L XI: DRUGS: 1. STATINS

Transcription

1 L XI: DRUGS: 1. STATINS Statins Classification Mechanism of action Pleiotropic effects Efficacy: -Lipid level -CV events Indications Aggressive lipid lowering Initiation and monitoring Toxicity and drug interaction

2 Statins Classification Source unatural: pravastatin, simvastatin, lovastatin usynthetic: atorvastatin, fluvastatin Solubility ulipophilic: simvastatin, atorvastatin, fluvastatin uhydrophilic: pravastatin, rosuvastatin How do statins work? Lipid lowering mechanisms: - Inhibit endogenous cholesterol synthesis. -Increase cholesterol clearance from the blood via increases in LDL-C receptor. Non-lipid (PLEIOTROPIC) effects

3 Mechanism of Action Competitive inhibition of HMG-CoA reductase Reduction in cholesterol synthesis Up-regulation of LDL receptor activity Potential Non Lipid Mechanisms-Pleiotropic Effects Plaque stability Endothelial Function enos expression Statins Anti-thrombotic Antinflammatory Vascular cytoprotection Anti-oxidant Immunomodulatory

4 Efficacy Lipid Level LDL-C: reduction: 18-55% HDL-C: increase: 5-15% TG: reduction: 7-30% CV Events Total mortality: 12-30% Coronary mortality: 24% Coronary events(ua/mi): 24-37% Stroke: 11-50% Indications of Statin Therapy Established CAD CAD equivalents Hypercholesterolemia Emerging/ Investigational Peripheral arterial disease Stroke Heart failure Dementia Macular degeneration Sepsis Hypertension Multiple sclerosis Renal failure Osteoporosis Graft vessel disease Prevention of diabetes Regression of atherosclerosis

5 Indications of Statin Therapy Established CAD CAD equivalents Hypercholesterolemia CAD Risk Equivalents* Diabetes mellitus (Patients >50 yrs + Microalbuminuria/Additional RFs) Symptomatic carotid art disease Peripheral art disease Abdominal aortic aneurysm Multiple risk factors that confer a 10-year risk of coronary events more than 20% (Framingham risk tables) *Patients with CAD have a risk of MI 20 times greater than those without CAD

6 Screening Egyptian Guidelines: Prevention of Atherosclerotic CVD Recommendations for Dyslipidemia Hypercholesterolemia Very high risk Start statins Physical activity Cholestrol lowering diet (3-6 6 months) Hypercholesterolemia Consider starting statins depending on: Risk profile LDL-C level No risk factors + LDL-C >210 mg/dl 1 RF + LDL-C >190 mg/dl >1 RF + LDL-C >160 mg/dl Diabetes with RF or Other CVD + LDL-C >130 mg/dl Initiation and Monitoring of Statin Therapy Life style modification should be stressed in all patients u u u Less calorie and weight reduction if overweight Low animal fat diet Physical exercise In chronic stable CAD start with a small or average dose of statin and increase every 6-8 weeks depending upon LDL-C level

7 Initiation and Monitoring of Statin Therapy (cont.) An elevation of LDL-C should be confirmed on at least two different laboratory measurements few days apart before considering statin therapy Statin therapy is generally a life long treatment. Discontinuation of statins is followed within few weeks by a rise in LDL-C to pretreatment levels Initiation and Monitoring of Statin Therapy (cont.) In ACS start with a large dose of statin aiming at aggressive lipid lowering and possible suppression of inflammatory reaction If large doses after titration fail to achieve the target LDL-C, combine statin with another lipid lowering agent in addition to aggressive dietary measures and weight reduction

8 Contraindications to Statins 1. Active or chronic liver disease 2. Unexplained persistent elevation of serum transaminases 3. Pregnant or lactating women 4. Conditions predisposing to renal failure secondary to rhabdomyolysis (sepsis, hypotension, trauma, severe endocrine or metabolic disorders) Initiation and Monitoring of Statin Therapy Alanine amino transferase (ALT), aspartate amino transferase (AST) and serum creatinine kinase (CK) should be measured before statin therapy Liver function values should be periodically monitored during treatment: u Approximately 12 weeks after starting therapy u Every 6-12 months thereafter Most ALT / AST elevations (< 3 times the upper limit of normal) are not a contraindication to initiating or continuing statintreatment as long as they are carefully monitored

