- Email: [email protected]
Discontinuation of statin therapy due to muscular side effects: A survey in real life
Nutrition, Metabolism & Cardiovascular Diseases (2013) 23, 871e875
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/nmcd
SHORT COMMUNICATION
Discontinuation of statin therapy due to muscular side effects: A survey in real life D. Rosenbaum a,b,*, J. Dallongeville c, P. Sabouret d, E. Bruckert a,b a Unite´ de Pre´vention Cardiovasculaire, Service d’Endocrinologie Me´tabolisme, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Assistance Publique-Hoˆpitaux de Paris, France b UPMC Universite´ Paris 06, UMR S 939, F-75013, France c Inserm, U744, Institut Pasteur de Lille, Universite´ Lille Nord de France, UDSL, Lille, France d Institut du Coeur, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Assistance Publique-Hoˆpitaux de Paris, France
Received 22 December 2011; received in revised form 20 April 2012; accepted 25 April 2012 Available online 29 June 2012
KEYWORDS Statins; Muscular symptoms; Side effects; Real life survey; Dyslipidemia
Abstract Backgrounds and aims: To assess the burden of statin related muscular symptom in real life. Methods and results: We conducted a wide survey on 10,409 French subjects. Among these, 2850 (27%) had hypercholesterolemia and 1074 were treated with statins. Muscular symptoms were reported by 104 (10%) statin treated patients and led to discontinuation in 30% of the symptomatic patients. The main prescribed statins were low doses rosuvastatin, atorvastatin and simvastatin. Pains were the most commonly described symptoms (87%) but many patients also reported stiffness (62%), cramps (67%), weakness or a loss of strength during exertion (55%). Pain was localized in 70% but mostly described as affecting several muscular groups. Approximately 38% of patients reported that their symptoms prevented even moderate exertion during everyday activities, while 42% of patients suffered major disruption to their everyday life. Conclusion: Muscular symptoms associated with average dosage statin therapy are more frequent than in clinical trials and have a greater impact on patients’ life than usually thought. ª 2012 Elsevier B.V. All rights reserved.
* Corresponding author. Unite ´ de Pre ´vention Cardiovasculaire, Service d’Endocrinologie Me ´tabolisme, Po ˆle Cardiologie-Me ´tabolisme, Groupe Hospitalier Pitie ´-Salpe ˆtrie `re, Assistance Publique-Ho ˆpitaux de Paris, 83, boulevard de l’Ho ˆpital, 75651 Paris Cedex 13, France. Tel.: þ33 1 42 17 78 41; fax: þ33 1 42 17 78 50. E-mail address: [email protected] (D. Rosenbaum). 0939-4753/$ - see front matter ª 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2012.04.012
872
D. Rosenbaum et al.
Introduction
Statistical analysis
After more than 20 years of statin therapy with millions of patients having been treated worldwide, large trials and extensive post-marketing experience have shown that longterm statin therapy is generally well tolerated and associated with a substantial decrease in cardiovascular events [1,2,3]. In randomized clinical trials, the incidence of severe myopathy is very low (less than 0.1% of patients receiving statin monotherapy) [1,2]. Conversely, mild symptoms are far more frequent, with up to 7% of outpatients complaining of muscle pain [4,5] with large differences across trials. As a cause of treatment discontinuation, the potential clinical impact of mild muscular side effects of statin treatment should not be underestimated [6]. Despite the wide utilization of statin to prevent cardiovascular disease, there is a paucity of data assessing muscular symptoms in real life and unselected patients. Given the more aggressive approach to lipid lowering therapy advocated by recent treatment guidelines [7] and as the incidence of muscular side effects with statin therapy increases with statin dosage [8] a better understanding of the nature and frequency of statin muscular side effects is of considerable importance. We therefore conducted a telephone interview in the general population to characterize the rate and impact of statin associated muscular symptoms.
