ANTHROMBOTICS AND THROMBOLYTICS

See also "Antithrombotics for prevention of CAD" and "Antithrombotics for the Prevention of Cancer"

Heparins Including Low-Molecular-Weight Heparins
 Heparin Analogues (Synthetic)
Warfarin
Non-Warfarin Oral Anticoagulants
Thrombolytics
Antiplatelets including Aspirin
Platelet Glycoprotein IIb/IIIa Inhibitors

I. Heparins:

  1. All Heparins work by forming a complex with Antithrombin III that more avidly inactivates thrombin and factor Xa
  2. Unfractionated Heparin
    1. Follow PTT & plat. count daily
    2. Anti-inflammatories increase t-1/2
  3. Low-molecular-weight heparins--result in less inhibition of thrombin than unfractionated Heparin
    1. Enoxaparin (Lovenox)
      1. See under "Preoperative Evaluation" for use of enoxaparin prior to invasive procedures for patients on Warfarin anticoagulation
      2. Renally cleared, dose should be reduced in patients with severe renal insufficiency
    2. Ardeparin
    3. Dalteparin (Fragmin) 100IU/kg SQ BID
    4. Tinzaparin (Innohep) 175IU/kg SQ QD
  4. Adverse effects
    1. Abnormal bleeding, including intracranial hemorrhage
    2. Thrombocytopenia--Caused by formation of IgG antibodies against completex of Platelet Factor 4 and Heparin; can recur with future challenge with Heparin; can be ass'd with thromboembolism as late as 2wks after cessation of treatment

II. Synthetic Heparin Analogues

  1. Bivalirudin
    1. A synthetic peptide derived from leech anticoagulant protein hirudin.  Binds to the thrombin catalytic active site & the substrate-binding exosite.
    2. Administered by IV infusion; PTT monitoring required; Coagulation time returns to baseline 1h after discontinuation (half-life around 25min)
    3. A possible alternative to heparin--doesn't cause thrombocytopenia like heparin; less incidence of major hemorrhage than heparin
  2. Fondaparinux (Arixtra) 2.5mg SQ QD
    1. A synthetic polysaccharide Heparin analogue
    2. Inhibits activated factor Xa without any inhibition of thrombin
    3. Does not cause thrombocytopenia
    4. Has been studied for treatment of pulmonary embolus and prevention of DVT as well as for Acute MI and Other Acute Coronary Syndromes (click on links for info)
  3. Org31540/SR90107A--A synthetic pentasaccharide that binds to and induces a structural change in aantithrombin which then inhibits activated factor X and interrupts the coagulation cascade.
  4. Otamixiban
    1. A direct-acting factor Xa inhibitor; administered IV
    2. Half-life about 30min
    3. No need for routine anticoagulation monitoring

III. Warfarin (Coumadin)

  1. Drugs which potentiate effect of warfarin (from Med. Clin. N. Am 2/96):
Acetaminophen*  
Amiodarone Fluconazole Phenylbutazone
Anabolic steroids Isoniazid Phenytoin
Cimetidine Ketoconazole Piroxicam
Clofibrate Lovastatin Propafenone
Danazol Metronidazole Propranolol
Disulfiram Miconazole Quinidine
Erythromycin Moricizine Sulfinpyrazone
Felbamate Omeprazole Trimethoprim-Sulfamethoxazole

