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4/5/2011 Describe significant updates in pharmacotherapy within the past year Compare and contrast the risks and benefits of anticoagulation with dabigatran versus warfarin 15th Annual Primary Care Conference Larissa H. Bossaer, Pharm.D., BCPS [email protected] March 31st, 2011 Identify patients with diabetes who are eligible for primary prevention with aspirin based on current recommendations List current calcium and vitamin D recommendations Cariology Dabigatran etexilate (Pradaxa) Drug combinations for hypertension Choice of thiazide diuretic Dronedarone safety concerns Proton pump inhibitors (PPIs) and clopidogrel Diabetes Aspirin for primary prevention Rosiglitazone (Avandia) prescribing Pioglitazone (Actos) safety concern Gabapentin for neuropathy Osteoporosis Calcium and vitamin D recommendations Denosumab (Prolia) Delayed‐release risedronate (Atelvia) Bisphosphonates safety concerns 1 4/5/2011 Prodrug Indications Reduce risk of stroke and systemic embolism Converted to active drug by plasma esterases in the liver to the oral direct thrombin inhibitor (DTI), dabigatran In patients with non‐valvular atrial fibrillation Storage and Handling g g 75 mg or 150 mg capsules Bottles of 60 capsules each or blister cards Should be dispensed and kept in original bottle or blister card Protect from moisture and loss of stability Once a bottle is opened, capsules must be used within 30 days Should not be chewed or broken open Product information for Pradaxa 2010 Image from medscape.com Product information for Pradaxa 2010 Dose Normal renal function CrCl > 50 mL/min Start warfarin 3 days before stopping dabigatran 150 mg PO BID CrCl 31‐50 mL/min CrCl 15‐30 mL/min* CrCl 15‐30 mL/min Start warfarin 2 days before stopping dabigatran Start warfarin 1 day before stopping dabigatran 75 mg PO BID No recommendation for CrCl d f l < 15 mL/min or dialysis / d l Switching from dabigatran to warfarin Switching from warfarin to dabigatran Stop warfarin Start dabigatran when INR < 2 Switching from parenteral anticoagulants to dabigatran Switching from dabigatran to parenteral anticoagulants Start dabigatran 2 hours before last dose of LMWH Start dabigatran at time of discontinuation of IV heparin CrCl ≥ 30 mL/min 12 hours should elapse between last dose of dabigatran and first dose of parenteral anticoagulant *CrCl = [(140 – age) x Wt in kg x 0.85 if female] / 72 x Cr Product information for Pradaxa 2010 CrCl < 30 mL/min 24 hours should elapse between last dose of dabigatan and first dose of parenteral anticoagulant Product information for Pradaxa 2010 2 4/5/2011 Missed doses Take as soon as possible If < 6 hours until next dose, skip dose Safety Overall bleeding with dabigatran comparable to warfarin 3.11% versus 3.36% per year Stopping dabigatran prior to surgery Statistically higher rate of GI bleeding with dabigatran Statistically more intracranial bleeding with warfarin Statistically higher rate of MI with dabigatran than warfarin Restarting dabigatran after surgery Mortality rates from any cause were similar Perioperative bridging CrCl ≥ 50 mL/min Stop 1‐2 days prior p y p CrCl < 50 mL/min Stop 3‐5 days prior 0.74% versus 0.53% per year May be restarted once bleeding has stopped Tolerability Dyspepsia most commonly reported adverse effect (~11%) No evidence or recommendation Usually will not require bridging, unless surgery is delayed or patients are unable to take oral medications Product information for Pradaxa 2010 Pharmacist’s Letter/Prescriber’s Letter 2011;27(3):270310 Efficacy Superior to warfarin for prevention of stroke and systemic embolism in patients with non‐valvular atrial fibrillation NNT = 169 patients treated for one year to prevent one event 6 fewer events per 1000 patients treated for one year versus warfarin Product information for Pradaxa 2010 N Engl J Med 2009;361:1139‐51 Simplicity Twice daily dosing Less drug interactions and food interactions No INR lab monitoring No antidote for reversal Discontinuation due to dyspepsia Price Dabigatran Approximately $240 per month Cost‐effectiveness analysis recently published Accounted for adverse effects, including increased risk of MI Appears to be most cost‐effective in high risk patients (CHADS2 score ≥ 2) Warfarin Approximately $80 per month, including lab monitoring Product information for Pradaxa 2010 N Engl J Med 2009;361:1139‐51 Product information for