Warfarin

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Structure of Warfarin.

Warfarin (IUPAC name 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-chromen-2-one), also widely called coumadin, is a an anticoagulant medication used prophylactically to suppress the formation of embolism and thrombosis. Originally designed to be a rat poison, it works as an anticogulant by suppressing the enzyme epoxide reductase in the liver, thereby suppresing the formation of the reduced form of vitamin K epoxide, which is needed for the synthesis of many coagulation factors. As a drug, it is often sold as the sodium salt of warfarin.

Discovery

The dangers of feeding livestock spoiled sweet clover hay were known in the 1920’s[1] and scientists at the University of Wisconsin-Madison were spearheading the problem on multiple fronts. R.A. Brink and W.K. Smith were attempting to breed a new variety of clover that was free of the toxic effect and Karl Paul Link's laboratory was attempting to isolate the killer compound. Farmers were already hurting due to the Great Depression and despite knowing they should not feed their livestock such hay, they could not afford to buy uncontaminated supplies. This disease that was affecting many livestock throughout the US became known as "sweet clover disease".[2]

The urgency of this work was punctuated in the winter of 1933 when Ed Carlson, a farmer from Deer Park, Wisconsin, came to Madison for help carrying a milk can of uncoagulated blood, a dead cow in his truck and a sample of the hay contaminated with the spoiled sweet clover. This spurred Link on and in 1940 he finally published the source of the hemorrhagic factor in sweet clover, 3,3'-methylene-bis[4-hyfroxycoumarin], known as coumarin.[3] The following year Link published the discovery of dicumarol, the oxidised form of coumarin that was present in the spoiled sweet clover; this became widely used as an oral anticoagulants for medical treatment.[4][5]

Given the death of cattle from hemorrhaging, Link began to realise that anticoagulants had potential to be rodenticides.

I had an intuitive feeling that this might be a good thing. A pretty bad thing for rats, but a good thing for humans. But the idea didn't come overnight. It came into my head and the heads of everyone in the lab over a period of years. [6]

Dicumarol turned out to be a poor rodenticide as it acted too slowly[7] but by 1948 Link had patented another coumarin derivative as a rodenticide. Research for both dicumarol and the new rodenticide was funded by the Wisconsin Alumni Research Foundation (WARF) and the brand name for these anticoagulating rat posions was coined 'Warfarin' after WARF. Later, the rodenticide was promoted for clinical applications under the brand name 'Coumadin'.

Mechanism of action

Warfarin therapy reduces the vitamin K dependent cofactors II, VII, IX, and X and the vitamin K dependent Protein C. The level of factor II is thought to most influence coagulation.[8][9] The levels of factor VII and Protein C fall the fastest after warfarin is started.[9] With the exception of Factor IX, these factors are from either the extrinsic pathway or the final common pathway.

The effect of warfarin is measured by the prothrombin time (or the International Normalized Ratio derived from the prothrombin time) although warfarin can also affect the partial thromboplastin time.[10][11]

Pharmacokinetics

Absorption

Distribution

Metabolism

Pharmacogenomics

Warfarin activity is determined partially by genetic factors.[12] The American Food and Drug Administration "highlights the opportunity for healthcare providers to use genetic tests to improve their initial estimate of what is a reasonable warfarin dose for individual patients".[13] A systematic review concluded that as of early 2009, there is insufficient benefit in genetic testing.[14]


VKORC1

Genetic polymorphisms in the vitamin K epoxide reductase complex 1 (VKORC1) gene explain 30% of the dose variation between patients[15]: particular mutations make VKORC1 less susceptible to suppression by warfarin[16] There are a main haplotypes that explain 25% of variation: low-dose haplotype group (A) and a high-dose haplotype group (B).[17] For the three combinations of the haplotypes, the mean daily maintenance dose of warfarin was:

  • A/A: 2.7+/-0.2 mg
  • A/B: 4.9+/-0.2 mg
  • B/B: 6.2+/-0.3 mg

VKORC1 polymorphisms also explain why African Americans are relatively resistant to warfarin (higher proportion of group B haplotypes), while Asian Americans are more sensitive (higher proportion of group A haplotypes).[17]

CYP2C9

CYP2C9 is an isoenzyme of cytochrome P-450. Polymorphisms of CYP2C9 explain another 10% of variation in warfarin dosing[15], mainly among Caucasian patients as these variants are rare in African American and most Asian populations.[18] A meta-analysis of mainly Caucasian patients found[18]:

  • CYP2C9*2 allele:
    • present in 12.2% of patients
    • mean reduction was in warfarin dose was 0.85 mg (17% reduction)
    • relative bleeding risk was 1.91
  • CYP2C9*3 allele:
    • present in 7.9% of patients
    • mean reduction was in warfarin dose was 1.92 mg (37% reduction)
    • relative bleeding risk was 1.77

Excretion

Availability

Generic preparations have similar pharmacology.[19]

Dosage

"After 4 to 5 days of concomitant warfarin and heparin therapy, heparin is discontinued when the INR has been in the therapeutic range on two measurements approximately 24 h apart."[20]

Loading regimens

Because of warfarin's difficult pharmacokinetics, researchers have proposed algorithms for warfarin loading.

Randomized controlled trials of warfarin loading algorithms[21][9][22][23][24][25]
Dosing Study Time till a therapeutic INR
(days)		 Rate of anticoagulation
(INR=2-3)		 Rate of over-coagulation
Kovacs 10 mg 10 mg/day for two days then
specified adjusted dosing		 Kovacs†[21] 4.2 83% by day 5 9% within 4 weeks(INR>5)
(most occurred after day 10)
Quiroz‡[23] 5
(two consecutive INRs≥2)		 56% at 5 days 0% within 5 days (INR>5)
Anderson‡[24]   69% at 5 days  
Harrison 10 mg 10 mg/day for one day then
flexible adjusted dosing		 Harrison¶[9]   63% at 3.5 days 17% within 3.5 days (INR>4.8)
Crowther¶[22]   69% at 5 days 0% within 5 days (INR>5)
24% within 5 days (INR>3)
Kovacs 5 mg 5 mg/day for two days then
specified adjusted dosing		 Kovacs†[21] 5.6 46% by day 5 11% within 4 weeks (INR>5)
(most occurred after day 10)
Harrison 5 mg 5 mg/day for one day then
flexible adjusted dosing		 Harrison¶ [9]   80% at 3.5 days 4% within 4.5 days (INR>4.8)
Crowther¶[22]   88% at 5 days 3% within 5 days (INR>5)
7% within 5 days (INR>3)
Quiroz‡[23] 5
(two consecutive INRs≥2)		 52% at 5 days 0% within 5 days (INR>5)
Anderson pharmacogenetic-guided algorithm Based on CYP2C9 and VKORC1 Anderson†[24]   70% at 5 days  
Caraco pharmacogenetic-guided algorithm Based on CYP2C9 Caraco[25] 4.8    
† Blinded study.
‡ Independent study not from original investigators.
¶ Same research group (Hamilton, Ontario).

Notes:
1. INR. International Normalized Ratio
2. The Kovacs 5 mg algorithm is the same as the Harrison 5 mg algorithm except that where Harrison gave a range warfarin of dosages based on the INR, Kovacs specified a dose (usually at the high end of the range offered by Harrison).[8]

Empiric dosing

On first look, the evidence table suggests that the Harrison 5 mg algorithm from Hamilton is the chest combination of efficacy and safety; however, two independent studies (Kovacs[21] and Quiroz in 2006 from the Massachusetts General Hospital[23]) have not been able to replicate the results of Hamilton group of Harrison and Crowther. One explanation may be that the personnel in the Harrison study were more expert and the flexibility in the algorithm allowed expression of their expertise. If so, then perhaps equally expert health care providers should use the Harrison 5 mg algorithm while other personnel should use the Kovacs 10 mg algorithm. Considering that the expertise of the Massachusetts General Hospital could not replicate the Hamilton results, perhaps most providers should use the Kovacs 10 mg algorithm, at least for inpatients.

A systematic review of the randomized controlled trials done through 2003 of 5 mg versus the 10 mg concluded that the Kovacs 10 mg regimen is best.[8] This conclusion was largely based on the inability of the results of the Harrison 5 mg flexible algorithm to be replicated by Kovacs.

Clinical practice guidelines in 2004 by the American College of Chest Physicians concluded that either 5 or 10 loads are acceptable.[26] The guidelines also state "if treatment is not urgent (eg, chronic stable atrial fibrillation), warfarin administration, without concurrent heparin administration, can be commenced out-of-hospital with an anticipated maintenance dose of 4 to 5 mg per day."[26]

Since publication of the systematic review[8] and clinical practice guidelines[26], a nonblinded, randomized controlled trial by Quiroz[23] found no difference between algorithms, but also achieved less frequent anticoagulation. The reason is not clear as the Kovacs 10 mg algorithm is very specific on each dose of warfarin. The Quiroz trial is also unique in that all patients were receiving a fondaparinux bridge.

