Anticoagulant therapy is prescribed to a variety of patients for a variety of clinical indications (1-5). For example, vitamin K antagonists (VKAs), such as warfarin, remain one of the most commonly utilised oral anticoagulants and are broadly used for: treatment of venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE), stroke prophylaxis in atrial fibrillation (AF) and to reduce the risk of prosthetic heart valve thrombosis and thromboembolism (1-3,6). Heparin moieties, for example either as unfractionated (UH), or as a low molecular weight heparin (LMWH), represent other commonly prescribed anticoagulants, albeit given parentally (either intravenous or subcutaneous) (1-4,6). More recently, the availability of direct inhibitors of either thrombin (factor IIa) or factor Xa (FXa), have revolutionised the landscape of oral anticoagulant therapy and given rise to the concept of ‘direct oral anticoagulants’ (or DOACs) (1-3,5,6). In this narrative review, we briefly outline the anticoagulants available in Australia, their relative strengths and weaknesses, and the ever-changing local landscape with regards to anticoagulation therapy.
Heparin anticoagulation therapy
As noted above, heparin therapy is reflected by different options, broadly reflective of UF, LMWH, and in some cases heparinoids and heparin-like molecules that indirectly or directly inhibit either thrombin (FIIa) or FXa. The main advantages and disadvantages of heparin therapy are provided in Table 1.
The main advantages are the low cost of therapy, rapid onset of action, clinical efficacy, and that (for UH at least) an antidote is readily available in the case of over-dose or need for reversal in the setting of bleeding or urgent surgery.
One easily identified limitation of heparin therapy is that it needs to be administered intravenously or subcutaneously to achieve anticoagulation, either regularly administered (1–2× per day) or by continuous infusion (UH). This may be inconvenient or undesired. Heparin therapy may also require laboratory monitoring, either by use of an activated partial thromboplastin (APTT) assay (for UH), or by a chromogenic anti-FXa assay (LMWH; sometimes UH) (Table 1, Figures 1 and 2). This adds cost and complexity to anticoagulant therapy management. Testing and clinical outcomes may also be compromised by poorly selected heparin therapeutic ranges, based on misunderstandings or limited assessment of reagent sensitivities (4). It is usual also to monitor platelet counts, as there is a small but significant risk of developing heparin induced thrombocytopenia (HIT), which may have significant adverse clinical sequelae, such as thrombosis and organ damage (7,8). This is known as ‘pathological HIT’ or HIT with thrombosis, sometimes abbreviated as HITT.
VKA anticoagulation therapy
Treatment with VKAs such as warfarin also carries both advantages and disadvantages (Table 2). VKAs represent cheap and clinically effective anticoagulants and are administered orally. There are antidotes available in the case of over-dose or therapy reversal (e.g., urgent surgery).
Among the limitations, VKAs are slow acting, there is a large inter-individual variation in anticoagulant response, and there are many drug and food interactions. These limitations mandate initial therapy with another agent (usually heparin), and regular laboratory monitoring, most typically using the prothrombin time (PT), converted to an international normalised ratio (INR) (Figure 1). This is problematic for many reasons, and not only for the regular (inconvenient, undesired, time consuming) venous punctures required for blood sampling. The INR, as a mathematical calculation of the laboratory test the PT, itself poses many problems, including limited accuracy (9-11).
Despite the clinical efficacy of anticoagulant agents such as heparin and VKAs, their limitations have driven continued advances in anticoagulant therapy, most recently epitomised by the release of several direct acting inhibitors of FIIa or FXa, and now generally known as DOACs. These include the agents dabigatran (anti-FIIa) and in Australia apixaban and rivaroxaban (both anti-FXa agents). Additional DOACs are available in other countries, including edoxaban and betrixaban (both anti-FXa agents). The clinical indications for the DOACs are similar to those of heparin and/or VKAs, and also similar to one another (Table 3). Such indications may be somewhat different in other countries, depending on local regulatory approvals/clearances.
