Target-Attainment Rates of Low-Density Lipoprotein Cholesterol Using Lipid-Lowering Drugs One Year After Acute Myocardial Infarction in Sweden

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1 Target-Attainment Rates of Low-Density Lipoprotein Cholesterol Using Lipid-Lowering Drugs One Year After Acute Myocardial Infarction in Sweden Kristina Hambraeus, MD a, *, Lars Lindhagen, PhD b, Patrik Tydén, MD, PhD c, Bertil Lindahl, MD, PhD d, and Bo Lagerqvist, MD, PhD d The objective of this prospective cohort study was to describe real-life use of lipid-lowering drugs and low-density lipoprotein cholesterol (LDL-C) target-attainment rates 1 year after acute myocardial infarction (AMI). LDL-C was recorded at hospital admission for AMI and at follow-up at 2 and 12 months after AMI in 17,236 patients in the Swedish heart registry, SWEDEHEART, from 2004 through Lipid-lowering treatments were identified using the Swedish Prescribed Drug Register. More than 90% of patients received statins after AMI. Simvastatin 40 mg was used by 80% of patients at discharge and at 2 months and 68% at 1 year after AMI. Intensive statin therapy (LDL-C-lowering capacity >40%) was prescribed for 8.4%, 11.9%, and 12.2% at these time points, and combinations of statin/ezetimibe for 1.1%, 2.8%, and 5.0%, respectively. The LDL-C target of <2.5 mmol/l (97 mg/dl) was achieved in 74.5% of patients at 2 months and 72.3% at 12 months after AMI. Treatment was intensified for only 21.3% of patients with LDL-C above target at 2 months. In multivariate analysis, higher LDL-C levels at admission and at 2 months correlated to increased risk for under treatment at 12 months after AMI. In conclusion, statin treatment after AMI in Sweden has become standard, but titration to reach recommended LDL-C levels is still suboptimal. Strategies to further improve implementation of guidelines are needed. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;113:17e22) Despite the overwhelming evidence for the benefit of lipid-lowering drugs in reducing cardiovascular events in patients with established cardiovascular disease or high risk profile 1e3 and clear recommendations for target levels in national and international guidelines, 4e7 repeated surveys in Europe have shown substantial room for improvement regarding target achievement in routine clinical practice. 8 The objective of the present study was to describe reallife use of lipid-lowering drugs and resulting low-density lipoprotein cholesterol (LDL-C) target attainment rates at 2 and 12 months after acute myocardial infarction (AMI) in a large unselected cohort of AMI patients in Sweden. Methods SWEDEHEART is a national registry prospectively collecting data regarding baseline characteristics, treatments a Department of Cardiology, Falun Hospital, Falun, and Department of Medical Sciences, Uppsala University, Uppsala, Sweden; b Uppsala Clinical Research Centre, Uppsala, Sweden; c Department of Cardiology, Skane University Hospital, Lund, Sweden; and d Uppsala Clinical Research Centre and Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Manuscript received June 3, 2013; revised manuscript received and accepted September 21, This study was an academic study which received financial support by an unrestricted grant from Schering-Plough/MSD, project number P05884 Schering-Plough/MSD played no role in the design of the study, choice of included patients, interpretation of data, or preparation or approval of the article. See page 21 for disclosure information. *Corresponding author: Tel: (þ46) ; fax: (þ46) address: Kristina.hambraeus@ltdalarna.se (K. Hambraeus). in hospital, medication at discharge, and outcome for consecutive patients with acute coronary syndromes treated in all Swedish coronary care units (CCU). 9 Participation in SWEDEHEART is voluntary for each hospital. Development and core management of the registry is funded by the Swedish Health Authorities, but participating hospitals receive no extra funding. A module covering secondary prevention and cardiac rehabilitation for patients up to 75 years of age in SWEDEHEART was launched in 2005, involving an increasing number of centers during the study period from 32 to 62 (84% of all Swedish hospitals providing care for AMI) in LDL-C was measured at admission to the CCU and at follow-up visits at 2 months and at 1 year after AMI, and recorded in the registry. LDL-C measurement was not mandatory in the registry, resulting in the differences in population sizes seen in Figure 1. The Swedish Prescribed Drug Register started in July 2005 and includes all dispensed prescriptions in Swedish pharmacies for all Swedish citizens. 10 It contains prescription and dispensing dates, dispensed amount of the drug, and personal identification number of each individual. Drugs are coded according to the World Health Organization Anatomical Therapeutic Chemical Classification. The database from SWEDEHEART for the period from December 2004 through June 2009 was merged with the Swedish Prescribed Drug Register creating an anonymous study database. December 2004 was chosen as study start to allow inclusion of baseline data for patients with their first follow-up visit in January Patients aged <75 years, participating in the 2-month and/or 1-year follow-up in the SWEDEHEART registry and with 1 purchase of any lipid-lowering drug (Anatomical Therapeutic Chemical /13/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved.

