Mild to Moderate Muscular Symptoms with High-Dosage Statin Therapy in Hyperlipidemic Patients The PRIMO Study

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1 Cardiovascular Drugs and Therapy C 2006 Springer Science + Business Media, Inc. Manufactured in The Netherlands. DOI: /s z Mild to Moderate Muscular Symptoms with High-Dosage Statin Therapy in Hyperlipidemic Patients The PRIMO Study Eric Bruckert 1, Gilles Hayem 2, Sylvie Dejager 3, Caroline Yau 3, and Bernard Bégaud 4 1 Department of Endocrinology, Hôpital de la Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris 83 Bd de L Hôpital, 75013, Paris, France; 2 Department of Rheumatology, Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France; 3 Clinical Research and Development, Novartis Pharma SAS, Rueil-Malmaison, France; 4 Université Victor Segalen Bordeaux 2, Bordeaux, France Published online: 31 January 2006 Summary. Objectives: To characterize the risk factors, rate of occurrence, onset, nature and impact of mild to moderate muscular symptoms with high-dosage HMG-CoA reductase inhibitor (statin) therapy in general practice. Methods: The Prédiction du Risque Musculaire en Observationnel (Prediction of Muscular Risk in Observational conditions, PRIMO) survey was an observational study of muscular symptoms in an unselected population of 7924 hyperlipidemic patients receiving high-dosage statin therapy in a usual care, outpatient setting in France. Information on patient demographics, treatment history and muscular symptoms was obtained by questionnaires. Results: Multivariate analysis revealed the strongest predictors for muscular symptoms to be a personal history of muscle pain during lipid-lowering therapy (odds ratio, OR, 10.12, 95% CI ; P < ), unexplained cramps (OR 4.14; 95% CI ; P < ) and a history of creatine kinase (CK) elevation (OR 2.04; 95% CI ; P < ). Overall, muscular symptoms were reported by 832 patients (10.5%), with a median time of onset of 1 month following initiation of statin therapy. Muscular pain prevented even moderate exertion during everyday activities in 315 patients (38%), while 31 (4%) were confined to bed or unable to work. Fluvastatin XL was associated with the lowest rate of muscular symptoms (5.1%) among individual statins. Conclusion: PRIMO demonstrated that mild to moderate muscular symptoms with high-dosage statin therapy may be more common and exert a greater impact on everyday lives than previously thought. Knowledge of the risk factors for muscular symptoms will allow identification and improved management of high-risk patients. The risk of muscular symptoms with fluvastatin XL treatment may be lower than with high dosages of other statins. Key Words: HMG-CoA reductase inhibitors, statins, myopathy, myotoxicity, epidemiology Introduction Lowering plasma low-density lipoprotein cholesterol (LDL-C) levels with statin therapy is known to reduce the risk of ischemic heart disease and stroke [1 6]. Large trials and extensive post-marketing experience (with millions of patients having been treated across the world since these drugs first appeared on the market almost two decades ago) have shown that longterm statin therapy is generally well tolerated [1,3,7 11]. Nevertheless, statin treatment is associated with an increased risk of muscular symptoms or myopathy. The incidence of severe myopathy is low, occurring in less than 0.1% of patients receiving statin monotherapy [12]. Conversely, mild symptoms are far more frequent, with up to 7% of outpatients on statins complaining of muscle pain [9,13 16]. The potential clinical impact of mild muscular side effects of statin treatment should not be underestimated, as hypercholesterolemic patients who experience adverse events are more likely to discontinue statin therapy [14]. Nevertheless, the risk factors, presentation and impact of mild to moderate muscular side effects of statin therapy are poorly understood [17]. Moreover, mild muscular symptoms are often overlooked by doctors, and their frequency is therefore probably underestimated [18]. The rate of occurrence of muscular symptoms is also likely to be underestimated in clinical trials due to the exclusion of high-risk patients, such as patients with a history of muscular symptoms or creatine kinase (CK) elevations, and the Address for correspondence: Eric Bruckert, Department of Endocrinology, Hôpital de la Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, 83 Bd de L Hôpital , Paris, France. Tel.: ; Fax: ; eric.bruckert@psl.ap-hop-paris.fr 403

