Niki Katsiki, MSc, PhD, MD, FRSPH
Daskalopoulou SS, Doonan RJ, Delaney JA, Pilote L. Different patterns of statin use in patients with acute myocardial infarction [published online September 18, 2012]. Curr Vasc Pharmacol.
Adherence to statin therapy in clinical practice is low, with 1-year discontinuation rates ranging from 30% to 55% in the United States and Canada. The aim of the study by Daskalopoulou and colleagues was to investigate the relationship between different patterns of statin use post—acute myocardial infarction (AMI) and 1-year all-cause mortality in a realworld setting. The possible impact of age and gender was also evaluated.
Daskalopoulou et al1 conducted a population- based cohort study of post-AMI patients surviving for ≥90 days. Data ere selected from the hospital discharge summary database (Med-Echo) and the provincial physician and drug claims database of Quebec, Canada (Régie de l’Assurance Maladie du Québec [RAMQ]). Inclusion criteria were admission for AMI between April 1, 2000 and March 31, 2007, survival ≥90 days post-discharge, and insurance with the RAMQ. Exclusion criteria included age >105 years, noncardiac surgical admission, transfer from another acute care facility, AMI coded as an in-hospital complication, and AMI admission within the past year. Patients who were not insured with RAMQ 100% of the time during the 90 days pre-AMI and 90 days postdischarge were also excluded.1 AMI patients were divided into 4 groups according to statin use: 1) did not receive statins pre- or post-AMI (nonusers), 2) started taking statins post-AMI (starters), 3) received statins pre-AMI but stopped taking them post-AMI (stoppers), and 4) received statins preand continued post-AMI (users).1 Statin use pre-AMI was defined by having filled a statin prescription in the 90 days pre- AMI; post-AMI statin use was having filled a statin prescription between discharge from hospital post-AMI and 90 days post-discharge.
Overall 48,229 patients who survived an AMI for ≥90 days were included (mean age, 70.1 ± 12.6 y): 11,657 (24%) nonusers, 22,452 (47%) starters, 488 (1%) stoppers, and 13,632 (28%) users.1 The median follow-up was 274 days.
Statin starters and users had a lower risk of all-cause mortality post-AMI, whereas statin stoppers had an increased risk compared with nonusers in age- and gender-adjusted models (hazard ratio [HR], 0.42, 95% CI, 0.39-0.46; HR, 0.80; 95% CI, 0.73-0.86; and HR, 1.60; 95% CI, 1.28-2.00, respectively).1 These associations remained significant after adjustment for all covariates (HR, 0.65; 95% CI, 0.59-0.71; HR, 0.81; 95% CI, 0.74-0.88; and HR, 1.36; 95% CI, 1.08- 1.70 for starters, users, and stoppers, respectively).
Similar results were obtained when patients ≥65 years were separately analyzed, whereas for those <65 years as well as for men and women, the above relationships were significant only for starters and users. 1 In adjusted models including age and gender interactions, the only association that was significant was the one between age and starters (ie, the higher the age, the lower the benefit of initiating a statin [P = 0.0009]). Stopping β-blockers, aspirin, or proton pump inhibitors after the AMI was not related to increased 1-year all-cause mortality in analyses that were adjusted for all covariates.
The authors concluded that statin discontinuation post-AMI can be more harmful than never taking statins, possibly representing a risk-treatment mismatch or a biological rebound phenomenon. Therefore, physicians should not withdraw statins and should reinforce adherence, especially post-AMI.1 There is also a need to determine such associations for other lipid-lowering drugs or combination therapies.
1. Daskalopoulou SS, Doonan RJ, Delaney JA, Pilote L. Different patterns of statin use in patients with acute myocardial infarction [published online September 18, 2012]. Curr Vasc Pharmacol. 2012 Sep 18.
2. Simpson RJ Jr, Mendys P. The effects of adherence and persistence on clinical outcomes in patients treated with statins: a systematic review. J Clin Lipidol. 2010;4:462-471.
3. Liberopoulos EN, Florentin M, Mikhailidis DP, Elisaf MS. Compliance with lipid-lowering therapy and its impact on cardiovascular morbidity and mortality. Expert Opin Drug Saf. 2008;7:717-725.