Different groups of patients were formed to analyzed differences between symptoms description, onset, permanence and tolerance according to gender, age (35e49, 50e64 and more than 65 years old), living area (rural/ urban, France areas), socioeconomic class and weekly exercise habits (none, >once a week, about once or twice week or more than twice a week). These groups were compared between using a two sided exact Fisher test with a p considered significant when <0.05.
Material and methods Study design and population The study was an observational telephone survey conducted in a large, unselected population throughout France. The number of patients selected was based on an estimated 10% incidence of muscular side effects. Each subject was contacted by telephone between December 2009 and January 2010. They were included in the survey if they were 35 years old or more had been prescribed statin therapy and had experience muscular pain. Patients were excluded if they were receiving statin treatment as part of a clinical trial or if they were included in any other study. This study complies with the Declaration of Helsinki of the World Medical Association. All patients gave informed consent and the study was conducted in accordance with the French Data Protection Authority (Commission Nationale Informatique et Liberte ´).
Results Overall 10,409 subjects were contacted through telephone interview. Among these subjects 2850 (27%) were having hypercholesterolemia and 1074 were treated with statin. Muscular symptoms were reported by 104 patients (10%) on statin therapy when asked “if they were currently having or previously had any muscular symptoms or pain related to the cholesterol treatment”. Among patients with muscular symptoms, 31 (30%) declared having stopped their medication. Demographic characteristics for subjects with muscular symptoms are presented in Table 1. The main prescribed statins were rosuvastatin, atorvastatin and simvastatin at low doses (5 mg for rosuvastatin, 10 mg for atorvastatin and 20 mg for simvastatin). Overall 22% of the symptomatic patients were treated with high dose statin: rosuvastatin 20 mg, atorvastatin > 10 mg and simvastatin, fluvastatin or pravastatin 40 mg and 2% reported being under another lipid lowering therapy. The distribution of times of onset for muscular symptoms showed an onset of symptoms more than 1month after the beginning of the treatment in 62% of the patients. Pains were the most commonly described muscular symptom (87%) but many patients also reported stiffness (62%) or cramps (67%), weakness or a loss of strength during exertion (55%) as seen in Fig. 1. Pain was widespread in 20% of patients and localized in 70% but mostly described as affecting several muscular groups. Tendonitis-associated
Table 1 Description of subjects with statin related muscular symptoms in France in December 2009. Patients with muscular complains N (%) Age e years old
Data collection
Gender
Information was recorded during a phone call. If muscular symptoms under a statin treatment were reported, a questionnaire on demographic data, lifestyle, personal and family medical history and current cardiovascular status was completed by the investigators also providing information on the type, location and duration of the symptoms. The choice of items included in the questionnaires was guided by previous clinical trials and post-marketing surveillance data.
Secondary prevention Diabetes Hypertension Physical activity
35e49 50e64 >65 Male Female 17 (16) 17 (16) 55 (53) None <1/week 1e2/week >2/week
5 (5) 49 (47) 50 (48) 51 (49) 53 (51)
21 17 24 42
(20) (16) (23) (40)
Discontinuation of statin therapy due to muscular side effects
Figure 1 Statin related muscular symptoms (in %) as described by 104 French subjects in December 2009 (sarcopenia equals to loss of muscular mass during treatment).
pain was reported by almost a half of patients, and it affected multiple tendons in more than half of cases. Muscular pain was continuous in about half of the patients who reported muscular symptoms, and was associated with exertion in 46% of patients reporting intermittent pain. Approximately 38% of patients reported that their muscular symptoms prevented even moderate physical exercise during everyday activities, while 42% of patients suffered major disruption to their everyday life (being confined to bed or unable to work) due to muscular pain. Subjects with no physical activity reported significantly less cramps but more joint pain than those exercising once a week (36% vs. 87% p < 0.001) or more (89%, p < 0.01). Tendonitis was more frequent in people less than 64 years old (60% vs. 39%, p Z 0.04). Retired and inactive people expressed more all kind of symptoms than those working. Women reported less sarcopenia (i.e. decrease of muscular mass) than men (35.2% vs. 15% p Z 0.02) but more permanent pain (60% vs.35%, p Z 0.01).