2 404 Bruckert et al. omission of mild symptoms in patient interviews and clinical trial adverse event reports. There is a clear need to characterize the risk factors and clinical presentation of mild to moderate muscular side effects of statins in general practice, such that patients at risk of muscular symptoms may be given closer medical supervision when receiving statin treatment. This is of particular importance when patients are titrated to high-dosage statin therapy, as the incidence of muscular side effects with statin therapy increases with statin dosage [19]. Indeed, the increased risk of muscular side effects with high-dosage statin therapy was recently illustrated by the Aggrastat to Zocor(AtoZ)trial[20]. Given the more aggressive approach to lipid-lowering therapy advocated by recent treatment guidelines [21] an increased understanding of the nature of statin muscular side effects is of considerable importance. The Prédiction du Risque Musculaire en Observationnel (Prediction of Muscular Risk in Observational conditions, PRIMO) study was a countrywide observational study conducted in a large, unselected population of hyperlipidemic patients receiving high-dosage statin therapy in a usual care, outpatient setting in France. The main objectives of the study were to identify the risk factors associated with muscular symptoms, establish the rate of occurrence of muscular symptoms with individual statins and to characterize the onset, nature and management of the symptoms. Methods Study design PRIMO was a countrywide observational survey of the risk factors and management of muscular side effects in patients receiving high-dosage statin treatment in general practice in France. In total, 7924 hyperlipidemic patients aged years who were seen in regular outpatient visits with their general practitioners (GPs) were entered in the study. The number of GPs selected (2752) was based on an estimated 15% of patients receiving high-dosage statin therapy and an a priori hypothesis of four consultations per year. GPs were asked to include the first three consecutive patients who satisfied the survey inclusion criteria during a period of up to 2 months following initiation of the study. Patients were included if they had been prescribed high-dosage statin treatment (fluvastatin 80 mg; atorvastatin 40 or 80 mg; pravastatin 40 mg; or simvastatin 40 or 80 mg) for at least 3 months prior to the study. Patients were also included if their regimen had been adjusted (statin withdrawal or dose reduction) within the last 3 months due to muscular pain. This was done to avoid sample bias that would otherwise be introduced by excluding patients who had reported muscular pain with statin therapy but were no longer receiving high-dosage treatment at the time of survey. The majority of patients in PRIMO receiving fluvastatin treatment were taking the extendedrelease formulation (fluvastatin XL), hence we refer to fluvastatin XL throughout the manuscript. Patients were excluded if they were receiving statin treatment as part of a clinical trial, or if they were included in any study during the observation period of the PRIMO survey. 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 Liberté [CNIL]). The PRIMO survey was designed by an independent scientific committee consisting of three members. Data collection Information on demographic data, lifestyle, personal and family medical history and current cardiovascular and concomitant treatment status was obtained by questionnaire completed by the GP in the presence of the patient. If muscular symptoms were reported, a second questionnaire was also completed in the presence of the patient providing information on the type, location, duration, possible causes and management of the symptoms. The choice of items included in the questionnaires were guided by previous clinical trials and post-marketing surveillance data, and by the results of a smaller-scale, pilot study [22]. In addition, fat mass was measured in all patients using a BF306 body fat monitor (OMRON Healthcare Europe B.V., Netherlands). Statistical analysis Descriptive statistics for each of the parameters assessed were compared in patients with and without muscular symptoms on the basis of mean values and standard deviations (continuous variables) or percentages (categorical variables). Univariate analysis was used to identify factors associated with an increased risk of muscle pain, and odds ratios (OR) with 95% two-sided confidence intervals (CI) were calculated. The number of patients necessary to provide sufficient precision (95% CI) for OR estimation was calculated with a prediction that 10% of patients would experience muscle pain. Pearson s Chi-square test for categorical variables and Student s t-test for continuous variables were used to compare the two groups. Multivariate logistic regression was then performed to calculate the adjusted ORs with 95% CIs to estimate the correlation between risk factors and muscular symptoms. Significant risk factors as determined by univariate analysis were included in the multivariate model. A stepwise method was used to select major risk factors to be kept in the model. The adequacy of the fitted model was evaluated by Hosmer-Lemeshow goodness of fit test. The significance threshold in two-tailed tests was taken as 0.05.