*--JAMA 279:657, 1998

  1. Drugs which reduce warfarin effect (ibid):
Barbiturates Nafcillin
Carbamazepine Penicillin
Chlordiazepoxide Rifampin
Cholestyramine SSRI's
Griseofulvin Sucralfate
?Lasix ?Dig
  1. Initiation of warfarin therapy-Dosing issues
    1. 53 pts randomized to 5mg QD vs. 10mg QD for starting dose of warfarin; PT's measured daily until therapeutic. % of pts who achieved two consecutive days with therapeutic INR by 5th day of tx was 66% in 5mg group vs. 24% in 10mg group. 5mg group also had fewer supratherapeutic INR's (Arch. Int. Med. 159:46, 1999--AFP)
    2. 201 outpatients with acute venous thromboembolism randomized to warfarin 5mg vs. 10mg QHS x 2d then adjusted according to INR; the 10mg group had sig. faster attainment of therapeutic INR (1.4d earlier); by 5d, 83% of 10mg group and 46% of 5mg group had therapeutic INRs.  No diff. in major bleeding or recurrent thromboembolism (Ann. Int. Med. 138:714, 2003--JW)
  1. Assessing warfarin-related bleeding risk--the "Outpatient Bleeding Risk Index"
    1. Originally derived in a retrospective study of 565 pts(Am. J. Med. 87:144, 1989)
      1. Age 65y or above = 1 point
      2. History of GIB = 1 point
      3. History of CVA = 1 point
      4. History of any of the items below = 1 point
        1. Recent MI
        2. Serum Cr > 1.5 mg/dl
        3. HCT < 30%
        4. DM
      5. 0 points = "low-risk," 1-2 points = "intermediate-risk," 3-4 points = "high-risk"
    2. Confirmed prospectively in a cohort of 286 pts starting warfarin tx on d/c from hospital (Am. J. Med. 105:91, 1998)
      1. Over 6y f/u, risk of major bleeding (loss of 2U in 7d or less or otherwise life-threatening e.g. intracranial) per 12mos of tx was 3% in low-risk pts, 8% in intermediate-risk pts, and 30% in high-risk pts. The index predicted major bleeding to a significant degree
      2. Physician estimate of bleeding risk at start of warfarin tx was not a significant predictor of major bleeding
      3. Most bleeding events were deemed preventable by better management of warfarin Rx.
  1. In one retrospective study, sig. predictors of risk of major bleeding on warfarin included the following (J. Gen. Int. Med. 13:311, 1998--AFP):
    1. Alcohol abuse
    2. Chronic renal insufficiency
    3. History of GIB
  1. Approach to pt with supratherapeutic INR:
  1. In an uncontrolled study of 81 pts who had INR > 5.0 but < 10.0 on warfarin anticoagulation and no sig. bleeding, strategy of a) withholding 1-2 doses of warfarin and b) administering 2.5mg PO of vit. K1 (phytonadione), measuring INR at 24-48h and then adjusting the warfarin dose, was successful in 96% of pts at lowering the INR to < 5.0 without inducing resistance to further anticoagulation. (Ann. Int. Med 126:959, 1997-abst)
  2. Vitamin K vs. placebo
    1. In a study in 99pts with INR 4.5-10 randomized to Vitamin K 1mg PO x 1 vs. placebo, the vit. K recipients were sig. more likely (56% vs. 20%) to have INR in the 1.8-3.2 range after 24h and sig. less likely to have clinical bleeding (Lancet 356:1551, 2000--AFP)
    2. In a study in 724 pts with INR 4.5-10 randomized to vitamin K 1.25mg vs. placebo, INR decreased more rapidly in vitamin K recipients, but there was no sig. diff. in pts > 70yo in incidence of major bleeding, thromboembolism, or death (Ann. Int. med. 150:293, 2009-JW)
  3. Vitamin K comparisons of one route to another
    1. In a randomized trial of 51 pts with INR 4.6-10 with no evident hemorrhage randomized to vi. K 1mg PO vs. vit. K 1mg SQ.  The PO group had sig. higher incidence of INR in the 1.8-3.2 range the next day (58% vs. 24%); INRs in the SQ group tended to be higher (Ann. Int. Med. 137:251, 2002--JW)
    2. Vitamin K PO (2.5-5mg, depending on INR) vs. IV (0.5-1mg, depending on INR) was ass'd with equally rapid decline in INR in patients with INR > 10 and slightly less rapid decline in INR in patients with INR 6-10 in a randomized trial in 61 pts with over-anticoagulation (INR 6.1-19.4, mean 9.2) but no major bleeding (Arch. Int. Med. 163:2469, 2003--JW)
  4. In severe cases, can use fresh-frozen plasma or IV recombinant factor VIIa concentrate ("Novo-Seven")
  1. Risk with concurrent use of warfarin and aspirin--These are all the studies that turned up in a Medline search 1985-11/96 for trials with sig. #'s of pts looking at bleeding risk of ASA + warfarin, esp. c/w either alone.
    1. The Thrombosis Prevention Trial in the UK is looking at low-dose ASA (75mg QD) vs. low-dose warfarin (INR 1.5) vs. both vs. double-placebo in men 45-69yo at high risk of CAD. In preliminary data from first 3,600 pts entered, no diff. in risk of major GI bleeding between the 3 active regimens. More "intermediate" and "minor" bleeding episodes with combination than with either alone (mostly epistaxis and bruises). (Thrombosis & Hemostasis 68:1, 1992)
    2. A retrospective study looked at this question by reviewing records of 3,100 pts in a hospital's outpt department who were receiving warfarin (target INR's between 2.5 and 4.2); 1100 of whom also got ASA 150mg QD (those had target INR's 2.2-2.8). 175 bleeding episodes noted; 18 were fatal. Minor bleed sig. higher with combined tx (2.9 vs. 1.4%); no diff. in risk for major bleeding (J. Int. Med 236:299, 1994)
    3. 370 pts with mechanical or bioprosthetic heart valves on warfarin (INR 3.0-4.5) randomized to ASA 100mg QD vs. placebo and f/u'd for avg. 2.5y. Risk of systemic embolism sig. less in ASA group. Bleeding incidents sig. higher with ASA (RR 1.55; 35% vs. 22% with placebo); "major bleeding" nonsig. higher with ASA (24 vs. 19 pts; RR 1.27; p = 0.43) (NEJM 329:524, 1993)