4. Fu AZ, Zhang Q, Davies MJ, Pentakota SR, Radican L, Seck T. Underutilization of statins in patients with type 2 diabetes in US clinical practice: a retrospective cohort study. Curr Med Res Opin. 2011;27:1035-1040.
5. Simons LA, Ortiz M, Calcino G. Long term persistence with statin therapy--experience in Australia 2006-2010. Aust Fam Physician. 2011;40:319-322.
6. Ko DT, Mamdani M, Alter DA. Lipid-lowering therapy with statins in high-risk elderly patients: the treatment-risk paradox. JAMA. 2004;291:1864-1870.
7. Daskalopoulou SS, Delaney JA, Filion KB, Brophy JM, Mayo NE, Suissa S. Discontinuation of statin therapy following an acute myocardial infarction: a population-based study. Eur Heart J. 2008;29:2083-2091.
8. Tziomalos K, Athyros VG, Mikhailidis DP. Statin discontinuation: an underestimated risk? Curr Med Res Opin. 2008;24:3059-3062.
9. Gomez Sandoval YH, Braganza MV, Daskalopoulou SS. Statin discontinuation in highrisk patients: a systematic review of the evidence. Curr Pharm Des. 2011;17:3669-3689.
10. Pineda A, Cubeddu LX. Statin rebound or withdrawal syndrome: does it exist? Curr Atheroscler Rep. 2011;13:23-30.
11. Daskalopoulou SS. When statin therapy stops: implications for the patient. Curr Opin Cardiol. 2009;24:454-460.
12. JasiÅ„ska-Stroschein M, Owczarek J, Wejman I, Orszulak-Michalak D. Novel mechanistic and clinical implications concerning the safety of statin discontinuation. Pharmacol Rep. 2011;63:867-879.
13. Puccetti L, Pasqui AL, Scarpini F, et al. Statins discontinuation in compliant chronic users induces atherothrombotic profile despite baseline clinical setting and treatments. Int J Cardiol. 2011;153:328-329.
14. Tziomalos K, Athyros VG, Karagiannis A, Mikhailidis DP. Management of statin-intolerant high-risk patients. Curr Vasc Pharmacol. 2010;8:632-637.
15. Gazi IF, Daskalopoulou SS, Nair DR, Mikhailidis DP. Effect of ezetimibe in patients who cannot tolerate statins or cannot get to the low density lipoprotein cholesterol target despite taking a statin. Curr Med Res Opin. 2007;23:2183-2192.
16. Wierzbicki AS, Mikhailidis DP, Wray R, et al. Statin-fibrate combination: therapy for hyperlipidemia: a review. Curr Med Res Opin. 2003;19:155-168.
17. Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. Dyslipidaemia of obesity, metabolic syndrome and type 2 diabetes mellitus: the case for residual risk reduction after statin treatment. Open Cardiovasc Med J. 2011;5:24-34.
18. Handelsman Y, Fonseca V, Rosenstock J. Is combination therapy an effective way of reaching lipid goals in type 2 diabetes mellitus? Expert Rev Clin Pharmacol. 2012;5:43-54.
19. Davidson MH, Stein EA, Bays HE, et al; COMBination of prescription Omega-3 with Simvastatin (COMBOS) Investigators. Efficacy and tolerability of adding prescription omega- 3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study. Clin Ther. 2007;29:1354-1367.
20. Kennedy SP, Barnas GP, Schmidt MJ, Glisczinski MS, Paniagua AC. Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance. J Clin Lipidol. 2011;5:308-315.
21. Florentin M, Elisaf MS, Mikhailidis DP, Liberopoulos EN. Vitamin D and metabolic syndrome: is there a link? Curr Pharm Des. 2010;16:3417-3434.
22. Katsiki N, Athyros VG, Karagiannis A, Mikhailidis DP. Vitamin D deficiency, statinrelated myopathy and other links with vascular risk. Curr Med Res Opin. 2011;27:1691-1692.
23. Athyros VG, Tziomalos K, Gossios TD, et al; GREACE Study Collaborative Group. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet. 2010;376:1916-1922.