3 Muscular Symptoms with High-Dosage Statin Therapy 405 For patients who exhibited muscular symptoms during high-dosage statin therapy, a descriptive statistical analysis of the type of symptoms and causative factors was carried out. Data for the time of onset of muscular symptoms after initiation of statin therapy, or introduction of high-dosage statin therapy, were log-transformed to verify that time of onset was unimodal. Statistical analyses were planned and reviewed by the scientific committee before database lock and performed using SAS software, version 8.2 (SAS Institute Inc. Cary, NC, USA). Results Demographic and baseline characteristics Demographic characteristics for patients assessed in the PRIMO study with and without muscular symptoms, are presented in Table 1. The mean age of the population as a whole was 58.4 ± 10.8 years, men outnumbered women almost two-fold, and the patients tended to be overweight (mean body mass index [BMI] = 27 kg/m 2 ). The only significant demographic difference observed between the two subgroups was in the mean percentage body fat mass, which was lower in those reporting muscular symptoms than in the nonsymptomatic population (28.8% vs. 29.7%; P = 0.004). No parallel differences were observed in either mean BMI or the percentage of obese subjects. There were no significant differences in mean age, age analyzed by quintiles, the percentage of subjects aged over 65 years, or sex ratio between patients with muscular symptoms and asymptomatic patients. Alcohol and tobacco consumption, and physical activity Alcohol consumption was similar in patients with and without muscular symptoms, with only 7.1% of patients overall being heavy drinkers (greater than 40 g per day) (Table 1). Approximately 20% of the non-symptomatic population were current smokers (Table 1). The proportion of smokers was slightly lower in the symptomatic population (20.1% vs. 16.8%; P = 0.046), but it should be noted that smokers were less physically active than non-smokers (60.3% of active smokers exercised regularly vs. 70.9% active nonsmokers; P < ). Symptomatic patients tended to be more active than the population as a whole (Table 2); the incidence of muscle pain increased with the level of physical activity, from 10.8% in those practising only leisure-type activities to 14.7% in those regularly practising some intense form of sport. Table 1. Demographic and baseline characteristics of patients with and without muscular symptoms in the PRIMO study Patients with muscular Patients without muscular symptoms symptoms Characteristic (N = 7092) (N = 832) Age, years 58.4 ± ± 10.9 Patients aged > 65 years, N (%) 2131 (30.2%) 262 (31.6%) Sex, % male 64.9% 66.1% BMI, kg/m ± ± 4.4 Obese a patients, N (%) 1556 (22.2%) 175 (21.3%) Body fat mass, % 29.7 ± ± 8.0 Current smokers, N (%) 1066 (20.1%) 107 (16.8%) Alcohol consumption, N (%) <2 drinks per day (<20 g/day) 4491 (67.3%) 523 (66.7%) 2 4 drinks per day (20 40 g/day) 1706 (25.6%) 205 (26.2%) >4 drinks per day (>40 g/day) 477 (7.1%) 56 (7.1%) Co-medications (>2concomitant),N (%) 4601 (65.8%) 559 (68.8%) Beta-blockers 2126 (30.0%) 251 (30.2%) Antidiabetic agents 1178 (16.6%) 118 (14.2%) Anxiolytics 992 (14.0%) 103 (12.4%) Antidepressants 568 (8.0%) 44 (5.3%) Corticosteroids 48 (0.7%) 6 (0.7%) BMI: body mass index. Data are presented as mean ± SD unless otherwise stated. Percentage values are expressed as a percentage of the total number of patients with or without symptoms as appropriate, excluding patients with missing values. a Obesity was defined as body mass index >30 kg/m 2 b Regular physical activity ranged from hobby-based activities such as walking and gardening to weekly practice of endurance sports such as jogging or cycling.

4 406 Bruckert et al. Table 2. Univariate risk factor analysis comparing non-symptomatic patients and patients with muscular symptoms in the PRIMO study Non symptomatic patients (n = 7092) Patients with muscular symptoms (n = 832) OR (95% CI) P value Regular physical activity a, N (%) 4830 (68.35%) 622 (74.85%) 1.38 ( ) < Level 1 b 2690 (60.61%) 325 (56.03%) Level 2 b 732 (16.49%) 115 (19.83%) 1.30 ( ) Level 3 b 830 (18.70%) 108 (18.62%) 1.08 ( ) Level 4 b 186 (4.19%) 32 (5.52%) 1.42 ( ) Muscular pain with another 395 (5.58%) 341 (41.23%) ( ) < lipid-lowering agent, N (%) Unexplained cramps, N (%) 929 (13.15%) 375 (45.96%) 5.62 ( ) < History of elevated CK associated 234 (82.69%) 135 (92.47%) 2.57 ( ) with LLT c, N (%) History of elevated CK, N (%) 301 (4.35%) 161 (19.75%) 6.01 ( ) < History of muscular symptoms, N 245 (3.48%) 95 (11.49%) 3.61 ( ) < (%) Family history of muscular 84 (1.19%) 36 (4.34%) 4.08 ( ) < symptoms with LLT, N (%) Family history of muscular 87 (1.27%) 27 (3.37%) 2.71 ( ) < symptoms, N (%) Hypothyroidism, N (%) 166 (2.35%) 33 (3.97%) 1.74 ( ) Background of fibromyalgia-like 358 (5.06%) 118 (14.25%) 3.12 ( ) < symptoms, N (%) Treatment with antidepressants, N (%) 568 (8.01%) 44 (5.29%) 0.64 ( ) Duration of statin treatment, N (%) Less than 3 months 463 (6.82%) 106 (13.10%) More than 3 months 6330 (93.18%) 703 (86.90%) 0.48 ( ) < CI: confidence interval; CK: creatine kinase; LLT: lipid-lowering therapy; OR: odds ratio. Odds ratios and their respective two-sided 95% confidence intervals were calculated and comparisons between groups carried out using Pearson s Chi-square test. a Levels of physical activity were categorized from 1 (lowest) to 4 (highest). b Among patients with physical activity. c Among patients who previously had CK elevation.

