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Efficacy and Safety of High-intensity Statins in Patients With Acute Myocardial Infarction: An Asian Perspective
Journal Pre-proof Efficacy and Safety of High-intensity Statins in Patients with Acute Myocardial Infarction: An Asian Perspective Po-Sheng Chen, MD, Sheng-Hsiang Lin, PhD, Cheng-Han Lee, MD, PhD, Hui-Wen Lin, MSc, Yi-Heng Li, MD, PhD PII:
S0828-282X(19)31375-3
DOI:
https://doi.org/10.1016/j.cjca.2019.10.027
Reference:
CJCA 3493
To appear in:
Canadian Journal of Cardiology
Received Date: 9 August 2018 Revised Date:
11 October 2019
Accepted Date: 16 October 2019
Please cite this article as: Chen P-S, Lin S-H, Lee C-H, Lin H-W, Li Y-H, Efficacy and Safety of Highintensity Statins in Patients with Acute Myocardial Infarction: An Asian Perspective, Canadian Journal of Cardiology (2019), doi: https://doi.org/10.1016/j.cjca.2019.10.027. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the Canadian Cardiovascular Society.
Efficacy and Safety of High-intensity Statins in Patients with Acute Myocardial Infarction: An Asian Perspective Running title: Statin Intensity in Acute Myocardial Infarction Po-Sheng Chen, MD,a,b; Sheng-Hsiang Lin, PhD,b,c,d; Cheng-Han Lee, MD, PhD,a,e; Hui-Wen Lin, MSc,c; Yi-Heng Li, MD, PhDa a
Department of Internal Medicine, National Cheng Kung University Hospital, College of
Medicine, National Cheng Kung University, Tainan, Taiwan b
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University,
Tainan, Taiwan c
Biostatistics Consulting Center, National Cheng Kung University Hospital, College of
Medicine, National Cheng Kung University, Tainan, Taiwan d
Department of Public Health, College of Medicine, National Cheng Kung University, Tainan,
Taiwan e
School of Pharmacy and Institute of Clinical Pharmacy and Pharmaceutical Sciences,
College of Medicine, National Cheng Kung University, Tainan, Taiwan
Corresponding author: Yi-Heng Li, MD, PhD, Department of Internal Medicine, National Cheng Kung University Hospital, 138 Sheng Li Road, Tainan 704, Taiwan. Tel: +886-6-2353535 ext 2382; Fax: +886-6-2753834; Email: [email protected]
Word count of text: 4419 Number of tables: 4; Number of figures: 1; Supplemental tables: 4 Key Words: statin, acute myocardial infarction, Asian, adverse effect 1
Brief Summary Little is known about the efficacy and safety of high-intensity statin (HIS) in Asians. In this analysis using Taiwan National Health Insurance Research Database, patients with acute myocardial infarction receiving HIS had similar clinical outcomes to those with non-HIS. HIS did not increase the risk of severe myopathy and hepatitis that need admission. Our findings indicate that HIS therapy for effective reduction of low-density lipoprotein cholesterol is safe in Asians.
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Abstract Background: 2013 ACC/AHA cholesterol guideline recommends high-intensity statin (HIS) in patients with atherosclerotic cardiovascular disease, but little is known about the efficacy and safety of HIS in Asian ethnicity. We assessed the effects of HIS in Taiwanese with acute myocardial infarction (AMI). Methods: Consecutive patients admitted for new AMI between January 2010 to December 2013 without prior statin use were enrolled from the Taiwan National Health Insurance Research Database. Patients were grouped based on the intensity of statin they took after discharge. The primary endpoint was the composite outcome of all-cause mortality, recurrent myocardial infarction and stroke. We also compared the incidences of severe hepatitis and myopathy that need admission between HIS and non-HIS groups. We used propensity score analysis to match covariates between groups and Cox proportional hazards models with adjustment to estimate the risks of clinical outcomes. Results: After 1:4 propensity score match, there were 4402 patients in HIS group and 17608 patients in non-HIS group. After follow-up for 3 years, 668 (15.2%) in HIS group and 2749 (15.6%) in non-HIS group patients had the primary composite endpoint. Cox proportional-hazards analyses showed that HIS did not further reduce composite endpoint (adjusted HR, 0.975; 95% CI, 0.896-1.062); however, HIS-patients had a lower risk of ischemic stroke at 3-year follow-up. Regarding safety, HIS did not increase hospitalization-rates for severe hepatitis and myopathy. Conclusions: AMI patients in Taiwan with HIS had similar clinical outcomes to those with non-HIS. Using HIS for effective reduction of low-density lipoprotein cholesterol is safe in Taiwan.
3
Statins effectively reduce low-density lipoprotein cholesterol (LDL-C) which is regarded as a key determinant in the development of atherosclerotic cardiovascular disease (ASCVD). Clinical trials and meta-analyses have demonstrated the clinical benefits of statins in primary and secondary prevention of ASCVD,1-6 and current clinical guidelines all recommend statin therapy in high risk patients. High-intensity statin (HIS) is more effective in risk reduction in patients with ASCVD compared with moderate- or low-intensity statin.7-9 Based on results of these studies, the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Cholesterol Guideline and 2018 ACC/AHA updated guideline recommend HIS in patients who are ≤ 75 years with clinical ASCVD.10,11 Several studies validated the clinical benefits of HIS in patients with ASCVD following the recommendation of 2013 ACC/AHA cholesterol guideline12,13 and the prescription rate of HIS for ASCVD patients increased progressively.14,15 However, there are several concerns about using HIS in Asian patients with coronary heart disease (CHD). First, there seemed to be no sufficient data to support the clinical benefits of HIS in Asian population. Few Asian subjects were enrolled in previous studies evaluating clinical efficacy of HIS.16 One prospective, randomized, open-label trial failed to demonstrate more benefits of higher dose atorvastatin (20-40 mg daily) in Chinese patients with acute coronary syndrome.17 Second, Asians are more vulnerable to statin-related adverse effect18, 19 and safety issue is always a major concern of using HIS in Asians population. Current Taiwan Lipid Guideline emphasizes the importance of “treat-to-target”, but not “statin intensity”. Consideration of safety and magnitude of LDL-C lowering in high risk patients, current Taiwan Lipid Guideline recommends either moderate-intensity statin or HIS can be used based on individual clinical characteristic and baseline LDL-C level.20 The Taiwan Lipid Guideline is not specifically in favor of or against HIS use and suggests that titration to the highest recommended or tolerable statin dose to reach the LDL-C target is necessary.20 4
Actually, clinical studies are rare to evaluate whether HIS is more effective in cardiovascular risk reduction or induces more statin-associated hepatitis or myopathy in Asian patients. Therefore, the aims of the present study were to assess (1) whether HIS therapy in Asian patients with acute myocardial infarction (AMI) would be associated with fewer major adverse cardiovascular events compared with low- or moderate-intensity statin and (2) whether HIS therapy in Asian patients would be associated with higher risk of severe hepatitis or myopathy. Methods Data source We used the National Health Insurance Research Database (NHIRD) released by the Taiwan National Health Research Institute for this study. National Health Insurance (NHI), a mandatory-enrollment and single-payment insurance program, is launched since 1995 and provides comprehensive medical care in Taiwan. More than 99% of Taiwan’s 23 million residents are covered by the NHI. In this study, we retrieved data from NHIRD which derived from the claim data of NHI program. The data components of each subject in NHIRD contain demographic characteristic, medical diagnoses, procedures, and prescriptions of all inpatient treatment and outpatient follow-up. For privacy protection, personal information of each subject has been encrypted, but it is feasible to link and follow all the claim data of the same patient in the NHIRD. The Institutional Review Board of the National Cheng Kung University Hospital approved this study (IRB No: A-EX-106-020). Study population We screened all patients who were admitted to hospitals for AMI from January 2010 to December 2013. Patients who survived to discharge with a major discharge diagnosis of AMI (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9 CM] code 410.xx) were included in this study (n=112318). The accuracy of AMI diagnosis based 5