Additional algorithms:

  • The Tait 5 mg regimen is for outpatient anticoagulation. Patients are given 5 mg of warfarin per day for 5 days and then the INR is checked on day 5 to determine further dosing. (summary)[27]
  • The Fennerty 10 mg regimen is an older regimen that has not been studied in an randomized controlled trial.[28][29]

Pharmacogenetic guided dosing

  • A pharmacogenetic-guided algorithm using only CYP2C9 compared to a local algorithm led to less minor bleeding (3.2 vs 12.5%, P<0.02).[25]
  • The Kovacs 10 mg algorithm performed similarly to a pharmacogenetic-guided algorithm using 3CYP2C9 and VKORC1.[24] The proportion of patients who did not have an out-of-range International Normalized Ratio statistically insignificantly 1.04 times higher in the pharmacogenetic group (69% vs 67%).
  • A pharmacogenetic-guided algorithm using 3CYP2C9 and VKORC1 outperformed an unvalidated, clinical algorithm in modeled results.[30] In this cohort study of 5052 patients, the pharmacogenetic estimated a dose within 20% of the actual dose 1.2 times more often than the clinical algorithm (46% vs 38%).
  • A pharmacogenetic-based model from a cohort of orthopedic patients using 3CYP2C9 and VKORC1 genotype results predicted 80% of the variation in warfarin doses. It is awaiting validation in larger populations and has not been reproduced in those who require warfarin for other indications.[31]

Cost-benefit analysis[32] and decision analysis[33] concluded that patients at average risk do not benefit from testing for CYP2C9.

Adjusting the maintenance dose

Recommendations by the American College of Chest Physicians[26] have been distilled into a table to help manage dose adjustments.[34][35]

If the goal INR is 2 to 3, then adjustments should be made when the INR is 1.7 or less or when 3.3 or greater.[36]

The optimal INR is unclear.[37]

Discontinuation before procedures

Details have been provided by the American College of Chest Physicians at The Perioperative Management of Antithrombotic Therapy.

Management of warfarin around invasive procedures has been reviewed[38] and new bridges have been studied.[39]

For procedures that need discontinuation of anticoagulation, a cohort study that found that interruption for 5 days or less was generally safe.[40]

For patients needing a bridge, low molecular weight heparin is preferable to intravenous infusion of unfractionated heparin.[41] For patients needing a low molecular weight heparin bridge, a protocol is available.[42] One bridge before coronary artery bypass grafting is to stop 6 days before and give 5 mg/day of vitamin K on the day of warfarin cessation and use low molecular weight heparin with last dose the night before surgery.[43]However, bridging with low molecular weight heparin increases bleeding as compared to no bridging.[44]

Interactions and contraindications

Warfarin interacts with many medications. A proposed classifications of mechanisms is:[45]

  • Interference with platelet function
  • Injury to gastrointestinal mucosa
  • Reduced synthesis of vitamin K by intestinal flora
  • Interference with warfarin metabolism by cytochrome P-450 CYP2C9 isoenzyme.
  • Interruption of the vitamin K cycle

Some foodstuffs have also been reported to interact with warfarin.[46]

Adverse effects

Elderly patients

Patients aged 80 years or more may be especially susceptible to bleeding complications with a rate of 13 bleeds per 100 person-years.[47]

Patients with prior intracranial hemorrhage from warfarin

These patients are at high risk of bad outcomes regardless of whether anticoagulation is resumed.[48]

Patients with cancer

Rates of major bleeding and recurrent venous thromboembolism (VTE)
using warfarin with a target INR of 2.0 and 3.0
among patients with cancer.
No cancer Cancer
Stage I or II Stage III Stage IV
Major
bleeding		 Events per
100 patient-years		 8.6 3.4 19.1 42.8
Hazard ratio 1 0.5 2.15 4.8
Recurrent
VTE		 Events per
100 patient-years		 12.8 14.5 44.1 54.1
Hazard ratio 1 1.9 5.3 4.6
Adapted from Table 3 of Prandoni et al.[49]

Patients with cancer are more likely to have bleeding complications, especially if they have Stage III (regionally extensive) or IV (metastatic) cancer.[49] Regardless of the extent of cancer, the risk of bleeding was less than the risk of recurrent embolism and thromboembolism:

Unstable anticoagualation

Supplementing warfarin with 150 micrograms of vitamin k may reduce the frequency of unstable anticoaguation among patients who are difficult to anticoagulate.[50] This amount of vitamin k led to 16% increase in the warfarin dose from 3.8 mg per day to 4.4 mg per day after one week.