5 Muscular Symptoms with High-Dosage Statin Therapy 407 Table 3. Multivariate model taking into account all significant factors associated with muscle pain during high-dosage statin treatment in the PRIMO study OR 95% CI P value History of muscle pain with another LLT < Unexplained cramps < History of elevated CK < Family history of muscular symptoms Family history of muscular symptoms with LLT Hypothyroidism Duration of statin treatment More than 3 months < Treatment with antidepressants Type of statin a Atorvastatin Simvastatin < Fluvastatin XL < CI, confidence interval; CK, creatine kinase; LLT, lipid-lowering therapy; OR, odds ratio; Multivariate logistic regression was performed to calculate the adjusted odds ratios with 95% confidence intervals. a Odds ratios were calculated using pravastatin as the reference. Univariate analysis of risk factors for muscular symptoms A comparison of the medical history of patients with and without muscular symptoms revealed several clinical predictors for mild to moderate muscular symptoms with high-dosage statin therapy. Odds ratios are shown in Table 2. Age, gender, and BMI were not risk factors for muscular symptoms. Significant clinical predictors identified were: history of muscle pain with another lipid-lowering therapy (LLT); unexplained cramps related to LLT, especially if cramps were experienced more than once a week; history of CK elevations whether associated with LLT or not; a personal history of muscle pain; a family history of muscular symptoms, whether associated with LLT or not; intercurrent, untreated hypothyroidism (although patients with a personal or family history of hypothyroidism but with normal thyroid function were not at increased risk); and a background of fibromyalgia-like symptoms (as defined by a positive answer to the question Has the patient experienced generalized pain unrelated to LLT for a period of over 3 months? ). Treatment with beta-blockers, beta-mimetics, anxiolytics, corticosteroids, antidiabetic medication, and vitamin E or multivitamins were not significantly associated with muscular symptoms. Neither depression (current or historical) nor impaired kidney function were found to have any impact on the risk of mild to moderate muscular symptoms with high-dosage statin therapy. However, treatment with antidepressants and taking statins for more than 3 months were associated with a decreased risk of muscular symptoms. personal history of muscle pain in the course of LLT, which was associated with a 10-fold increase in the risk of muscular symptoms (OR 10.12, 95% CI ; P < ) (Table 3). In the majority of these patients muscular pain had been associated with statin (83.1%) or fibrate (13.5%) therapy. Other significant, independent risk factors were unexplained cramps (OR 4.14; 95% CI ; P < ), a history of CK elevations (OR 2.04; 95% CI ; P < ), a family history of muscular symptoms with (OR 1.89; 95% CI ; P = 0.017) or without LLT (OR 1.93; 95% CI ; P = 0.022) and current hypothyroidism (OR 1.71; 95% CI ; P = 0.017). Treatment with statins for more than 3 months (OR 0.28; 95% CI ; P < ) and concomitant antidepressant medication (OR 0.51; 95% CI ; P = ) were associated with a significantly lower prevalence of muscular symptoms. Despite being associated with a decreased risk of muscular symptoms by univariate analysis, smoking was not a predictor of muscular symptoms under multivariate analysis. The type of statin used was an independent predictor of muscular symptoms under multivariate analysis. Odds ratio calculations for the risk of muscular symptoms, using high-dosage pravastatin as the reference, show that both high-dosage atorvastatin and simvastatin treatment were associated with a significantly higher (P = and P < respectively) rate of occurrence of muscular symptoms compared with pravastatin (Table 3). Fluvastatin XL treatment was associated with a significantly lower (P < ) risk of muscular symptoms compared with pravastatin. Multivariate analysis of risk factors for muscular symptoms Multivariate analysis revealed that the strongest independent risk factor for muscular symptoms was a Rate of occurrence of muscular symptoms with individual statins Overall, muscular symptoms were reported by 10.49% of patients receiving high-dosage statin therapy in the

6 408 Bruckert et al. Table 4. History of muscular symptoms and usage and rate of occurrence of muscular symptoms with individual statins in the PRIMO study Number of patients receiving high-dosage Personal history of muscular or tendonitisassociated side effects during lipid-lowering Personal history of muscular pathology, N Family history of muscular pathology, N Muscular symptoms, N (%)a Percentage of patients receiving statin with muscular Statin therapy therapy, N (%) (%) (%) Yes No symptoms Pravastatin (8.2%) 86 (4.5%) 21 (1.1%) 208 (25.1%) 1693 (24.0%) 10.9% Atorvastatin (10.7%) 83 (4.5%) 32 (1.8%) 274 (33.1%) 1570 (22.2%) 14.9% Simvastatin (9.8%) 55 (5.4%) 13 (1.3%) 187 (22.6%) 840 (11.9%) 18.2% Fluvastatin XL (8.8%) 115 (3.7%) 47 (1.6%) 159 (19.2%) 2962 (41.9%) 5.1% Table excludes 31 patients for whom data on the individual statin were missing. a % values relative to the total number of patients with or without muscular symptoms. indicates significant difference (P < 0.05) as determined by Pearson s Chi-squared test. PRIMO study. Fluvastatin XL treatment was associated with the lowest numerical rate of occurrence of muscular symptoms (5.1%); the highest risk of muscular symptoms was observed among patients receiving treatment with high-dosage simvastatin (18.2%) (Table 4). The baseline characteristics of patients assessed in the PRIMO study were similar across different individual statin treatments. However, the mean age of patients receiving high-dosage pravastatin treatment in PRIMO (59.6 years, CI ) was slightly higher than for patients receiving either high-dosage atorvastatin (58.3 years, CI ), simvastatin (58.7 years, CI ), or fluvastatin XL (57.7 years, CI ). In addition, there