on ICD-9 CM code 410.xx recorded in the NHIRD was validated and the positive predictive value was over 90%.21 Patients were excluded if they: (1) were older than 75 or less than 18 years old (n=25745), (2) had AMI within 2 years before enrollment (n=36113), (3) had < 2 days of hospitalization (n=4125), (4) had incomplete registry data (n=990) and (5) patients having less than 2 prescriptions of statin within the first year after discharge (n=16467). The 2013 ACC/AHA cholesterol guideline suggests HIS for patients with ASCVD who are 75 years of age or younger. In the present study, we would like to validate this recommendation in our AMI patients, therefore, patients who were older than 75 or less than 18 years old were excluded. We also want to enroll patients who do have new AMI during index hospitalization, so the patients who had diagnosis of AMI within 2 years before enrollment were excluded. Short duration of hospitalization less than 2 days might imply that these AMI patients died early or the diagnosis of AMI were doubtful because AMI patients generally had 3 or more days of hospital stay in Taiwan. This group of patients were excluded to ensure the diagnostic accuracy of AMI. Patients with incomplete registry data were excluded because they could not provide correct baseline characteristics. Finally, we also excluded patients who had no or only one reimbursement for statin prescription within one year after discharge because we thought these AMI patients did not receive statin regularly after discharge. Then, we grouped the remaining patients based on the intensity of statin they used. We defined the intensity of statin according to the ACC/AHA cholesterol guidelines.10 Among these eligible subjects, 4402 patients having more than 2 prescriptions of atorvastatin ≥ 40 mg or rosuvastatin ≥ 20 mg daily were recognized as HIS group and the other 24476 patients were regarded as non-HIS group. The flowchart of categorization of subjects was presented in the Figure 1. Study endpoint and follow up All patients were followed up for 3 years since the date of discharge from index hospitalization. ICD-9 CM was replaced by ICD-10 CM for NHI from 2016 in Taiwan. 6
Therefore, both ICD 9 and 10 codes were used to identify efficacy and safety endpoint during follow up. The primary efficacy endpoint was a composite endpoint of all-cause mortality, recurrent myocardial infarction (ICD-9 CM code 410.xx or ICD-10 CM code I21, I22, I23), ischemic stroke (ICD-9 CM code 433, 434, 436, 437.1, 437.9 or ICD-10 CM code I63), and hemorrhagic stroke (ICD-9 CM code 431 or ICD-10 CM code I61), whichever came first. Death of the enrolled subjects was recognized if they had records of death in the NHIRD or they had no claim data in the NHIRD for more than 30 days. Secondary endpoint was the individual component of the primary endpoint. We compared the differences of primary and secondary efficacy endpoint between the two statin intensity groups at the end of 1-year and 3-year follow up. For safety concern of HIS, eligible patients being admitted to hospitals with the diagnosis of myopathy (ICD-9 CM code 729.1, 359.4, 359.8, 359.9 or ICD-10 CM code G72.0) and hepatitis (ICD-9 CM code 573.3 or ICD-10 CM code K71.1) in the follow up after initiating statin therapy were regarded as those with severe statin-related adverse effects. We compared the difference of incidence of statin-related adverse effect between two groups. During follow up, statin discontinuation was defined if there was not any statin refill longer than 90 days. Statin dose reduction was defined as the daily statin dose was reduced than previous refill within 90 days. Statin switch was defined as different statin was used compared with the previous refill within 90 days. Statistical analysis The baseline characteristics, comorbid diseases, and medical histories of each patient were retrieved and analyzed from the data registered in the NHIRD. Continuous variables are presented as means ± standard deviations (SDs) and categorical variables are presented as numbers and percentages. The clinical characteristics of the groups were compared using the chi-square test for categorical variables and student’s t-test for normally distributed continuous variables. Statistical significance was set at p < 0.05 (2-tailed). Multivariate Cox 7
proportional hazards model was used to examine the relationship between endpoint and statin intensity. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated. SAS 9.4 for Windows (SAS Institute Inc., Cary, NC) was used for all data analyses. For propensity match analysis, we conducted a multivariable logistic regression model that predicted statin use in all patients. The propensity score for each patient was calculated from medical comorbidities, demographic characteristics and concurrent use of other cardiovascular-related medications. Propensity score analysis with a matching ratio of 1:4 was used to recalculate the HR and 95% CI of statin use on the study endpoints in a Cox proportional hazards model. Results During the study period, 28878 AMI patients with statin therapy after discharge that fulfilled the inclusion and exclusion criteria were included in this study. Among them, 4402 patients (15.2%) were treated with HIS (Figure 1). Patients in non-HIS group were older and had higher proportion of hypertension, diabetes, hyperlipidemia and peripheral artery disease. Moreover, more patients in non-HIS group received bypass surgery and intra-aortic balloon pumping during the index hospitalization. On the other hand, patients in HIS group were more male and had higher proportion of prescriptions of anti-platelet agents, angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB) and beta-blocker at discharge of hospitalization (Supplemental table S1). All included patients had the follow up data. At the end of 1-year follow-up, 2531 patients (8.8%) met one of the primary composite endpoints: 369 (8.4%) were in the HIS group and 2162 (8.8%) in the non-HIS group (Supplemental table S2). There was no difference in primary endpoint between two groups (adjusted HR: 1.040, 95% CI: 0.930-1.163). In the analysis of secondary endpoint, patients in HIS group had similar incidences of all-cause mortality (adjusted HR: 1.144, 95% CI: 0.996-1.134), myocardial infarction (adjusted HR: 1.071, 95% CI: 0.858-1.338) and hemorrhagic stroke (adjusted HR: 1.287, 95% CI: 0.700-2.364). There was a tendency that 8
patients receiving HIS had a lower incidence of ischemic stroke (adjusted HR: 0.779, 95% CI: 0.606-1.002). After 3-year follow up, the results were similar to the findings of 1-year follow up (Supplemental table S2). There were no differences in the incidence of primary endpoint and most of secondary endpoint. However, patients in HIS group had a lower rate of ischemic stroke (adjusted HR: 0.807, 95% CI: 0.677-0.963). After propensity score 1:4 matching, all 4402 subjects in HIS group and 17608 matched subjects with non-HIS therapy were included for further analysis. Baseline characteristics of two groups were presented in the Table 1. No matter at the end of 1-year or 3-year follow up, there was no difference in primary endpoint between two groups (adjusted HR: 1.026 and 0.975, respectively; 95% CI: 0.915-1.151 and 0.896-1.057, respectively) (Table 2). Additionally, patients in both groups had similar incidence of all-cause mortality, recurrent myocardial infarction, and hemorrhagic stroke in the follow up period. Although there was no difference in the incidence of ischemic stroke between two groups at the end of 1-year follow up, patients in HIS group had a lower rate of ischemic stroke when compared to those in non-HIS group (adjusted HR: 0.803, 95% CI: 0.670-0.961) at 3 year follow up. Subgroup analysis defined by gender and age was conducted for 3-year follow up results. In male patients, there was no difference in the primary and secondary endpoints between HIS and non-HIS groups in the follow up period. On the other hand, female patients had lower ischemic stroke rate at the end of 3-year follow up (adjusted HR: 0.657; 95% CI: 0.449-0.692) (Supplemental table S3). For different age groups, there was no difference in the primary and secondary endpoints between HIS and non-HIS groups (Supplemental table S4). For evaluation of safety of HIS, we compared the rate of hospitalization for myopathy and hepatitis in the follow-up of two groups. At the end of 3-year follow up, there was no difference of hospitalization for myopathy and hepatitis between the two groups (Table 3). In the real-world practice, however, admission is usually not necessary if patients only 9
