Anticoagulation

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More complicated than most people think.
Most people think it is complicated

This shows worst case curves at upper limit of 95% CI based on INR at time of presentation with stroke in patients anticoagulated for atrial fibrillation[1]

A fair bit is known about the benefits and risks of anticoagulation. This is not a simple area although the benefits in several areas such as preventing ischaemic stroke in non-rheumatic atrial fibrillation in people over 65 years old or preventing pulmonary embolism are very well defined. Most is known with warfarin, although the size of the phase III trials of drugs such as dabigatran etexilate, rivaroxaban and apixaban in their various indications gives us an evidence base superior to most drugs new to market.

The curve for benefit in reducing ischaemic stroke with warfarin anticoagulation is J-shaped, with the risk of ischaemic stroke increasing if anticoagulation is controlled outside the range of 2 to 2.5.

Info bulb.pngDoctors may find the real life clinical observation that patients with an INR >4.5 are at as great a risk of ischaemic stroke as those on no warfarin in non-rheumatic atrial fibrillation so counterintuitive that they fail to evaluate it for the true message of just how important good anticoagulation control is for outcome, or incorrectly tell the patient only that it is their risk of bleeding that increases with increasing INR.

Another example with warfarin is that the risk of intracranial haemorrhage is an exponential function of INR while the relative risk of a subdural haematoma remains flat for INRs less than 2.4 and then suddenly quadruples. There is more information on the issue of drugs, not just anticoagulants, increasing bleeding risk, here.

However the newer direct thrombin and factor Xa inhibitors do not have the intracranial bleed risk of warfarin (or other Vitamin K anagonists), and indeed it is this that is the major factor in their clinical trial superiority to warfarin.

Risk with anticoagulation is commonly understood to increase with age, but actually it doesn't in the age range from 60 to 80 in Western populations then suddenly doubles in the over 85s compared to those less than 80.[2][3]

Unhappily this complexity along with difficulties in managing the knowledge service causes doctors to simplify anticoagulation decisions, regarding it as an art and often making decisions where the science indicates otherwise.

Contents

Choice of anticoagulant

Event comparison of the anticoagulants dabigatran etexilate, rivaroxaban and apixaban in the indication of non-rheumatic atrial fibrillation against warfarin

Essentially for years this was between parentally administered heparin and orally administered coumadin analogues such as warfarin. Heparin was used for initiation in lifethreating thromboembolic disease, the pregnant and thromboprohylaxis and coumadin analogues in maintenance. Comparative trials have tended to favour low molecular weight heparins over unfractionated heparin in terms of convenience and safety. There is evidence that heparins can be more clinically effective in some indications than warfarin but no evidence for a mortality benefit [4]. Again the limited head to head trials of LMWH products seem to show no definite difference at effective dose but there are certainly slightly different indications and the effective dose is indication dependent. As a rule the new anticoagulants (anti-factor Xa agents and direct thrombin inhibitors) tend to be oral, be at least equivalent to LMWH in efficacy, but as new products their long term safety record is yet to be established. One, apixaban has demonstrated mortality benefit over warfarin in patients with atrial fibrillation[5]. However for the next few years cost is likely to be a major factor in choice for most patients.

Length of anticoagulation

Guidelines exist and balance risk against benefit assuming single pathology and the population median change with time[6]. It is an area where ever more refined information allowing evaluation of risk for individuals will accumulate. For example unprovoked thromboembolism has long been known to be associated with a higher risk of recurrent thromboembolism than in patients where the risk factor is addressed. It has only recently been demonstrated that in unprovoked thromboembolism it is females less than 65, with no lower leg hyperpigmentation, oedema or redness of either leg, low D-dimer while taking warfarin and a body mass index less than 30 kg/m that have the lowest risk for recurrence when warfarin is discontinued. Accordingly an argument can now be made, all other things being equal in unprovoked thromboembolism to continue anticoagulation long term in all males and all elderly females or young females with obesity, continued activation of D-dimer or chronic lower leg pathology[7].

Reversing anticoagulation

Most of the evidence comes from warfarin and unfractionated heparin where its both easiest and large numbers of patients have been studied. It is possible to reverse vitamin K antagonists such as warfarin by giving vitamin K within hours or in minutes if desired by sufficient fresh frozen plasma or specific recombinant factors. Intravenous unfractionated heparin has a plasma half life of less than two hours but protamine is the classic immediate reversal agent. Protamine only partially reverses the anti-Xa activity with low molecular weight heparins but is still recommended given the half life of several hours with life threatening haemorrhage[8]. The new oral anticoagulants are more challenging to reverse promptly[9]. Prothrombin complex concentrate rapidly reverses rivaroxaban but does not work for dabigatran[10].

Reversal before surgery

There is a large evidence base for this improving outcomes in a large number of procedures, both emergency and elective. Local and national guidelines can be expected to exist. Usual practice before elective procedures is to withhold the agent and aim for a subtherapeutic degree of coagulation relevant to the evidence base for that procedure or similar procedures.