Pradaxa 2010 N Engl J Med 2009;361:1139‐51 3 4/5/2011 Bridging with dabigatran to warfarin Pros Safety beyond 2 years is unknown More data needed Rapid onset Cons Additional issues Effects do not wear off for about 2 days ff d ff f b d Not approved for conditions requiring bridging (e.g.,DVT/PE, valves) No evidence for bridging with dabigatran in warfarin patients May increase INR Difficult to dispense a limited day supply In severe renal impairment To address increased incidence of MI To address increased incidence of GI bleeding dd i d i id f bl di To assess safety and efficacy with other antiplatelet agents Bottom Line Continue to use heparin or LMWH for bridging Pharmacist’s Letter/Prescriber’s Letter 2011;27(3):270310 Drug combinations Pharmacist’s Letter/Prescriber’s Letter 2010;26(11):261101 Most patients need multiple drugs to reach goal blood pressure Initiating 2 agents initially recommended if: 20 mmHg above systolic goal or 10 mmHg above diastolic goal Numerous drug combination products on the market New ones include: Amturnide (aliskiren/amlodipine/hydrochlorothiazide) Tekamlo (aliskiren/amlodipine) Tribenzor (olmesartan/amlodipine/hydrochlorothiazide) Consider data/characteristics of drugs to make decisions ACEI/ARB/aliskiren + thiazide Reduces risk of hypokalemia with thiazide Added blood pressure reduction PROGRESS trial Reduction of stroke with ACEI/thiazide combination ADVANCE trial Reduction of diabetes complications with ACEI/thiazide combination Beckett et al Reduction of mortality with ACEI/thiazide combination ACE/ARB + diuretic: good option for kidney disease patients Some patients may require loop diuretic JNC 7 J Am Soc Hypertens 2010;4:42‐50 JNC 7 J Am Soc Hypertens 2010;4:42‐50 Lancet 2007;370:829‐40 N Engl J Med 2008;358:1887‐98 Stroke 2002;33:319‐20 Pharmacists’ Letter/Prescribers’ Letter 2010;26(10):261001 4 4/5/2011 Beta‐blockers + thiazide Added blood pressure reduction Thiazides improve beta‐blocker efficacy in African‐Americans Beta‐blockers less effective than other drugs for hypertension Most data with atenolol Reserve beta‐blockers for patients with hypertension plus another i di ti (h t f il indication (heart failure, post‐MI, angina, etc.) t MI i t ) Potassium‐sparing diuretic + thiazide Reduces risk of hypokalemia with thiazide Risk of hyperkalemia in patients with CrCl < 50 mL/min No outcomes data Calcium channel blocker + ACEI or ARB ACEI/ARB offset CCB edema Added blood pressure reduction ACCOMPLISH trial Calcium channel blocker + thiazide No added blood pressure reduction Both cause renal sodium excretion and vasodilation Hypokalemia with thiazide VALUE trial CCB + thiazide was as effective as ARB + thiazide in reducing cardiovascular (CV) events with better blood pressure control ACEI + CCB superior to ACEI + thiazide for CV outcomes in high‐risk patients J Am Soc Hypertens 2010;4:42‐50 Lancet 2004;363:2022‐31 Pharmacists’ Letter/Prescribers’ Letter 2008;24(12)241206 Pharmacists’ Letter/Prescribers’ Letter 2010;26(10):261001 Additional combinations Aliskiren + ARB – no outcomes data Dihydropyridine CCBs + beta‐blockers – no outcomes data ACEI + ARB – minimal added blood pressure reduction, risk for side effects, may be recommended by specialists for systolic heart failure or proteinuria ACEI/ARB + beta‐blocker – minimal added blood pressure reduction, appropriate to combine these for systolic heart failure or post‐MI Nondihydropyridine CCBs + beta‐blockers – risk of heart block or bradycardia Methyldopa + beta‐blocker – risk of heart block or bradycardia, rebound hypertension Clonidine + beta‐blocker – risk of heart block or bradycardia, rebound hypertension Alpha‐blockers – lack of good outcomes data J Am Soc Hypertens 2010;4:42‐50 Pharmacists’ Letter/Prescribers’ Letter 2010;26(10):261001 JNC 7 J Am Soc Hypertens 2010;4:42‐50 N Engl J Med 2008;359:2417‐28 Pharmacists’ Letter/Prescribers’ Letter 2010;26(10):261001 Hydrochlorothiazide Chlorthalidone Indapamide Most commonly prescribed (at lower doses than original studies) ANBP2 trial – Blood pressure reduction similar in hctz and enalapril groups; enalapril superior in men for CV outcomes ACCOMPLISH – benazepril/amlodipine superior to benazepril/hctz for CV outcomes Meta‐analysis – hctz inferior to ACEI/ARB/CCB/BB for 24‐hour blood pressure control MRFIT – mortality trend unfavorable to hctz versus chlorthalidone ALLHAT – slightly better blood pressure control