10/11/2014. Laura C. Halder, Pharm.D. Postgraduate Year Two Pharmacy Resident Cardiology Abbott Northwestern Hospital Allina Health October 30, 2014

Transcription

1 Laura C. Halder, Pharm.D. Postgraduate Year Two Pharmacy Resident Cardiology Abbott Northwestern Hospital Allina Health October 30,

2 1. List two major changes to the 2013 cholesterol treatment guidelines. 2. Classify a statin as low, moderate, or high intensity. 3. Describe the recommended management of statin induced myopathy. Statins: Pravastatin (Pravachol) Atorvastatin (Lipitor) Rosuvastatin (Crestor) Simvastatin (Zocor) Niacin Fibrates Fish oil 2

3 Treat to target Issues with treat to target: 1. Unclear target in current clinical trial data 2. Unclear magnitude of risk reduction with each different target 3. Does not consider potential adverse effects from multidrug therapy 3

4 1 Clinical ASCVD Acute coronary syndrome History of MI Stable or unstable angina Coronary revascularization Stroke TIA Peripheral arterial disease No clinical ASCVD: 2 LDL 190 mg/dl 3 Diabetes age & LDL mg/dl 4 LDL mg/dl & estimated 10 year ASCVD risk 7.5% Exclusions: heart failure and dialysis ASCVD: atherosclerotic cardiovascular disease Low Intensity LDL <30% Pitavastatin 1 mg Fluvastatin mg Lovastatin 20 mg Pravastatin mg Simvastatin 10 mg High Intensity LDL 50% Atorvastatin mg Rosuvastatin mg Moderate Intensity LDL 30% - <50% Atorvastatin mg Pitavastatin 2 4 mg Fluvastatin 40 mg BID Fluvastatin XL 80 mg Lovastatin 40 mg Pravastatin mg Simvastatin mg Rosuvastatin 5-10 mg 4

5 Statin for secondary prevention 1 Clinical ASCVD Age 75 Age > 75 High intensity Moderate or high intensity* *Consider statin benefits, risks, and patient preferences No 2 LDL 190 mg/dl Yes Yes 3 Diabetes Age No High intensity Moderate intensity Yes Yes 4 ASCVD 7.5% No ASCVD risk 7.5% high intensity Moderate to high intensity Statin benefit unclear ASCVD risk calculated using 2 LDL 190 mg/dl High intensity statin Statin as primary prevention If age 21 and LDL 190: high intensity statin If unable to tolerate use highest intensity tolerated Evaluate for secondary causes Intensify statin for 50% decrease in LDL May add non-statin drug once statin maximized 5

6 3 Diabetes Age Moderate intensity ASCVD risk 7.5% high intensity If diabetes and LDL : Moderate intensity statin 10 year ASCVD risk 7.5%: high intensity statin If age <40 or >75, consider risks, benefits, and patient preferences when starting statin 4 ASCVD 7.5% Moderate to high intensity Statin benefit unclear If age 40 75, no diabetes, and LDL : Calculate 10 year ASCVD risk Risk 7.5%: moderate or high intensity Risk 5 7.5%: consider moderate intensity Risk < 5%: discussion about statin benefits, risks, and patient preferences New onset diabetes: cases per 100 patients Statins caused 54 new cases of DM but prevented 134 vascular events Hemorrhagic stroke: 0.01 cases per 100 patients Cognitive decline: no published evidence Similar rates to placebo in randomized trials 6

7 Multiple comorbidities Muscle disorders Renal or hepatic function dysfunction Previous statin intolerance Previous hemorrhagic stroke ALT > 3x ULN Drug interactions Age > 75 years Asian ancestry ULN: upper limit of normal Muscle symptoms Myalgia: Normal CK Myositis: Elevated CK Rhabdomyolysis: CK > 3x ULN CK: creatinine kinase Rate of muscle symptoms in trials: 1.5 5% Rate of muscle symptoms in practice: 5 10% Establish baseline muscle symptoms: Arthritis symptoms Muscle aches during activity Risk factors: Older age Female gender Smaller body size Hypothyroidism History of muscular problems 7