Antagonism and reversal

A detailed table on reversing warfarin are provided in clinical practice guidelines from the American College of Chest Physicians.[20] For patients who are not bleeding and have an International Normalized Ratio (INR) between 4.5 and 10.0, either withholding warfarin[51] or 1 mg of oral vitamin K is effective[52]. Vitamin K should not be given subcutaneously, even at low doses then can lower the INR too much.[53]

Drug interactions

Acetaminophen

Acetaminophen in doses of 2 grams per day or more for several consecutive days may interact with warfarin.[54][55]

Anti-platelet agents

Patients taking aspirin, clopidogrel, or dipyridamole may be at higher risk of hemorrhage.[56]

Antilipemic agents

Medications, such as the antilipemic agents atorvastatin, simvastatin, or gemfibrozil that are metabolized by cytochrome P-450 CYP3A4 may increase bleeding when added to patients taking warfarin.[57]

Antibiotics

Antibiotics metabolized by cytochrome P-450 CYP2C9, such as trimethoprim-sulfamethoxazole and ciprofloxacin may increase risk of hospitalization for gastrointestinal hemorrhage.[58]

References

  1. ↑ Wardrop D, Keeling D (2008) The story of the discovery of heparin and warfarin Brit J Haematol 141:757-63
  2. ↑ Duxbury BM, Poller L (2001) The oral anticoagulant saga: past, present, and future Clin Appl Thrombosis/Hemostasis 7:269–75 PMID 11697707
  3. ↑ Campbell HA et al. (1940) Studies on the hemorrhagic sweet clover disease. I. The preparation of hemorrhagic concentrates. J Biol Chem, 136, 47–55.
  4. ↑ Campbell HA et al. (1941) Studies on the hemorrhagic sweet clover disease. II. The bioassay of hemorrhagic concentrates by following the prothrombin level in the plasma of rabbit blood. J Biol Chem 138:1–20
  5. ↑ Stahmann MA et al. (1941) Studies on the hemorrhagic sweet clover disease. V. Identification and synthesis of the hemorrhagic agent J Biol Chem 138:513–27
  6. ↑ Karl Paul Link, Societal Contributions hosted by Wisconsin Alumni Research Foundation
  7. ↑ Last JA (2002) The missing link: the story of Karl Paul Link. Toxicol Sci 66:4–6.
  8. ↑ 8.0 8.1 8.2 8.3 Eckhoff CD, Didomenico RJ, Shapiro NL (2004). "Initiating warfarin therapy: 5 mg versus 10 mg". Ann Pharmacother 38: 2115–21. DOI:10.1345/aph.1E083. PMID 15522981. Research Blogging. Cite error: Invalid <ref> tag; name "pmid15522981" defined multiple times with different content Cite error: Invalid <ref> tag; name "pmid15522981" defined multiple times with different content
  9. ↑ 9.0 9.1 9.2 9.3 9.4 Harrison L et al. (1997). "Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy". Ann Intern Med 126: 133–6. PMID 9005747. [e] Cite error: Invalid <ref> tag; name "pmid9005747" defined multiple times with different content
  10. ↑ Bell DF et al. (1988). "Elevated partial thromboplastin time as an indicator of hemorrhagic risk in postoperative patients on warfarin prophylaxis". J Arthroplasty 3: 181–4. PMID 3397749.
  11. ↑ Hauser VM, Rozek SL (1986). "Effect of warfarin on the activated partial thromboplastin time". Drug Intell Clin Pharm 20: 964–7. PMID 3816546.
  12. ↑ Kamali F, Wynne H (2010). "Pharmacogenetics of warfarin.". Annu Rev Med 61: 63-75. PMID 19686083.
  13. ↑ FDA Approves Updated Warfarin (Coumadin) Prescribing Information. Retrieved on 2007-08-20.
  14. ↑ Kangelaris KN et al. (2009). "Genetic testing before anticoagulation? A systematic review of pharmacogenetic dosing of warfarin". J Gen Intern Med 24: 656–64. PMID 19306050.
  15. ↑ 15.0 15.1 Wadelius M et al (2005). "Common VKORC1 and GGCX polymorphisms associated with warfarin dose". Pharmacogenomics J 5: 262-70. PMID 15883587.
  16. ↑ Rost S et al (2004). "Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2". Nature 427: 537–41. PMID 14765194.
