Open access peer-reviewed chapter
Positive signals for statins related to motor disorders reported as ADR in VigiAccess™ not stated in the summaries of product characteristics (SPCs).
Abstract
The most spread drugs to treat dyslipidemia alone or with hypertriglyceridemia are statins. These active ingredients are considered safe and effective. But, with all drugs, there are adverse reactions related to them, in this case, muscular disorders such as myalgia and the complication of rhabdomyolysis. Furthermore, other adverse reactions are less studied but interesting to know, such as motor disorders. Pharmacovigilance tools must maintain the tracing of risks for effects that appear and search for positive signals; one of them is to analyze suspected adverse drug reactions of active ingredients reported through the international repository of the World Health Organization with an adaptation of data mining Bayesian methodology. Surprisingly, almost all positive motor signals are not stated as adverse drug reactions in technical factsheets and, at the same time, are related to some pleiotropic effects of statins. This chapter tries to summarize this evidence for specific pairs of statins and potential motor disorders for further investigation.
Keywords
- statin
- adverse reaction
- motor disorders
- pleiotropic effect
- positive signals
1. Introduction
HMG-CoA reductase inhibitors, most known as statins, are active ingredients capable of blocking the endogenous synthesis of cholesterol with the intention to reduce the high levels of LDL-cholesterol in blood. They are prescribed for hypercholesterolemia, with or without hypertriglyceridemia [1].
The safety of these drugs has been studied and followed up over time. The low occurrence of severe adverse events (e.g., rhabdomyolysis and increased transaminases) and widespread use lead to a relaxation in the observation and prevention of other events, less frequent or severe but the quality of life of patients [2].
We must consider that one of the former statins, cerivastatin, was withdrawn due to an adverse drug reaction (ADR) classified as rare such as rhabdomyolysis with potential lead to kidney failure [3, 4]. So, it could be interesting to get inside potential rare or very rare ADRs with statins stated or not stated in fact sheets.
Most adverse reactions with statins reported in summaries of product characteristics (SPCs) as rare or very rare are associated with blood (anemia, thrombocytopenia), gastrointestinal disorders (constipation, abdominal pain, flatulence, dyspepsia, diarrhea, nausea, vomiting, pancreatitis), hepatobiliary disorders (cholestasis, hepatic failure), immune system disorders (anaphylaxis), musculoskeletal and connective tissue disorders (myopathy, myositis, rhabdomyolysis, tendinopathy including rupture), nervous system (headache, paresthesia, dizziness, peripheral neuropathy), skin and subcutaneous disorders (angioneurotic oedema, dermatitis bullous), reproductive system and breast disorders (gynecomastia), sense disorders (visual disturbance, hearing loss), and general disorders (asthenia, fatigue) [3, 5].
But, beyond these last general disorders and musculoskeletal-related reactions, no one motor disorder appears as ADR in SPCs.
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2. What motor disorders are candidates
VigiBase® is the unique World Health Organization (WHO) global database for suspected ADRs maintained by the Uppsala Monitoring Centre (UMC) since 1968. It is a starting point to offer a reference view of early signals of statin’s adverse reactions related to motor disorders to consider in therapeutics and future clinical research.
The free-user interface VigiAccess™ of this database allows one to search for all data coming from over 110 countries, undersigning a statement of the responsibility for the appropriate use and interpretation of data [6]. Nowadays, free access to national and international reporting ADR databases is essential for investigating new signals and possible risks of drugs.
For the present review, there are included data of the entire chemical subgroup of the Anatomical Therapeutic Chemical (ATC) Classification System C10AA “HMG CoA reductase inhibitors”—atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin [7]. Signals for cerivastatin—withdrawn in 2001—are included and analyzed as of contrast.
In this database, it is plausible to approach the frequency of suspected ADR using the data mining methodology developed and is used by de UMC as the WHO Collaborating Centre for International Drug Monitoring that is Bayesian Confidence Propagation Neural Network (BCPNN) [8], extensions [9, 10, 11, 12, 13] and adaptations with a correct interpretation of the signals [14, 15, 16, 17, 18].
The R® free software v3.4.1. R [19] and PhViD® Package v1.0.8 [20] were applied to obtain positive signals. Details of the algorithm performed are reported in Appendix A.
All signals of statins related to motor disorders were extracted among the positive ones and categorized according to the Medical Dictionary for Regulatory Activities (MedDRA) [21]. The aggrupation for statin-positive signals obtained was related to similar pathology following MedDRA, e.g., ataxia (that includes general and cerebellar); Parkinson (that includes disease, Parkinsonism) (see Appendix B).