than lisinopril and amlodipine, better than amlodipine for heart failure risk, better than lisinopril for stroke risk SHEP – chlorthalidone +/‐ atenolol reduced stroke and CV events Reduced stroke, heart failure, all‐cause mortality in HTN pts 80 years and older J Am Coll Cardiol 2011;57:590‐600 N Engl J Med 2003;348:583‐92 N Engl J Med 2008;359:2417‐28 Pharmacists’ Letter/Prescribers’ Letter 2011;27(3):270304 5 4/5/2011 Hydrochlorothiazide Still has a role in hypertension Especially in combination with other drugs Chlorthalidone Consider in difficult to control blood pressure Provides better, more sustained BP control than hydrochlorothiazide without a higher risk of hypokalemia Safety issues Liver failure Reports, including 2 requiring transplantation Heart failure 1 in 4 reports involve cases of new or worsening heart failure Contraindicated in NYHA class IV or class II‐III with decompensation i di di l l i hd i Kidney failure Cases of kidney failure or reduced kidney function Arrhythmias Atrial tachycardia, bradycardia, ventricular tachycardia Indapamide Elevated INR with warfarin Consider especially in very elderly patients > 30 case reports, metabolized by CYP3A4 Improves CV outcomes in patients age 80 years and older Pharmacists’ Letter/Prescribers’ Letter 2010;26(10):261001 Pharmacists’ Letter/Prescribers’ Letter 2011;27(3):270304 http://www.fda.gov/Drugs/DrugSafety/ucm240011.htm Pharmacists’ Letter/Prescribers’ Letter 2011;27(2):20206 Proton Pump Inhibitors (PPIs) and clopidogrel Interaction with strong to moderate CYP2C19 inhibitors Omeprazole can decrease the antiplatelet effect by 20‐40% May increase cardiovascular events Avoid omeprazole or esomeprazole use with clopidogrel H2‐blockers may be a good alternative (not cimetidine) Consider pantoprazole if a PPI is required More information likely to come regarding this interaction Product information for Plavix 2011 Pharmacotherapy 2010;30:275‐89 Pharmacists’ Letter/Prescribers’ Letter 2009 (update December 2010);25(7):250706 6 4/5/2011 Previous recommendations Aspirin for primary prevention in diabetes patients Patients already being treated with rosiglitazone (Avandia) Patients with type 2 diabetes whose disease cannot be adequately managed with other antidiabetic medications and who are unable and unwilling to take pioglitazone (Actos) Over age 40 years Current recommendations Low‐dose aspirin (75‐162 mg/day) L d i i ( 6 /d ) 10‐year risk of CV disease > 10% AND not at risk for bleeding Includes most men over age 50 years or women over age 60 years with at least one other major CV risk factor, such as smoking, hypertension, dyslipidemia, family history, albuminuria Use risk factor calculators that include diabetes: Diabetes Care. 2010 Jun;33(6):1395‐402. http://www.fda.gov/newsevents/newsroom/pressannouncements/UCM226975.htm Bladder Cancer Ongoing, 10‐year epidemiological study to evaluate risk of bladder cancer with pioglitazone (Actos) No statistically significant association at the 5‐year mark No statistically significant association at the 5 year mark Further analyses showed increased risk among patients with the longest exposure and in those with the highest cumulative dose No conclusion yet to this safety concern Requirements for Use Providers prescribing rosiglitazone will have to attest to and document their patients’ eligibility Patients will have to review statements describing CV safety concerns and acknowledge they understand the risks http://www.dtu.ox.ac.uk/riskengine/index.php http://www.aricnews.net/riskcalc/html/RC1.html http://www.diabetes.org/phd Restricted Use Skepticism about off‐label uses Comparison of published reports versus the drug company’s internal documentation showed manipulation of primary outcomes Outcomes were changed to produce desired results and negative outcomes were not reported Independent reviewer compiled published and unpublished data into a review and concluded the following: Benefits for neuropathy are minimal Results with gabapentin should be seen within the first couple of days Doses > 900 mg/day may produce more side effects than benefits Consider findings when choosing drug therapy for diabetic peripheral neuropathy and other off‐label uses of gabapentin Pharmacists’ Letter/Prescribers’ Letter 2010;26(10):261002 N Engl J Med 2009;361:1963‐71 http://dida.library.ucsf.edu/tid/oxx18p10 7 4/5/2011 Meta‐analysis Showed that patients > 40 years old who