was a slightly higher proportion of men receiving treatment with simvastatin compared with pravastatin (68.3% vs 64.6%, P < 0.05), and a higher percentage of patients receiving atorvastatin had a personal history of muscular or tendonitisassociated side effects during lipid-lowering therapy, compared with pravastatin (10.7% vs 8.2%, P < 0.05) (Table 4). No other significant differences in age, sex or personal history of side effects during lipid-lowering therapy were observed, and there were no significant differences between individual statins in the proportion of patients reporting either a personal history or family history of muscular symptoms. Time of onset and triggering factors for muscular symptoms Of 832 patients who reported muscular symptoms with statin therapy in the study, 41% noted a potential triggering factor for muscular symptoms. The most commonly reported factors were unusual physical exertion (53%) and taking a new medication (30%) (Table 5). The distribution of times of onset for muscular symptoms showed a single peak shortly after either initiation of statin therapy (Fig. 1a), or titration to a high dosage of statin (Fig. 1b). The median time of onset was 1 month for muscular symptoms following initiation of statin therapy (Fig. 1c), and titration to a high dosage of statin (Fig. 1d). Log transformation confirmed that the time of onset of muscular symptoms was unimodal for both initiation and titration of statin. Clinical description of muscular symptoms Muscular pains were most commonly manifested as heaviness, stiffness or cramps, with many patients also reporting weakness or a loss of strength during exertion (Table 5). Pain was widespread in the majority of patients, and generally affected the lower limbs (thighs, calves). Tendonitis-associated pain was reported by almost a quarter of patients, and affected multiple tendons in more than half of cases. More than 80% of patients had not experienced similar symptoms before beginning statin treatment. Duration and impact of muscular symptoms Muscular pain was continuous in more than a quarter of the patients who reported muscular symptoms, and was associated with exertion in 46% of patients reporting intermittent pain (Table 6). Nearly 39% of patients had used analgesics for pain relief of their muscular symptoms. Approximately 38% of patients reported that their muscular symptoms prevented even moderate exertion during everyday activities, while 4% of patients suffered major disruption to their everyday life (being confined to bed or unable to work) due to muscular pain. Clinical management of muscular symptoms The most common approach to managing muscular symptoms in the PRIMO study was to switch the patient to a different lipid-lowering agent; this occurred in 57% of patients with symptoms (of which 61% were switched to another statin, and 28% to a fibrate). Treat-

7 Muscular Symptoms with High-Dosage Statin Therapy 409 Table 5. Time of onset, triggering factors and clinical description of muscular symptoms reported in the PRIMO study Characteristic Description Number of patients %of patients Possible triggering factors of symptoms a No Yes Unusual physical exertion 178 Taking a new medication 101 Resting or lying down 44 Cold 30 Unknown 9 Legionella infection 1 Unknown Type of pain Heaviness/stiffness/cramps Weakness and/or loss of strength during exertion, with or without other symptoms Stiffness/cramps Weakness/heaviness/loss of strength during exertion/stiffness/cramps Unknown Widespread pains Yes No Unknown Predominant site of pains Thighs/calves All over Calves Thighs Trunk Arm/forearm No predominant site Unknown Tendonitis-associated pain No Yes Multiple tendons 109 Single tendon 75 Unknown 19 Unknown Similar symptoms experienced before statin treatment No Yes Unknown a Some patients reported multiple triggering factors, hence the number of patients reporting individual factors exceeds the total number of patients reporting a possible triggering factor. ment with the same statin was continued at a lower dosage in 17% of patients, while statin treatment was discontinued completely in 20% of patients with muscular symptoms (Table 6). Discussion The PRIMO study provides the first large-scale, comprehensive investigation into the risk, causes, nature and management of mild to moderate muscular symptoms in patients receiving high-dosage statin therapy in clinical practice. Several strong predictors of muscular symptoms associated with statin therapy were revealed, the absence or presence of which can be ascertained in the course of a brief interview in the physician s office (as implicit in the methodology of this observational study). Identification of strong predictive factors for statin-associated muscular symptoms will improve management of high-risk patients, enhancing compliance and allowing optimum dosing at a time when more aggressive management of LDL-C is advo-

8 410 Bruckert et al. Fig. 1 Distribution of the time of onset of muscular symptoms following (a) initiation of statin therapy; or (b) titration to high-dosage statin therapy. The median time of onset was 1 month following both initiation of statin therapy, and titration to a high dosage of statin. Table 6 Frequency, impact on everyday life and management of muscular symptoms reported in the PRIMO study Characteristic Description Number of patients %of patients Frequency of pain Continuous Intermittent Unknown Duration of intermittent pain Unknown Several minutes Several hours Associated with exertion Several minutes/associated with exertion Several hours/associated with exertion Pain requiring symptomatic treatment No Yes Unknown Level of disruption of daily life Minor disruption Interferes with major exertion Interferes with moderate exertion Major disruption (confined to bed or stopped work) Unknown Clinical management of symptoms Switch to a different lipid-lowering agent Statin 287 Fibrate 133 Other 44 Unknown 8 Discontinuation of statin Reduction in dosage of statin Unknown cated [23]. The rate of occurrence of muscular symptoms in patients receiving high-dosage statin therapy (10.5%) was considerably higher than the 1 5% reported in clinical trials [24], and symptoms were found to have a greater impact on everyday life than previously thought. The risk factor analysis in PRIMO was consistent with the results of a preliminary study [22], confirming that a personal or family history of muscular symptoms, cramps, hypothyroidism and elevated CK levels are major risk factors for muscular symptoms during high-dosage statin therapy. Interestingly, although