In terms of advantages, all the DOACs have proven efficacy and safety. Indeed, studies show either similar or superior outcomes with the DOACs in comparison to comparator drugs (12-14). The DOACs were also developed and are marketed as not requiring laboratory monitoring, and so are far more convenient than alternative classical anticoagulant agents. Testing, if required, van be performed (5,15). Idarucizumab is available for reversal of dabigatran in the setting of urgent surgery or life-threatening bleeding (16); however, specific antidotes for the Factor Xa inhibitors are not yet available in Australia, although under clinical trial.
In terms of disadvantages, DOACs are more expensive than heparin or VKAs (Figure 3), although cost-benefit data may suggest indirect cost savings to the health system with their implementation (e.g., reduction in bleeding and hence less hospital admissions and no requirement for routine laboratory monitoring). Since routine laboratory monitoring is not undertaken, there is a potential risk of both over-dosing and under-dosing, with consequent increased risk of bleeding or thrombosis, respectively, in particular in non-compliant patients or those with relevant co-morbidities. Indeed, compliance is a big issue with the DOACs. With VKAs, a missed dose could be adjusted for. With DOACs, a missed dose leads to lack of anticoagulant cover for 12–24 hours depending on the agent. In addition, should patients miss a dose, they may be tempted to take a double dose the next time, which would place them at higher risk for a bleeding event. Although antidotes are available or imminent for DOACs, they are very expensive relative to those used for heparin and VKAs. Although regular monitoring of anticoagulant therapy is not needed, ongoing risk assessment of renal or liver dysfunction (and monitoring of appropriate parameters) is required because of the risk of drug accumulation in these settings which may result in an increased risk of bleeding.
Other anticoagulant agents
In Australia, several other anticoagulants are available for various clinical indications, as summarised in Table 4 (2). These drugs tend to have fairly restricted applications in hospital settings, and are not broadly available for community use. They tend to need close monitoring and are also relatively expensive to use (Figure 2, Table 4).
Because of apparent benefits, DOACs are becoming increasingly prescribed by clinicians and utilised by patients. Indeed, local Australian prescription data shows that DOACs have now replaced VKA therapy as the most often prescribed anticoagulant drugs (Figure 3). The clear ongoing reduction in warfarin prescribing contrasts the steady increase in prescriptions for all the DOACs, although most notably for the anti-activated factor X (FXa) agents (rivaroxaban and apixaban). The preferential uptake of the anti-FXa agent rivaroxaban and apixaban over dabigatran may be partly related to the Australian setting, where the price of dabigatran is not subsidised by the government for treatment of DVT/PE. What this data also seems to show is that the total number of prescriptions for all oral anticoagulants (warfarin, apixaban, rivaroxaban and dabigatran) has also increased substantially over the data collection period. However, there are limitations in the direct comparability of this data, given this details prescription counts for each drug, with each being available in several forms, which may not be ‘analogous’ (e.g., warfarin is available in 1, 2, 3 and 5 mg tablets; rivaroxaban is available in 10, 15 or 20 mg tablets, of various pack sizes). Nevertheless, these trends appear to evidence that DOACs are not only replacing warfarin, but are also potentially being increasingly prescribed in previously anticoagulant-naïve patients. Another possible contributor to these trends is that more patients are remaining on long-term VTE prophylaxis with reduced dose anti-FXa agents. The available data does not provide any detail to offer any reassurance or otherwise regarding the appropriateness of these prescriptions, although because the risk/benefit ratio of DOACs is typically identified as being superior to VKAs, clinicians may be more comfortable starting anticoagulant therapy in some patients previously deemed unsuitable for VKA, or in extending their anticoagulation for longer/indefinitely at reduced prophylactic doses of anti-FXa agents.
Of importance is that any list of drug indications is usually counterbalanced by a sometimes longer list of ‘contraindications’, which for the oral anticoagulants is summarised in Table 5. Accordingly, although these are considered ‘safe drugs’, no drug should be prescribed without due consideration of associated risks in each individual patient.
Another limitation in the script-based data analysis is that parental agents are primarily used within hospitals, and thus very few scripts would be written for community use. This is relevant since DOAC use may in part be replacing heparin use, in particular LWMHs such as enoxaparin.