take >/= 500 mg supplemental calcium without vitamin D have increased MI risk Did not address supplements with vitamin D No adequate control of other causes for increased CV risk BMJ 2010;341:c3691 Women: Up to age 50 ‐ 1,000 mg of elemental calcium After age 50 ‐ 1,200 mg of elemental calcium Men: Up to age 70 ‐ 1,000 mg of elemental calcium After age 70 ‐ 1,200 mg of elemental calcium Adults Up to age 70 years ‐ 600 IU After age 70 years ‐ 800 IU Higher levels associated with lower risk of falls, cancer, heart g , , disease, autoimmune disorders, etc. Try not exceed 2,000 mg of elemental calcium per day from food and supplements (average intake in an adult is 300‐600 mg/day from diet) Most experts recommend 1,000‐2,000 IU daily Upper limit of intake 4,000 IU of vitamin D daily (controversial) Monitor levels if higher doses are used IOM 2011 NOF Guidelines 2010 IOM 2011 NOF Guidelines 2010 8 4/5/2011 Indications Treatment of postmenopausal women with osteoporosis at high risk for fracture (i.e., a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other therapy Dose 60 mg subcutaneously Administered by a healthcare professional once every 6 months Injection sites include upper arm, upper thigh, or abdomen Let stand at room temperature for 15‐30 minutes prior to injection Product information for Prolia 2010 Image from medscape.com Safety Contraindicated in severe uncorrected hypocalcemia May exacerbate pre‐existing hypocalcemia May increase risk of infections Infections of the skin, abdomen, urinary tract, ear, and endocarditits were reported more frequently in studies; however, overall incidence of i f ti infection was similar between groups i il b t g Consider risk/benefits in immunosuppressed patients Product information for Prolia 2010 Increases bone mineral density Decreases non‐vertebral, vertebral, and hip fractures in post‐ menopausal women Lack of evidence for comparison with other drugs Tolerability Most common adverse effects include back pain, pain in extremities, hypercholesterolemia, musculoskeletal pain, and cystitis Pancreatitis was reported in studies Dermatitis, eczema, and rash occurred at a higher rate in studies Osteonecrosis of the jaw (ONJ) has been reported Product information for Prolia 2010 N Engl J Med 2009;361:756‐65 Efficacy Price $1600 per year, $130 per month Simplicity Every 6 month dosing Must be administered by healthcare provider N Engl J Med 2009;361:756‐65 Pharmacists’ Letter/Prescribers’ Letter 2010;26(8):260803 9 4/5/2011 Atelvia Long‐term bisphosphonate effects Several studies show up to 10 years of alendronate associated with sustained increases in BMD with no apparent harm Taken after breakfast Designed to reduce interference with cations Still advised to separate cations (e.g., calcium, iron) Still need to take with plenty of water and remain upright Cost similar to risedronate Risedronate will be generic in 2014 Should not take with antacids/H2 blockers/PPIs May be useful if patients are nonadherent to risedronate Only approved for treatment of osteoporosis, not prevention Only available as a weekly formulation FLEX Bone et al Watts et all N Engl Med 2004;350:1189‐99 JAMA 2006;296:2927‐38 Osteoporos Int 2008;19:365‐72 Product information for Atelvia 2010 Limited evidence 2 retrospective reviews No causal relationship proven Cohort study – no increased risk Case‐control study – increased risk No causal relationship proven Re‐evaluate use annually after initial 5 years of treatment Consider stopping bisphosphonates after 5 years in low risk patients Good response Total hip BMD >‐3.5 No steroids No history/risk of fractures Re‐evaluate at least every other year if stopped Restart if BMD falls more than 4‐5% at the spine or hip J Bone Joint Surg Br 2007:89:349‐53 Injury 2008;39:224‐31 Limited/conflicting evidence Actual risk is small b/c esophageal cancer is uncommon Unknown if risk occurs in weekly/monthly vs. daily regimens Pathophysiology makes sense Ensure proper patient counseling JAMA 2010;304:657‐63 BMJ 2010;341:c4444 10 4/5/2011 Describe significant updates in pharmacotherapy within the past year Compare and contrast the risks and benefits of anticoagulation with dabigatran versus warfarin Identify patients with diabetes who are eligible for primary prevention with aspirin based on current recommendations List current calcium and vitamin D recommendations 11
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