experience mild statin-associated adverse effects. Clinicians may discontinue statin, taper dosage of original statin or shift to another statin when facing statin-associated adverse effects. Therefore, we further assessed the rates of statin discontinuation, statin dose reduction and statin switch in each group. We found that the statin discontinuation and switch rates were not higher in HIS group. Patients in HIS group only had higher statin dose reduction rate (Table 4). Discussion In the present cohort study of AMI patients in Taiwan who were less than 75 years old and had statin therapy after index hospitalization, HIS was not commonly used and the clinical outcomes after 3-year follow up were similar between patients treated with HIS and non-HIS. HIS did not increase the incidence of severe statin associated adverse events that need admission. LDL-C plays a pivotal role in the development of ASCVD. Most modern lipid guidelines take “treat-to-target” strategy and LDL-C target to less than 70 or 55 mg/dL in high and very high risk population is recommended.20,22,23 These guidelines consider the on-treatment LDL-C level is more closely related to clinical outcomes and HIS is an effective way to reach the LDL-C target.24 One the other hand, 2013 ACC/AHA cholesterol guideline takes “statin intensity” strategy and evokes a new insight in the management of dyslipidemia.10 In patients with clinical ASCVD which is defined as a statin benefit group, ACC/AHA guideline recommends HIS in all patients who are less than or equal to 75 years. Actually, HIS was not commonly used for ASCVD in the real world clinical practice. Among the 8,762 Medicare beneficiaries < 75 years of age in the United States, only 27% received HIS in their first post-discharge fills after hospitalization for a CHD event.25 In 509,766 adult patients (21-84 years) with ASCVD treated in the Veterans Affairs (VA) health care system in the United States, 29.6% received HIS therapy.12 In this outpatient cohort analysis of VA health care system, HIS user was associated with a small but significant reduction of 1-year 10
mortality (adjusted HR: 0.91, 95% CI: 0.88-0.93) compared with moderate-intensity statin.12 However, this mortality benefit of HIS in ASCVD has not been found in previous randomized clinical trials using HIS.26,27 Whether HIS is appropriate for all Asian patients with ASCVD is still questionable. Our study found that Taiwanese AMI patients taking HIS had a similar primary composite endpoint compared with non-HIS therapy in 1- and 3-year follow up. In the Korea AMI Registry, 11,368 AMI patients discharged with statin therapy were analyzed. Among them, HIS was more commonly used in patients with higher baseline LDL-C and the 1-year LDL-C mean levels were similar between HIS and non-HIS groups.28 The composite endpoint of cardiac death, non-fatal myocardial infarction, and repeat revascularization at 1 year was similar between HIS and non-HIS groups. In a registry study from Taiwan, when both statin intensity and achieved LDL-C levels were taken into consideration in patients with stable ASCVD, achieved LDL-C was more significantly associated with clinical outcome than statin intensity.29 Another study in China assessed the difference between high- and moderate-intensity atorvastatin (40 mg/day vs. 20 mg/day) on clinical outcomes in Chinese patients treated with percutaneous coronary intervention (PCI). They found that patients with high-intensity atorvastatin after PCI had lower LDL-C level (68.4 vs. 79.8 mg/dL) and less major adverse cardiovascular events at 1-year follow up.13 A single-center PCI registry study from Korea demonstrated that, in patients that already achieved LDL-C target (time-averaged LDL-C < 70 mg/dL) during follow up, the composite outcome of cardiac death, myocardial infarction, or stroke was significantly lower in patients treated with HIS than non-HIS.30 The mean time-averaged LDL-C levels during follow-up were 59 vs. 62 (p=0.03) in HIS and non-HIS groups. All these data indicate that the on-treatment achieved LDL level is the major predictor of clinical outcomes in ASCVD. It seems that, if similar LDL-C levels can be achieved, the influence of statin intensity alone on prognosis becomes less significant. 11
However, we do find a lower risk of ischemic stroke in HIS group at 3 year follow up. In a real world study of patients with history of ischemic stroke in Korea, HIS was significantly associated with a lower risk of primary composite outcome including recurrent stroke, MI, and all-cause death. Further analysis showed most benefit of HIS came from the risk reduction of recurrent ischemic stroke and mortality.31 In their study, the risk of hemorrhagic stroke was also not increased in HIS group. Since prevention of stroke is especially important in Asia, further large scale randomized clinical trials for Asian patients with HIS should be performed to confirm its effects. Safety consideration is one of the major reasons that prevent prescribing HIS for Asian patients. Higher statin dose is associated with increased risk of myopathy and elevated aminotransferase level.32, 33 Some Asian countries recommends lower statin dose due to the concern of adverse effects20, 34 and the 2013 ACC/AHA guideline also makes cautions to use HIS in Asian patients.10 The incidences of muscle and liver side effects of HIS in Asians were rarely reported. Our study found that the hospitalization rate of myopathy and hepatitis after statin initiation was similar between HIS and non-HIS groups in a 3-year follow up. The result might lessen the safety concern of long-term HIS in Asian patients. In our cohort, the statin dose reduction rate was higher in HIS group, but the statin discontinuation and switch rate were not increased in HIS group. Dose reduction of HIS could be due to some mild side effects of statins. The other possible reason is due to the previous Taiwan NHI reimbursement regulation suggesting statin dose reduction if LDL-C treatment goal is achieved. Based on current scientific evidences, this regulation has been removed. Overall, the discontinuation rate of HIS is < 2% in our cohort. The data indicate that HIS is safe and well-tolerated for Taiwanese patients with AMI. The strength of the present study was that our data derived from a nationwide dataset of NHI which covers almost all 23 million residents in Taiwan. This dataset facilitated the 12
cohort study with sufficient information including diagnoses, health services utilization, prescribed medication and follow up. However, there were several limitations in the present study. First, due to the observational study design, some unmeasured confounding factors could not be ruled out completely. We used propensity score analysis as a matching procedure to balance all observed covariates in HIS and non-HIS groups. This statistical method could reduce the bias and mimic randomization by creating groups that are comparable on all observed covariates. It was appropriately used in our study. Second, there were several exclusion criteria and many AMI patients were excluded from our study. Therefore, the effect of HIS on those excluded patients is unknown. For those AMI > 75 years and patients with recent recurrent AMI, the benefit of HIS needs further study. The influence of HIS versus non-HIS on in-hospital mortality of AMI is also unknown because only patients who survived to discharge were included in our study. Third, the baseline and on-treatment LDL-C levels were not available from the NHIRD, therefore, we could not compare LDL-C levels between groups and evaluate the influence of LDL-C levels on the clinical outcomes. Fourth, we could not exclude the possibility that patients purchase self-paid statins which might result in misclassification of the exposure. Fortunately, this misclassification is less likely because all statins are reimbursable by Taiwan’s NHI and the chance that patients purchase statins themselves is very low. Finally, because of the inherent limitations of NHIRD, we had no information about some individual characteristics, such as smoking status, body weight, and dietary habits, which might contribute to the occurrence of cardiovascular events. Conclusions Our study revealed AMI patients in Taiwan taking HIS had similar clinical outcomes to those treated with non-HIS. Moreover, HIS was not associated with higher rate of severe statin-related adverse effects. The results of our study indicate that using HIS to effectively 13
reduce LDL-C is safe in Taiwan.
Funding Sources This study was funded by Sanofi Taiwan Co. Ltd. The funding organizations had no role in the design, performance, or analysis of this study or decision to submit the manuscript for publication.
Disclosures The authors declare no financial or other conflicts of interest.