Discussion This study provides a large-scale investigation into the occurrence, nature and impact of muscular symptoms in patients prescribed statin therapy in real life. The rate of occurrence of muscular symptoms in patients receiving statin therapy (10%) was higher than in clinical trials [9] but our population had similar symptoms frequency as compared to previous studies and a similar distribution across statin as compared to French treated patients [10]. Such striking differences with clinical trials might be explained by 1) exclusion of high-risk patients, such as patients with a history of muscular symptoms or creatine kinase elevations, 2) lack of reporting of mild symptoms such as pain after exercise and 3) by run-in phases that tend to eliminate problem patients likely to develop myopathy in short term clinical trials. In contrast, our finding, are similar to previous study conducted in real life practice [6] such as in the PRIMO study [11] where 10.5% of patients on
873 high-dosage statin therapy complained of muscle pain. It is a well known fact that statin side effects are dose-related but despite the low doses prescribed in our population, symptoms had a significant impact on everyday life. In the present study, symptoms were most commonly manifested as heaviness, stiffness or cramps thus confirming observations made in a preliminary study [12]. Self reported side effects occurred for 62% patients after the first month of intake as in PRIMO and may be explained by 1) a delayed diagnosis or by 2) the time needed for the cell to be depleted in sarcomeral cholesterol, CoQ10 or isoprenoid which are plausible mechanisms of statin myopathy. Statin related muscular side effects were more present in older people. This finding confirms previous report, which identified age and low body mass index to be risk factors for statin-induced myopathy [12,13]. It can be postulate that elder patients more likely have other conditions that can interfere with statin metabolism (such as renal insufficiency) or mimic statin muscular side effects and that statin pharmacokinetics is different in this population. Also it is possible that some elder patients have inherent isoprenoid or CoQ10 depletion [14] and decrease sarcomeral cholesterol. Importantly, the results of our study indicate that muscular symptoms associated with average dosage statin therapy may have a greater impact on the everyday life of patients than was previously reported. Thus, muscular pain was continuous in 48% of patients. Moreover, 38% of patients reported that their muscular symptoms prevented even moderate exertion during everyday activities, while 42% of patients suffered major disruption to their everyday life. These findings are of considerable importance, because patients who experience adverse events during statin treatment are more likely to discontinue therapy [6]. Indeed, poor patient compliance is a major issue for statin therapy; a study showed that more than half of elderly patients initiating treatment may receive no or limited benefit from statins due to premature discontinuation [15]. According to the French medical agency (Haute Autorite ´ de Sante ´) 37% of patients under statin do not reach LDL targets and up to 60% of patients are not compliant [10,16]. Attitudes of physicians regarding statin therapy, which were not assessed in our study because of its design, could have been proposed to maintain statin therapy in intolerant patients: prescribe statin every other day or twice a week [17,18], consider an association with ezetimibe and/or Vitamin D supplementation [19]. The study has limitations. As this was an observational study, randomization did not take place leading to an inevitable imbalance in sample size between groups and there was no control group in this study. With regard to the causal relationship between statin treatment and muscular symptoms, the questionnaires relied upon the chronological occurrence of statin treatment and muscular pain and no questions were asked about any current conditions that may induce muscular pain (such as hypothyroidism, hypokalaemia, vitamin D deficiency or about any history of CK elevation). Symptoms were self described and no actual medical data was collected to support the patients’ claims. Due to the design of the study, no data are available neither on who gave the suggestion to stop the medication nor on what the changes in blood lipid were. Methods for assigning
874 causal probabilities to drug-induced events, such as the Naranjo algorithm, were not used. Furthermore, the lack of control group and the relatively small size of symptomatic patients group did not allow us to correlates side effects and the prescribed statins. The strength of our study is the systematic and anonymous interview without interference of the patients’ general practitioner. Despite the fact that statins have been available for nearly 30 years, the exact frequency of their muscular side effects is still unknown. All study designs have their flaws and limitations: placebo controlled studies give results that may greatly differs from real life practice, short term studies don’t evaluate side effects that might appear after longer period of statin intake. Poor statin compliance is a major issue, which can lead to increase cardiovascular mortality. The only way to better answer the difficult question of statin side effects is to gather data from studies with different design. Our results show that muscular side effects occur in approximately 10% of patients treated with statins with a significant proportion of subjects who declared having stopped their medication for this reason. More evidence will be available when detailed results from the STOMP study will be published [20] but early presented results of this randomized study showed, as in our work, a 10% increase in muscular side effects under statin treatment.