  17. ↑ 17.0 17.1 Rieder MJ et al (2005). "Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose". N Engl J Med 352: 2285-93. PMID 15930419. Cite error: Invalid <ref> tag; name "pmid15930419" defined multiple times with different content
  18. ↑ 18.0 18.1 Sanderson S, Emery J, Higgins J (2005). "CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis". Genet Med 7: 97-104. PMID 15714076.
  19. ↑ Dentali F et al. (2011). "Brand name versus generic warfarin: a systematic review of the literature.". Pharmacotherapy 31 (4): 386-93. PMID 21449627.
  20. ↑ 20.0 20.1 Ansell J et al. (2008). "Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)". Chest 133 Suppl: 160S-98S. PMID 18574265. Cite error: Invalid <ref> tag; name "pmid18574265" defined multiple times with different content
  21. ↑ 21.0 21.1 21.2 21.3 Kovacs MJ, Rodger M, Anderson DR, et al (2003). "Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial". Ann Intern Med 138: 714-9. PMID 12729425. [e]
  22. ↑ 22.0 22.1 22.2 Crowther MA et al. (1999). "A randomized trial comparing 5-mg and 10-mg warfarin loading doses". Arch Intern Med 159: 46–8. PMID 9892329.
  23. ↑ 23.0 23.1 23.2 23.3 23.4 Quiroz R et al. (2006). "Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism". Am J Cardiol 98: 535–7. PMID 16893712.
  24. ↑ 24.0 24.1 24.2 24.3 Anderson JL et al. (2007). "Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation". Circulation 116: 2563–70. PMID 17989110.
  25. ↑ 25.0 25.1 25.2 Caraco Y et al. (2008). "CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study". Clin Pharmacol Ther 83: 460–70. PMID 17851566. Cite error: Invalid <ref> tag; name "pmid17851566" defined multiple times with different content
  26. ↑ 26.0 26.1 26.2 26.3 Ansell J et al. (2004). "The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy". Chest 126 (3 Suppl): 204S–33S. PMID 15383473. Cite error: Invalid <ref> tag; name "pmid15383473" defined multiple times with different content
  27. ↑ Tait RC, Sefcick A (1998). "A warfarin induction regimen for out-patient anticoagulation in patients with atrial fibrillation". Br. J. Haematol. 101 (3): 450-4. DOI:10.1046/j.1365-2141.1998.00716.x. PMID 9633885. Research Blogging.
  28. ↑ Fennerty A et al. (1984). "Flexible induction dose regimen for warfarin and prediction of maintenance dose". Br Med J (Clin Res Ed) 288: 1268–70. PMID 6424820. [PubMed Central]
  29. ↑ Fennerty A et al. (1988). "Anticoagulants in venous thromboembolism". BMJ 297 (6659): 1285-8. PMID 3144365.
  30. ↑ Klein TE et al. (2009). "Estimation of the warfarin dose with clinical and pharmacogenetic data". N. Engl. J. Med. 360: 753–64. PMID 19228618.
  31. ↑ Millican E et al. (2007). "Genetic-based dosing in orthopaedic patients beginning warfarin therapy" 110 (5): 1511-5. PMID 17387222. Online tool based on the study.
  32. ↑ Eckman MH et al. (2009). "Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation.". Ann Intern Med 150: 73-83. PMID 19153410.
  33. ↑ Eckman MH, et al. (2009). "Should we test for CYP2C9 before initiating anticoagulant therapy in patients with atrial fibrillation?". J Gen Intern Med 24: 543–9. PMID 19255811.
  34. ↑ Ebell MH (2005). "Evidence-based adjustment of warfarin (Coumadin) doses.". Am Fam Physician 71: 1979-82. PMID 15926414 url=http://www.aafp.org/afp/2005/0515/p1979.html.
  35. ↑ Ebell MH (2005). "A systematic approach to managing warfarin doses.". Fam Pract Manag 12 (5): 77, 79-80, 83. PMID 15929383. [e]
  36. ↑ Rose AJ, Ozonoff A, Berlowitz DR, Henault LE, Hylek EM (January 2009). "Warfarin dose management affects INR control". J. Thromb. Haemost. 7 (1): 94–101. DOI:10.1111/j.1538-7836.2008.03199.x. PMID 18983486. Research Blogging.
  37. ↑ Torn M et al. (July 2009). "Optimal level of oral anticoagulant therapy for the prevention of arterial thrombosis in patients with mechanical heart valve prostheses, atrial fibrillation, or myocardial infarction: a prospective study of 4202 patients". Arch Intern Med 169: 1203–9. PMID 19597069.