24. Athyros VG, Giouleme O, Ganotakis ES, et al. Safety and impact on cardiovascular events of long-term multifactorial treatment in patients with metabolic syndrome and abnormal liver function tests: a post hoc analysis of the randomised ATTEMPT study. Arch Med Sci. 2011;7:796-805.
25. Katsiki N, Athyros VG, Karagiannis A, Mikhailidis DP. Hyperuricaemia and non-alcoholic fatty liver disease (NAFLD): a relationship with implications for vascular risk? Curr Vasc Pharmacol. 2011;9:698-705.
26. Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia. 2012;55:885-904.
27. Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769-1818.
28. Genest J, McPherson R, Frohlich J, et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult--2009 recommendations. Can J Cardiol. 2009; 25:567-579.
29. Athyros VG, Mikhailidis DP, Liberopoulos EN, et al. Effect of statin treatment on renal function and serum uric acid levels and their relation to vascular events in patients with coronary heart disease and metabolic syndrome: a subgroup analysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study. Nephrol Dial Transplant. 2007;22:118-127.
30. Athyros VG, Karagiannis A, Ganotakis ES, et al; Assessing The Treatment Effect in Metabolic syndrome without Perceptible diabeTes (ATTEMPT) Collaborative Group. Association between the changes in renal function and serum uric acid levels during multifactorial intervention and clinical outcome in patients with metabolic syndrome: a post hoc analysis of the ATTEMPT study. Curr Med Res Opin. 2011;27:1659-1668.
31. Kalaitzidis RG, Elisaf MS. The role of statins in chronic kidney disease. Am J Nephrol. 2011;34:195-202.
32. Campese VM, Ku E, Bigazzi R, Bianchi S. Do HMG-CoA reductase inhibitors improve kidney function? The saga continues. J Nephrol. 2011;24:550-553.
33. Takagi H, Umemoto T. A meta-analysis of randomized trials for effects of atorvastatin on renal function in chronic kidney disease. Int J Cardiol. 2011;152:242-244.
34. Wong MC, Jiang JY, Griffiths SM. Adherence to lipid-lowering agents among 11,042 patients in clinical practice. Int J Clin Pract. 2011;65(7):741-748.
35. Karagiannis A, Hatzitolios AI, Athyros VG, et al. Implementation of guidelines for the management of arterial hypertension. The impulsion study. Open Cardiovasc Med J. 2009;3:26-34.
36. Hatzitolios AI, Athyros VG, Karagiannis A, et al; IMPROVE Collaborative Group. Implementation of strategy for the management of overt dyslipidemia: the IMPROVE-dyslipidemia study. Int J Cardiol. 2009;134:322-329.
37. Athyros VG, Hatzitolios A, Karagiannis A, et al; INDEED Collaborative Group. Initiative for a new diabetes therapeutic approach in a Mediterranean country: the INDEED study. Curr Med Res Opin. 2009;25:1931-1940.
More Evidence on Statins’ Benefit
As discussed by Daskalopoulou et al,1 better adherence and longer statin treatment duration are associated with beneficial outcomes.2,3 Unfortunately, compliance with statins represents an important problem in clinical practice. In this context, in a recent US retrospective cohort study (n = 125,464), more than onethird of patients with type 2 diabetes who were eligible for statins did not receive one during follow-up; 13% of these patients were on a statin at baseline.4 Similarly, in Australian patients who were started on a statin, 23% of the study population did not refill their prescription at the first month; statin discontinuation within 6 months was observed in 43% of the patients.5 Furthermore, median persistence time was <1 year for the total population (n = 77,867), 3 to 6 months for patients aged <55 years, and 19 months for those aged 65 to 74 years.5 Paradoxically, statin discontinuation occurs most frequently in high-risk patients—those who will benefit most from their use—thus representing a risk-treatment mismatch. 6-8 In this context, a recent systematic review found that high-risk patients who were nonadherent to statins or stopped taking them experienced significantly more cardiovascular (CV) and cerebrovascular events, and had significantly increased all-cause mortality than statin users in both primary and secondary prevention settings.9 These detrimental effects of statin discontinuation particularly occur when statins are stopped after acute vascular events10 and are also observed in comparison with never-users, possibly representing a rebound phenomenon.11 Indeed, statin cessation has been associated with endothelial dysfunction,
increases in inflammatory [eg, C-reactive protein and vascular cell adhesion molecule 1], prothrombotic [eg, plasminogen activator inhibitor type-1 and platelet activity], and oxidative stress markers [eg, thiobarbituric acid reactive substance and ferric-reducing ability of plasma], and angiotensin II type 1 up-regulation and increased isoprenoids. 12-13
Therefore, physicians should encourage persistent statin treatment. In this context, in statin-intolerant patients the use of combinations of lower statin doses with other lipidreducing drugs14 including ezetimibe,15 fibrates,16 niacin,17 colesevelam,18 and Omacor (in the presence of hypertriglyceridemia), 19 may be beneficial. Administering a statin (especially statins with a long half-life) on a less-than-daily basis could be another option.20 However, these options require event-based evidence.