Almost the totality of the positive signals observed in this preliminary analysis is not reported in SPCs. Subgroups of positive signals were stratified and summarized considering signals of motor disorders in the following: ataxia, Parkinson, movement disorders, (see Table 1) and other symptoms related to motor disorder conditions such as akathisia, akinesia, cogwheel rigidity, joint stiffness, musculoskeletal stiffness, muscle rigidity, fatigue, tremor (see Table 2). Fatigue for pravastatin was the only one reported in fact sheets.
| Statin/ADR | Ataxia and related | Parkinson and related | Movement disorders and related |
|---|---|---|---|
| Cerivastatin | movement disorders | ||
| Atorvastatin | Parkinson’s disease | ||
| Fluvastatin | general | ||
| Lovastatin | general | ||
| Pitavastatin | Parkinsonism | ||
| Pravastatin | eye movement disorder | ||
| Rosuvastatin | Parkinson’s disease | ||
| Simvastatin | general; cerebellar | Parkinsonism |
Table 1.
| Statin/ADR | akathisia | akinesia | cogwheel rigidity | joint stiffness | Musculo skeletal stiffness | muscle rigidity | fatigue | tremor |
|---|---|---|---|---|---|---|---|---|
| Cerivastatin | x | |||||||
| Atorvastatin | x | x | ||||||
| Fluvastatin | ||||||||
| Lovastatin | ||||||||
| Pitavastatin | x | x | ||||||
| Pravastatin | x | |||||||
| Rosuvastatin | x | x | ||||||
| Simvastatin | x | x | x | x |
Table 2.
Other positive signals for statins related to motor disorders reported as ADR in VigiAccess™ not stated in the summaries of product characteristics (SPCs).
The following is an analysis of the evidence on the possible pleiotropic effects of statins related to the selected motor adverse reactions. All searches for evidence were made in the Medline database via Pubmed® [22].
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3. Pleiotropic effects and positive motor disorders
There is wide evidence that statins reduce vascular events such as coronary atherosclerotic heart disease and ischemic stroke. This treatment for dyslipidemias is almost constitutive in people over 65 years of age, and more in people over 80 [23]. But increasing age gets an implicit risk factor for adverse events such as myopathy, cognitive impairment, or motor disorders related to pleiotropic effects.
3.1 Deficient synthesis of coenzyme Q and ataxia
In the preliminary analysis, simvastatin is the only one that showed a positive signal of cerebellar ataxia and elevated numbers for general ataxia. Followed in the distance by lovastatin and fluvastatin that present only signals of general ataxia, these two last ones can be used as a control in studies to differentiate general ataxia from cerebellar ataxia for statins. The rest of the statins do not appear to generate situations related to ataxia, a fact to consider in the prescription of patients with a risk of this condition.
Some studies focus on the influence of coenzyme Q10 (CoQ10) deficiency-related to motor symptoms such as Friedreich’s ataxia, Parkinson’s, and Huntington’s diseases [24]. CoQ10 is an antioxidant component of oxidative phosphorylation in mitochondria. Due to farnesyl pyrophosphate being a critical intermediate for CoQ10 synthesis, blockage of this step by statins may be important in the occurrence of myopathy and also has been associated with encephalomyopathy, severe infantile multisystemic disease, cerebellar ataxia, nephrotic syndrome, and isolated myopathy [25].
There are case series of patients with cerebellar ataxia due to statins use, which the authors considered probably related to coenzyme Q10 deficiency [26]. But the exposures to CoQ10, statins, and vitamin E did not appear to influence the clinical progression of spinocerebellar ataxia within 2 years [27].
Additionally, decreased levels of Coenzyme Q-10 have been demonstrated in diseased myocardium and Parkinson’s disease [25]. Again, statins interfere with the synthesis of coenzyme Q10, and its deficiency is related to motor symptoms [24].
3.2 Inhibition of statin metabolism and masking neuromuscular disorder
All statins, except pravastatin, are metabolized by the CYP450, any drug that induces or inhibits CYPs can alter statin levels. Pravastatin is eliminated virtually unchanged by phase II reactions (conjugation to increase water solubility). This situation leads to underdose or overdose of statins [28].
Ataxia is an ADR also observed with another drug as carbamazepine or ergotamine, following the addition of a CYP3A4 inhibitor.