9 Initiation and Monitoring of Statin Therapy (cont.) Evaluate muscle symptoms and CK before starting therapy Evaluate muscle symptoms 6 to 12 weeks after starting therapy and at each follow-up visit Obtain a CK measurement when persons have muscle symptoms Muscle Toxicity Ranges from mild myopathyto frank rhabdomyolysis (incidence - 1 to 7%) Dose-dependant Possible differences in myotoxic potential between individual statins Lipophilic statins are potentially more myotoxic

10 Myopathy Associated with Statin Therapy Myalgias -Muscle aches, soreness, or weakness Myopathy -Abnormal condition of the muscular tissues characterized by myalgias and CK levels >10x ULN Rhabdomyolysis -An acute, potentially fatal disease of skeletal muscle that entails destruction of skeletal muscle as evidenced by myoglobinemia and myoglobinuria Initiation and Monitoring of Statin Therapy (cont.) If muscle symptoms appear, withholding of statin treatment and measurement of CK If there is no CK elevation or if the CK value is < 3 times the upper limit of normal, statin use can continue with careful monitoring Discontinuation of statin treatment is mandatory for CK elevations >10 times the upper limit of normal

11 Muscle Soreness or Tenderness Creatine Kinase Estimation (ULN) < > 10 o Continue statin o Check thyroid o Continue statin o Close monitoring o Repeat weekly CK Stop statin Hepatotoxicity Almost any drug can cause an elevation in liver-enzyme levels 1 The incidence of elevated serum transaminases more than 3 times the upper limit of normal ranges from 0.1% to 2.7% with statin use * These elevations appear to be dose-related * The majority of patients with abnormal findings are asymptomatic: no evidence of cholestasis, jaundice, or other clinical symptoms of liver disease 1. Pratt DS, et al. N Engl J Med. 2000;342: Prescribing Information for Pravachol, Zocor, Lipitor, Baycol, Lescol, Mevacor

12 Hepatic Toxicity Progression to liver failure: exceedingly rare Reversal of transaminase elevation is frequent with reduction in dose No exacerbation of liver disease No worsening of outcome in persons with chronic transaminase elevations due to hepatitis B or C Treatment of hyperlipidemia may improve transaminase elevations in individuals with fatty liver Increased Risks of Statins Toxicity Elderly age (>80 yrs) more in women Small body frame Multisystem disease (e.g., chronic renal disease) Multiple medications Perioperative periods Specific concomitant drugs - Fibrates and nicotinic acid -Cardiovascular drugs: verapamil, amiodarone -Cyclosporine, antifungals,macrolide antibiotics

13 Variation in Response to Statins Response to statintherapy show considerable individual variation Reduction in LDL-C with the same agent can range from 76% to no change using the same dose Variation in response can be due to diet, concomitant drug therapy, time of administration Variation in Response to Statins (cont.) A reduced LDL-C response could be expected when statins are given with cytochrome P450 inducers (e.g. phenytoin, rifampicin, carbamazepine) An increased LDL-C response occurs with co-administration of cytochrome P450 inhibitors (e.g. cycloposprin, amiodarone, diltiazem, etc.,) which can increase risk of toxicity Differences in response may be due to genetic factors

14 Lessons from Statins Trials Statins reduce coronary events to patients with or without CAD. Relative risk reduction (RRR) increases as duration of therapy lengthens 1-2 y 3-4 y 5-6 y RRR 29 % 36% 55 % Event reduction is proportional to LDL-C lowering Across range of LDL-C studied lower is better Statins are safe Statins decrease incidence of coronary events in women Statins improve outcome in diabetics Statins reduce events to older patients (> 65 y) Statins reduce stroke/tia in patients with CAD Dosage of Statins Agent Trade Name Standard Daily Starting (mg) Range (mg) Atorvastatin Lipitor Fluvastatin Lescol Pravastatin Lipostat Simvastatin Zocor Rosuvastatin Crestor

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