8 Mild moderate muscle symptoms: 1. Stop statin and evaluate possible causes 2. If symptoms resolve, give original or lower dose to establish causal relationship a) If causal relationship, switch to original or lower dose b) Once low dose tolerated, increase dose as tolerated 3. If symptoms do not resolve, consider other causes a) If other causes found, resume at original dose Severe muscle symptoms Immediately stop statin Check CK, creatinine, urinalysis No target LDL Baseline fasting lipid panel Repeat 4 12 weeks after initiating statin to assess adherence and response to therapy Two consecutive LDL < 40, reasonable to reduce statin dose 8

9 Baseline ALT and CK Check ALT & CK if signs of statin intolerance No longer check LFTs regularly Evaluation of diabetes onset per screening guidelines Few trials, most are observational No evidence of improved ASCVD outcomes when used in place of or in addition to statin May consider role in statin intolerance or less than anticipated response to statins Currently no evidence Choose best statin intensity for select patients Limited use of LDL levels Statin myopathy is not always a contraindication Role of non-statin agents still uncertain Therapeutic lifestyle modifications still have a role Unanswered questions: Role of non-statin agents in severe statin intolerance Statins in chronic kidney disease and HF 9

10 1. Identify three benefits of the novel oral anticoagulants compared to warfarin. 2. Compare the key differences between the novel oral anticoagulants. 3. Recognize two limitations of the novel oral anticoagulants. Warfarin Apixaban Rivaroxaban Dabigatran 10

11 Dabigatran (Pradaxa ) 2010 Rivaroxaban (Xarelto ) 2011 Apixaban (Eliquis ) 2012 Compared to warfarin: + Rapid onset of action + No routine lab monitoring + Few drug or dietary interactions + More predictable anticoagulant effect + Fixed dosing Lack of reversal agents Limited indications No indication for: Thromboembolism in oncology patients Mechanical valves Thrombophilia Pregnancy Cash price: NOAC: ~$3000/year Warfarin: ~48/year 11

12 Non Valvular A Fib VTE Treatment VTE Prophylaxis Dabigatran Yes Yes No No Rivaroxaban Yes Yes Yes Yes Apixaban Yes Yes Yes Yes Post Op VTE Prophylaxis Indication Dose CrCl (ml/min) Adjustment DVT & PE 150 mg BID > 30: none < 30 ml/min: not studied Atrial fibrillation 150 mg BID > 50 ml/min: none ml/min: 75 mg BID <30 ml/min: not studied Take with a full glass of water, with or without food Low protein binding dialyzable Half life: Normal: hours Elderly hours Mild to moderate renal impairment: hours Severe renal impairment: 28 hours Time to peak: 1 hour quick effect no bridging 12

13 Indication VTE treatment Dose 15 mg BID x 21 days, then 20 mg daily CrCl (ml/min) Dose Adjustment 30: none < 30: avoid use VTE prevention 20 mg daily 30: none < 30: avoid use Atrial fibrillation 20 mg daily > 50: none 15-50: 15 mg daily <15: avoid use HD: avoid use Post Op DVT prevention 10 mg daily > 50: none 30-50: none, use caution <30: avoid use HD: avoid use Bioavailability is dose dependent: 10 mg: % 20 mg: 66% 15 or 20 mg doses: administer with evening meal or largest meal of the day 10 mg dose: with or without food High absorption rate in stomach avoid use in feeding tubes distal to stomach Absorption: Rapid no bridging Max: 2 4 hours after administration Protein binding: high not dialyzable Half-life: Normal: 5 9 hours Elderly: hours 13