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release of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Cholesterol Management Guideline in a Large US Health Plan. J Am Heart Assoc 2017;6:e005205. 16. Dai W, Huang XS, Zhao SP. No evidence to support high-intensity statin in Chinese patients with coronary heart disease. Int J Cardiol 2016;204:57-8. 17. Zhao SP, Yu BL, Peng DQ, Huo Y. The effect of moderate-dose versus double-dose statins on patients with acute coronary syndrome in China: Results of the CHILLAS trial. Atherosclerosis 2014;233:707-12. 18. Liao JK. Safety and efficacy of statins in Asians. Am J Cardiol 2007;99:410-4. 19. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013;34:1279-91. 20. Li YH, Ueng KC, Jeng JS, et al; Writing Group of 2017 Taiwan Lipid Guidelines for High Risk Patients. 2017 Taiwan lipid guidelines for high risk patients. J Formos Med Assoc 2017;116:217-48. 21. Cheng CL, Lee CH, Chen PS, Li YH, Lin SJ, Yang YH. Validation of acute myocardial infarction cases in the National Health Insurance Research Database in Taiwan. J Epidemiol 2014;24:500-7. 22. Mach F, Baigent C, Catapano AL, et al; ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J 2019; Aug 31: https://doi.org/10.1093/eurheartj/ehz455. 23. Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Association of Clinical 17
Enodcrinologists and Amercian College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract 2017;23(Suppl 2):1-87. 24. Li YH, Yeh HI, Jeng JS, Charng MJ. Comparison of the 2017 Taiwan lipid guidelines and the Western lipid guidelines for high risk patients. J Chin Med Assoc 2018;81:853-9. 25. Rosenson RS, Kent ST, Brown TM, et al. Underutilization of high-intensity statin therapy after hospitalization for coronary heart disease. J Am Coll Cardiol 2015;65:270-7. 26. Barter PJ. High- versus low-dose statin: effects on cardiovascular events and all-cause death. Circulation 2018;137:2013-5. 27. Nguyen PV, Biron P. Underutilization of high-intensity statin therapy after hospitalization for coronary heart disease: a cause for concern, but a few words of caution. J Am Coll Cardiol 2015;65:2768-9. 28. Hwang D, Kim HK, Lee JM, et al; KAMIR Investigators. Effects of statin intensity on clinical outcome in acute myocardial infarction patients. Circ J 2018;82:1112-20. 29. Yeh YT, Yin WH, Tseng WK, et al; Taiwanese Secondary Prevention for Patients with AtheRosCLErotic Disease (T-SPARCLE) Registry Investigators. Lipid lowering therapy in patients with atherosclerotic cardiovascular diseases: Which matters in the real world? Statin intensity or low-density lipoprotein cholesterol level? Data from a multicenter registry cohort study in Taiwan. PLoS One 2017;12:e0186861. 30. Kim J, Park KT, Jang MJ, et al. High-intensity versus non-high-intensity statins in patients achieving low-density lipoprotein cholesterol goal after percutaneous coronary intervention. J Am Heart Assoc 2018;7:e009517. 31. Kim J, Lee HS, Nam CM, Heo JH. Effects of statin intensity and adherence on the long-term prognosis after acute ischemic stroke. Stroke 2017;48:2723-30. 32. LaRosa JC, Grundy SM, Waters DD, et al; Treating to New Targets (TNT) Investigators. 18
Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35. 33. Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study. Cardiovasc Drugs Ther 2005;19:403-14. 34. Naito R, Miyauchi K, Daida H. Racial differences in the cholesterol-lowering effect of statin. J Atheroscler Throm 2017;24:19-25.
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Figure legends Figure 1. Flow chart for inclusion and exclusion of study patients.
20
Table 1. Baseline characteristics of AMI patients with and without HIS after propensity score matching Characteristics
HIS therapy (n=4402)
Non-HIS therapy (n=17608)
Male Age (mean ± SD) 18-49 50-64 65-75 Comorbidities Hypertension
3638 (82.6) 57.9 ± 10.1 932 (21.2) 2204 (50.1) 1266 (28.8)
14544 (82.6) 58.1 ± 10.2 3729 (21.2) 8686 (49.3) 5193 (29.5)
Diabetes mellitus Hyperlipidemia Congestive heart failure Peripheral artery disease Atrial fibrillation Chronic obstructive lung disease Malignancy Peptic ulcer disease Chronic kidney disease Interventions during index hospitalization Percutaneous coronary intervention Bypass surgery Intra-aortic balloon pumping Extracorporeal membrane oxygenation
1807 (41.1) 1673 2568 825 121
(38.0) (58.3) (18.7) (2.8)
7606 (43.2)* 6803 10470 3233 476
(38.6) (59.5) (18.4) (2.8)
216 (4.9) 360 (8.2) 139 (3.2)
817 (4.6) 1432 (8.3) 549 (3.1)
472 (10.7) 446 (10.1)
1865 (10.6) 1783 (10.1)
3460 (78.6)
13813 (78.5)
149 (3.4) 222 (5.0) 12 (0.27)
586 (3.3) 918 (5.2) 48 (0.27)
Mechanical ventilation Medications at discharge of index hospitalization Aspirin Clopidogrel ACEi/ARB Beta blockers
367 (8.3)
4233 4188 2227 920
(96.2) (95.1) (50.6) (20.9)
1446 (8.2)
16938 16754 8491 2870
(96.2) (95.2) (48.2)* (16.3)*
ACEi, angiotensin converting enzyme inhibitor; AMI, acute myocardial infarction; ARB, angiotensin receptor blocker; HIS, high-intensity statin. Age was presented as mean ± SD. Other data were presented as N (%); *p<0.05 compared to HIS group
Table 2. Composite endpoint and secondary endpoint in AMI patients with and without HIS therapy after propensity score matching HIS group (n=4402)
Non-HIS group (n=17608)
1-year follow-up Composite end points, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI) All-cause mortality, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI) Myocardial infarction, n (%) Unadjusted HR (95% CI)
369 1.025 1.026 244 1.134 1.124 93 1.055
(8.4) (0.914-1.149) (0.915-1.151) (5.5) (0.984-1.308) (0.974-1.296) (2.1) (0.840-1.326)
1438 (8.2) 1 1 861 (4.9) 1 1 352 (2.0) 1
Adjusted HR (95% CI) Ischemic stroke, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI)
1.046 70 0.797 0.788
(0.831-1.315) (1.6) (0.617-1.030) (0.609-1.019)
1 350 (2.0) 1 1
Hemorrhagic stroke, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI)
13 (0.3) 1.331 (0.710-2.493) 1.289 (0.686-2.421)
39 (0.2) 1 1
3-year follow-up Composite end points, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI)
668 (15.2) 0.972 (0.893-1.057) 0.975 (0.896-1.062)
2749 (15.6) 1 1
All-cause mortality, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI)
485 (11.0) 1.033 (0.935-1.142) 1.033 (0.934-1.142)
1886 (10.7) 1 1
Myocardial infarction, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI) Ischemic stroke, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI) Hemorrhagic stroke, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI)
138 1.062 1.055 143 0.805 0.803 22 0.957 0.934
(3.1) (0.880-1.281) (0.874-1.274) (3.3) (0.672-0.963) (0.670-0.961) (0.5) (0.601-1.524) (0.585-1.489)
520 (3.0) 1 1 708 (4.0) 1 1 92 (0.52) 1 1
AMI, acute myocardial infarction; CI, confidence interval; HIS, high-intensity statin; HR, hazard ratio. Patients in non-HIS group were recognized as reference group. Adjusted variables included sex, age, comorbidities, interventions during index hospitalization and medications at discharge.
Table 3. The rate of hospitalization for hepatitis and myopathy in AMI patients with and without HIS therapy after propensity score matching HIS group (n=4402)
Non-HIS group (n=17608)
1-year follow-up Hepatitis, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI) Myopathy, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI) 3-year follow-up
4 0.639 10.620 4 0.695 0.714
(0.09) (0.222-1.836) (0.215-1.791) (0.09) (0.240-2.008) (0.246-2.068)
25 (0.14) 1 1 23 (0.13) 1 1
Hepatitis, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI) Myopathy, n (%)
13 0.963 0.978 14
(0.30) (0.526-1.765) (0.533-1.794) (0.32)
54 (0.31) 1 1 49 (0.28)
Unadjusted HR (95% CI) Adjusted HR (95% CI)
1.143 (0.631-2.070) 1.128 (0.621-2.047)
1 1
AMI, acute myocardial infarction; CI, confidence interval; HIS, high-intensity statin; HR, hazard ratio. Patients in non-HIS group were recognized as reference group. Adjusted variables included sex, age, comorbidities, interventions during index hospitalization and medications at discharge.
Table 4. The rates of statin discontinuation, statin dose reduction, and statin switch in AMI patients with and without HIS therapy in 3-year follow-up HIS group (n=4402) Statin discontinuation, n (%) Statin dose reduction, n (%) Statin switch, n (%)
85 (1.9) 359 (8.2) 606 (13.8)
AMI, acute myocardial infarction; HIS, high-intensity statin. *p<0.05 compared with HIS group.
Non-HIS group (n=17608) 691 (3.9)* 251 (1.4)* 2491 (14.2)
Figure 1 Patients who were admitted to hospital for acute myocardial infarction (AMI) from January 2010 to December 2013 (n=112318) Patients were excluded 1. were > 75 or < 18 years (n=25745) 2. had AMI within 2 years before enrollment (n=36113) 3. had < 2 days of hospitalization (n=4125) 4. had incomplete registry data (n=990) Patients had new AMI (n=45345) Patients were excluded 1. had less than 2 reimbursement for statin prescription within one year after discharge (n=16467) AMI patients had statin therapy after discharge (n=28878)
AMI patients had high-intensity statin (HIS) therapy (n=4402)
AMI patients had non-HIS therapy (n=24476)
S0828-282X(19)31375-3
DOI:
https://doi.org/10.1016/j.cjca.2019.10.027
Reference:
CJCA 3493
To appear in:
Canadian Journal of Cardiology
Received Date: 9 August 2018 Revised Date:
11 October 2019
Accepted Date: 16 October 2019
Please cite this article as: Chen P-S, Lin S-H, Lee C-H, Lin H-W, Li Y-H, Efficacy and Safety of Highintensity Statins in Patients with Acute Myocardial Infarction: An Asian Perspective, Canadian Journal of Cardiology (2019), doi: https://doi.org/10.1016/j.cjca.2019.10.027. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the Canadian Cardiovascular Society.
Efficacy and Safety of High-intensity Statins in Patients with Acute Myocardial Infarction: An Asian Perspective Running title: Statin Intensity in Acute Myocardial Infarction Po-Sheng Chen, MD,a,b; Sheng-Hsiang Lin, PhD,b,c,d; Cheng-Han Lee, MD, PhD,a,e; Hui-Wen Lin, MSc,c; Yi-Heng Li, MD, PhDa a
Department of Internal Medicine, National Cheng Kung University Hospital, College of
Medicine, National Cheng Kung University, Tainan, Taiwan b
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University,
Tainan, Taiwan c
Biostatistics Consulting Center, National Cheng Kung University Hospital, College of
Medicine, National Cheng Kung University, Tainan, Taiwan d
Department of Public Health, College of Medicine, National Cheng Kung University, Tainan,
Taiwan e
School of Pharmacy and Institute of Clinical Pharmacy and Pharmaceutical Sciences,
College of Medicine, National Cheng Kung University, Tainan, Taiwan
Corresponding author: Yi-Heng Li, MD, PhD, Department of Internal Medicine, National Cheng Kung University Hospital, 138 Sheng Li Road, Tainan 704, Taiwan. Tel: +886-6-2353535 ext 2382; Fax: +886-6-2753834; Email: [email protected]
Word count of text: 4419 Number of tables: 4; Number of figures: 1; Supplemental tables: 4 Key Words: statin, acute myocardial infarction, Asian, adverse effect 1
Brief Summary Little is known about the efficacy and safety of high-intensity statin (HIS) in Asians. In this analysis using Taiwan National Health Insurance Research Database, patients with acute myocardial infarction receiving HIS had similar clinical outcomes to those with non-HIS. HIS did not increase the risk of severe myopathy and hepatitis that need admission. Our findings indicate that HIS therapy for effective reduction of low-density lipoprotein cholesterol is safe in Asians.
2
Abstract Background: 2013 ACC/AHA cholesterol guideline recommends high-intensity statin (HIS) in patients with atherosclerotic cardiovascular disease, but little is known about the efficacy and safety of HIS in Asian ethnicity. We assessed the effects of HIS in Taiwanese with acute myocardial infarction (AMI). Methods: Consecutive patients admitted for new AMI between January 2010 to December 2013 without prior statin use were enrolled from the Taiwan National Health Insurance Research Database. Patients were grouped based on the intensity of statin they took after discharge. The primary endpoint was the composite outcome of all-cause mortality, recurrent myocardial infarction and stroke. We also compared the incidences of severe hepatitis and myopathy that need admission between HIS and non-HIS groups. We used propensity score analysis to match covariates between groups and Cox proportional hazards models with adjustment to estimate the risks of clinical outcomes. Results: After 1:4 propensity score match, there were 4402 patients in HIS group and 17608 patients in non-HIS group. After follow-up for 3 years, 668 (15.2%) in HIS group and 2749 (15.6%) in non-HIS group patients had the primary composite endpoint. Cox proportional-hazards analyses showed that HIS did not further reduce composite endpoint (adjusted HR, 0.975; 95% CI, 0.896-1.062); however, HIS-patients had a lower risk of ischemic stroke at 3-year follow-up. Regarding safety, HIS did not increase hospitalization-rates for severe hepatitis and myopathy. Conclusions: AMI patients in Taiwan with HIS had similar clinical outcomes to those with non-HIS. Using HIS for effective reduction of low-density lipoprotein cholesterol is safe in Taiwan.
3
Statins effectively reduce low-density lipoprotein cholesterol (LDL-C) which is regarded as a key determinant in the development of atherosclerotic cardiovascular disease (ASCVD). Clinical trials and meta-analyses have demonstrated the clinical benefits of statins in primary and secondary prevention of ASCVD,1-6 and current clinical guidelines all recommend statin therapy in high risk patients. High-intensity statin (HIS) is more effective in risk reduction in patients with ASCVD compared with moderate- or low-intensity statin.7-9 Based on results of these studies, the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Cholesterol Guideline and 2018 ACC/AHA updated guideline recommend HIS in patients who are ≤ 75 years with clinical ASCVD.10,11 Several studies validated the clinical benefits of HIS in patients with ASCVD following the recommendation of 2013 ACC/AHA cholesterol guideline12,13 and the prescription rate of HIS for ASCVD patients increased progressively.14,15 However, there are several concerns about using HIS in Asian patients with coronary heart disease (CHD). First, there seemed to be no sufficient data to support the clinical benefits of HIS in Asian population. Few Asian subjects were enrolled in previous studies evaluating clinical efficacy of HIS.16 One prospective, randomized, open-label trial failed to demonstrate more benefits of higher dose atorvastatin (20-40 mg daily) in Chinese patients with acute coronary syndrome.17 Second, Asians are more vulnerable to statin-related adverse effect18, 19 and safety issue is always a major concern of using HIS in Asians population. Current Taiwan Lipid Guideline emphasizes the importance of “treat-to-target”, but not “statin intensity”. Consideration of safety and magnitude of LDL-C lowering in high risk patients, current Taiwan Lipid Guideline recommends either moderate-intensity statin or HIS can be used based on individual clinical characteristic and baseline LDL-C level.20 The Taiwan Lipid Guideline is not specifically in favor of or against HIS use and suggests that titration to the highest recommended or tolerable statin dose to reach the LDL-C target is necessary.20 4
Actually, clinical studies are rare to evaluate whether HIS is more effective in cardiovascular risk reduction or induces more statin-associated hepatitis or myopathy in Asian patients. Therefore, the aims of the present study were to assess (1) whether HIS therapy in Asian patients with acute myocardial infarction (AMI) would be associated with fewer major adverse cardiovascular events compared with low- or moderate-intensity statin and (2) whether HIS therapy in Asian patients would be associated with higher risk of severe hepatitis or myopathy. Methods Data source We used the National Health Insurance Research Database (NHIRD) released by the Taiwan National Health Research Institute for this study. National Health Insurance (NHI), a mandatory-enrollment and single-payment insurance program, is launched since 1995 and provides comprehensive medical care in Taiwan. More than 99% of Taiwan’s 23 million residents are covered by the NHI. In this study, we retrieved data from NHIRD which derived from the claim data of NHI program. The data components of each subject in NHIRD contain demographic characteristic, medical diagnoses, procedures, and prescriptions of all inpatient treatment and outpatient follow-up. For privacy protection, personal information of each subject has been encrypted, but it is feasible to link and follow all the claim data of the same patient in the NHIRD. The Institutional Review Board of the National Cheng Kung University Hospital approved this study (IRB No: A-EX-106-020). Study population We screened all patients who were admitted to hospitals for AMI from January 2010 to December 2013. Patients who survived to discharge with a major discharge diagnosis of AMI (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9 CM] code 410.xx) were included in this study (n=112318). The accuracy of AMI diagnosis based 5