It is well recognized that statins affect muscular tissue adversely but, at the same time, these agents may act as unmasking agents in asymptomatic patients with a latent neuromuscular disorder. Muscular symptoms or increased serum CK levels persisting after statin treatment discontinuation should alert the clinician to pursue further diagnostic evaluations for the detection of potential underlying neuromuscular diseases [29].
Also, this situation can occur in patients with central nervous system metabolic disorders; as reported in cases of acute ataxia coincident with statin onset in individuals with bipolar disorder [30].
3.3 Hydrophilic: lipophilic balance and Parkinson risk
In the preliminary analysis, the statins more related to Parkinsonism were simvastatin and pitavastatin and Parkinson disease (PD) for atorvastatin and rosuvastatin.
Due to that plasma (S)24-OH-cholesterol seems inversely linked to Parkinson’s disease [31], it could lead to those higher levels of total and low-density lipoprotein cholesterol over time indicating a decreased PD risk [32].
The authors of a recent publication also consider that statin use may have a detrimental effect on baseline nigrostriatal dopamine degeneration and long-term outcomes in patients with Parkinson’s disease [33].
The use of lipophilic statin (simvastatin, lovastatin, atorvastatin, fluvastatin, and pitavastatin) was associated with a higher risk of PD, and the stronger association in initial use suggests a facilitating effect [34], but the effect in long-term studies fades as the evidence of their benefits in Parkinsonism [35].
But hydrophobicity is a key determinant for blood-brain barrier penetrance, and this recently suggests that hydrophilic, but not lipophilic, statins may be associated with faster PD progression [36].
There is an ongoing randomized control trial “PD STAT” for simvastatin as a neuroprotective treatment for PD with no results posted at the present [37].
The reality is that in patients with Parkinson, statins are less used without clear evidence. In a study, it was observed that over 60% of recent-onset PD patients have high or medium cardiovascular risk, which is associated with a worse motor and cognitive phenotype, but statins are underused in these patients [38].
3.4 Dopamine levels and negative motor symptoms in schizophrenia
Some symptoms of Parkinsonism, such as slowness of movements, muscle rigidity, increased appetite, and decreased energy were the most common adverse effects described in a randomized control trial with lovastatin versus placebo in schizophrenic drug-treated patients [39].
Nonetheless, there is conflicting evidence around statins as adjuvant therapy in schizophrenic drug-treated patients. The named trial did not observe differences between lovastatin and placebo [39], but a posterior meta-analysis concluded statins could improve psychiatric symptoms, either positive symptoms or negative symptoms [40]. In a recent review, authors indicate that, in patients with schizophrenia, negative motor symptoms may be reduced by adjuvant statin therapy [41].
In this sense, it would be interesting to deeply study the effect of statins—simvastatin, atorvastatin, pitavastatin—in schizophrenia.
3.5 Exclusive eye of movement disorders and underdiagnosis of Huntington/Parkinson disease
In the preliminary analysis, it was observed a unique positive movement disorder signal for pravastatin and eye movement disorder with high sensitivity. Perhaps this ADR could be used as an alarm for surrounding movement disease not diagnosed.
Concerning general movement disorders, it is difficult to extract conclusions from former studies [42] but now statins seem to be protective [43, 44].
Also, there is evidence of movement disorders that appear as ADR due to a delay in the diagnosis in patients with Huntington’s disease with premotor symptoms [45] or Parkinson’s disease [43].
3.6 Changes in electric transmission and motor neuropathy
A study of long-term statin use revealed an increased risk of peripheral neuropathy [46], ADR reported in fact sheets. Electrodiagnostic changes have been detected in motor and sensory nerves in nerve conduction studies of these patients. If motor nerves are affected the movement is compromised.
The authors consider that early detection of peripheral neuropathy and changing hypercholesterolemia treatment may prevent permanent nerve damage. They offer also as a reference that the assessment of neurological symptoms, like tingling, numbness, pain, tremor in the hands and feet, and unsteadiness during walking may be useful in the follow-up of the patients on long-term statin treatment.
3.7 Anti-inflammatory and immunosuppressor effect and less join pain/stiffness
Regarding to other positive signals related to motor disorders observed (akathisia, akinesia, cogwheel rigidity, joint stiffness, musculoskeletal stiffness, muscle rigidity, fatigue, tremor), the signals with more sensitivity in the analysis were akathisia with simvastatin, muscle rigidity with pravastatin, and signals of musculoskeletal stiffness and tremor for the more recent included pitavastatin. Only fatigue is reported in SPCs of pravastatin. Fluvastatin and lovastatin are free of all these signals and can be candidates for statin interchange.
