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. Dosing
      1. For venous thromboembolism, usually 80 units/kg bolus then 18 units/kg/h infusion
      2. For acute coronary syndrome, usually 60 units/kg bolus then 16 units/kg/h infusion
    2. Must monitor activated partial thromboplastin time (aPTT) with treatment goal 1.5-2.5x normal
    3. Consider daily platelet count to monitor for heparin-induced thrombocytopenia
    4. Anti-inflammatories increase half life
  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
      1. Caused by formation of IgG antibodies against complex of Platelet Factor 4 and Heparin; can recur with future challenge with Heparin
      2. Onset can be as late as 2wks after cessation of treatment
      3. Can be associated with arterial or venous thrombosis
      4. Highest risk is with subcutaneous administration of unfractionated heparin

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. Recombinant hirudin (Iprivask)
    1. Works by directly inhibiting thrombin
    2. Administered by SQ injection (15mg Q12h)
    3. Effect can be measured with aPTT
    4. Shown to be effective in DVT prophylaxis in pts undergoing total hip replacement
  3. 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)
  4. 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.
  5. 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. Initiation of warfarin therapy-Dosing issues
    1. Warfarin can cause hemorrhage, particularly if dosing exceeds a narrow therapeutic window that tends to vary from patient to patient
    2. Patients of Asian ancestry have, on average, greater sensitivity to warfarin than other patients.
    3. 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)
    4. 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 gastrointestinal bleeding
  1. Genetic variations
    1. The "A" allele of VKORC1  (most common in Asians) is associated with reduced dosing needs, particularly in homozygotes
    2. The "*2" an "*3" alleles of the CYP2CP gene (in the cytochrome P450 system) is associated with reduced dosing needs
  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. In a study in 5,407 pts post-hip replacement surgery randomized to apixaban 2.5mg PO BID, initiated 12-24h after wound closure vs. enoxaparin 40mg SQ 12h prior to surgery then Q24h, both continued x 35d.  Incidence of major VTE was sig. lower in apixaban recipients (1.1% vs. 3.6%) as was incidence of (DVT, nonfatal PE, or death) (1.4% vs. 3.9%); no sig. diff. in incidence of major bleeding. (NEJM 363:2487, 2010-JW)
    4. See also Atrial Fibrillation section for info on clinical trials for that indication
  3. Rivaroxaban (Xarelto)
    1. An oral Factor Xa inhibitor that requires no laboratory monitoring
    2. Standard dosing is 10mg PO QD
    3. In a study in 3,449 pts with acute, symptomatic proximal DVT randomized to rivaroxaban 15mg BID x 3wks then 20mg QD vs. enoxaparin SQ followed by warfarin, continued for either 3, 6, or 12mos, incidence of recurrent venous thromboembolism was lower in rovaroxaban recipients (2.1% vs. 3.0%) and there was no diff. in bleeding incidence.  Pts who completed 6mos or 12mos of therapy underwent another randomization to rovaroxaban 20mg QD vs. placebo for 6-12mos more; rivaroxaban pts had sig. lower incidence of recurrent VTE during this period (1.3% vs. 7.1%) but higher incidence of major bleeding (0.7% vs. 0%) (NEJM 363:2499, 2010-JW)
    4. See also Atrial Fibrillation section for info on clinical trials for that indication
  4. Dabigatran etexilate (Pradaxa) 150mg BID (if CrCl is 15-30mL/min, then 75mg BID)
    1. Metabolized to a direct thrombin inhibitor
    2. No anticoagulation monitoring needed though does increase aPTT
    3. If currently on warfarin, can start dabigatran after d/c of warfarin when the INR is <2.0
    4. With new Dx of atrial fibrillation can start treatment immediately; steady state is achieved in 2-3 days
    5. Associated with increased risks for dyspepsia and GI bleeding, particularly if using NSAIDs or renal disease is present
    6. Rifampin reduces serum levels
    7. Us in patients undergoing surgery: Stop tx 1-2 days prior to surgery if CrCl is ≥50 mL/min, or 3 to 5 days prio if the CrCl is <50 mL/min; can resume as soon as the risk of major bleeding is deemed to be minimal.
    8. Side effects: dyspepsia (around 1/3 of pts); no reports of hepatotoxicity as of 2011
    9. In a study in 2,500 pts with acute venous thromboembolism randomized to receive (after initial heparin therapy) dabigatran 150mg BID vs. adjusted-dose warfarin (target INR 2.0-3.0), dabigatran was associated with no sig. diff. in incidence of recurrent venous thromboembolism BUT sig. lower incidence of (major or "clinically relevant") bleeding (5.6% vs. 8.8%). (NEJM 361:2342, 2009-abst)
    10. See also Atrial Fibrillation section for info on clinical trials for that indicationA

V. Thrombolytics--click on link for info,

VI. Antiplatelets--See also "Acute MI," "Cerebrovascular Disease," and "Prevention of CAD" and Oncology 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. In a study in 156 pts with upper GI bleeding while taking ASA (325mg/d or less) for secondary prevention of cardiovascular or cerebrovascular disease, randomized to 8wks of ASA 80mg/d vs. placebo (all received daily oral proton pump-inhibitors), there was no sig. diff. in 30d incidence of recurrent ulcer bleeding but ASA group had sig. lower 8wk all-cause mortality (1.3% vs. 9.0%) (in intention-to-treat analysis) (Ann. Int. Med. 152:1, 2010-JW;AFP)
      3. 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)
      4. 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. Risk of GI ulceration and bleeding
    1. Clopidogrel was not ass'd with lower incidence of GI bleeding c/w ASA + PPI in pts with h/o GI bleed--Click HERE for details
    2. In a study in 165 adults with h/o peptic ulcer (but none at baseline), with contraindications to aspirin, all of whom were put on clopidogrel and randomized to esomeprazole vs. placebo, and all of whom underwent upper endoscopy at 6mos, prevalence of gastroduodenal ulceration was sig. lower in esomeprazole group (1% vs. 11%). (Gastroent. 140:791, 2011-JW)
  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
  8. Proton-Pump Inhibitors may interfere with the antiplatelet effects of clopidogrel.
    1. Use of PPIs were associated with increased mortality risk in first 1y post-MI (HR 2.4) in a retrospective study; no differences were noted among different PPIs.  NO such elevation in risk was associated with H-2 blockers (BMJ 342:d2690, 2011-JW)
    2. On the other hand, in a study in 3,873 pts on clopidogrel + aspirin randomized to omeprazole vs. placebo, there was no sig. diff. in incidence of (cardiovascular death, MI, coronary revascularization, or CVA) ("COGENT" trial; NEJM 363:1909, 2010-JW)
  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
  2. P2Y12 Antagonists
    1. Ticagrelor
      1. Inhibits platelet aggregation faster and more consistently than clopidogrel
  3. Platelet Glycoprotein IIb/IIIa inhibitors

(Sources include Core Content Review of Family Medicine, 2012)