Conclusions In a real life broad observational survey on 10,409 French subjects, muscular symptoms were reported by 10% of statin treated patients. More than a third of them claimed that their symptoms prevented moderate exertion or everyday life although they were treated with average dosage statin therapy. Our study highlights the fact that statins have a greater impact than usually thought.
Acknowledgments The study was supported by an unrestricted grant to the new French Society of Atherosclerosis by Merck Sharp Dohme. Merck Sharp Dohme had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; nor in the decision to submit the paper for publication. Pierre Sabouret has had a financial arrangement with the organizations listed below: Assistance-publique des Ho ˆpitaux de Paris (APHP) for the Endpoint Comittee for ATTOLL trial, consulting fees for Lilly and Novartis, oral presentations for Merck-Sharp and Dhome-Chibret, Sanofi-Aventis, Bristol-Myers Squibb, Ipsen, Pfizer. David Rosenbaum has received fees for presentations and travel compensations from: Daiichi-Sankyo, Pfizer, Takeda, AstraZeneca, Novartis, Ipsen, Menarini, MerckSharp Dhome and Sanofi-Aventis. Eric Bruckert has received fees for presentations and participation to boards: Merck, Pfizer, Astra Zeneca, Abott, California Almond Board, Unilever, Danone, Sanofi-Avantis, MSD, Shering Plough, Servier, Genfit, AMT and NovoNordisk. Jean Dallongeville has received fees for research, presentations and participation to boards for Astra Zeneca,
D. Rosenbaum et al. Danone, Merck Sharpe & Dohme, Novartis, Pfizer and Sanofi-Aventis.
References [1] Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. The New England Journal of Medicine 1998;339:1349e1357. [2] Pedersen TR, Kjekshus J, Berg K, Haghfelt T, Faergeman O, Faergeman G, et al. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383e9. [3] Bonovas S, Nikolopoulos G, Sitaras NM. Efficacy and safety of more intensive lowering of LDL cholesterol. Lancet 2011;377: 715e6. 715; author reply. [4] Bertolini S, Bon GB, Campbell LM, Farnier M, Langan J, Mahla G, et al. Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia. Atherosclerosis 1997;130:191e7. [5] Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. The New England Journal of Medicine 2002; 346:539e40. [6] Lambrecht LJ, Malini PL. Efficacy and tolerability of simvastatin 20 mg vs pravastatin 20 mg in patients with primary hypercholesterolemia. European Study Group. Acta Cardiologica 1993;48:541e54. [7] Ballantyne CM, Corsini A, Davidson MH, Holdaas H, Jacobson TA, Leitersdorf E, et al. Risk for myopathy with statin therapy in high-risk patients. Archives of Internal Medicine 2003;163:553e64. [8] Sinzinger H, Wolfram R, Peskar BA. Muscular side effects of statins. Journal of Cardiovascular Pharmacology 2002;40: 163e71. [9] Franc S, Dejager S, Bruckert E, Chauvenet M, Giral P, Turpin G. A comprehensive description of muscle symptoms associated with lipid-lowering drugs. Cardiovascular Drugs and Therapy/Sponsored by the International Society of Cardiovascular Pharmacotherapy 2003;17:459e65. [10] Haute Autorite ´ de Sante ´. Efficacite ´ et efficience des hypolipe ´miants: une analyse centre ´e sur les statines. Juillet; 2010. [11] Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patientsethe PRIMO study. Cardiovascular Drugs and Therapy/Sponsored by the International Society of Cardiovascular Pharmacotherapy 2005;19:403e14. [12] Abd TT, Jacobson TA. Statin-induced myopathy: a review and update. Expert Opinion on Drug Safety 2011;10:373e87. [13] Pasternak RC, Smith Jr SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation 2002;106:1024e8. [14] Chatzizisis YS, Vaklavas C, Giannoglou GD. Coenzyme Q10 depletion: etiopathogenic or predisposing factor in statin associated myopathy? The American Journal of Cardiology 2008;101:1071. [15] Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA: the Journal of the American Medical Association 2002;288:462e7. [16] Johnson SS, Paiva AL, Cummins CO, et al. Transtheoretical model-based multiple behavior intervention for weight management: effectiveness on a population basis. Preventive Medicine 2008;46:238e46. [17] Gadarla M, Kearns AK, Thompson PD. Efficacy of rosuvastatin (5 mg and 10 mg) twice a week in patients intolerant to daily statins. The American Journal of Cardiology 2008;101:1747e8.
