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Sheldon Gottlieb, M.D. and Paul A. Pham, Pharm.D.
01-26-2011
- Aspirin: primary prevention of cardiovascular events in diabetes: no FDA indication; absolute benefit small, NNT approx. 500. Older diabetic male smokers may benefit (Haynes, De Berardis, ATT collaboration), also patients with yearly risk of major vascular event greater than 1.5% to 3% per year ([older smokers, hypertension, obesity, albuminuria, dyslipidemia] may benefit (American Heart Association, ADA position statements, US Preventive Services Task Force).
- Aspirin: secondary prevention: Treatment of TIA and ischemic stroke; prevent recurrent MI; reduces risk of MI or sudden death in unstable angina and chronic stable angina; after angioplasty, CABG, carotid endarterectomy (FDA.gov, ATT collaboration, AHA, ADA position statements).
- Clopidogrel (Plavix): primary prevention: not established.
- Clopidogrel (Plavix): secondary prevention: acute coronary syndromes (unstable angina, non-ST elevation MI including those who are to be managed with coronary revascularization, ST elevation MI, after MI, stroke, established peripheral vascular disease (FDA drug information, March 2010)
- Warfarin: primary indication: not established.
- Warfarin: secondary indication: prophylaxis or treatment of thromboembolism in atrial fibrillation, mechanical heart valves; reduce risk of stroke or recurrent MI after MI; prophylaxis or treatment of venous thrombosis or thromboembolism in high-risk patients (FDA package insert).
- ASA is also indicated for reducing fever and in relief of minor muscular aches and joint pains. In combination with butalbital and caffeine, indicated for migraines.
- Anti-inflammatory (e.g pericarditis)
- Aspirin: irreversibly binds to (acetylates) and inhibits cyclo-oxygenase, thereby preventing formation of platelet aggregating factor thromboxane A2.
- Clopidogrel (Plavix): The active metabolite of clopidogrel irreversibly binds to the P2Y12 class of platelet ADP receptors thereby inhibiting platelet aggregation.
- Warfarin: inhibits vitamin K-dependent coagulation factors thereby inhibiting blood coagulation.
- Aspirin: 75-325 mg daily.
- Clopidogrel (Plavix) 75 mg daily. No dose adjustment in elderly.
- Warfarin: dose is highly individualized and depends greatly on genetic factors (CYP2C9 and VKORC1 genotypes), vitamin K intake, and co-administered drug. Usual daily dose ranges between 2 to 7.5 mg. Lower doses recommended in the elderly and pts with CYP2C9 and VKORC1 genotypes.
- Aspirin: avoid in severe renal failure (GFR<10mL/min).
- Clopidogrel (Plavix): "limited data, use with caution".
- Warfarin: lower doses in advanced renal failure. Use in dialysis patients with great caution, benefit may be low and warfarin may cause increased of vascular calcifications. See Bennett Clin J Am Soc Nephrol 1: 1357-1359, 2006.
- Aspirin: Avoid in "severe hepatic insufficiency".
- Clopidogrel (Plavix): no dose adjustment.
- Warfarin: use with caution, dosing is highly individualized, risk of bleeding complications is high in moderate to severe hepatic insufficiency.
- Aspirin: use "only if clearly needed" in category C in the first and second trimester of pregnancy. Contraindicated after third trimester due to potential effects on fetal circulation (potential closure of ductus arteriosus) and maternal bleeding.
- Clopidogrel (Plavix): pregnancy category B. Animal-reproduction studies have not demonstrated a fetal risk, but no human data.
- Warfarin: pregnancy risk category X. Contraindicated in woman who are or who may become pregnant. Warfarin passes placental barrier. High risk of fetal mortality and malformations.
- Aspirin: excreted in breast milk and should be avoided if possible. The American Academy of Pediatrics recommends that aspirin be used cautiously during breast-feeding.
- Clopidogrel (Plavix): avoid -- not known if excreted in human breast milk.
- Warfarin: high protein binding in maternal circulation, little is excreted in milk and warfarin is considered safe to use while breastfeeding (American Academy of Pediatrics).
- All anticoagulants may increase risk for bleed.
- ASA: GI intolerance (dose dependent)
- ASA: Tinnitus (with high-dose and/or long-term aspirin)
- ASA: esophageal, gastric, peptic ulcer
- ASA: nephrotoxicity (e.g AIN, pre-renal ATN)
- ASA: increased uric acid (dose dependent)
- ASA: rebound headache (with chronic use)
- ASA: acid base disturbance with overdose (e.g metabolic acidosis, raspatory alkalosis)
- Warfarin: Purple-toe syndrome secondary to cholesterol microembolization (onset between 3 and 10 weeks). Presents with purple discoloration, pain and tenderness of the toes. If warfarin is not discontinued, may result in gangrene and tissue necrosis.
- Warfarin: tracheobronchial calcification
- Warfarin: rash; ASA: allergic reaction, rash;
- ASA: pancytopenia (e.g leukopenia, thrombocytopenia, agranulocytosis, aplastic anemia)
- ASA: anaphylaxis reaction
- ASA: Reye syndrome (following varicella infection)
- ASA: hepatitis
- Clopidogrel: neutropenia, TTP, allergic reactions, anaphylaxis, hepatitis
- Aspirin: nonsteroidal anti inflammatory drugs interfere with the platelet binding of aspirin. Most side effects are dose related.
- Clopidogrel (Plavix): conversion to active metabolite by CYP2C19, whose inhibitors (e.g omeprazole, esomeprazole, cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine) may decrease the efficacy of clopidogrel. Avoid co-administration.
- Warfarin: potential interactions due to impaired hemostasis or clotting factor synthesis, competitive vitamin K antagonism, pharmacokinetic interactions due to hepatic enzyme induction (e.g rifampin) or inhibition (e.g fluconazole), reduced plasma binding, or due to multiple mechanisms. Specific diseases include but are not limited to blood dyscrasias, cancer, collagen vascular diseases, heart failure, diarrhea, elevated temperature, hepatic disorders, hyperthyroidism, poor nutritional state including vitamin K deficiency, steatorrhea.
- Warfarin's anticoagulant effect increased with cotrimoxazole, erythromycin, fluconazole, isoniazid, metronidazole, amiodarone, clofibrate, propafenone, propranolol, and sulfinpyrazone; phenylbutazone; piroxicam; alcohol, cimetidine, and omeprazole.
- Warfarin anticoagulant effect decreased with griseofulvin, rifampin, and nafcillin, barbiturates, carbamazepine, and chlordiazepoxide, cholestyramine, sucralfate.
- Individual drug interactions with warfarin are too numerous to list. See web site for additional drug interactions: http://www.drugs.com/drug-interactions/warfarin.html
- Patients need to be educated on possible drug interactions. See Table 2.
- The evidence for benefit of aspirin in primary prevention of CVD in diabetes is inconclusive and controversial (see Price and also Haynes).
- Our practice is to recommend preventive use of aspirin in people with diabetes judged to be a increased risk of CVD, e.g. those with type 1 for >20 years, or with type 2 plus other risk factors for CVD.
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