  38. ↑ Kearon C, Hirsh J (1997). "Management of anticoagulation before and after elective surgery". N Engl J Med 336: 1506–11. PMID 9154771.
  39. ↑ Pengo V, Cucchini U, Denas G, et al. (2009). "Standardized low-molecular-weight heparin bridging regimen in outpatients on oral anticoagulants undergoing invasive procedure or surgery: an inception cohort management study". Circulation 119: 2920–7. PMID 19470892.
  40. ↑ Garcia DA et al. (2008). "Risk of thromboembolism with short-term interruption of warfarin therapy". Arch Intern Med 168: 63–9. PMID 18195197.
  41. ↑ Douketis JD et al. (2008). "The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)". Chest 133 (6 Suppl): 299S-339S. PMID 18574269.
  42. ↑ Douketis JD, Johnson JA, Turpie AG (June 2004). "Low-molecular-weight heparin as bridging anticoagulation during interruption of warfarin: assessment of a standardized periprocedural anticoagulation regimen". Arch Intern Med 164: 1319–26. PMID 15226166.
  43. ↑ Whitlock RP et al. (2007). "Warfarin cessation before cardiopulmonary bypass: lessons learned from a randomized controlled trial of oral vitamin K". Ann Thorac Surg 84 (1): 103–8. PMID 17588394.
  44. ↑ Witt DM et al. (2009). "Incidence and predictors of bleeding or thrombosis after polypectomy in patients receiving and not receiving anticoagulation therapy.". J Thromb Haemost 7: 1982-9. PMID 19719825.
  45. ↑ Juurlink DN (2007). "Drug interactions with warfarin: what clinicians need to know". CMAJ : Canadian Medical Association journal &#61; journal de l'Association medicale canadienne 177: 369–71. PMID 17698826.
  46. ↑ Holbrook AM et al. (2005). "Systematic overview of warfarin and its drug and food interactions". Arch. Intern Med. 165: 1095–106. PMID 15911722.
  47. ↑ Hylek EM et al. (2007). "Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation". Circulation 115: 2689-96. PMID 17515465.
  48. ↑ Claassen DO et al. (2008). "Restarting anticoagulation therapy after warfarin-associated intracerebral hemorrhage". Arch Neurol 65: 1313–8. PMID 18852344.
  49. ↑ 49.0 49.1 Prandoni P, Lensing AW, Piccioli A, et al (2002). "Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis". Blood 100 (10): 3484–8. DOI:10.1182/blood-2002-01-0108. PMID 12393647. Research Blogging.
  50. ↑ Sconce E et al. (2007). "Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin". Blood 109: 2419–23. PMID 17110451.
  51. ↑ 1Crowther, MA; et al. (2009-03-03). "Oral Vitamin K Versus Placebo to Correct Excessive Anticoagulation in Patients Receiving Warfarin: A Randomized Trial". Ann Intern Med 150: 293-300.
  52. ↑ Crowther MA et al. (2002). "Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. A randomized, controlled trial". Ann Intern Med 137: 251-4. PMID 12186515.
  53. ↑ Dezee KJ et al. (2006). "Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis". Arch Intern Med 166: 391–7. PMID 16505257.
  54. ↑ Hughes GJ, Patel PN, Saxena N.. Effect of Acetaminophen on International Normalized Ratio in Patients Receiving Warfarin Therapy. Pharmacotherapy 2011 June;31(6):591–597.
  55. ↑ Zhang Q et al. (2011). "Interaction between acetaminophen and warfarin in adults receiving long-term oral anticoagulants: a randomized controlled trial.". Eur J Clin Pharmacol 67: 309-14. PMID 21191575.
  56. ↑ Johnson SG et al. (2008). "Outcomes associated with combined antiplatelet and anticoagulant therapy". Chest 133 (4): 948–54. PMID 18198244.
  57. ↑ Schelleman H et al. (2010). "Fibrate/Statin initiation in warfarin users and gastrointestinal bleeding risk.". Am J Med 123: 151-7. PMID 20103024.
  58. ↑ Fischer, HD; et al. (2010-04-12). "Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract anti-infective agents: a population-based study". Arch Intern Med 170: 617-621. DOI:10.1001/archinternmed.2010.37. Research Blogging.
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