9 Muscular Symptoms with High-Dosage Statin Therapy 411 only a small number of patients were able to report on parents or siblings experiencing muscle pain under LLT, the presence of such a family history almost doubled the risk of the adverse reaction under multivariate analysis. These results probably grossly underestimate family history as a risk factor, since relatively few patients have family members being treated with LLT and even many of those who do will be unaware of the fact. Thus, a genetic predisposition may be key in determining whether a patient will develop muscle pain while receiving statin therapy, a possibility that deserves further investigation. In the Australian Adverse Drug Reactions Bulletin, the Adverse Drug Reactions Advisory Committee (ADRAC) reported a list of factors associated with an enhanced risk of suffering muscle problems in patients receiving simvastatin and atorvastatin [25]; the conclusions were that high doses of statins should be used with caution in the elderly (over 70 years of age), and in patients with renal or hepatic deficiency, hypothyroidism or diabetes. The questionnaires in the PRIMO study did not specifically address diabetes or liver function, but we failed to detect any impact of impaired kidney function (although renal function data were not available for 13.8% of patients). We also observed no age-dependent differences, and it seems unlikely that the oldest patients are at higher risk, because the incidence of muscular symptoms in this subgroup (17.8% [1411] of patients in the PRIMO study population were over 70 years of age) was no different to that observed in the population as a whole. Age, gender and BMI were not identified as risk factors by univariate analysis, although both lower body fat mass and regular physical activity were associated with a greater incidence of muscle pain. Symptomatic patients were generally more active than the population as a whole; this may be because active patients are more likely to sustain the type of low-level injury that is exacerbated by statins [26]. High alcohol consumption is described as a cause of the potentially fatal adverse event, rhabdomyolysis [27], but in this population light to moderate consumption was not associated with any increase in the incidence of muscular symptoms. The observation that smokers were less likely to experience muscle pain is secondary to the fact that they were less physically active and explains why this risk factor disappears in multivariate analysis. Although CK levels were not measured in the present study, a history of elevated levels of this marker emerged as a significant risk factor for muscular symptoms. This finding suggests that sub-clinical myopathy may predispose to statin-induced symptoms. However, it remains difficult to advocate the systematic assay of CK activity in every candidate for LLT. The reduced risk of muscular symptoms in patients receiving antidepressants may be due to the recognized decrease in physical activity in these patients, although this should have been precluded in the multivariate analysis which adjusted for physical activity, or the non-specific analgesic effect of the antidepressants. The lower prevalence of LLT-related muscular symptoms in patients treated for more than 3 months is explained by the fact that the majority of cases of LLT myotoxicity are clinically apparent within the first 3 months. In the PRIMO study population, 10.5% of patients on high-dosage statin therapy complained of muscle pain, a figure which is considerably higher than that reported previously for clinical trials [24]. This result is, however, consistent with a preliminary study [22], and we believe it provides a more accurate reflection of statin tolerability in general practice (at least for high-dosage statin therapy) than clinical trial data. The methodology used in PRIMO precludes various skewing factors introduced by the rigorous patient selection procedures of controlled studies (e.g. excluding groups such as elderly and diabetic patients, those with renal or hepatic impairment or patients with a history of muscular symptoms or CK elevations). Moreover, unless patients are specifically asked, mild symptoms such as pain after exercise may not necessarily be reported and may not be recorded in clinical trial adverse event reports. Marked differences in the risk of muscular symptoms with individual statins were observed; fluvastatin XL treatment was associated with the lowest rate of muscular symptoms (5.1% of patients), while patients receiving high-dosage simvastatin showed the highest rate (18.2%). In comparing the rate of occurrence of muscular symptoms observed with individual statins in the present study, it is important to note that this was an observational study and as a result there was an inevitable imbalance in sample size across treatment groups. This was particularly evident between the fluvastatin and simvastatin groups where the sample sizes were 3121 and 1027 patients, respectively. Hence comparisons between the groups should be interpreted with caution. It should also be noted that the dosages of each statin were not equivalent with regard to lipid-lowering efficacy. Thus, atorvastatin, mg/day and simvastatin, mg/day lower LDL-C levels to a greater extent compared with either fluvastatin, 80 mg/day or pravastatin, 40 mg/day [28]. A higher risk of muscular adverse effects would be anticipated with more aggressive lipid lowering [19]. Nevertheless, the risk of muscular symptoms with fluvastatin XL in the PRIMO study was less than half of that observed with pravastatin, despite the fact that fluvastatin XL, 80 mg/day would be expected to lower LDL-C levels more effectively than pravastatin, 40 mg/day. However, it is difficult to compare the results of fluvastatin XL and pravastatin in terms of safety due to their differing pharmacokinetic and physicochemical properties. Nevertheless, it seems reasonable to conclude that fluvastatin XL

