Statin Muscle-related Adverse Events Sharmisa Martin, APRN, MSN, - PowerPoint PPT Presentation

. Statin Muscle-related Adverse Events Sharmisa Martin, APRN, MSN, ANCC RIHVH Cardiology .

. Introduction • Statins: cholesterol lowering for both primary and secondary prevention. • Effective and generally safe. • Approximately 10% pts experience myalgias • Clinical Rhabdomyolysis: rare, perhaps 0.1% of Pts. Ann intern med 2002;137:617, JAMA 2004; 292:2585 • .

. Outline • Pathogenesis • Definition • Epidemiology • Risk factors • Clinical features • Diagnosis • Management .

. Pathogenesis • Mechanism for muscle toxicity not well understood. • Reduction in ubiquinone (Coenzyme Q10) • Increased fatty acid oxidation in statin intolerant pts. • Gene polymorphisms J Am Coll Cardio 2013; 61:44 • .

. Outline • Pathogenesis • Definition • Risk factors • Clinical features • Diagnosis • Management .

. Definitions: • Myalgia: a symptom of muscle discomfort, including muscle aches, soreness, stiffness, tenderness or cramps with or soon after exercise with a normal creatine kinase (CK). Myalgia symptoms can be described as similar to what would be experienced with a viral syndrome such as influenza. .

. Definitions: cont • Myopathy: muscle weakness (not due to pain) with or without elevation in CK level. • Myositis: muscle inflammation. .

. Definitions: cont • Myonecrosis: elevation in muscle enzymes compared to either baseline CK levels (While not on statin therapy) or the upper limit of normal that has been adjusted for age, race and sex: • Mild: 3 fold to 10 fold elevation in CK • Moderate: 20 fold to 50 fold elevation in CK. • Severe: 50 fold or greater elevation in CK .

. Definitions: cont • Clinical rhabdomyolysis: defined by the task force as myonecrosis with myoglobinuria or acute renal failure (an increase in serum creatinine of at least 0.5 mg/dl [44 micromol/L] ) Defined by 2014 National lipid association statin muscle task force. J Clin Lipidol 2014; 8:S58 • .

. Outline • Pathogenesis • Definition • Epidemiology • Risk factors • Clinical features • Diagnosis • Management .

. Epidemiology • Meta analysis of 42 randomized trials of statins found little or no excessive risk of myalgias, CK elevations, Rhabdo or discontinuation vs placebo. Am Heart J 2014;168:6 • Perceived side effects are common- esp muscle (60%) J Clin Lipidol 2012; 6:208 • Myonecrosis- CK 10x normal with muscle sx in less than 0.5% in trials . Arch Int Med 1996; 156:2085 .

. Outline • Pathogenesis • Definition • Epidemiology • Risk factors • Clinical features • Diagnosis • Management .

. Risk factors : Pt Characteristics • Genetics: esp. with Simvastatin. Chinese, esp with Simvastatin and Niacin. • Age >80, frail, female, small body frame, Liver disease and severe renal disease. • Pre-existing neuromuscular disorders. Esp. ALS, need cholesterol, increased survival Natl Acad Sci USA 2004; 101:11159 • Hypothyroidism, Low Vitamin D N Engl J Med 2008; 359:789, Can J Cardio 2013; 29:1553 • .

. Risk factors : Drug Therapy • Statin Characteristics: higher doses, increased incidence. • Hydrophilic vs hydrophobic : muscle penetration of statin. • CYP3A4 metabolism: Increased interactions with Simvastatin, Lovastatin . • Pravastatin, rosuvastatin: Hydrophilic, not extensively metabolized by CYP3A4 • Many drug interactions : HIV, antifungals, others J Am Coll Cardio 2017;70:1290 • .

. Risk factors : cont. • Exercise: unaccustomed vigorous exercise, increase in muscle injury. • Disease becomes clinically apparent with statins: Myasthenia gravis, myopathies, motor neuropathies. • Grapefruit juice: inhibits CYP3A4. Consumption of 8 oz or less, or ½ half grapefruit unlikely adverse interaction. Br J Clin Pharm 2011; 72:34 • .

. Outline • Pathogenesis • Definition • Epidemiology • Risk factors • Clinical features • Diagnosis • Management .

. Clinical features • Proximal, symmetrical muscle weakness and/or soreness, tenderness. • Possible functional impairment such as difficulty raising arms above head, arising from a seated position or stair climbing. • May include cramping, possibly nocturnal. • Elevations in serum CK in some but not all. • Onset: weeks to months. BMJ 2008; 337:a2286 • .

. Outline • Pathogenesis • Definition • Epidemiology • Risk factors • Clinical features • Diagnosis • Management .

. Diagnosis • Serum Creatine kinase (CK) elevation, 3 to 10 fold elevation. May be due to exercise, impact • Statin assoc muscle sx clinical index (SAMS-CI) • May have muscle sx with out CK elevation • Take history for other causes of myalgias • Muscle biopsy not typically used, unless sx don’t resolve with statin discontinuation. Ann intern med 2002;137:6581 • .

. What it is not • Joint pain esp if pre-existing. • Usually not unilateral. • Pts report pain after being warned of muscle side effects. Concerns may heighten perception of pain from other causes. • Single pt trials for statin myalgia Ann intern med 2014; 160:301 • .

. Outline • Pathogenesis • Definition • Epidemiology • Risk factors • Clinical features • Diagnosis • Management .

. Management • Discontinue therapy • If CK elevated, large amount of fluids to facilitate excretion on myoglobin • Assess drug interactions: HIV drugs, amiodarone, cyclosporine, fibrates, colchicine, niacin. • Assess for Vitamin D deficiency and hypothyroidism and correct. Then resume statin with careful monitoring. J Pharm2017; 30:521 • .

. Management • If Rhabdomyolysis: should not be treated with statin again due to risk of reoccurrence. • Switch statin :pravastatin, fluvastatin, pitavastatin – have fewer interactions • Alternate day dosing • May need lipid control for Coronary disease, consider lipid clinic referral for PCSK9 inhibitor J Pharm2017; 30:521 • .

. Management- other therapy • CoQ10: may play a role in myalgias but little evidence showing benefit. Anecdotal evidence for 30-250 mg QD. J Am Coll Cardio 2012;110:526 • Red yeast Rice: compound similar to lovastatin. May be tolerated but lack of outcome studies. Supplements not regulated Eur J Intern Med 2014; 25:592 • Niacin: Not recommended due to lack of evidence. .

. Summary • Myalgias and myopathy frequency 2-11%. • Severe myonecrosis, Rhabdo are rare, 0.5- 1.0%. • Can have myalgias without CK elevations. • Muscle injury risk higher with lovastatin, simvastatin and atrovastatin when taken with a drug that interferes with CYP3A4. .

. Summary- cont. • Increased susceptibility to myopathy in renal , liver disease and hypothyroidism. • Muscle symptoms may begin within weeks of starting and usually return to normal over days to weeks after discontinuation of statin. • CK: no routine monitoring, may check prior to initiation. Elevated with exercise. • Check interactions, Vit D, Thyroid . .

. Closing thought • Many pts complain of myalgias that they feel are due to the statin. Upon careful evaluation and discussion this may not be the case. .

. Questions .