2 18 The American Journal of Cardiology ( Figure 1. Population sizes: number of patients with recorded LDL-C measurements at different time points. Table 1 Absolute (mmol/l) and percentage reductions in low-density cholesterol according to statin and daily dose Daily Dose, mg (Reductions in LDL-C) Statin Rosuvastatin 1.84 (38%) 2.08 (43%) 2.32 (48%) 2.56 (53%) 2.80 (58%) Atorvastatin 1.51 (31%) 1.79 (37%) 2.07 (43%) 2.36 (49%) 2.64 (55%) Simvastatin 1.08 (23%) 1.31 (27%) 1.54 (32%) 1.78 (37%) 2.01 (42%) Fluvastatin 0.46 (10%) 0.74 (15%) 1.02 (21%) 1.30 (27%) 1.58 (33%) Pravastatin 0.73 (15%) 0.95 (20%) 1.17 (24%) 1.38 (29%) 1.60 (33%) Modified from Law et al. 11 Intensive statin therapy in shadowed area. Only statins available in Sweden are shown. Classification code C10 A) during the study period were identified (n ¼ 17,236). This constituted nearly half of the total number of AMI patients (38,818) in this age group admitted to a CCU in Sweden during the study period. LDL-C was measured in 78% (13,383) of patients at admission for AMI, 63% (10,107) of the 15,995 patients completing the 2-month follow-up and in 66% (8,192) of the 12,355 patients completing the 1-year follow-up: 989 patients died during the study period, and 3,276 patients were censored for the 1-year, but not the 2-month, follow-up because of closure of the study database in June Treatment before admission for AMI was unknown for 3,027 patients admitted in 2004 through 2005 because the Swedish Prescribed Drug Register started in July These patients were included in the study to contribute to the description of current post-ami treatment practices. Patients with registered LDL-C values at each time point are shown in Figure 1. According to Swedish law, no written informed consent is needed for registration of a patient in the SWEDEHEART registry. All patients are informed of their participation in the registry and have the right to withdraw their participation; no patients within this study have chosen to do so. This study was approved by the Uppsala Ethical Review Board. On the basis of a meta-analysis of the relative effect of statins, 11 statins at doses capable of lowering LDL-C by >40% were considered as a group ( intensive statin therapy ) compared with a group of statins at doses capable of LDL-C lowering of <40% ( moderate statin therapy ). Treatment with combinations of statin and ezetimibe were also analyzed. To define the lipid-lowering drug treatment used before a visit, a run-in period of 6 months was used. This run-in period can be justified using the waiting-time distribution, in this case allowing for varying time intervals between patients drug purchases. 12 The most potent statin (according to Table 1), if >1, dispensed at the latest dispensation date during the 6 months before the visit was selected. The same was done for nonstatins, allowing for combination treatments. Treatment after a follow-up visit was defined similarly, with a time interval from 2 weeks before the visit to 2 weeks after the visit. This 4-week interval was included because protocol allowed for LDL-C analyses during this period, and treatment could thus be altered accordingly. To describe the physician s treatment strategy in response to current lipid status, prescription dates instead of dispensation dates were used. If there were no new prescriptions during these 4 weeks, the patient was considered to have continued the same treatment as before the visit. Univariate comparison of target attainment rate for dichotomous variables was done using 2-sided Fischer s exact test. For each follow-up visit, the probability of reaching the treatment target of LDL-C 2.5 mmol/l (97 mg/dl) was assessed, for patients with results greater than the LDL-C target at the previous visit, using a logistic regression model. As explanatory variables, the models included gender, age (linear term), diabetes, previous myocardial infarction, stroke, previous revascularization, hypertension, statin treatment before admission, smoking status, year of AMI, treated and untreated LDL-C (linear term), and statin treatment before follow-up visit. The model

3 Coronary Artery Disease/LDL-C Target-Attainment Rates After AMI in Sweden 19 Table 2 Baseline characteristics Total (n ¼ 17,236) Percentage (n) Mean SD Male 73.9% (12,745) Female 26.1% (4,491) Age (yrs) Diabetes mellitus 19.7% (3,392) Previous myocardial infarction 15.9% (2,741) Previous percutaneous coronary intervention 10.1% (1,736) Previous coronary artery bypass surgery 6.4% (1,111) Hypertension 40.4% (6,958) Statin treatment before admission* 27.4% (3,888) Smoker at admission 31.6% (5,444) Body mass index Percutaneous coronary intervention during 69.8% (12,031) hospital stay LDL-C at admission (n ¼ 13,383) LDL-C at 2 months after AMI (n ¼ 10,107) LDL-C at 1 year after AMI (n ¼ 8192) Figure 3. Frequency of LDL-C-levels 1 year after AMI in different groups. MI, myocardial infarction. * Statin treatment before admission (n ¼ 14,209) was unknown for patients with AMI in 2005, which was before initiation of the Prescribed Drug Register. BMI (n ¼ 13,604) and LDL-C were not recorded for all patients. Figure 4. Titration of treatment for patients not reaching LDL-C target at 2 and at 12 months after AMI. Figure 2. Frequency of LDL-C-levels 2 months after AMI in different groups. MI, myocardial infarction. for the first follow-up thus included only patients with LDL- C >2.5 mmol/l at admission, and the model for the second follow up included only patients with LDL-C >2.5 mmol/l at the first follow-up. The model was applied to the subset of patients with LDL-C measured on 2 consecutive occasions and having complete information from the Prescribed Drug Registry. All analyses were performed with the statistical program R version Results Baseline characteristics of the total study population are outlined in Table 2, including sociodemographic factors, medical history, previous and new coronary interventions, and mean LDL-C-levels at admission for AMI and at the first and second follow-ups. The proportion of patients using lipidlowering treatment before admission for AMI was 27.4%, and LDL-C at admission was 2.5 mmol/l (97 mg/dl) for 63.8% of those patients (data not shown). Target LDL-C was achieved in 74.5% of all patients 2 months after AMI and in 72.3% at 1 year. Patients with diabetes had better lipid control rates: 79.1% and 79.5% versus 73.4% and 70.6% at 2 and 12 months after AMI (p <0.001 for both time points). There were only small differences in lipid control rates between men and women (31.3% vs 29.1% at admission, 75.4% vs 72.1% at 2 months and 72.8% vs 70.8% at 12 months; Figures 2 and 3). Within 14 days of the discharge date after AMI, 95.3% of all patients used a lipid-lowering drug, according to definition of treatment in the Methods section. This proportion decreased to 92.9% at 1 year. Among patients not reaching LDL-C treatment target at follow-up 2, the corresponding proportion was 88.7% at 1 year. The most frequent lipid-lowering drug after AMI was simvastatin 20 or 40 mg, which was prescribed for 80.5% of patients at discharge, 78.0% after 2 months, and 68.0% after 1 year. Intensive statin therapy (simvastatin 80 mg, atorvastatin 20 to 80 mg, or rosuvastatin 10 to 80 mg) was prescribed for 8.4% of the patients at discharge, 11.9% after 2 months, and 12.2% after 1 year. Corresponding proportions for the combination of a statin and ezetimibe were 1.1%, 2.8%, and 5.0%. Total use of nonstatins other than ezetimibe was <2.5% at all time points (data not shown). The most frequent drug in the intensive statin therapy group was 80 mg atorvastatin at discharge and after 2 months (3.9% and 4.7%) and atorvastatin 40 mg after 1 year (4.0%). Treatment was intensified (i.e., increased dose or switch to a more potent drug) for 21.3% of patients with LDL-C above recommended level at the first follow-up, and for 12.0% of such patients at the second follow-up (Figure 4).

4 20 The American Journal of Cardiology ( Table 3 Multivariable analysis of factors associated with low-density lipoprotein >2.5 mmol/l at 2 months (follow-up 1) and 1 year (follow-up 2) after myocardial infarction Variable Follow-up 1 Follow-up 2 Univariate Multivariate Univariate Multivariate Female gender 1.19 ( ) (0.96e1.32) (0.75e1.30) (0.60e1.15) 0.26 Age (by SD) 0.95 (0.89e1.01) (0.89e1.03) (0.94e1.21) (0.79e1.08) 0.34 Diabetes mellitus 0.88 (0.72e1.07) (0.57e0.90) (0.59e1.20) (0.44e1.07) Previous MI 2.15 (1.75e2.64) < (1.15e2.10) (0.85e1.70) (0.66e1.92) 0.67 Previous stroke 1.55 (1.12e2.15) (0.91e1.91) (0.71e2.29) (0.56e2.14) 0.79 Previous revascularization 1.98 (1.58e2.47) < (0.74e1.44) (0.99e2.13) (0.82e2.74) 0.19 Hypertension 0.97 (0.85e1.11) (0.74e1.00) (0.89e1.51) (0.74e1.38) 0.95 Smokers 1.47 (1.26e1.72) < (1.36e1.93) < (0.73e1.35) (0.69e1.43) 0.97 LDL-C measured at 2.20 (2.01e2.40) < (2.23e2.71) < (1.61e3.76) < (1.94e5.40) <0.001 admission; treated; by 1 mmol/l LDL-C measured at 1.29 (1.03e1.62) (1.06e1.75) (1.16e1.62) < (1.33e1.98) <0.001 admission; untreated; by 1 mmol/l Statin treatment before 2.94 (2.47e3.50) < (13.1e82.1) <0.001 admission LDL-C measured at follow-up 1; treated; by 1 mmol/l 2.18 (1.57e3.03) < (1.49e3.31) <0.001 At the 2-month follow-up, patients with diabetes were more likely to reach the target, whereas previous statin treatment, higher LDL-C at admission (both treated and untreated values), smoking at admission, and history of myocardial infarction were factors correlating to increased risk of not reaching treatment target. At the 1-year followup, higher LDL-C at admission (both treated and untreated values) and higher LDL-C at follow-up 1 were associated with increased risk of not reaching treatment target (Table 3). Discussion In this observational study, we examined prescription patterns regarding type and dose of lipid-lowering drugs (mainly statins) and LDL-C-goal attainment rate at 2 time points during the first year after an AMI. The study cohort included nearly half of the population of AMI patients aged <75 years in Sweden during this time period, with followup data collected by 84% of the Swedish hospitals; it therefore likely provides a good estimate of treatment strategies and goal attainment rates in everyday practice. By linking registry data from SWEDEHEART with the Swedish Prescribed Drug register, information on drug purchases was provided, giving a better estimate of drug adherence than what can be obtained by records of issued prescriptions from each center. Baseline characteristics of the study population are similar to data from randomized trials such as the Pravastatin or Atorvastatin Evaluation and Infection Therapy study (PROVE-IT) 13 and observational data such as US Get With The Guidelines (GWTG) database. 14 One in 4 patients were treated for hypercholesterolemia before admission, which was associated with an increased risk of not reaching treatment target at early follow-up. The reason for this is unclear but might reflect higher pretreatment values, lower patient level adherence, or reluctance from patient or physician to change an ongoing medication. Lipid control rates in patients with coronary artery disease have been reported in the EUROASPIRE I, II, and III studies. These studies demonstrated improving target attainment over time: 54% of patients reached the goal of total cholesterol <4.5 mmol/l in the latest study EURO- ASPIRE III, reflecting an increasing proportion of patients being prescribed statins at discharge. 15 The results from our study, with 3/4 of patients at goal after 1 year, compare favorably with these and are in fact comparable to the aggressive treatment arm of the Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) study, where patients were managed at dedicated research centers focusing on treating hyperlipidemia with atorvastatin. 