Discontinuation of statin therapy due to muscular side effects [18] Athyros VG, Tziomalos K, Kakafika AI, Koumaras H, Karagiannis A, Mikhailidis DP. Effectiveness of ezetimibe alone or in combination with twice a week atorvastatin (10 mg) for statin intolerant high-risk patients. The American Journal of Cardiology 2008;101:483e5. [19] Glueck CJ, Budhani SB, Masineni SS, Abuchaibe C, Khan N, Wang P, et al. Vitamin D deficiency, myositis-myalgia, and
875 reversible statin intolerance. Current Medical Research and Opinion 2011;27:1683e90. [20] Thompson PD, Parker BA, Clarkson PM, et al. A randomized clinical trial to assess the effect of statins on skeletal muscle function and performance: rationale and study design. Preventive Cardiology 2010;13: 104e11.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/nmcd
SHORT COMMUNICATION
Discontinuation of statin therapy due to muscular side effects: A survey in real life D. Rosenbaum a,b,*, J. Dallongeville c, P. Sabouret d, E. Bruckert a,b a Unite´ de Pre´vention Cardiovasculaire, Service d’Endocrinologie Me´tabolisme, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Assistance Publique-Hoˆpitaux de Paris, France b UPMC Universite´ Paris 06, UMR S 939, F-75013, France c Inserm, U744, Institut Pasteur de Lille, Universite´ Lille Nord de France, UDSL, Lille, France d Institut du Coeur, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Assistance Publique-Hoˆpitaux de Paris, France
Received 22 December 2011; received in revised form 20 April 2012; accepted 25 April 2012 Available online 29 June 2012
KEYWORDS Statins; Muscular symptoms; Side effects; Real life survey; Dyslipidemia
Abstract Backgrounds and aims: To assess the burden of statin related muscular symptom in real life. Methods and results: We conducted a wide survey on 10,409 French subjects. Among these, 2850 (27%) had hypercholesterolemia and 1074 were treated with statins. Muscular symptoms were reported by 104 (10%) statin treated patients and led to discontinuation in 30% of the symptomatic patients. The main prescribed statins were low doses rosuvastatin, atorvastatin and simvastatin. Pains were the most commonly described symptoms (87%) but many patients also reported stiffness (62%), cramps (67%), weakness or a loss of strength during exertion (55%). Pain was localized in 70% but mostly described as affecting several muscular groups. Approximately 38% of patients reported that their symptoms prevented even moderate exertion during everyday activities, while 42% of patients suffered major disruption to their everyday life. Conclusion: Muscular symptoms associated with average dosage statin therapy are more frequent than in clinical trials and have a greater impact on patients’ life than usually thought. ª 2012 Elsevier B.V. All rights reserved.