Some of these symptoms are shared with other co-morbidities as rheumatoid arthritis. There is evidence of the pleiotropic effects of statins on ameliorating rheumatoid arthritis activity and mediating clinically apparent anti-inflammatory effects in the related autoimmune inflammation, which lead the authors to recommend statins as a potent treatment for these patients [47].
Other investigators have established that associations between statin use, and poor physical functioning, and self-rated health may be explained by factors other than joint pain/stiffness, e.g., muscle pain [48]. So, the affectation of statins in these other motor symptoms would be complicated to differentiate from the known effect of myalgia by statin use rather than the real appearance of these conditions.
This deduction could be plausible with respect to akathisia, akinesia, cogwheel rigidity, joint stiffness, muscle rigidity, and musculoskeletal stiffness, but less simple to understand the relationship between fatigue and tremor. At the same time, there is no evidence that statin use was protective in essential tremor [49].
As summary, due to the scarcity of strong evidence, it is relevant to propose a list of each statin and motor disorders with potential pleiotropic correlation (Table 3).
| Statin | ADR |
|---|---|
| Atorvastatin | Parkinson (disease) |
| Others: joint stiffness; musculoskeletal stiffness. | |
| Fluvastatin | Ataxia (general) |
| Lovastatin | Ataxia (general) |
| Pitavastatin | Parkinson (Parkinsonism) |
| Others: Musculoskeletal stiffness*; tremor*. | |
| Pravastatin | Movement disorders (eye movement disorder*) |
| Others: Muscle rigidity* | |
| Rosuvastatin | Parkinson (disease) |
| Others: Musculoskeletal stiffness; tremor. | |
| Simvastatin | Ataxia (general; cerebellar) |
| Parkinson (Parkinsonism*) | |
| Others: akathisia*; cogwheel rigidity; fatigue; tremor. |
Table 3.
List of early positive signals of motor and related disorders detected for each statin agent and proposed to priority clinical investigation.
High specificity and sensitivity.
3.8 Limitations of the study
In the preliminary analyses, values of specificity and sensitivity of the BCPNN methodology, it is known that are typically low (21). Nonetheless, it is acceptable with very high specificity and low but conservative sensitivity, as it can be observed with typical positive signals of rhabdomyolysis and myopathy with statins, among others (see Appendix C).
Data analyzed are previous and not influenced by interactions with SARS-CoV-2 infections, pharmacological treatments, or vaccines.
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4. Conclusions
In the sight of the evidence collected, statins—beyond are considered equivalent and interchangeable regarding efficacy—are different in the interaction with patients with specific comorbidities or risk factors. So, the prescription of an indiscriminate statin converts the possibility to suffer a motor disorder into an ADR random discovery.
According with the pleiotropic effects discussed, several motor signals detected and proposed to further investigation such as musculoskeletal stiffness and tremor for pitavastatin, musculoskeletal rigidity and eye movement disorder for pravastatin, and Parkinsonism and akathisia for simvastatin.
This review may perform as a reference to statin interchange in case of detecting any early motor ADRs, as well as a starting point for future research. In both cases, due to the low positive motor signals detected, fluvastatin and lovastatin were positioned as the safer candidates.
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Acknowledgments
To the European University of Miguel de Cervantes (UEMC, Valladolid, Spain), for giving me time and permission to perform this study.
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A.1 Fundamentals of the method
This method to detect adverse drug reaction (ADR) signals was improved by Uppsala Monitoring Centre of the World Health Organization with an extension to the multiple comparison setting. The key estimator is the calculated Bayesian false discovery rate (FDR) and the threshold to a positive signal fixed in FDR < 0.05 [12, 13].
Obviously, adaptations of this methodology can be valuable and trustworthy with a correct interpretation of the signals [14]. The adaptation applied in this study consists in contrasts all the ADR of a specific ATC subgroup isolated from the integral database. In this case, the chemical subgroup C10AA “HMG CoA reductase inhibitors” [15] was considered in the analysis. This adaptation was previously applied and approved robustness and consistency with other specific groups of drugs [16, 17, 18].
