273 (30.0a) 259 (28.3a) 48 (5.2a) 68 (7.5a) 33 (3.6a) 6 (3) 842 (86.4)
195 (28.2) 53 (8.2a) 19 (3.0a) 42 (6.6a) 127 (19.8a) 32 (5.0a) 32 (5.1a) 218 (34.0a) 207 (32.0a) 74 (11.5a) 58 (9.1a) 26 (4.1a) 5 (4) 388 (56.1)
0.01 0.14 0.07 0.06 0.001 0.11 0.05 0.10 0.11 b0.0001 0.25 0.60 b0.0001 b0.0001
389 (39.9) 519 (53.2) 51 (5.2) 16 (1.6)
249 (36.0) 398 (57.1) 31 (4.5) 14 (2.0)
795 (81.5) 730 (74.8) 275 (28.4a)
502 (72.5) 503 (72.7) 155 (22.6a)
b0.0001 0.32 0.01
902 (92.5) 804 (82.5)
578 (83.5) 449 (64.9)
b0.0001 b0.0001
0.14
0.38 0.01 0.56 0.75 0.02
0.29
SPM secondary prevention medication (4 SPM was defined as combined use of antiplatelet agent, beta-blocker, statin and renin-angiotensin-aldosteron system blocker), AMI acute myocardial infarction, ATC anatomical therapeutic chemical, IQR interquartile range (25th and 75th percentiles), WHODAS World Health Organization Disability Schedule, STEMI ST-segment elevation myocardial infarction, NSTEMI Non-ST segment elevation myocardial infarction, PCI percutaneous coronary intervention. a Percentage value were calculated based on total available data for each variable. b Higher scores reflect more disability.
AMI survivors taking 4 SPM significantly (p b 0.05) differed from their counterparts with 3 or less SPM use by not only follow-up time but also general health status, median number of medications at followup, polypharmacy, diabetes, depression, lung disorders, hypertension, obesity, receiving of any revascularization therapy, and taking 4 SPM at hospital discharge. 3.2. SPM and total medication use At hospital discharge after the index AMI, the proportion of patients taking antiplatelet agents, beta-blockers, statins, and RAAS blockers were 97.5%, 96.2%, 92.7%, and 83.6% respectively. In the follow-up survey, the respective proportions of patients taking these drug classes were 90.9%, 86.7%, 85.4%, and 79.3%. In total, 975 (58.5%) study participants received 4 SPM and 1466 (86.7%) used at least 3 SPMs at followup. Differences by sex regarding follow-up SPM use were only observed
with regard to antiplatelet agents, but not for 4 SPM use (Table 2). 120 persons (7.2%) reported more than one antiplatelet agent at follow-up, and polypharmacy was observed in 73.8% of the study population. Altogether, 10,422 different medications were reported by the study population at follow-up. Fig. 1 provides an overview of medication use by ATC code. Within the CV system group, lipid modifying agents followed by beta-blockers and RAAS blockers were the most frequently taken. Regarding single drug use, the most frequently used chemical substances were acetylsalicylic acid (ASS) and clopidogrel for antiplatelet agents; simvastatin and combination products with ezetimibe and atorvastatin for statins; Ramipril and combination products with hydrochlorothiazide for RAAS blockers; and bisoprolol and metoprolol for beta-blockers. The most frequently used non-SPM was torasemide (diuretic agent), followed by amlodipine (calcium channel blocker), pantoprazole (proton pump inhibitor), and allopurinol (anti-gout agent) (Table 3).
Please cite this article as: Amann U, et al, Medication use in long-term survivors from the MONICA/KORA Myocardial Infarction Registry, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.011
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U. Amann et al. / European Journal of Internal Medicine xxx (2017) xxx–xxx
Table 2 SPM use at index AMI (hospital discharge) and at follow-up survey. Drug class/SPM combination
Antiplatelet agents Beta-blockers Statins RAAS blockers 4 SPM At least 3 of the drug classes
All (n = 1667)
Men (n = 1311)
p Valuea
Women (n = 356)
Discharge
Follow-up
Discharge
Follow-up
Discharge
Follow-up
1625 (97.5) 1604 (96.2) 1545 (92.7) 1393 (83.6) 1253 (75.2) 1590 (95.4)
1515 (90.9) 1445 (86.7) 1424 (85.4) 1322 (79.3) 975 (58.5) 1466 (87.9)
1281 (97.7) 1268 (96.7) 1225 (93.4) 1089 (83.1) 991 (75.6) 1257 (96.0)
1202 (91.7) 1143 (87.2) 1126 (85.9) 1043 (79.6) 779 (59.4) 1162 (88.6)
344 (96.6) 336 (94.4) 320 (89.9) 304 (85.4) 262 (73.6) 333 (93.5)
313 (87.9) 302 (84.8) 298 (83.7) 279 (78.4) 196 (55.1) 304 (85.4)
0.03 0.25 0.30 0.62 0.14 0.10
SPM secondary prevention medication (4 SPM was defined as combined use of antiplatelet agent, beta-blocker, statin and renin-angiotensin-aldosteron system blocker), AMI acute myocardial infarction, RAAS renin-angiotensin-aldosteron system. a p Value calculated to assess differences between men and women regarding follow-up SPM use.