* Corresponding author. Unite ´ de Pre ´vention Cardiovasculaire, Service d’Endocrinologie Me ´tabolisme, Po ˆle Cardiologie-Me ´tabolisme, Groupe Hospitalier Pitie ´-Salpe ˆtrie `re, Assistance Publique-Ho ˆpitaux de Paris, 83, boulevard de l’Ho ˆpital, 75651 Paris Cedex 13, France. Tel.: þ33 1 42 17 78 41; fax: þ33 1 42 17 78 50. E-mail address: [email protected] (D. Rosenbaum). 0939-4753/$ - see front matter ª 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2012.04.012
872
D. Rosenbaum et al.
Introduction
Statistical analysis
After more than 20 years of statin therapy with millions of patients having been treated worldwide, large trials and extensive post-marketing experience have shown that longterm statin therapy is generally well tolerated and associated with a substantial decrease in cardiovascular events [1,2,3]. In randomized clinical trials, the incidence of severe myopathy is very low (less than 0.1% of patients receiving statin monotherapy) [1,2]. Conversely, mild symptoms are far more frequent, with up to 7% of outpatients complaining of muscle pain [4,5] with large differences across trials. As a cause of treatment discontinuation, the potential clinical impact of mild muscular side effects of statin treatment should not be underestimated [6]. Despite the wide utilization of statin to prevent cardiovascular disease, there is a paucity of data assessing muscular symptoms in real life and unselected patients. Given the more aggressive approach to lipid lowering therapy advocated by recent treatment guidelines [7] and as the incidence of muscular side effects with statin therapy increases with statin dosage [8] a better understanding of the nature and frequency of statin muscular side effects is of considerable importance. We therefore conducted a telephone interview in the general population to characterize the rate and impact of statin associated muscular symptoms.
Different groups of patients were formed to analyzed differences between symptoms description, onset, permanence and tolerance according to gender, age (35e49, 50e64 and more than 65 years old), living area (rural/ urban, France areas), socioeconomic class and weekly exercise habits (none, >once a week, about once or twice week or more than twice a week). These groups were compared between using a two sided exact Fisher test with a p considered significant when <0.05.
Material and methods Study design and population The study was an observational telephone survey conducted in a large, unselected population throughout France. The number of patients selected was based on an estimated 10% incidence of muscular side effects. Each subject was contacted by telephone between December 2009 and January 2010. They were included in the survey if they were 35 years old or more had been prescribed statin therapy and had experience muscular pain. Patients were excluded if they were receiving statin treatment as part of a clinical trial or if they were included in any other study. This study complies with the Declaration of Helsinki of the World Medical Association. All patients gave informed consent and the study was conducted in accordance with the French Data Protection Authority (Commission Nationale Informatique et Liberte ´).
Results Overall 10,409 subjects were contacted through telephone interview. Among these subjects 2850 (27%) were having hypercholesterolemia and 1074 were treated with statin. Muscular symptoms were reported by 104 patients (10%) on statin therapy when asked “if they were currently having or previously had any muscular symptoms or pain related to the cholesterol treatment”. Among patients with muscular symptoms, 31 (30%) declared having stopped their medication. Demographic characteristics for subjects with muscular symptoms are presented in Table 1. The main prescribed statins were rosuvastatin, atorvastatin and simvastatin at low doses (5 mg for rosuvastatin, 10 mg for atorvastatin and 20 mg for simvastatin). Overall 22% of the symptomatic patients were treated with high dose statin: rosuvastatin 20 mg, atorvastatin > 10 mg and simvastatin, fluvastatin or pravastatin 40 mg and 2% reported being under another lipid lowering therapy. The distribution of times of onset for muscular symptoms showed an onset of symptoms more than 1month after the beginning of the treatment in 62% of the patients. Pains were the most commonly described muscular symptom (87%) but many patients also reported stiffness (62%) or cramps (67%), weakness or a loss of strength during exertion (55%) as seen in Fig. 1. Pain was widespread in 20% of patients and localized in 70% but mostly described as affecting several muscular groups. Tendonitis-associated
Table 1 Description of subjects with statin related muscular symptoms in France in December 2009. Patients with muscular complains N (%) Age e years old
Data collection
Gender
Information was recorded during a phone call. If muscular symptoms under a statin treatment were reported, a questionnaire on demographic data, lifestyle, personal and family medical history and current cardiovascular status was completed by the investigators also providing information on the type, location and duration of the symptoms. The choice of items included in the questionnaires was guided by previous clinical trials and post-marketing surveillance data.