IV. Non-Warfarin Oral Anticoagulants

  1. Ximelagatran (Exanta)
    1. A direct thrombin inhibitor; requires no coagulation monitoring
    2. Has been associated with elevations of hepatic transaminases and ? of increased risk of coronary events c/w warfarin
    3. As effective as adjusted-dose warfarin for prevention of DVT after knee replacement surgery in one randomized trial (Ann. Int. Med. 137:648, 2002--JW)
    4. See links for data on Ximelagatran for Treatment of DVT, Primary DVT Prophylaxis, Secondary DVT Prophylaxis, Acute Myocardial Infarction, and Atrial Fibrillation
    5. Never released for use in U.S.
  2. Apixaban
    1. An oral Factor Xa inhibitor that requires no laboratory monitoring
    2. In a study in 3,195 pts undergoing total knee replacement randomized to apixaban vs. subcutaneous enoxaparin x 10-14d postoperatively, incidence of (DVT, PE, or death) was not sig. diff. between the two groups, bust apixaban pts had sig. lower incidence of (major bleeding or clinically relevant nonmajor bleeding) (2.9% vs. 4.3%) (NEJM 361:594, 2009-JW)
  3. Rivaroxaban
    1. An oral Factor Xa inhibitor that requires no laboratory monitoring
  4. Dabigatran etexilate
    1. Metabolized to a direct thrombin inhibitor
    2. No anticoagulation monitoring needed
    3. Associated with increased risks for dyspepsia and GI bleeeding
    4. In a study in 18,113 pts with atrial fibrillation with at least one of (prior CVA, low LVEF, or age > 75yo) randomized to dabigatran 110mg BID vs. 150mg BID vs. warfarin, over median 2y f/u:
      1. Dabigatran 110mg pts had no sig. diff. in incidence of CVA and sig. lower incidence of major bleeding events c/w warfarin
      2. Dabigatran 150mg pts had sig. reduction in incidence of (CVA or systemic embolism) with no sig. diff. in incidence of major hemorrhage c/w warfarin
      3. ("RE-LY" trial; (NEJM e-publication 8/30/09 (10.1056/NEJMoa905561-FP News)