16 Some inconsistencies were found when examining prescription and drug-purchase patterns in the Swedish Prescribed Drug Register, for example, varying time intervals between drug purchases. This may reflect varying patient level adherence but might also be influenced by the 12-month time period for subsidization of prescribed drugs to patients in Sweden, which determines patients cost for the individual purchase. The 6-month run-in period used to determine ongoing treatment was chosen to allow for these variations. Treatment with moderate-dose simvastatin as a first-line treatment is in accordance with Swedish guidelines during the study period. However, in the majority of cases, this was not followed by a treat-to-target strategy, with subsequent titration in case LDL-C remaining above the guidelinedefined target of 2.5 mmol/l. The titration, or treat to target, strategy has not been specifically evaluated in any

5 Coronary Artery Disease/LDL-C Target-Attainment Rates After AMI in Sweden 21 major prospective randomized controlled trial for AMI patients, compared with a strategy of a fixed dose of 20 or 40 mg of simvastatin without any subsequent changes. An observational study suggested that adherence might be better with a treat to target strategy compared with a fire and forget strategy without repeated measuring of LDL-C. 17 This study, however, could not discriminate between the effects of repeated measuring, which in itself might increase motivation for patients, and of the titration. Intensive lipid-lowering therapy, defined as statins with an LDL-C-lowering capacity >40% or combination therapy with ezetimibe, was used in only 9.5% of patients at discharge, which is considerably lower compared with data from the GWTG database in which 38.3% of patients were discharged with intensive lipid-lowering therapy 14 and not in accordance with the latest European guidelines. 18 The question of which strategy is the most cost-effective remains to be resolved, and because the answer depends on the current cost of the drug, it will be strongly influenced by patent processes. 19 Nonrandomized registry studies have several obvious drawbacks, and the results need to be interpreted with some caution. Even though this material represents nearly half of all patients <75 years of age with myocardial infarction in throughout a country during this time period, there is potential for systematic bias regarding characteristics of participants in the SWEDEHEART registry compared with nonparticipants. Year of AMI, reflecting increasing number of participating centers and therefore increasing proportions of participating versus nonparticipating patients, was, however, not an independent predictor of target attainment rate according to the multivariate analysis. We have previously compared baseline data from AMI patients with and without recorded follow-up data in the SWEDEHEART registry, revealing that nonparticipants somewhat more often had previous myocardial infarction, PCI, and diabetes in their medical history but were similar in other aspects. 20 Even though patients with recurrent disease have worse prognosis regarding morbidity and mortality, it is not known whether they are less likely to achieve secondary prevention targets, in which case overall target attainment levels in Sweden would be overestimated in this study. Cholesterol was measured at each center using various commercially available analysis tools, allowing for variations in reported cholesterol levels. This also reflects real life practice. Acknowledgment: The authors thank all participating centers in the SWEDEHEART registry for collection of data. Disclosures The authors have no conflicts of interest to disclose. 1. 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