Also relevant to workers in the field and healthcare practice are the changing costs in anticoagulant practice and the potential effect of changing anticoagulant usage on pathology test practice, including laboratory monitoring of anticoagulant therapy. For the latter, laboratory monitoring of VKA therapy, for example, is a key activity of pathology laboratories, and the PT/INR is the most commonly performed coagulation test, and within haematology, perhaps second only to the full blood count. The APTT is the other more commonly performed coagulation test, in some occasions performed for heparin therapy monitoring. Evidence that test numbers are decreasing for performance PT/INR and the APTT, as derived from Medicare data, and for a similar data period of 2011–2017, is shown in Figure 4. This decreasing trend in test requests in Australia is consistent with a reduction in VKA use and associated anticoagulant monitoring (6).
This drop in laboratory PT/INR/APTT testing is not countered by a replacement growth in laboratory DOAC testing, with such requests currently totaling <200/year in our facility, and as compared to nearly 500 requests for LMWH anti-Xa testing and over 70,000 PT/INRs/APTTs (Figure 5). DOAC measuring tests, unlike PT/INR/APTT, do not currently attract Medicare funding in Australia, and thus there is no available national data on test numbers from government sites to our knowledge.
A final consideration is whether the increased usage of DOACs is otherwise affecting haematology laboratory practice, and indeed this is the case. Although, as an example, we are performing a total of <200 tests per year to ‘measure’ drug levels of DOACs, patients on DOACs had well over 2,000 routine coagulation tests performed during the same period in an audit of recent activities (6). This is over 20× the rate of specific DOAC measuring assays. At least some of the routine tests performed on these patients will raise clinical concern with ‘unexpectedly raised’ test times. Further tests (e.g., factor assays) may also be initiated in response, to help explain ‘abnormal’ test findings. Also, many thrombophilia related requests are inappropriately performed on patients on DOACs, and these may cause a range of problems, including misidentification of congenital defects or false identification of lupus anticoagulant (5,17-22).
The use of DOACs continues to grow, both in Australia and worldwide, partly as replacement for VKA therapy, partly as replacement for LMWH therapy, and partly for potentially ‘new’ (previously non-anticoagulated or extended secondary VTE prophylaxis) patients. This trend is expected to continue, in part also considering increases of life expectancy, and since increasing age elevates the risk of many prothrombotic conditions (i.e., VTE, AF). Laboratory test practice is changing in response to these events, with reduced test numbers for PT/INR/APTT, the requirement to measure DOACs on occasion, and the generation of additional haemostasis tests and further complications to laboratory practice associated with DOAC use and effect on a variety of assays. If DOAC influence of test results for other hemostasis assays is not recognised, then this can lead to high potential for disease misdiagnosis. Hematology laboratories worldwide need to be aware of these issues to enable proactive management of changes to testing services. We suspect the situation in Australia is not unique, and we look forward to laboratories in other geographical to share their experience within this issue of the journal.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Disclaimer: The opinions expressed in this review are those of the authors, and not necessarily those of NSW Health Pathology.