All signals of statins were obtained. Those ADRs related to motor disorders were extracted among the positive ones and categorized according to the standard terminology used in VigiAccess™, in essence, high-level terms (HLT) including preferred terms (PT) of the Medical Dictionary for Regulatory Activities (MedDRA) [21].
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A.2 Details of algorithm performed
In this analysis, the algorithm was performed with the following arguments: value of the relative risk (RR) proven to be higher than 1 (RR < 1); minimum number of cases per pair [drug-adverse reaction] to be potentially considered as a signal (N = 1); rule of decision for the generation of signals: false discovery rate (FDR); limit or threshold for the decision rule: FDR > 0.05; statistics used for ordering the drug-ADR pairs: posterior probability of the null hypothesis (post.H0); calculation of the distribution of the statistic of interest: by approximation to the normal distribution [8, 50] and using empirical estimation through Monte Carlo simulations (NB.MC = 10,000) [51]. The estimator of FDR < 0.05 and specificity (Sp) ≥0.99 are considered to interpret the results. Sensitivity (Se) values are typically low in the BCPNN approach [52], Se ≥0.20 is considered as reference.
The estimator FDR assures that at least 95% of the signals detected are positive (only 5% of false positives). Moreover, if the estimator of false negatives (FNR) is 50% or lower, it implicates that, at least, half of the signals rejected are effectively negative. In the results presented, all the FNR were lower than 49%.
Detailed results of positive signals (FDR < 0.05; Specificity ≥0.99) of motor disorders related with statins reported as adverse drug reaction (ADR) in VigiAccess™ database and analyzed by a contrasted approach of Bayesian Confidence Propagation Neural Network (BCPNN) extended to the multiple comparison setting for active ingredients groups.
Interpretation of items: drug code: active ingredient reported; event effect: ADR reported; count: number of couples “active ingredient-ADR” reported; post.H0: posterior probability of null hypothesis; FDR: False Discovery Rate; FNR: False Negative Rate; Se: Sensitivity (* ≥ 0.20); Sp: Specificity.
Ataxia, cerebellar ataxia.
| Drug Code | Event Effect | Count | Post.H0 | FDR | FNR | Se | Sp |
|---|---|---|---|---|---|---|---|
| Fluvastatin | Ataxia | 11 | 0.044 | 0.009 | 0.448 | 0.149 | 0.999 |
| Lovastatin | Ataxia | 39 | 0.000 | 0.000 | 0.482 | 0.023 | 1 |
| Simvastatin | Ataxia | 87 | 0.000 | 0.000 | 0.475 | 0.051 | 1 |
| Simvastatin | Cerebellar ataxia | 7 | 0.101 | 0.025 | 0.435 | *0.198 | 0.995 |
Parkinsonism, Parkinson’s disease.
| Drug Code | Event Effect | Count | Post.H0 | FDR | FNR | Se | Sp |
|---|---|---|---|---|---|---|---|
| Pitavastatin | Parkinsonism | 3 | 0.119 | 0.032 | 0.431 | *0.212 | 0.993 |
| Simvastatin | Parkinsonism | 20 | 0.104 | 0.026 | 0.434 | *0.200 | 0.995 |
| Atorvastatin | Parkinson’s disease | 63 | 0.045 | 0.009 | 0.448 | 0.149 | 0.999 |
| Rosuvastatin | Parkinson’s disease | 54 | 0.000 | 0.000 | 0.474 | 0.055 | 1 |
Movement disorders; eye movement disorder.
| Drug Code | Event Effect | Count | Post.H0 | FDR | FNR | Se | Sp |
|---|---|---|---|---|---|---|---|
| Pravastatin | Eye movement disorder | v5 | 0.107 | 0.027 | 0.434 | *0.202 | 0.995 |
| Cerivastatin | Movement disorder | 90 | 0.000 | 0.000 | 0,480 | 0.034 | 1 |
Other motor symptoms related: akathisia, akinesia, cogwheel rigidity, joint stiffness, musculoskeletal stiffness, muscle rigidity, fatigue, tremor.