Secondary prevention Diabetes Hypertension Physical activity
35e49 50e64 >65 Male Female 17 (16) 17 (16) 55 (53) None <1/week 1e2/week >2/week
5 (5) 49 (47) 50 (48) 51 (49) 53 (51)
21 17 24 42
(20) (16) (23) (40)
Discontinuation of statin therapy due to muscular side effects
Figure 1 Statin related muscular symptoms (in %) as described by 104 French subjects in December 2009 (sarcopenia equals to loss of muscular mass during treatment).
pain was reported by almost a half of patients, and it affected multiple tendons in more than half of cases. Muscular pain was continuous in about half of the patients who reported muscular symptoms, and was associated with exertion in 46% of patients reporting intermittent pain. Approximately 38% of patients reported that their muscular symptoms prevented even moderate physical exercise during everyday activities, while 42% of patients suffered major disruption to their everyday life (being confined to bed or unable to work) due to muscular pain. Subjects with no physical activity reported significantly less cramps but more joint pain than those exercising once a week (36% vs. 87% p < 0.001) or more (89%, p < 0.01). Tendonitis was more frequent in people less than 64 years old (60% vs. 39%, p Z 0.04). Retired and inactive people expressed more all kind of symptoms than those working. Women reported less sarcopenia (i.e. decrease of muscular mass) than men (35.2% vs. 15% p Z 0.02) but more permanent pain (60% vs.35%, p Z 0.01).
Discussion This study provides a large-scale investigation into the occurrence, nature and impact of muscular symptoms in patients prescribed statin therapy in real life. The rate of occurrence of muscular symptoms in patients receiving statin therapy (10%) was higher than in clinical trials [9] but our population had similar symptoms frequency as compared to previous studies and a similar distribution across statin as compared to French treated patients [10]. Such striking differences with clinical trials might be explained by 1) exclusion of high-risk patients, such as patients with a history of muscular symptoms or creatine kinase elevations, 2) lack of reporting of mild symptoms such as pain after exercise and 3) by run-in phases that tend to eliminate problem patients likely to develop myopathy in short term clinical trials. In contrast, our finding, are similar to previous study conducted in real life practice [6] such as in the PRIMO study [11] where 10.5% of patients on
873 high-dosage statin therapy complained of muscle pain. It is a well known fact that statin side effects are dose-related but despite the low doses prescribed in our population, symptoms had a significant impact on everyday life. In the present study, symptoms were most commonly manifested as heaviness, stiffness or cramps thus confirming observations made in a preliminary study [12]. Self reported side effects occurred for 62% patients after the first month of intake as in PRIMO and may be explained by 1) a delayed diagnosis or by 2) the time needed for the cell to be depleted in sarcomeral cholesterol, CoQ10 or isoprenoid which are plausible mechanisms of statin myopathy. Statin related muscular side effects were more present in older people. This finding confirms previous report, which identified age and low body mass index to be risk factors for statin-induced myopathy [12,13]. It can be postulate that elder patients more likely have other conditions that can interfere with statin metabolism (such as renal insufficiency) or mimic statin muscular side effects and that statin pharmacokinetics is different in this population. Also it is possible that some elder patients have inherent isoprenoid or CoQ10 depletion [14] and decrease sarcomeral cholesterol. Importantly, the results of our study indicate that muscular symptoms associated with average dosage statin therapy may have a greater impact on the everyday life of patients than was previously reported. Thus, muscular pain was continuous in 48% of patients. Moreover, 38% of patients reported that their muscular symptoms prevented even moderate exertion during everyday activities, while 42% of patients suffered major disruption to their everyday life. These findings are of considerable importance, because patients who experience adverse events during statin treatment are more likely to discontinue therapy [6]. Indeed, poor patient compliance is a major issue for statin therapy; a study showed that more than half of elderly patients initiating treatment may receive no or