10 412 Bruckert et al. treatment may be associated with a lower risk of muscular symptoms compared with other statins. Fluvastatin demonstrated an incidence of CK elevations similar to placebo in a pooled analysis of 8951 patients receiving fluvastatin or fluvastatin XL treatment in clinical studies [29]. Moreover, fluvastatin treatment has also been associated with the lowest number of published cases of rhabdomyolysis [30], and the lowest published incidence of fatal rhabdomyolysis [12], among statins in clinical practice. Confirmation of the lower risk of muscular symptoms associated with fluvastatin compared with other statins, could be provided by future prospective, randomized clinical studies with dosages of statins that have equal lipidlowering efficacy and a specific endpoint of mild to moderate muscular symptoms. It is notable that although concomitant medication per se was not associated with a significantly higher risk of muscular symptoms in the PRIMO study (OR 1.15; 95% CI ; P = 0.081), starting a new medication was identified as a triggering factor for muscular symptoms by 30% of patients who reported potential factors. It is well known that the risk of muscular side effects with statin therapy is increased by drug interactions with agents that interfere with statin elimination [30]. Indeed, most of the clinically important drug-drug interactions that occur with statins are attributable to the concurrent use of statins that are recognized by cytochrome P450 (CYP) isoform 3A4 (such as atorvastatin and simvastatin) and other agents that are potent inhibitors of this enzyme [19]. The low incidence of muscular side effects observed with fluvastatin may reflect the fact that it is primarily metabolised by CYP2C9 [31], and not CYP3A4. The median time of onset of muscular symptoms was 1 month after initiation of statin therapy and titration to a higher dosage of statin treatment. This finding is similar to results obtained in the Heart Protection Study (HPS), where approximately 5% of the 32,145 patients entering the pre-randomisation run-in period (during which time patients received simvastatin, 40 mg daily for 4 6 weeks) were excluded from the study due to biochemical abnormalities or reported adverse effects [32]. In the present study, muscular pains were most commonly manifested as heaviness, stiffness or cramps and generally affected the lower limbs (thighs and calves). These findings confirm observations made in a preliminary study [22]. In accordance with guidelines for the use of statin therapy [23], muscular symptoms were managed either by switching the patient to a different lipid-lowering agent (generally another statin), continuing the same statin at a lower dosage, or discontinuing statin therapy completely. Multivariate analysis demonstrated that a history of muscle pain with another LLT was the strongest predictor for muscular symptoms. Therefore switching to a different statin might not necessarily be expected to reduce muscular symptoms, although the results of PRIMO suggest that the risk may vary depending on the statin to which symptomatic patients are switched. Importantly, the results of the present study indicate that muscular symptoms associated with highdosage statin therapy may have a greater impact on the everyday life of patients than was previously thought. Thus, muscular pain was continuous in 25% of patients, while 39% of patients reported using an analgesic for pain relief of their muscular symptoms. Moreover, 38% of patients reported that their muscular symptoms prevented even moderate exertion during everyday activities, while 4% of patients suffered major disruption to their everyday life (being confined to bed or unable to work) due to muscular pain. These findings are of considerable importance, because patients who experience adverse events during statin treatment are more likely to discontinue therapy [14]. Indeed, poor patient compliance is a major issue for statin therapy; a recent study showed that more than half of elderly patients initiating treatment may receive no or limited benefit from statins due to premature discontinuation [33]. It is important to note the limitations of the PRIMO study. Patients with muscular symptoms in whom the drug had been withdrawn or the dosage reduced more than 3 months prior to the consultation would have been missed. However, this would constitute a relatively small number of patients, as most cases of LLTrelated myotoxicity were apparent within the first 3 months of treatment. Moreover, the occurrence rates for muscular symptoms observed in the PRIMO study were obtained with the highest approved dosages of each individual statin in France at the time of study, and cannot be extrapolated to lower dosages of each drug. As PRIMO was an observational study, randomization did not take place leading to an inevitable imbalance in sample size between treatment groups. In order to limit selection bias, GPs were asked to include consecutive patients. With regard to the causal relationship between statin treatment and muscular symptoms, the PRIMO questionnaires relied upon the chronological occurrence of statin treatment and muscular pain; methods for assigning causal probabilities to drug-induced events, such as the Naranjo algorithm, were not used. Finally, it is important to draw attention to the possibility that the risk factors for mild to moderate muscular symptoms and those for severe rhabdomyolysis might be quite distinct, a possibility which is all the more likely since it is well documented that rhabdomyolysis may occur without any prior symptoms at all [34]. As this life-threatening side effect is extremely rare, only retrospective studies in survivors will be able to confirm whether the risk factors identified in this study are also risk factors for rhabdomyolysis. In summary, the PRIMO study provides the first large-scale, comprehensive investigation into the risk, causes, rate of occurrence, nature and management of muscular symptoms in patients receiving high-dosage