on ICD-9 CM code 410.xx recorded in the NHIRD was validated and the positive predictive value was over 90%.21 Patients were excluded if they: (1) were older than 75 or less than 18 years old (n=25745), (2) had AMI within 2 years before enrollment (n=36113), (3) had < 2 days of hospitalization (n=4125), (4) had incomplete registry data (n=990) and (5) patients having less than 2 prescriptions of statin within the first year after discharge (n=16467). The 2013 ACC/AHA cholesterol guideline suggests HIS for patients with ASCVD who are 75 years of age or younger. In the present study, we would like to validate this recommendation in our AMI patients, therefore, patients who were older than 75 or less than 18 years old were excluded. We also want to enroll patients who do have new AMI during index hospitalization, so the patients who had diagnosis of AMI within 2 years before enrollment were excluded. Short duration of hospitalization less than 2 days might imply that these AMI patients died early or the diagnosis of AMI were doubtful because AMI patients generally had 3 or more days of hospital stay in Taiwan. This group of patients were excluded to ensure the diagnostic accuracy of AMI. Patients with incomplete registry data were excluded because they could not provide correct baseline characteristics. Finally, we also excluded patients who had no or only one reimbursement for statin prescription within one year after discharge because we thought these AMI patients did not receive statin regularly after discharge. Then, we grouped the remaining patients based on the intensity of statin they used. We defined the intensity of statin according to the ACC/AHA cholesterol guidelines.10 Among these eligible subjects, 4402 patients having more than 2 prescriptions of atorvastatin ≥ 40 mg or rosuvastatin ≥ 20 mg daily were recognized as HIS group and the other 24476 patients were regarded as non-HIS group. The flowchart of categorization of subjects was presented in the Figure 1. Study endpoint and follow up All patients were followed up for 3 years since the date of discharge from index hospitalization. ICD-9 CM was replaced by ICD-10 CM for NHI from 2016 in Taiwan. 6
Therefore, both ICD 9 and 10 codes were used to identify efficacy and safety endpoint during follow up. The primary efficacy endpoint was a composite endpoint of all-cause mortality, recurrent myocardial infarction (ICD-9 CM code 410.xx or ICD-10 CM code I21, I22, I23), ischemic stroke (ICD-9 CM code 433, 434, 436, 437.1, 437.9 or ICD-10 CM code I63), and hemorrhagic stroke (ICD-9 CM code 431 or ICD-10 CM code I61), whichever came first. Death of the enrolled subjects was recognized if they had records of death in the NHIRD or they had no claim data in the NHIRD for more than 30 days. Secondary endpoint was the individual component of the primary endpoint. We compared the differences of primary and secondary efficacy endpoint between the two statin intensity groups at the end of 1-year and 3-year follow up. For safety concern of HIS, eligible patients being admitted to hospitals with the diagnosis of myopathy (ICD-9 CM code 729.1, 359.4, 359.8, 359.9 or ICD-10 CM code G72.0) and hepatitis (ICD-9 CM code 573.3 or ICD-10 CM code K71.1) in the follow up after initiating statin therapy were regarded as those with severe statin-related adverse effects. We compared the difference of incidence of statin-related adverse effect between two groups. During follow up, statin discontinuation was defined if there was not any statin refill longer than 90 days. Statin dose reduction was defined as the daily statin dose was reduced than previous refill within 90 days. Statin switch was defined as different statin was used compared with the previous refill within 90 days. Statistical analysis The baseline characteristics, comorbid diseases, and medical histories of each patient were retrieved and analyzed from the data registered in the NHIRD. Continuous variables are presented as means ± standard deviations (SDs) and categorical variables are presented as numbers and percentages. The clinical characteristics of the groups were compared using the chi-square test for categorical variables and student’s t-test for normally distributed continuous variables. Statistical significance was set at p < 0.05 (2-tailed). Multivariate Cox 7
proportional hazards model was used to examine the relationship between endpoint and statin intensity. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated. SAS 9.4 for Windows (SAS Institute Inc., Cary, NC) was used for all data analyses. For propensity match analysis, we conducted a multivariable logistic regression model that predicted statin use in all patients. The propensity score for each patient was calculated from medical comorbidities, demographic characteristics and concurrent use of other cardiovascular-related medications. Propensity score analysis with a matching ratio of 1:4 was used to recalculate the HR and 95% CI of statin use on the study endpoints in a Cox proportional hazards model. Results During the study period, 28878 AMI patients with statin therapy after discharge that fulfilled the inclusion and exclusion criteria were included in this study. Among them, 4402 patients (15.2%) were treated with HIS (Figure 1). Patients in non-HIS group were older and had higher proportion of hypertension, diabetes, hyperlipidemia and peripheral artery disease. Moreover, more patients in non-HIS group received bypass surgery and intra-aortic balloon pumping during the index hospitalization. On the other hand, patients in HIS group were more male and had higher proportion of prescriptions of anti-platelet agents, angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB) and beta-blocker at discharge of hospitalization (Supplemental table S1). All included patients had the follow up data. At the end of 1-year follow-up, 2531 patients (8.8%) met one of the primary composite endpoints: 369 (8.4%) were in the HIS group and 2162 (8.8%) in the non-HIS group (Supplemental table S2). There was no difference in primary endpoint between two groups (adjusted HR: 1.040, 95% CI: 0.930-1.163). In the analysis of secondary endpoint, patients in HIS group had similar incidences of all-cause mortality (adjusted HR: 1.144, 95% CI: 0.996-1.134), myocardial infarction (adjusted HR: 1.071, 95% CI: 0.858-1.338) and hemorrhagic stroke (adjusted HR: 1.287, 95% CI: 0.700-2.364). There was a tendency that 8
patients receiving HIS had a lower incidence of ischemic stroke (adjusted HR: 0.779, 95% CI: 0.606-1.002). After 3-year follow up, the results were similar to the findings of 1-year follow up (Supplemental table S2). There were no differences in the incidence of primary endpoint and most of secondary endpoint. However, patients in HIS group had a lower rate of ischemic stroke (adjusted HR: 0.807, 95% CI: 0.677-0.963). After propensity score 1:4 matching, all 4402 subjects in HIS group and 17608 matched subjects with non-HIS therapy were included for further analysis. Baseline characteristics of two groups were presented in the Table 1. No matter at the end of 1-year or 3-year follow up, there was no difference in primary endpoint between two groups (adjusted HR: 1.026 and 0.975, respectively; 95% CI: 0.915-1.151 and 0.896-1.057, respectively) (Table 2). Additionally, patients in both groups had similar incidence of all-cause mortality, recurrent myocardial infarction, and hemorrhagic stroke in the follow up period. Although there was no difference in the incidence of ischemic stroke between two groups at the end of 1-year follow up, patients in HIS group had a lower rate of ischemic stroke when compared to those in non-HIS group (adjusted HR: 0.803, 95% CI: 0.670-0.961) at 3 year follow up. Subgroup analysis defined by gender and age was conducted for 3-year follow up results. In male patients, there was no difference in the primary and secondary endpoints between HIS and non-HIS groups in the follow up period. On the other hand, female patients had lower ischemic stroke rate at the end of 3-year follow up (adjusted HR: 0.657; 95% CI: 0.449-0.692) (Supplemental table S3). For different age groups, there was no difference in the primary and secondary endpoints between HIS and non-HIS groups (Supplemental table S4). For evaluation of safety of HIS, we compared the rate of hospitalization for myopathy and hepatitis in the follow-up of two groups. At the end of 3-year follow up, there was no difference of hospitalization for myopathy and hepatitis between the two groups (Table 3). In the real-world practice, however, admission is usually not necessary if patients only 9