| Drug Code | Event Effect | Count | Post.H0 | FDR | FNR | Se | Sp |
|---|---|---|---|---|---|---|---|
| Simvastatin | Akathisia | 5 | 0.149 | 0.043 | 0.424 | *0.237 | 0.990 |
| Cerivastatin | Akinesia | 4 | 0.136 | 0.038 | 0.427 | *0.227 | 0.991 |
| Simvastatin | Cogwheel rigidity | 5 | 0.053 | 0.011 | 0.446 | 0.158 | 0.998 |
| Pravastatin | Fatigue | 626 | 0.004 | 0.000 | 0.466 | 0.087 | 1 |
| Simvastatin | Fatigue | 2174 | 0.002 | 0.000 | 0.468 | 0.078 | 1 |
| Atorvastatin | Joint stiffness | 211 | 0.071 | 0.016 | 0.442 | 0.174 | 1 |
| Pravastatin | Muscle rigidity | 12 | 0.146 | 0.042 | 0.424 | *0.235 | 0.990 |
| Atorvastatin | Musculoskeletal stiffness | 610 | 0.016 | 0.003 | 0.458 | 0.115 | 1 |
| Pitavastatin | Musculoskeletal stiffness | 25 | 0.154 | 0.046 | 0.422 | *0.243 | 0.989 |
| Rosuvastatin | Musculoskeletal stiffness | 416 | 0.000 | 0.000 | 0.477 | 0.043 | 1 |
| Pitavastatin | Tremor | 28 | 0.106 | 0.027 | 0.434 | *0.201 | 0.995 |
| Rosuvastatin | Tremor | 400 | 0.009 | 0.001 | 0.461 | 0.103 | 1 |
| Simvastatin | Tremor | 394 | 0.024 | 0.004 | 0.455 | 0.126 | 0.999 |
Detailed results of positive signals (FDR < 0.05; Specificity ≥0.99) of disorders referred in main manuscript related to statins reported as ADR in VigiAccess™ database and analyzed by a contrasted approach of Bayesian Confidence Propagation Neural Network (BCPNN) extended to the multiple comparison setting for active ingredients groups
Interpretation of items: drug code: active ingredient reported; event effect: ADR reported; count: number of couples “active ingredient-ADR” reported; expected count: couples “active ingredient-ADR” expected; post.H0: posterior probability of null hypothesis; n11/E: ratio between the count observed and the count expected of the corresponding couple; drug margin: number of reports of a drug; event margin: number of reports of an event; FDR: False Discovery Rate; FNR: False Negative Rate; Se: Sensitivity(* ≥ 0.20); Sp: Specificity.
Rhabdomyolysis.
| Drug Code | Event Effect | Count | Post.H0 | FDR | FNR | Se | Sp |
|---|---|---|---|---|---|---|---|
| Cerivastatin | Rhabdomyolysis | 5219 | 0 | 0.000 | 0.488 | 0.001 | 1 |
| Simvastatin | Rhabdomyolysis | 4873 | 0.000 | 0.000 | 0.487 | 0.004 | 1 |
Transaminases increased.
| Drug Code | Event Effect | Count | Post.H0 | FDR | FNR | Se | Sp |
|---|---|---|---|---|---|---|---|
| Fluvastatin | Transaminases increased | 128 | 0.000 | 0.000 | 0.487 | 0.010 | 1 |
| Atorvastatin | Transaminases increased | 787 | 0.000 | 0.000 | 0.477 | 0.048 | 1 |
| Simvastatin | Transaminases increased | 467 | 0.000 | 0.000 | 0.474 | 0.059 | 1 |
Myalgia.
| Drug Code | Event Effect | Count | Post.H0 | FDR | FNR | Se | Sp |
|---|---|---|---|---|---|---|---|
| Simvastatin | Myalgia | 11,860 | 0.000 | 0.000 | 0.487 | 0.005 | 1 |
| Fluvastatin | Myalgia | 1588 | 0.000 | 0.000 | 0.487 | 0.007 | 1 |
| Pravastatin | Myalgia | 3209 | 0.000 | 0.000 | 0.485 | 0.014 | 1 |
| Lovastatin | Myalgia | 2278 | 0.071 | 0.016 | 0.442 | 0.174 | 0.997 |
Myopathy.
| Drug Code | Event Effect | Count | Post.H0 | FDR | FNR | Se | Sp |
|---|---|---|---|---|---|---|---|
| Lovastatin | Myopathy | 499 | 0.000 | 0.000 | 0.487 | 0.006 | 1 |
| Cerivastatin | Myopathy | 566 | 0.000 | 0.000 | 0.486 | 0.010 | 1 |
| Simvastatin | Myopathy | 1327 | 0.000 | 0.000 | 0.485 | 0.014 | 1 |
| Fluvastatin | Myopathy | 171 | 0.000 | 0.000 | 0.479 | 0.035 | 1 |
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