- Favaloro EJ. Anticoagulant therapy: present and future. Semin Thromb Hemost 2015;41:109-12. [Crossref] [PubMed]
- Favaloro EJ, Lippi G, Koutts J. Laboratory testing of anticoagulants - the present and the future. Pathology 2011;43:682-92. [Crossref] [PubMed]
- Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest 2018;154:1121-201. [Crossref] [PubMed]
- Baluwala I, Favaloro EJ, Pasalic L. Therapeutic monitoring of unfractionated heparin - trials and tribulations. Expert Rev Hematol 2017;10:595-605. [Crossref] [PubMed]
- Favaloro EJ, Pasalic L, Curnow J, et al. Laboratory monitoring or measurement of direct oral anticoagulants (DOACs): Advantages, limitations and future challenges. Curr Drug Metab 2017;18:598-608. [Crossref] [PubMed]
- Favaloro EJ, Pasalic L, Lippi G. Replacing warfarin therapy with the newer direct oral anticoagulants, or simply a growth in anticoagulation therapy? Implications for Pathology testing. Pathology 2017;49:639-43. [Crossref] [PubMed]
- Favaloro EJ, McCaughan G, Pasalic L. Clinical and laboratory diagnosis of heparin induced thrombocytopenia: An update. Pathology 2017;49:346-55. [Crossref] [PubMed]
- Favaloro EJ, McCaughan G, Mohammed S, et al. HIT or miss? A comprehensive contemporary investigation of laboratory tests for heparin induced thrombocytopenia. Pathology 2018;50:426-36. [Crossref] [PubMed]
- Favaloro EJ. Optimizing the Verification of Mean Normal Prothrombin Time (MNPT) and International Sensitivity Index (ISI) for Accurate Conversion of Prothrombin Time (PT) to International Normalized Ratio (INR). Methods Mol Biol 2017;1646:59-74. [Crossref] [PubMed]
- Bonar R, Favaloro EJ. Explaining and reducing the variation in inter-laboratory reported values for International Normalised Ratio. Thromb Res 2017;150:22-9. [Crossref] [PubMed]
- Favaloro EJ, McVicker W, Mohammed S, et al. Mathematical rounding as a post-analytical issue in pathology reporting: generation of bias in INR resulting. Pathology 2018;50:459-61. [Crossref] [PubMed]
- Jun M, Lix LM, Durand M, et al. Canadian Network for Observational Drug Effect Studies (CNODES) Investigators. Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study. BMJ 2017;359:j4323. [Crossref] [PubMed]
- Lim HY, Nandurkar H, Ho P. Direct Oral Anticoagulants and the Paradigm Shift in the Management of Venous Thromboembolism. Semin Thromb Hemost 2018;44:261-6. [Crossref] [PubMed]
- Eikelboom J, Merli G. Bleeding with direct oral anticoagulants vs warfarin: clinical experience. Am J Emerg Med 2016;34:3-8. [Crossref] [PubMed]
- Iapichino GE, Bianchi P, Ranucci M, et al. Point-of-Care Coagulation Tests Monitoring of Direct Oral Anticoagulants and Their Reversal Therapy: State of the Art. Semin Thromb Hemost 2017;43:423-32. [Crossref] [PubMed]
- Brennan Y, Favaloro EJ, Pasalic L, et al. Lessons learnt from local real-life experience with idarucizumab for the reversal of dabigatran. Intern Med J 2018. [Epub ahead of print]. [Crossref] [PubMed]
- Favaloro EJ, Mohammed S, Curnow J, et al. Laboratory testing for lupus anticoagulant (LA) in patients taking direct oral anticoagulants (DOACs): potential for false positives and false negatives. Pathology 2018. In Press.
- Favaloro EJ. Danger of false negative (exclusion) or false positive (diagnosis) for ‘congenital thrombophilia’ in the age of anticoagulants. Clin Chem Lab Med 2018. [Epub ahead of print]. [Crossref]
- Bonar R, Favaloro EJ, Mohammed S, et al. The effect of dabigatran on haemostasis tests: a comprehensive assessment using in-vitro and ex-vivo samples. Pathology 2015;47:355-64. [Crossref] [PubMed]
- Bonar R, Favaloro EJ, Mohammed S, et al. The effect of the direct factor Xa inhibitors apixaban and rivaroxaban on haemostasis tests: a comprehensive assessment using in vitro and ex vivo samples. Pathology 2016;48:60-71. [Crossref] [PubMed]
- Favaloro EJ, Lippi G. Laboratory testing in the era of direct or non-vitamin k antagonist oral anticoagulants: a practical guide to measuring their activity and avoiding diagnostic errors. Semin Thromb Hemost 2015;41:208-27. [Crossref] [PubMed]
- Gosselin RC, Adcock DM, Bates SM, et al. International Council for Standardization in Haematology (ICSH) Recommendations for Laboratory Measurement of Direct Oral Anticoagulants. Thromb Haemost 2018;118:437-50. [Crossref] [PubMed]
Cite this article as: Favaloro EJ, McCaughan GJ, Mohammed S, Pasalic L. Anticoagulation therapy in Australia. Ann Blood 2018;3:48.