3.3. Factors associated with SPM use at follow-up
4. Discussion
In the multivariable logistic regression analysis, we found that the following factors were associated with use of all 4 SPM at follow-up: any revascularization therapy at index AMI, 4 SPM prescription at hospital discharge, history of hypertension, and the number of medications taken at follow-up. In contrast, persons suffering from lung disorders, neurological disorders (without stroke), cancer, depression, joint disorders, or diabetes at follow-up were less likely to take 4 SPM at followup (Table 4).
In the present, registry-based study of 1667 participants with a survived AMI between 2000 and 2008who responded to a postal follow-up survey in September 2011 and reported medication intake within 7 days prior to the survey, we found that almost 60% of these post-AMI patients were taking all 4 SPM. SPM use at follow-up was associated with SPM prescription at hospital discharge, receiving invasive treatment strategy, hypertension, number of medications used at follow-up, and absence of lung disorders, neurological disorders, cancer,
Fig. 1. Total medication use in % of total count and count of medications of the cardiovascular system taken by AMI survivors at follow-up.
Please cite this article as: Amann U, et al, Medication use in long-term survivors from the MONICA/KORA Myocardial Infarction Registry, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.011
U. Amann et al. / European Journal of Internal Medicine xxx (2017) xxx–xxx Table 3 Top 20 most frequently used drugs in AMI survivors (n = 1667) at follow-up. ATC code
Chemical substance(s)
Count (%)a
SPM yes (drug class)/no
B01AC06 C10AA01 C09AA05 C07AB07 C07AB02 C09BA25 C03CA04 C08CA01 A02BC02 M04AA01 B01AC04 A10BA02 H03AA01 C10BA02 B01AA04 A02BC01 G04CA02 C10AA05 A10BB12 M01AB05 Total top 20
Acetylsalicylic acid Simvastatin Ramipril Bisoprolol Metoprolol Ramipril and HCT Torasemid Amlodipin Pantoprazole Allopurinol Clopidogrel Metformin Levothyroxine sodium Simvastatin and Ezetimibe Phenprocoumon Omeprazol Tamsulosin Atorvastatin Glimepiride Diclofenac
1393 (13.4) 1018 (9.8) 671 (6.4) 645 (6.2) 640 (6.1) 353 (3.4) 279 (2.7) 253 (2.4) 240 (2.3) 221 (2.1) 217 (2.1) 213 (2.0) 191 (1.8) 187 (1.8) 124 (1.2) 121 (1.2) 92 (0.9) 85 (0.8) 76 (0.7) 74 (0.7) 7093 (68.1)
yes (antiplatelet agent) yes (statin) yes (RAAS blocker) yes (beta-blocker) yes (beta-blocker) yes (RAAS blocker) no no no no yes (antiplatelet agent) no no yes (statin) no no no yes (statin) no no
SPM secondary prevention medication, AMI acute myocardial infarction, ATC anatomical therapeutic chemical, HCT hydrochlorothiazide, RAAS renin-angiotensin-aldosteron system. a Count and percentage of all reported medications (n = 10,422) with specified ATC code within the study sample.
depression, joint disorders, and/or diabetes. To our knowledge, previous studies have not analyzed total medication use in AMI survivors. The present study showed a high frequency of polypharmacy and identified frequently used drugs. Our finding about high SPM use several years after AMI demonstrates that quality improvement interventions to maximize guideline-recommended therapies after AMI have worked sufficiently. Our results are in agreement with a recent German follow-up study in STelevation MI survivors with available information on drug use which reported similar rates after a median follow-up period of 3 years of 90.8%, 87.5%, 88.2% and 79.2% for ASS, beta-blockers, statins and ACE-inhibitors or ARB, respectively [14]. However, Reuter et al. [14] reported lower adherence to beta-blockers in women compared to men, while in our study which included all types of AMI differences in SPM use by sex, a lower adherence was only observed for antiplatelet agents. When comparing results of different studies on long-term adherence to SPM after AMI it is mandatory to consider drug prescription at the time of hospital discharge, because discharge after a survived AMI is a critical time in Table 4 Factors associated with 4 SPM use at follow-up in AMI survivors (n = 1468a).