Vitamin D deficiency has been implicated in elevated vascular risk.21 Interestingly, vitamin D supplementation in deficient patients with statin-induced myopathy may represent a potential option for use in tackling statin intolerance. 22
A well-known contraindication for statin use is raised transaminases levels (greater than 3 times the upper limit of normal). However, post hoc analyses of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study23 and the Assessing The Treatment Effect in Metabolic Syndrome without Perceptible Diabetes (ATTEMPT) study24 showed that patients with moderately abnormal liver tests at baseline (<3 times the upper limit of normal), possibly due to non-alcoholic fatty liver disease (NAFLD), benefited more from statin therapy in terms of both CV risk reduction and liver function improvement compared with those with normal liver tests.
Furthermore, non-alcoholic fatty liver disease, a common hepatic disorder linked to increased CV risk,25 may be improved by several measures including lifestyle intervention26 and insulin sensitizers such as metformin.26 Consequently, physicians should evaluate transaminases on the basis of the recent evidence before discontinuing a statin. Another issue would be the selection of a kidney-friendly statin in cases of chronic kidney disease (CKD) in order to avoid potential adverse effects. CKD, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2, is associated with increased CV risk.27,28 Statins were shown to improve renal function (assessed by increases in eGFR) in the GREACE study,29 the ATTEMPT study,30 and several other trials.31,32 However, conflicting data also exist,33,32 except with respect to atorvastatin, which was found to exert renoprotective effects in a recent meta-analysis.33
Patient participation (particularly an awareness of why the statin is needed) may contribute to achieving medication adherence. Optimal follow-up time rather than “fire and forget” will lead to better compliance.
In this context, it was recently shown that older age, co-morbidities, follow-up visits, and attendance in specialist clinics were related to optimal lipid-lowering drug adherence.34 Furthermore, continuing education, including printed guidelines and brochures, as well as attendance at scientific meetings, was found to motivate physicians and patients to implement guidelines in clinical practice, thus achieving multiple CV risk factor goals (eg, control of hypertension, dyslipidemia, and diabetes).35-37 This treatment strategy also reinforces patient awareness.
In conclusion, statin discontinuation is linked to harmful CV effects, an issue that needs to be more widely appreciated by both physicians and patients. Measures to deal with statin intolerance (eg, combinations of statins at lower dose with other lipid-reducing drugs, vitamin D supplementation in vitamin D-deficient patients, and NAFLD treatment) may contribute to better compliance. Continuing education will reinforce the awareness of statin treatment efficacy and safety.
About the Authors
Niki Katsiki, MSC, PhD, MD, FRSPH, is a specialist in internal medicine and a researcher at the Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece. Her clinical and research interests involve cardiovascular disease prevention and treatment, with a special focus on dyslipidemias. Dr Katsiki serves as a reviewer for several cardiovascular journals and is the editorial manager of Angiology and section editor of Archives of Medical Science. She was assisted in the writing of this article by Dimitri P. Mikhailidis, BSc, MSc, MD, FRSPH, FCP, FFPM, FRCP, FRCPath, Academic Head of the Department of Clinical Biochemistry (Vascular Disease Prevention Clinics),and Department of Surgery, Royal Free Campus, University College London Medical School, UCL, London, UK. He is Editor-in-Chief of several journals including Current Medical Research and Opinion, Current Vascular Pharmacology, and Expert Opinion on Pharmacotherapy.