limited benefit from statins due to premature discontinuation [15]. According to the French medical agency (Haute Autorite ´ de Sante ´) 37% of patients under statin do not reach LDL targets and up to 60% of patients are not compliant [10,16]. Attitudes of physicians regarding statin therapy, which were not assessed in our study because of its design, could have been proposed to maintain statin therapy in intolerant patients: prescribe statin every other day or twice a week [17,18], consider an association with ezetimibe and/or Vitamin D supplementation [19]. The study has limitations. As this was an observational study, randomization did not take place leading to an inevitable imbalance in sample size between groups and there was no control group in this study. With regard to the causal relationship between statin treatment and muscular symptoms, the questionnaires relied upon the chronological occurrence of statin treatment and muscular pain and no questions were asked about any current conditions that may induce muscular pain (such as hypothyroidism, hypokalaemia, vitamin D deficiency or about any history of CK elevation). Symptoms were self described and no actual medical data was collected to support the patients’ claims. Due to the design of the study, no data are available neither on who gave the suggestion to stop the medication nor on what the changes in blood lipid were. Methods for assigning
874 causal probabilities to drug-induced events, such as the Naranjo algorithm, were not used. Furthermore, the lack of control group and the relatively small size of symptomatic patients group did not allow us to correlates side effects and the prescribed statins. The strength of our study is the systematic and anonymous interview without interference of the patients’ general practitioner. Despite the fact that statins have been available for nearly 30 years, the exact frequency of their muscular side effects is still unknown. All study designs have their flaws and limitations: placebo controlled studies give results that may greatly differs from real life practice, short term studies don’t evaluate side effects that might appear after longer period of statin intake. Poor statin compliance is a major issue, which can lead to increase cardiovascular mortality. The only way to better answer the difficult question of statin side effects is to gather data from studies with different design. Our results show that muscular side effects occur in approximately 10% of patients treated with statins with a significant proportion of subjects who declared having stopped their medication for this reason. More evidence will be available when detailed results from the STOMP study will be published [20] but early presented results of this randomized study showed, as in our work, a 10% increase in muscular side effects under statin treatment.
Conclusions In a real life broad observational survey on 10,409 French subjects, muscular symptoms were reported by 10% of statin treated patients. More than a third of them claimed that their symptoms prevented moderate exertion or everyday life although they were treated with average dosage statin therapy. Our study highlights the fact that statins have a greater impact than usually thought.
Acknowledgments The study was supported by an unrestricted grant to the new French Society of Atherosclerosis by Merck Sharp Dohme. Merck Sharp Dohme had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; nor in the decision to submit the paper for publication. Pierre Sabouret has had a financial arrangement with the organizations listed below: Assistance-publique des Ho ˆpitaux de Paris (APHP) for the Endpoint Comittee for ATTOLL trial, consulting fees for Lilly and Novartis, oral presentations for Merck-Sharp and Dhome-Chibret, Sanofi-Aventis, Bristol-Myers Squibb, Ipsen, Pfizer. David Rosenbaum has received fees for presentations and travel compensations from: Daiichi-Sankyo, Pfizer, Takeda, AstraZeneca, Novartis, Ipsen, Menarini, MerckSharp Dhome and Sanofi-Aventis. Eric Bruckert has received fees for presentations and participation to boards: Merck, Pfizer, Astra Zeneca, Abott, California Almond Board, Unilever, Danone, Sanofi-Avantis, MSD, Shering Plough, Servier, Genfit, AMT and NovoNordisk. Jean Dallongeville has received fees for research, presentations and participation to boards for Astra Zeneca,
D. Rosenbaum et al. Danone, Merck Sharpe & Dohme, Novartis, Pfizer and Sanofi-Aventis.
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