Sex (men vs. women) Characteristics assessed at follow-up Age (cont.) Lung disorders (yes vs. no) Neurological disorders (yes vs. no) Cancer (yes vs. no) Depression (yes vs. no) Joint disorders (yes vs. no) Diabetes (yes vs. no) Number of medications (cont.) Characteristics assessed at index AMI 4 SPM prescription at discharge (yes vs. no) Hypertension (yes vs. no) Any revascularization therapy (yes vs. no)
OR [95% CI]
p Value
1.30 [0.97–1.74]
0.076
0.99 [0.98–1.00] 0.17 [0.10–0.30] 0.34 [0.18–0.67] 0.45 [0.25–0.79] 0.53 [0.37–0.75] 0.75 [0.57–0.97] 0.75 [0.57–0.99] 1.48 [1.38–1.58]
0.073 b0.0001 0.002 0.005 0.001 0.029 0.042 b0.0001
2.68 [2.05–3.52] 1.48 [1.12–1.95] 2.46 [1.66–3.65]
b0.0001 0.006 b0.0001
SPM secondary prevention medication (4 SPM was defined as combined use of antiplatelet agent, beta-blocker, statin and renin-angiotensin-aldosteron system blocker), AMI acute myocardial infarction, OR odds ratio, CI confidence interval. a Note: 199 observations were deleted due to missing values for the explanatory variables.
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which use and prescription of SPM is very important for optimal longterm management [4]. For example, in a prior US study which reported low 3-year medication continuation rates with b50% for statins, betablockers and ACE-inhibitors/ARB, the medication use at discharge was not as high as observed in our study [15]. A Dutch primary care study within diabetes patients with a previous MI evaluated repeat prescriptions of SPM (anti-thrombotic agent, beta-blocker and statin) at 6 months, 1 year, 2 years and 5 years and found that prescription rates of each single drug and all 3 medications remained quite stable over the observed follow-up time up after AMI [16]. The high frequency of polypharmacy we observed was obviously caused by SPM and other CV medications (e.g. diuretics and calcium channel blockers), however diabetes drugs (e.g. metformin and glimepiride) and other medications may also be contributing to polypharmacy in AMI survivors. It has been demonstrated in prior studies that CV drugs are the most commonly used drugs in polypharmacy cohorts [6]. Our study adds the finding that AMI survivors may receive drugs with potential risks, especially when used in multimorbid patients and/or in combination with CV drugs. Within the most frequently used drugs, we observed that diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), and phenprocoumon, a vitamin K antagonist, both chemical substances prone to pharmacodynamic and pharmacokinetic drug interactions may cause gastrointestinal bleeding in patients with concomitant use of both drugs [17]. Furthermore, combined use of a NSAID with a diuretic and/or a RAAS blocker was associated with an increased risk of acute kidney injury by 60% [18]. In addition, we observed that 7% of long-term AMI survivors were using more than one antiplatelet agent. We did not know the current ischaemic risk of these participants. However, an extended dual antiplatelet therapy beyond the recommended 12 months (up to 24 or 30 months) after a PCI was found to be associated with more major bleeding and possible with increased all-cause mortality in a recent meta-analysis [19], and thus, should be prescribed deliberately. Our results with regard to factors associated with SPM use are in concordance with earlier studies of a shorter follow-up period which reported that patients' comorbidities such as depression [7,20,21], cancer [7,21] and neurological disorders [7,21] were associated with nonadherence. Conversely, SPM use at discharge [22,23] and hypertension [7,14,20] were strongly associated with long-term adherence. In contrast to earlier studies, we did not observe that the female sex [21] and being of older age [16,21,23] determined non-use. This finding emphasizes that sex and age did not influence physicians prescribing in our study region. In addition to earlier studies, we observed that patients receiving any revascularization therapy at index AMI were 2.5 times more likely to use 4 SPM at follow-up. One explanation might be that the hospital treatment strategy, including invasive and medication treatment following AMI, has worked very successful, showing that these patients had a strong belief in the efficacy of continuous SPM use. However, one should keep in mind that adherence is a multidimensional issue and may change over time as medical conditions alter. For example, it could be possible that some persons in our study received additional cardiac interventions after discharge or prior to the index AMI, and were therefore more prone to take all SPM regardless of other influencing variables analyzed in this study. Previous studies have shown that discharge prescriptions for secondary prevention treatments after ACS are associated with improved outcomes [4–6]. Additionally, it has been reported that special populations (e.g., women, elderly and frail patients) or patients with a potential worse prognosis after ACS (e.g., patients with chronic kidney disease or heart failure) were less likely to receive evidence-based treatments [1] even though they would have profited. Considering most of the drug efficacy trials were conducted in the pre-reperfusion era and the fact that acute treatment after AMI has changed tremendously since then, with PCI and stent implantation considered the standards of care, questions arose about the long-term (N3 years) benefit impact of SPM, especially in persons without any symptoms of angina pectoris
Please cite this article as: Amann U, et al, Medication use in long-term survivors from the MONICA/KORA Myocardial Infarction Registry, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.011
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or with preserved cardiac ejection fraction [6,24]. In 2011, “recommendations on secondary prevention therapy for beta-blocker therapy have been clarified to reflect the fact that evidence supporting their efficacy is greatest among patients with recent myocardial infarction (b3 years) and/or left ventricular systolic dysfunction (left ventricular ejection fraction ≤ 40%)” [3]. In conclusion, we believe that further effectiveness studies are necessary to find out which patient groups will benefit from long-term SPM use. Also we would like to recommend to the prescribing physicians to consider potential side effects due to routine prescribing praxis, such as hypotension on exercise and bradycardia due to long-term beta-blocker use [25], risk of severe angioedema with ACEinhibitors [26], potential beta-blocker or statin-induced diabetes [27], or increased risk of statin-related adverse events in older adults, including cognitive impairment, falls, neuropathy, and muscle damage [6]. 4.1. Limitations One of the main limitations of the study was related to the study design of an observational study with data collection at index AMI and later at a follow-up survey. No information was available on clinical treatment, medication use, or further cardiac intervention during the period between the index AMI and the data collection at follow-up. In addition, the variable of interest (4 SPM use at follow-up) was collected at the same time as most of the other variables. Furthermore, as we do not have information on adherence rates, possible side effects and contraindications of SPM therapy in our survey, we were not able to analyze relevant potential determinants of long-term drug use. Therefore, the results of our analysis regarding factors associated with 4 SPM use should be interpreted carefully. Secondly, medication intake was selfreported by patients and might therefore have been susceptible to recall bias. However, as observed SPM use at follow-up was high and in concordance with another recent study in Germany [14], we do not assume a relevant medication underreporting, especially for CV drugs. 5. Conclusions As recent studies with a prolonged follow-up period are rare, our study provides interesting results of medication use in long-term AMI survivors. SPM use was high after a median period of 6 years post AMI and was strongly associated with the following factors: any revascularization therapy at index AMI, SPM prescription at discharge, and patient's comorbidities. Further research seems necessary to assess the risk-benefit ratio of SPM use beyond 3 years, particularly in polypharmacy cohorts and in multimorbid patients. Authors' contributions UA and CM conceived the study. UA performed the statistical analyses and drafted the manuscript. CM, IK, MH, CT, and BK contributed to data acquisition and to the design of the study. CM, IK, MH, CT, and BK critically revised the manuscript. All authors have read and approved the final manuscript. Acknowledgements The KORA research platform and the MONICA Augsburg studies were initiated and financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education, Science, Research and Technology and by the State of Bavaria. Since the year 2000, the collection of MI data has been co-financed by the German Federal Ministry of Health to provide population-based MI morbidity data for the official German Health Report (see www.gbe-bund.de). Steering partners of the MONICA/KORA Infarction Registry, Augsburg, include the KORA research platform, Helmholtz Zentrum München and the Department of Internal Medicine I, Cardiology, Central Hospital of Augsburg.
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Please cite this article as: Amann U, et al, Medication use in long-term survivors from the MONICA/KORA Myocardial Infarction Registry, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.011