The following list refers to classes of oral anticoagulation regimens for use in chronic atrial fibrillation:
- Antiplatelet agents
- Vitamin K antagonists
- Antithrombin agents
- Anti Xa agents
a) Give an example of a drug for each class of drug listed. (10% marks)
b) Compare and contrast these regimens specifically with respect to:
- The relative advantages and disadvantages
- The appropriate laboratory tests to assess coagulation status
- Management of life-threatening bleeding
(You may tabulate your answer.) (90% marks)
College Answer
| Regimen / Agent | Advantages / Disadvantages | Assessment of coagulation status | Life-threatening bleeding |
| Anti-platelet agentsAspirin, clopidogrel, ticagrelor |
A – Simple, no testing .D – Poor efficacy; prolonged action; limited reversibility, Minor increased risk of (non- traumatic) ICH |
APTT, INR, platelets Bleeding time, TEG/ROTEM, Platelet function tests | Platelet transfusion |
| Vit K anatagonistsWarfarin |
A – Remains gold standard; easy reversibility. D – Requires frequent monitoring; multiple drug (and alcohol) interactions. 3-4% risk of (any) bleeding; 2-5x risk of ICH (absolute risk .3-0.8%) |
APTT, INR, platelets | Vit K / Prothrombin complex concentrate (Prothrombinex) / FFP |
| Direct antithrombin agentsDabigatran |
A – No testing. D – Twice daily dosing; not suitable in severe renal impairment (80% renally cleared); no direct antidote; interacts with amiodarone. ICH risk lower than warfarin in some patient groups, but ischaemic stroke risk raised in prosthetic heart valves |
No specific tests | Activated charcoal if recent ingestionAntifibrinolytic (tranexamic acid)
Dialysis if co- existing renal impairment |
| Anti Xa agentsRivaroxaban, apixaban |
A – No testing. D – Twice daily dosing for apixaban; no direct antidote (yet); dose modification in renal impairment (33% & 27% renally cleared) |
Anti-Xa levels |
Activated charcoal if recent ingestion Antifibrinolytic (tranexamic acid) |
Additional comments:
Some candidates included agents given by intravenous or subcutaneous routes instead of
focusing on oral agents as asked.
Discussion
The college table is probably as succinct an answer as one can manage in under ten minutes. FOAM and non-FOAM resources to help answer this question include the following:
- LITFL: New Oral Anticoagulants (NOACs)
- LITFL: Rivaroxiban and bleeding
- LITFL: Dabigatran and Bleeding
- Tran et al (2014) - an excellent overview of oral anticoagulants
- Ansell et al (2004) - a brief tour of warfarin and its chemical relatives
- AHA/ACC/HRS Guidelines for AF (2014) - mainly to help with some specific recommendations.
- Stangier et al (2009) - pharmacology of dabigatran
- Kreutz (2010) - pharmacology of rivaroxaban
- Frost et al (2013) - pharmacology of apixaban
This bibliography is perhaps more extensive than is reasonable for a single SAQ. In order to answer the question, the table offered below has been reassembled from the following chapters:
| Advantages | Disadvantages | Tests | Reversal |
| Antiplatelet agents- aspirin, clopidogrel | |||
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| Vitamin K antagonists - warfarin | |||
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| Direct Thrombin Inhibitors - dabigatran | |||
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| Factor Xa inhibitors- apixaban, rivaroxaban | |||
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But, let us say that instead of wanting to answer a fellowship exam question you actually wanted to anticoagulate somebody for AF. Which drugs are best? What do the guidelines say? AHA/ACC/HRS (2014) make some specific recommendations:
- AF and mechanical valves: warfarin; but not dabigatran (evidence of harm)
- AF with normal valves, with prior stroke or CHADS-VASC >2: warfarin (level A), novel oral agents (level B). If INR control is poor, go with novel oral agents (level C)
- AF with CHADS-VASC =1: aspirin or novel oral agents (level C)
- AF post revascularisation: clopidogrel and novel oral agents, without aspirin (level B)
In this grand list of reversal agents, it is also worth mentioning idarucizumab (which already well known but not yet trialed in Phase II trails until August of 2015 by Pollack et al, well after this paper was sat and graded). Also in late 2015 the ANNEXA-A and ANNEXA-R trials (Siegal et al, 2015) demonstrated the efficacy of andexanet alfa in reversing rivaroxaban and apixaban. Future iterations of this question will expect these details. In coming years the availability of the "universal" reversal agent ciraparantag will likely render all this primitive witchcraft obsolete (Galliazzo et al, 2018) - this substance binds all the heparins and DOACS by hydrogen bonds, disabling them and neutralising their effects.
References
Tran, Huyen, et al. "New oral anticoagulants: a practical guide on prescription, laboratory testing and peri‐procedural/bleeding management." Internal medicine journal 44.6 (2014): 525-536.
Ansell, Jack, et al. "The pharmacology and management of the vitamin K antagonists." Chest 126.suppl 3 (2004): 204S-233S.
January, Craig T., et al. "2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary." J Am College Cardiol (2014).
Stangier, Joachim, and Andreas Clemens. "Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor." Clinical and Applied Thrombosis/Hemostasis (2009).
Kreutz, Reinhold. "Pharmacodynamic and pharmacokinetic basics of rivaroxaban." Fundamental & clinical pharmacology 26.1 (2012): 27-32.
Perzborn, Elisabeth, et al. "Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro." Thrombosis research 133.4 (2014): 671-681.
Scaglione, Francesco. "New oral anticoagulants: comparative pharmacology with vitamin K antagonists." Clinical pharmacokinetics 52.2 (2013): 69-82.
Frost, Charles, et al. "Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects." British journal of clinical pharmacology 75.2 (2013): 476-487.
Ward, Christopher, et al. "Practical management of patients on apixaban: a consensus guide." Thromb J 11.1 (2013): 27.
Pollack Jr, Charles V., et al. "Idarucizumab for dabigatran reversal." New England Journal of Medicine 373.6 (2015): 511-520.
Siegal, Deborah M., et al. "Andexanet alfa for the reversal of factor Xa inhibitor activity." New England Journal of Medicine373.25 (2015): 2413-2424.
Galliazzo, S., M. P. Donadini, and W. Ageno. "Antidotes for the direct oral anticoagulants: What news?." Thrombosis research164 (2018): S119-S123.