V. Thrombolytics--click on link for info,

VI. Antiplatelets--See also "Acute MI," "Cerebrovascular Disease," and "Prevention of CAD" for info on clinical uses.

  1. Aspirin:
    1. Inhibits cyclooxygenase-1, preventing formation of Thromboxane A2, in turn inhibiting platelet aggregation
    2. Interactions with NSAIDs
      1. Antiplatelet effect of Aspirin is negated by pre-treatment with NSAIDs (but not COX-2 inhibitors), which reversibly inhibit COX-1 (NEJM 345:1809, 2001--JW)
      2. However, only routine use of NSAIDs, not occasional use, seems to be associated with significant interference with Aspirin's antiplatelet activity, and the interaction may not occur for enteric-coated aspirin.  Also, interaction may be avoided by taking ibuprofen > 8h before, or > 30min after, aspirin (FDA announcement 2006)
    3. Risk of intracerebral hemorrhage
      1. In a case-control study of 331 pts with primary intracerebral hemorrhage and 331 age- & sex-matched controls, after controlling for confounding factors, OR for ICH was 0.86 (nonsig.) with ASA < 1,225mg/wk and 3.05 (sig.) with higher doses of ASA (BMJ 318:759, 1999--JW)
    4. Risk of (upper) GI bleeding
      1. In a meta-analysis of 24 randomized trials involving 65,987 pts with ASA doses 50-1500mg/d (median duration of tx 28mos), excluding pts at high risk of GI hemorrhage; overall rate of GI hemorrhage was 2.47% in pts on ASA vs. 1.42% in pts on placebo (OR 1.68); no sig. difference in GIB risk in pts on lower-doses of ASA (162.5mg/d or less) than higher doses (BMJ 321:1183, 2000--AFP)
      2. Risk may be ass'd with Helicobacter Pylori infection
        1. 61 healthy volunteers randomized to ASA (either 81mg QD or 325mg Q3d) vs. placebo; half were seropositive for H. pylori. After 45d, all had EGD; incidence of GI mucosal injury among ASA recipients was sig. higher among those who were H. pylori-seropositive (Am. J. Gastroenterol. 96:1751, 2001--JW)
      3. See section on NSAIDS re: use of Proton-Pump Inhibitors and other drugs to reduce risk of GI bleeding in pts on chronic ASA
    5. See section on Colorectal Cancer for data on ASA's effects on this.
  1. Clopidogrel--similar chemically to Ticlopidine (a "thienopyridine"; inhibits platelet activation); has largely replaced Ticlopidine in clinical use
  1. Acts by blocking the ADP-mediated pathway of platelet activation
  2. Most common side f/x are rash, diarrhea, abd. pain, and dyspepsia (4-6% for each; Med Lett. 40:59, 1998)
  3. There have been case reports of Thrombotic Thrombocytopenic Purpura in pts on Clopidogrel, mostly in the first 2wks of use (NEJM 342:1773, 2000--JW)
  4. Avoid use along with other drugs that can cause bleeding, e.g. NSAIDs, heparin, ASA, or warfarin
  5. At high doses, clopidogrel may decrease metabolism of phenytoin, tamoxifen, tolutamide, warfarin, torsemide, fluvastatin, and various NSAIDs
  6. Not ass'd with lower incidence of GI bleeding c/w ASA + PPI in pts with h/o GI bleed--Click HERE for details
  7. Studies of clinical efficacy
    1. In a randomized of 19,185 pts >21yo with recent CVA, MI, or PVD to clopidogrel 75mg/d vs. ASA 325mg/d; followed for average 1.9y, risk of ischemic CVA, MI, or vascular death was 5.32% with clopidogrel vs. 5.83% with ASA; just barely statistically significant; no sig. diff in risk of mortality alone; similar safety & side effect profiles ("CAPRIE" trial; Lancet 348:1329, 1996-JW)
    2. See under Treatment of Stable Coronary Artery Disease for info on Clopidogrel after percutaneous coronary interventions
  1. NO-Aspirin (aka NCX-4016)
    1. Nitric oxide may protect against the GI toxicity of NSAIDs, hence the idea of NO-releasing NSAIDs
    2. NO-Aspirin ass'd with less endoscopic GI toxicity compared with equimolar doses of aspirin, with no difference in platelet-inhibiting or thromboxane-synthesis-inhibiting properties as ASA in one randomized trial (Gastroent. 124:842, 2003--JW)
  1. Dipyridamole
    1. Inhibits adenosine uptake; also a weak phosphodiesterase inhibitor
    2. May cause GI side f/x, including diarrhea
    3. Aspirin-Dipyridamole combination (25mg/200mg BID, "Aggrenox") for prevention of CVA--See under "Cerebrovascular Disease"
  1. Ticlopidine 250mg BID--Generally replaced by Clopidogrel
    1. Slightly better for secondary prophylaxis of cerebrovascular events than ASA--see under "Cerebrovascular Disease"
    2. Also commonly used in combination with ASA for short (e.g. 4wk) courses to prevent restenosis after PTCA and/or intracoronary stent implantation
    3. Can cause neutropenia (2.5%) so check CBC w/diff every 1-2 weeks over first 3 mos of tx
    4. Causes more diarrhea (10%) and rash (5%) than ASA
    5. Associated with Thrombotic Thrombocytopenic Purpura (risk for the latter approx 1:5,000-JAMA 281:806, 1999)
  1. Prasugrel
    1. A "thienopyridine"
    2. Inhibits platelet activation more than clopidogrel
    3.  
  2. P2Y12 Antagonists
    1. Ticagrelor
      1. Inhibits platelet aggregation faster and more consistently than clopidogrel
  3. Platelet Glycoprotein IIb/IIIa inhibitors