11 Muscular Symptoms with High-Dosage Statin Therapy 413 statin therapy in real life clinical practice. Several strong predictors of muscular symptoms were identified, providing a basis for a brief, simple interview before a statin is prescribed, which may improve management of patients at high risk of muscular symptoms and thus improve patient compliance and minimize discontinuation. The results of PRIMO also indicate that mild to moderate muscular symptoms may be more common and exert a greater influence on the quality of life of patients than previously thought; the study therefore highlights the importance of consideration of the risk of these symptoms when prescribing statins and increasing dosages. The risk of muscular symptoms with fluvastatin XL appears to be lower than with high dosages of other statins. Acknowledgments This study was supported by Novartis Pharma SAS. Sylvie Dejager and Caroline Yau are employees of Novartis Pharma SAS. The steering committee members were Eric Bruckert, Gilles Hayem and Bernard Bégaud. References 1. Scandinavian Simvastatin Survival Study Investigators. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344(8934): The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339(19): Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: two-year efficacy and safety follow-up. Am J Cardiol 1994;74(7): Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AF- CAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279(20): Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335(14): Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333(20): The Pravastatin Multinational Study Group for Cardiac Risk Patients. Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/liter (200 to 300 mg/dl) plus two additional atherosclerotic risk factors. Am J Cardiol 1993;72(14): Bakker-Arkema RG, Nawrocki JW, Black DM. Safety profile of atorvastatin-treated patients with low LDL-cholesterol levels. Atherosclerosis 2000;149(1): Bertolini S, Bon GB, Campbell LM, et al. Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia. Atherosclerosis 1997;130(1 2): Nawrocki JW, Weiss SR, Davidson MH, et al. Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. Arterioscler Thromb Vasc Biol 1995;15(5): Steinhagen-Thiessen E. Comparative efficacy and tolerability of 5 and 10 mg simvastatin and 10 mg pravastatin in moderate primary hypercholesterolemia. Simvastatin Pravastatin European Study Group. Cardiology 1994;85(3 4): Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med 2002;346(7): Lambrecht LJ, Malini PL. Efficacy and tolerability of simvastatin 20 mg vs pravastatin 20 mg in patients with primary hypercholesterolemia. European Study Group. Acta Cardiol 1993;48(6): Bruckert E, Simonetta C, Giral P. Compliance with fluvastatin treatment characterization of the noncompliant population within a population of 3845 patients with hyperlipidemia. CREOLE Study Team. J Clin Epidemiol 1999;52(6): Dart A, Jerums G, Nicholson G, et al. A multicenter, doubleblind, one-year study comparing safety and efficacy of atorvastatin versus simvastatin in patients with hypercholesterolemia. Am J Cardiol 1997;80(1): Jokubaitis LA. Updated clinical safety experience with fluvastatin. Am J Cardiol 1994;73(14):18D 24D. 17. Grundy SM. Can statins cause chronic low-grade myopathy? Ann Intern Med 2002;137(7): Sinzinger H, Wolfram R, Peskar BA. Muscular side effects of statins. J Cardiovasc Pharmacol 2002;40(2): Ballantyne CM, Corsini A, Davidson MH, et al. Risk for myopathy with statin therapy in high-risk patients. Arch Intern Med 2003;163(5): De Lemos JA, Blazing MA, Wiviott SD, et al. Early Intensive vs a Delayed Conservative Simvastatin Strategy in Patients With Acute Coronary Syndromes: Phase Z of the A to Z Trial. JAMA 2004;292: Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110(2): Franc S, Dejager S, Bruckert E, Chauvenet M, Giral P, Turpin G. A comprehensive description of muscle symptoms associated with lipid-lowering drugs. Cardiovasc Drugs Ther 2003;17(5 6): Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002;40(3): Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA 2003;289(13): Adverse Drug Reactions Advisory Committee (ADRAC). Risk factors for myopathy and rhabdomyolysis with the statins. Aust Adv Drug Reactions Bull 2004;23(1): Thompson PD, Zmuda JM, Domalik LJ, Zimet RJ, Staggers J, Guyton JR. Lovastatin increases exercise-induced skeletal muscle injury. Metabolism 1997;46(10): Sauret JM, Marinides G, Wang GK. Rhabdomyolysis. Am Fam Physician 2002;65(5):

12 414 Bruckert et al. 28. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326(7404): Benghozi R, Bortolini M, Jia Y, Isaacsohn JL, Troendle AJ, Gonasun L. Frequency of creatine kinase elevation during treatment with fluvastatin. Am J Cardiol 2002;89(2): Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reductase inhibitors. Ann Pharmacother 2001;35(9): Fischer V, Johanson L, Heitz F, et al. The 3-hydroxy- 3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: effect on human cytochrome P-450 and implications for metabolic drug interactions. Drug Metab Dispos 1999;27(3): MRC/BHF Heart Protection Study Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360(9326): Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 2002;288(4): Koppel C. Clinical features, pathogenesis and management of drug-induced rhabdomyolysis. Med Toxicol Adverse Drug Exp 1989;4(2):