Reversal with acute haemorrhage

In large trauma series there is no definite evidence that reversing warfarin anticoagulation changes outcome in terms of mortality or morbidity[11][12] with one exception in traumatic intracranial haemorrhage[13]. With non- traumatic intracranial haemorrhage on warfarin prompt intervention does influence successful reversal of anticoagulation and haemorrhage size but without changing outcome[14], notably in the FAST trial[15]. One post-hoc analysis suggests rFVIIa 80 µg/kg may have morbidity benefit in non- traumatic intracranial haemorrhage patients younger than 70 years, with a volume less than 60 ml, an intraventricular haemorrhage volume less than 5 ml, and time to treatment up to 2.5 hours[16]. Prothrombin complex concentrates are the most successful product at reducing inter-cranial haemorrhage size in warfarinised neurosurgical patients[17]. The use of rapid reversal increases venous thrombolism[18]. From animal models four-factor prothrombin complex concentrate appears to be the best for warfarin anticoagulation reversal at a potential risk of more thrombotic events so until comparative trials exist three-factor prothrombin complex concentrate and adherence to protocol is acceptable clinical practice[19].

See Also


References

  1. Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. The New England journal of medicine. 2003;349:1019-26. (Direct link – subscription may be required.)
  2. Fang MC, Chang Y, Hylek EM, Rosand J, Greenberg SM, Go AS, et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Annals of internal medicine. 2004;141:745-52.
  3. Odén A, Fahlén M, Hart RG. Optimal INR for prevention of stroke and death in atrial fibrillation: a critical appraisal. Thrombosis research. 2006; 117(5):493-9.(Link to article – subscription may be required.)>
  4. Akl E, Barba M, Rohilla S, Terrenato I, Sperati F, Muti P, Schünemann H. Anticoagulation for the long term treatment of venous thromboembolism in patients with cancer. Cochrane database of systematic reviews (Online). 2008; (2):CD006650.(Epub) (Link to article – subscription may be required.)
  5. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L. Apixaban versus warfarin in patients with atrial fibrillation. The New England journal of medicine. 2011 Sep 15; 365(11):981-92.(Link to article – subscription may be required.)
  6. http://www.bcshguidelines.com/publishedHO.asp?tf=Haemostasis%20and%20Thrombosis&status=#147 BCSH guidelines on anticoagulation with warfarin 2005
  7. Rodger MA, Kahn SR, Wells PS, Anderson DA, Chagnon I, Le Gal G, Solymoss S, Crowther M, Perrier A, White R, Vickars L, Ramsay T, Betancourt MT, Kovacs MJ. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2008 Aug 26; 179(5):417-26.(Link to article – subscription may be required.)
  8. van Veen JJ, Maclean RM, Hampton KK, Laidlaw S, Kitchen S, Toth P, Makris M. Protamine reversal of low molecular weight heparin: clinically effective? Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis. 2011 Oct; 22(7):565-70.(Link to article – subscription may be required.)
  9. Ghanny S, Warkentin TE, Crowther MA. Reversing Anticoagulant Therapy. Current drug discovery technologies. 2011 Oct 21.(Epub ahead of print)
  10. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011 Oct 4; 124(14):1573-9.(Link to article – subscription may be required.)
  11. Nishijima DK, Dager WE, Schrot RJ, Holmes JF. The efficacy of factor VIIa in emergency department patients with warfarin use and traumatic intracranial hemorrhage. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2010 Mar; 17(3):244-51.(Link to article – subscription may be required.)
  12. Dossett LA, Riesel JN, Griffin MR, Cotton BA. Prevalence and implications of preinjury warfarin use: an analysis of the National Trauma Databank. Archives of surgery (Chicago, Ill. : 1960). 2011 May; 146(5):565-70.(Link to article – subscription may be required.)
  13. Ivascu FA, Howells GA, Junn FS, Bair HA, Bendick PJ, Janczyk RJ. Rapid warfarin reversal in anticoagulated patients with traumatic intracranial hemorrhage reduces hemorrhage progression and mortality. The Journal of trauma. 2005 Nov; 59(5):1131-7; discussion 1137-9.
  14. Goldstein JN, Thomas SH, Frontiero V, Joseph A, Engel C, Snider R, Smith EE, Greenberg SM, Rosand J. Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke; a journal of cerebral circulation. 2006 Jan; 37(1):151-5.(Link to article – subscription may be required.)
  15. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. The New England journal of medicine. 2008 May 15; 358(20):2127-37.(Link to article – subscription may be required.)
  16. Mayer SA, Davis SM, Skolnick BE, Brun NC, Begtrup K, Broderick JP, Diringer MN, Steiner T. Can a subset of intracerebral hemorrhage patients benefit from hemostatic therapy with recombinant activated factor VII? Stroke; a journal of cerebral circulation. 2009 Mar; 40(3):833-40.(Link to article – subscription may be required.)
  17. Huttner HB, Schellinger PD, Hartmann M, Köhrmann M, Juettler E, Wikner J, Mueller S, Meyding-Lamade U, Strobl R, Mansmann U, Schwab S, Steiner T. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke; a journal of cerebral circulation. 2006 Jun; 37(6):1465-70.(Link to article – subscription may be required.)
  18. Yuan ZH, Jiang JK, Huang WD, Pan J, Zhu JY, Wang JZ. A meta-analysis of the efficacy and safety of recombinant activated factor VII for patients with acute intracerebral hemorrhage without hemophilia. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2010 Jun; 17(6):685-93.(Link to article – subscription may be required.)
  19. Barillari G, Pasca S, Barillari A, De Angelis V. Emergency reversal of anticoagulation: from theory to real use of prothrombin complex concentrates. A retrospective Italian experience. Blood transfusion = Trasfusione del sangue. 2012 Jan; 10(1):87-94.(Link to article – subscription may be required.)