14 Indication Dose Renal Dose Adjustment Atrial fibrillation 5 mg BID VTE treatment 10 mg BID x 7 days, then 5 mg BID VTE Prophylaxis 2.5 mg BID after 6 months treatment 2.5 mg BID if two of the following: -- Age Body weight 60 kg -- SCr 1.5 No dose adjustment SCr > 2.5 or CrCl <25: not studied No dose adjustment SCr > 2.5 or CrCl <25: not studied Post Op DVT prevention 2.5 mg daily No dose adjustment CrCl <30: not studied First NOAC to consider weight and age for dosing! Take with or without food High protein binding not dialyzable Rapid onset no bridging Half-life: ~ 12 hours Dyspepsia (dabigatran) GI bleeding Hemorrhage Hematuria Anemia Epistaxis Bruising Bleeding risk factors: Concomitant anticoagulants Renal impairment Elderly Low body weight 14

15 Anticoagulants Antiplatelets CYP 3A4 inducers or inhibitors Amiodarone Dronedarone Azoles Carbamazepine Dabigatran Rivaroxaban Apixaban Thrombin Time (TT) Yes No No Activated Partial Thrombin Time (aptt) Yes Yes Yes Prothrombin time (PT) No Yes Yes International Normalized Ratio (INR) Specific Assay* No Yes Yes Peak 184 ng/ml 290 ng/ml 1.3 units/ml Trough 90 ng/ml 32 ng/ml 0.84 units/ml * Not readily available at most institutions * Does not assess efficacy of anticoagulation Always consider risk of thrombosis versus procedural risk of bleeding Planning is key with no reversal agents Rapid onset/offset = short period to hold drug 15

16 NOAC CrCl (ml/min) Last Dose Before Surgery (hrs) Resumption After Surgery (hrs) Major Minor Major Minor Dabigatran Rivaroxaban Apixaban General principles: 1. Discontinue NOAC 2. Baseline lab assessment Hgb, aptt, PT, TT Drug level Renal function 3. Supportive care Surgical procedures as appropriate Hydration Transfusion 4. Activated charcoal Must be given within 2 hours of last NOAC dose No specific agent or guidelines available Dialysis only an option for dabigatran Potential options PCC or Factor VII Not FDA approved Prothrombotic risk Limited evidence Conflicting data on impact of coagulation parameters Unknown efficacy on bleeding 16

17 Edoxaban (Lixiana ) Approved in Japan Factor Xa inhibitor Once daily Indications: A. fib and VTE treatment and prevention Renal dose adjusted Mechanism of action: Direct thrombin inhibitor: dabigatran Factor X inhibitor: rivaroxaban, apixaban Indications vary for each NOAC Dose varies based on indication and renal function Apixaban dose based on age, weight, and creatinine Rivaroxaban must be taken with food Poor candidates for NOAC: Active bleeding Hematologic disorder Prosthetic heart valve Poor renal function Pregnancy or breast feeding Liver disease Stable on warfarin (INR in range > 65%) Compliance and education is important! Careful perioperative management to limit bleeding risk Few options for reversal Individual drug levels are limited and facility specific 17

18 Levy JH. Pharmacology and Safety of New Oral Anticoagulants. Clin Lab Med. 2014; 34: Tran H, Joseph J, Young L, et al. New oral anticoagulants: a practical guide on prescription, laboratory testing, and peri-procedural/bleeding management. International Medicine Journal. 2014; 44: Lip GY and Agnelli G. Edoxaban: a focused review of its clinical pharmacology. Eur Heart J. 2014; 35(18): Stone NJ, Robinson J, Lichtenstein AH, et al ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. Circulation. 2013; 00: Katz DH, Intwala SS, Stone NJ. Addressing Statin Adverse Effects in the Clinic: The 5 Ms. J Cardiovasc Pharmacol Ther. 2014; Lopez-Jimenez F, Simha V, Thomas RJ, et al. A Summary and Critical Assessment of the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults: Filling the Gaps. Mayo Clin Proc. 2014; 89(9): Rivaroxaban [package insert]. Gurabo,, PR: Janssen Ortho, LLC; Apixaban [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; Dabigatran [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc;