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Statins are used in the treatment of hyperlipidaemia. They are among the most commonly prescribed drugs worldwide. Statins have been linked to musculoskeletal adverse drug reactions. However muscle rupture has not been discussed as an adverse drug reaction to statins so far. The aim of this article is to give an overview of cases of muscle rupture associated with the use of statins.
We analyzed the cases of muscle rupture associated with the use of statins that were collected by the Netherlands Pharmacovigilance Centre Lareb complemented with the review of cases from the EudraVigilance database.
Fifteen cases of muscle rupture associated with statin use have been identified in the database of the Netherlands Pharmacovigilance Centre. Overall, there was a plausible temporal association of events in most cases. In addition, the EudraVigilance database contained 165 reports of muscle rupture reported in patients using statins. Muscle rupture was disproportionally associated with statin use in both databases. The reporting odds ratio was 23.4 (95% CI 11.9, 46.0) and 14.6 (95% CI 12.3, 17.2), respectively.
Data from spontaneous reporting systems suggest that use of statins is associated with muscle rupture. Physicians and patients should be aware that this can occur.
Statins are used for the primary and secondary prevention of coronary atherosclerotic disease. They are potent inhibitors of cholesterol biosynthesis by inhibiting the enzyme 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase (HMG‐CoA‐reductase). This enzyme plays an essential role in the synthesis of cholesterol by catalyzing the conversion of HMG‐CoA to mevalonate. Statins are usually well tolerated. However 10–15% of statin users develop statin‐related musculoskeletal side effects. These musculoskeletal side effects vary from temporarily disabling muscle cramps and myalgia to serious and life‐threatening rhabdomyolysis. Rhabdomyolysis is the rapid breakdown of skeletal muscle with marked creatine kinase elevation and creatinine elevation with brown urine and urinary myoglobin. Risk factors for statin‐induced myopathy include patient‐related factors such as age, genetics and co‐morbidities as well as other factors such as dose, metabolism and drug interactions. Advanced age, female gender, renal failure, family history of hereditary muscular disorders, history of liver disease and/or alcohol abuse and higher doses of the statins all increase the risk for myopathy 1.
In addition to the well‐known musculoskeletal side effects of statins, cases of muscle rupture in relation to statins have been reported to the Netherlands Pharmacovigilance Centre. Muscle rupture is a contraction‐induced injury in which muscle fibres tear. It mostly occurs as a result of a powerful eccentric contraction or overstretching of the muscle and is therefore a typical injury during explosive movements, such as sprinting, lunging or jumping 2. Historically, acute muscle injuries have been classified as strains (grade I), partial tears (grade II) and complete tears (grade III) 3. Spontaneous muscle ruptures that occur without intense muscle contraction are very rare. In this article we will summarize cases of muscle rupture associated with the use of statins reported to the Netherlands spontaneous reporting system as well as data available in the EudraVigilance database.
The Netherlands Pharmacovigilance Centre has collected reports of suspected adverse drug reactions since 1990. Up to the present, the database has accumulated over 188000 reports. The reports are primarily received from physicians, pharmacists and consumers, either directly or via pharmaceutical manufacturers. Reports are coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology 4. Trained assessors evaluate all reports by using the Naranjo algorithm to establish a causal relationship 5. All reports are included in the database regardless of causality or severity. The search included all reports entered into the database from the start in 1991 up to January 2016.
The European Union (EU) has a spontaneous reporting system that is called EudraVigilance (EV). EV was established in 2001 to collect safety reports of (serious) adverse drug reactions to medicines licensed within the EU. These safety reports are received indirectly through EU national competent authorities and pharmaceutical companies. Reports are coded using the MedDRA terminology 4. All reports entered into the database up to January 2016 were included.
We searched both databases using the MedDRA preferred term ‘muscle rupture’. Reports in relation to statins that are authorized in the Netherlands (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) were included.
The reporting odds ratio (ROR) was calculated as a measure of disproportionality. The ROR represents the extent to which the association between the adverse drug reaction and suspect drug stands out in respect to its background frequency in the database. If the ROR is statistically significant then the adverse drug reaction is significantly associated with the suspect drug in reference to other reports in the database 6.
In the Netherlands Pharmacovigilance database we identified 15 cases of muscle rupture associated with the use of statins received from February 2006 until November 2015 (Table 1). Of the 15 cases, 12 were in males and three were in females. The median age of the patients was 63 years (range 42–73 years). Median time to onset was 19 months (range 1–84 months). Dosage was mentioned in all but one report and was within the labelling recommendation in all patients. Eleven patients were using concomitant drugs. Of these 11 patients, two patients reported another suspect drug besides the statin. One patient reported ofloxacin of which muscle rupture is a known adverse drug reaction 7. Ofloxacin had been used for 3 days before the muscle rupture occurred. Another patient reported diltiazem as suspect drug. However, muscle rupture is not a known adverse drug reaction of diltiazem. Of the other nine patients who used concomitant drugs muscle rupture was not a known adverse drug reaction of the concomitant drugs used (Table 2). Four patients reported a rupture of the biceps, four patients reported a rupture of the calf muscle, two patients reported a hamstring rupture and one patient a quadriceps muscle rupture. In the other reports the muscle rupture was not further specified. In two patients, in addition to the muscle rupture, tendon rupture was reported as well and one patient had a medical history of tendonitis. In four cases it was mentioned that the muscle rupture occurred spontaneously during normal daily activities. In three cases exercise could have played a role in the occurrence of the muscle rupture. In eight cases it was unknown if the muscle rupture occurred during exercise or during normal daily activities. In two patients creatine kinase (CK) concentrations at the time of muscle rupture were reported. One female patient had CK concentrations ranging from 123 to 190 U l–1, which is just above the normal range (<170 U l–1). The other patient, a male, had a CK concentration of 310 U l–1 at the time of the muscle rupture (normal range <200 U l–1) 8. Within 1 month after withdrawal of the statin his CK level decreased to normal (121 U l–1). The Naranjo score was ‘possible’ in all the 15 cases. The association of statin use and muscle rupture was disproportionally present in the Netherlands Pharmacovigilance database with a reporting odds ratio of 23.4 (95% CI 11.9, 46.0).
Up to January 2016 the EV database contained 165 reports of muscle rupture associated with the use of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. All reports, the post‐marketing as well as the clinical trial reports, were included. Of these, 11 cases (Lareb cases excluded) concerned patients who did not use any other medication besides statins who reported a plausible time to event (weeks to months) and no alternative factors were reported that could explain the muscle rupture, such as relevant co‐medication, co‐morbidity or recent intensive exercise. Eight reports concerned males and three reports concerned females. The median age of the patients was 57 years (range 42–72 years). The association of statin use and muscle rupture was disproportionally present in the EudraVigilance database with a reporting odds ratio of 14.6 (95% CI 12.3, 17.2).
Myotoxicity is a well known side effect of statin treatment. Possible adverse drug reactions that are described in literature are myalgia, muscle cramps, myositis, rhabdomyolysis and increased serum concentrations of creatine kinase. Tendon ruptures are also described 9, 10. Mansi et al. reported in 2013 for the first time that statin use was associated with increased risk of dislocation/strain/sprain and maybe osteoarthritis 9. An association between treatment with statins and muscle rupture has not been described in the literature so far. Our data, however, suggest a possible association between muscle rupture and the use of statins. The statin‐induced muscle rupture can possibly occur without intense physical activities since the muscle rupture was reported in several patients during normal daily activities. In most cases there was a plausible temporal relationship between the administration of the statin and the occurrence of muscle rupture. However, in a few patients, it cannot be ruled out that concomitantly prescribed medication or exercise might have contributed to the occurrence of muscle rupture.
Because tendon ruptures have also been described as an ADR that could occur during the use of statins 9, 10, misclassification of tendon rupture as muscle rupture could provide a possible bias. Based on the information in the spontaneous cases Lareb received, we do believe that there is enough evidence that patients actually suffered from muscle rupture and not tendon rupture. A large part of the cases were reported by medical doctors (physicians, specialist doctors). In two cases the reporter explicitly stated that the rupture was not a rupture of the tendon. In addition to muscle rupture, tendon rupture was also reported in two cases as a separate event. For patient 6 both tendon and muscle rupture were observed during surgery and reported by the patient's treating specialist doctor. During surgery a clear distinction between these two conditions can be made. For patient 9, who suffered from three muscle ruptures in a period of months, the exact location of the rupture was known. The third rupture was located in the medial head of the gastrocnemius muscle. This was confirmed by ultrasound examination and a misclassification of a tendon rupture can therefore be ruled out. The muscle ruptures occurred spontaneously, without physical strain. According to the reporter (a physician) there were no other factors that could have caused or aggravated the muscle ruptures. For patient 11 we received the hospital's discharge letters and laboratory findings, showing an increase in CK values until the first muscle rupture and a decrease in CK values when the statin was withdrawn.
Many hypotheses have been proposed to explain the myotoxicity caused by statin use 11. Statins can weaken the integrity of skeletal muscles by reducing the cholesterol content in cell membranes 12. Another theory explains the myotoxicity by a reduction in the availability of the isoprenoid cometabolites farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (G‐PP), causing a reduction in the prenylation of small guanosine triphosphate‐binding proteins, such as Rac, Rho and Ras, which is thought to result in apoptosis of muscle cells 13, 14. Statins catalyze the synthesis of mevalonate. Mevalonate is an important precursor of cholesterol, but also of ubiquinone (coenzyme Q), dolichol and isopentenyl adenosine. Deficiencies in these products may affect the membrane of the myocyte adversely, predisposing the cell to myotoxic consequences 15. In addition, statins induce a sustained increase in cytosolic Ca2+ levels, which could lead to muscle dysfunction and dysregulation 16, 17. Statin use can also lead to secondary carnitine deficiency that may clinically manifest as myositis and/or myalgia 18, 19. Some evidence suggests that statins can inhibit lactic acid efflux from myocytes and thereby induce damage to muscle cells 20. Alterations of protein synthesis and protein degradation have also been implicated in statin‐induced myotoxicity 21. Furthermore, statin‐induced myopathy is associated with mitochondrial complex III inhibition 22. Damage of a considerable proportion of muscle tissue may eventually result in muscle rupture. Mild strains may heal quickly on their own with rest, but more severe tears may require surgery and a rehabilitation programme. Most patients recover within 6 months after statin withdrawal of myopathy. However muscle symptoms can linger beyond 14 months. Creatine kinase normalization often lags behind symptom improvement 23.
In conclusion our data suggest that statin‐induced muscle rupture can occur in patients receiving statins, also in the absence of intense physical activities. Physicians and patients should be aware that statin use can lead not only to the known musculoskeletal adverse reactions but that it can also lead to muscle rupture.
All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work
Ekhart C., de Jong L., Gross‐Martirosyan L., and van Hunsel F. (2016) Muscle rupture associated with statin use. Br J Clin Pharmacol, 82: 473–477. doi: 10.1111/bcp.12973.