experience mild statin-associated adverse effects. Clinicians may discontinue statin, taper dosage of original statin or shift to another statin when facing statin-associated adverse effects. Therefore, we further assessed the rates of statin discontinuation, statin dose reduction and statin switch in each group. We found that the statin discontinuation and switch rates were not higher in HIS group. Patients in HIS group only had higher statin dose reduction rate (Table 4). Discussion In the present cohort study of AMI patients in Taiwan who were less than 75 years old and had statin therapy after index hospitalization, HIS was not commonly used and the clinical outcomes after 3-year follow up were similar between patients treated with HIS and non-HIS. HIS did not increase the incidence of severe statin associated adverse events that need admission. LDL-C plays a pivotal role in the development of ASCVD. Most modern lipid guidelines take “treat-to-target” strategy and LDL-C target to less than 70 or 55 mg/dL in high and very high risk population is recommended.20,22,23 These guidelines consider the on-treatment LDL-C level is more closely related to clinical outcomes and HIS is an effective way to reach the LDL-C target.24 One the other hand, 2013 ACC/AHA cholesterol guideline takes “statin intensity” strategy and evokes a new insight in the management of dyslipidemia.10 In patients with clinical ASCVD which is defined as a statin benefit group, ACC/AHA guideline recommends HIS in all patients who are less than or equal to 75 years. Actually, HIS was not commonly used for ASCVD in the real world clinical practice. Among the 8,762 Medicare beneficiaries < 75 years of age in the United States, only 27% received HIS in their first post-discharge fills after hospitalization for a CHD event.25 In 509,766 adult patients (21-84 years) with ASCVD treated in the Veterans Affairs (VA) health care system in the United States, 29.6% received HIS therapy.12 In this outpatient cohort analysis of VA health care system, HIS user was associated with a small but significant reduction of 1-year 10
mortality (adjusted HR: 0.91, 95% CI: 0.88-0.93) compared with moderate-intensity statin.12 However, this mortality benefit of HIS in ASCVD has not been found in previous randomized clinical trials using HIS.26,27 Whether HIS is appropriate for all Asian patients with ASCVD is still questionable. Our study found that Taiwanese AMI patients taking HIS had a similar primary composite endpoint compared with non-HIS therapy in 1- and 3-year follow up. In the Korea AMI Registry, 11,368 AMI patients discharged with statin therapy were analyzed. Among them, HIS was more commonly used in patients with higher baseline LDL-C and the 1-year LDL-C mean levels were similar between HIS and non-HIS groups.28 The composite endpoint of cardiac death, non-fatal myocardial infarction, and repeat revascularization at 1 year was similar between HIS and non-HIS groups. In a registry study from Taiwan, when both statin intensity and achieved LDL-C levels were taken into consideration in patients with stable ASCVD, achieved LDL-C was more significantly associated with clinical outcome than statin intensity.29 Another study in China assessed the difference between high- and moderate-intensity atorvastatin (40 mg/day vs. 20 mg/day) on clinical outcomes in Chinese patients treated with percutaneous coronary intervention (PCI). They found that patients with high-intensity atorvastatin after PCI had lower LDL-C level (68.4 vs. 79.8 mg/dL) and less major adverse cardiovascular events at 1-year follow up.13 A single-center PCI registry study from Korea demonstrated that, in patients that already achieved LDL-C target (time-averaged LDL-C < 70 mg/dL) during follow up, the composite outcome of cardiac death, myocardial infarction, or stroke was significantly lower in patients treated with HIS than non-HIS.30 The mean time-averaged LDL-C levels during follow-up were 59 vs. 62 (p=0.03) in HIS and non-HIS groups. All these data indicate that the on-treatment achieved LDL level is the major predictor of clinical outcomes in ASCVD. It seems that, if similar LDL-C levels can be achieved, the influence of statin intensity alone on prognosis becomes less significant. 11
However, we do find a lower risk of ischemic stroke in HIS group at 3 year follow up. In a real world study of patients with history of ischemic stroke in Korea, HIS was significantly associated with a lower risk of primary composite outcome including recurrent stroke, MI, and all-cause death. Further analysis showed most benefit of HIS came from the risk reduction of recurrent ischemic stroke and mortality.31 In their study, the risk of hemorrhagic stroke was also not increased in HIS group. Since prevention of stroke is especially important in Asia, further large scale randomized clinical trials for Asian patients with HIS should be performed to confirm its effects. Safety consideration is one of the major reasons that prevent prescribing HIS for Asian patients. Higher statin dose is associated with increased risk of myopathy and elevated aminotransferase level.32, 33 Some Asian countries recommends lower statin dose due to the concern of adverse effects20, 34 and the 2013 ACC/AHA guideline also makes cautions to use HIS in Asian patients.10 The incidences of muscle and liver side effects of HIS in Asians were rarely reported. Our study found that the hospitalization rate of myopathy and hepatitis after statin initiation was similar between HIS and non-HIS groups in a 3-year follow up. The result might lessen the safety concern of long-term HIS in Asian patients. In our cohort, the statin dose reduction rate was higher in HIS group, but the statin discontinuation and switch rate were not increased in HIS group. Dose reduction of HIS could be due to some mild side effects of statins. The other possible reason is due to the previous Taiwan NHI reimbursement regulation suggesting statin dose reduction if LDL-C treatment goal is achieved. Based on current scientific evidences, this regulation has been removed. Overall, the discontinuation rate of HIS is < 2% in our cohort. The data indicate that HIS is safe and well-tolerated for Taiwanese patients with AMI. The strength of the present study was that our data derived from a nationwide dataset of NHI which covers almost all 23 million residents in Taiwan. This dataset facilitated the 12
cohort study with sufficient information including diagnoses, health services utilization, prescribed medication and follow up. However, there were several limitations in the present study. First, due to the observational study design, some unmeasured confounding factors could not be ruled out completely. We used propensity score analysis as a matching procedure to balance all observed covariates in HIS and non-HIS groups. This statistical method could reduce the bias and mimic randomization by creating groups that are comparable on all observed covariates. It was appropriately used in our study. Second, there were several exclusion criteria and many AMI patients were excluded from our study. Therefore, the effect of HIS on those excluded patients is unknown. For those AMI > 75 years and patients with recent recurrent AMI, the benefit of HIS needs further study. The influence of HIS versus non-HIS on in-hospital mortality of AMI is also unknown because only patients who survived to discharge were included in our study. Third, the baseline and on-treatment LDL-C levels were not available from the NHIRD, therefore, we could not compare LDL-C levels between groups and evaluate the influence of LDL-C levels on the clinical outcomes. Fourth, we could not exclude the possibility that patients purchase self-paid statins which might result in misclassification of the exposure. Fortunately, this misclassification is less likely because all statins are reimbursable by Taiwan’s NHI and the chance that patients purchase statins themselves is very low. Finally, because of the inherent limitations of NHIRD, we had no information about some individual characteristics, such as smoking status, body weight, and dietary habits, which might contribute to the occurrence of cardiovascular events. Conclusions Our study revealed AMI patients in Taiwan taking HIS had similar clinical outcomes to those treated with non-HIS. Moreover, HIS was not associated with higher rate of severe statin-related adverse effects. The results of our study indicate that using HIS to effectively 13
reduce LDL-C is safe in Taiwan.
Funding Sources This study was funded by Sanofi Taiwan Co. Ltd. The funding organizations had no role in the design, performance, or analysis of this study or decision to submit the manuscript for publication.
Disclosures The authors declare no financial or other conflicts of interest.
14
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release of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Cholesterol Management Guideline in a Large US Health Plan. J Am Heart Assoc 2017;6:e005205. 16. Dai W, Huang XS, Zhao SP. No evidence to support high-intensity statin in Chinese patients with coronary heart disease. Int J Cardiol 2016;204:57-8. 17. Zhao SP, Yu BL, Peng DQ, Huo Y. The effect of moderate-dose versus double-dose statins on patients with acute coronary syndrome in China: Results of the CHILLAS trial. Atherosclerosis 2014;233:707-12. 18. Liao JK. Safety and efficacy of statins in Asians. Am J Cardiol 2007;99:410-4. 19. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013;34:1279-91. 20. Li YH, Ueng KC, Jeng JS, et al; Writing Group of 2017 Taiwan Lipid Guidelines for High Risk Patients. 2017 Taiwan lipid guidelines for high risk patients. J Formos Med Assoc 2017;116:217-48. 21. Cheng CL, Lee CH, Chen PS, Li YH, Lin SJ, Yang YH. Validation of acute myocardial infarction cases in the National Health Insurance Research Database in Taiwan. J Epidemiol 2014;24:500-7. 22. Mach F, Baigent C, Catapano AL, et al; ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J 2019; Aug 31: https://doi.org/10.1093/eurheartj/ehz455. 23. Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Association of Clinical 17
Enodcrinologists and Amercian College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract 2017;23(Suppl 2):1-87. 24. Li YH, Yeh HI, Jeng JS, Charng MJ. Comparison of the 2017 Taiwan lipid guidelines and the Western lipid guidelines for high risk patients. J Chin Med Assoc 2018;81:853-9. 25. Rosenson RS, Kent ST, Brown TM, et al. Underutilization of high-intensity statin therapy after hospitalization for coronary heart disease. J Am Coll Cardiol 2015;65:270-7. 26. Barter PJ. High- versus low-dose statin: effects on cardiovascular events and all-cause death. Circulation 2018;137:2013-5. 27. Nguyen PV, Biron P. Underutilization of high-intensity statin therapy after hospitalization for coronary heart disease: a cause for concern, but a few words of caution. J Am Coll Cardiol 2015;65:2768-9. 28. Hwang D, Kim HK, Lee JM, et al; KAMIR Investigators. Effects of statin intensity on clinical outcome in acute myocardial infarction patients. Circ J 2018;82:1112-20. 29. Yeh YT, Yin WH, Tseng WK, et al; Taiwanese Secondary Prevention for Patients with AtheRosCLErotic Disease (T-SPARCLE) Registry Investigators. Lipid lowering therapy in patients with atherosclerotic cardiovascular diseases: Which matters in the real world? Statin intensity or low-density lipoprotein cholesterol level? Data from a multicenter registry cohort study in Taiwan. PLoS One 2017;12:e0186861. 30. Kim J, Park KT, Jang MJ, et al. High-intensity versus non-high-intensity statins in patients achieving low-density lipoprotein cholesterol goal after percutaneous coronary intervention. J Am Heart Assoc 2018;7:e009517. 31. Kim J, Lee HS, Nam CM, Heo JH. Effects of statin intensity and adherence on the long-term prognosis after acute ischemic stroke. Stroke 2017;48:2723-30. 32. LaRosa JC, Grundy SM, Waters DD, et al; Treating to New Targets (TNT) Investigators. 18
Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35. 33. Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study. Cardiovasc Drugs Ther 2005;19:403-14. 34. Naito R, Miyauchi K, Daida H. Racial differences in the cholesterol-lowering effect of statin. J Atheroscler Throm 2017;24:19-25.
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Figure legends Figure 1. Flow chart for inclusion and exclusion of study patients.
20
Table 1. Baseline characteristics of AMI patients with and without HIS after propensity score matching Characteristics
HIS therapy (n=4402)
Non-HIS therapy (n=17608)
Male Age (mean ± SD) 18-49 50-64 65-75 Comorbidities Hypertension
3638 (82.6) 57.9 ± 10.1 932 (21.2) 2204 (50.1) 1266 (28.8)
14544 (82.6) 58.1 ± 10.2 3729 (21.2) 8686 (49.3) 5193 (29.5)
Diabetes mellitus Hyperlipidemia Congestive heart failure Peripheral artery disease Atrial fibrillation Chronic obstructive lung disease Malignancy Peptic ulcer disease Chronic kidney disease Interventions during index hospitalization Percutaneous coronary intervention Bypass surgery Intra-aortic balloon pumping Extracorporeal membrane oxygenation
1807 (41.1) 1673 2568 825 121
(38.0) (58.3) (18.7) (2.8)
7606 (43.2)* 6803 10470 3233 476
(38.6) (59.5) (18.4) (2.8)
216 (4.9) 360 (8.2) 139 (3.2)
817 (4.6) 1432 (8.3) 549 (3.1)
472 (10.7) 446 (10.1)
1865 (10.6) 1783 (10.1)
3460 (78.6)
13813 (78.5)
149 (3.4) 222 (5.0) 12 (0.27)
586 (3.3) 918 (5.2) 48 (0.27)
Mechanical ventilation Medications at discharge of index hospitalization Aspirin Clopidogrel ACEi/ARB Beta blockers
367 (8.3)
4233 4188 2227 920
(96.2) (95.1) (50.6) (20.9)
1446 (8.2)
16938 16754 8491 2870
(96.2) (95.2) (48.2)* (16.3)*
ACEi, angiotensin converting enzyme inhibitor; AMI, acute myocardial infarction; ARB, angiotensin receptor blocker; HIS, high-intensity statin. Age was presented as mean ± SD. Other data were presented as N (%); *p<0.05 compared to HIS group
Table 2. Composite endpoint and secondary endpoint in AMI patients with and without HIS therapy after propensity score matching HIS group (n=4402)
Non-HIS group (n=17608)
1-year follow-up Composite end points, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI) All-cause mortality, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI) Myocardial infarction, n (%) Unadjusted HR (95% CI)
369 1.025 1.026 244 1.134 1.124 93 1.055
(8.4) (0.914-1.149) (0.915-1.151) (5.5) (0.984-1.308) (0.974-1.296) (2.1) (0.840-1.326)
1438 (8.2) 1 1 861 (4.9) 1 1 352 (2.0) 1
Adjusted HR (95% CI) Ischemic stroke, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI)
1.046 70 0.797 0.788
(0.831-1.315) (1.6) (0.617-1.030) (0.609-1.019)
1 350 (2.0) 1 1
Hemorrhagic stroke, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI)
13 (0.3) 1.331 (0.710-2.493) 1.289 (0.686-2.421)
39 (0.2) 1 1
3-year follow-up Composite end points, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI)
668 (15.2) 0.972 (0.893-1.057) 0.975 (0.896-1.062)
2749 (15.6) 1 1
All-cause mortality, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI)
485 (11.0) 1.033 (0.935-1.142) 1.033 (0.934-1.142)
1886 (10.7) 1 1
Myocardial infarction, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI) Ischemic stroke, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI) Hemorrhagic stroke, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI)
138 1.062 1.055 143 0.805 0.803 22 0.957 0.934
(3.1) (0.880-1.281) (0.874-1.274) (3.3) (0.672-0.963) (0.670-0.961) (0.5) (0.601-1.524) (0.585-1.489)
520 (3.0) 1 1 708 (4.0) 1 1 92 (0.52) 1 1
AMI, acute myocardial infarction; CI, confidence interval; HIS, high-intensity statin; HR, hazard ratio. Patients in non-HIS group were recognized as reference group. Adjusted variables included sex, age, comorbidities, interventions during index hospitalization and medications at discharge.
Table 3. The rate of hospitalization for hepatitis and myopathy in AMI patients with and without HIS therapy after propensity score matching HIS group (n=4402)
Non-HIS group (n=17608)
1-year follow-up Hepatitis, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI) Myopathy, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI) 3-year follow-up
4 0.639 10.620 4 0.695 0.714
(0.09) (0.222-1.836) (0.215-1.791) (0.09) (0.240-2.008) (0.246-2.068)
25 (0.14) 1 1 23 (0.13) 1 1
Hepatitis, n (%) Unadjusted HR (95% CI) Adjusted HR (95% CI) Myopathy, n (%)
13 0.963 0.978 14
(0.30) (0.526-1.765) (0.533-1.794) (0.32)
54 (0.31) 1 1 49 (0.28)
Unadjusted HR (95% CI) Adjusted HR (95% CI)
1.143 (0.631-2.070) 1.128 (0.621-2.047)
1 1
AMI, acute myocardial infarction; CI, confidence interval; HIS, high-intensity statin; HR, hazard ratio. Patients in non-HIS group were recognized as reference group. Adjusted variables included sex, age, comorbidities, interventions during index hospitalization and medications at discharge.
Table 4. The rates of statin discontinuation, statin dose reduction, and statin switch in AMI patients with and without HIS therapy in 3-year follow-up HIS group (n=4402) Statin discontinuation, n (%) Statin dose reduction, n (%) Statin switch, n (%)
85 (1.9) 359 (8.2) 606 (13.8)
AMI, acute myocardial infarction; HIS, high-intensity statin. *p<0.05 compared with HIS group.
Non-HIS group (n=17608) 691 (3.9)* 251 (1.4)* 2491 (14.2)
Figure 1 Patients who were admitted to hospital for acute myocardial infarction (AMI) from January 2010 to December 2013 (n=112318) Patients were excluded 1. were > 75 or < 18 years (n=25745) 2. had AMI within 2 years before enrollment (n=36113) 3. had < 2 days of hospitalization (n=4125) 4. had incomplete registry data (n=990) Patients had new AMI (n=45345) Patients were excluded 1. had less than 2 reimbursement for statin prescription within one year after discharge (n=16467) AMI patients had statin therapy after discharge (n=28878)
AMI patients had high-intensity statin (HIS) therapy (n=4402)
AMI patients had non-HIS therapy (n=24476)