Orally active small molecules that selectively and specifically inhibit coagulation serine proteases have been developed for clinical use. For some patients these oral direct inhibitors (ODIs) offer substantial benefits over oral vitamin K antagonists (VKA). However, for the majority of patients with good anticoagulant control with VKAs the advantages of the ODIs are primarily convenience and few drug interactions. The drugs are prescribed at fixed dose without the need for monitoring or dose adjustment in the majority of patients and the rapid onset of anticoagulation and short half-life make initiation and interruption of anticoagulation considerably easier than with VKAs. As yet, specific antidotes to ODIs are not available for clinical use but these are in development as rapid reversal agents. As with all anticoagulants produced so far, there is a correlation between intensity of anticoagulation and bleeding. Consequently, the need to consider the balance of benefit and risk in each individual patient is no less important than with VKA therapy. Dabigatran and rivaroxaban have been chosen for this review as examples of a thrombin inhibitor and an inhibitor of factor Xa respectively. The clinical application of these drugs is the focus of the review.

Drug development

For more than half a century vitamin K antagonists (VKA) have been used as oral anticoagulants to prevent and treat thromboembolism. However, limitations, side effects, complications and inconvenience with VKAs meant that development of new oral anticoagulant drugs aiming for the ‘ideal’ oral antithrombotic drug profile was always desirable. The ‘ideal’ drug would be one characterized by dissociation of the antithrombotic and anticoagulant effects: in other words, an antithrombotic that did not cause bleeding. So far a drug with this profile has not been realised. However, the new oral active site-specific inhibitors of coagulation serine proteases do offer an improvement over VKAs by virtue of:

predictable dose responses;
no need for routine monitoring;
reduced need for dose adjustment;
no food interactions;
limited drug interactions.

These direct inhibitors of serine proteases have been produced by structure-guided design and both inhibitors of thrombin and factor Xa have now been shown to be selective, orally active, safe and at least as effective as warfarin in clinical studies. Phase III anticoagulant drug development programmes typically begin with prevention of venous thrombosis in patients undergoing elective hip or knee replacement. The reason for this is that the endpoint (radiographically detectable venous thrombosis) occurs frequently within 14 d of surgery and therefore efficacy, compared to a traditional anticoagulant such as a low dose low molecular weight heparin, is demonstrable quickly in relatively small studies. Much larger studies conducted over several years are required to demonstrate efficacy in comparison to warfarin for stroke prevention in patients with atrial fibrillation and for prevention of recurrent venous thromboembolism. Ximelegatran, a prodrug of melagatran, was the first oral direct inhibitor (ODI) of thrombin and was an effective antithrombotic drug compared to warfarin with a target International Normalized Ratio (INR) of 2·5. Liver toxicity with long-term dosing resulted in a failed approval in the United States and withdrawal in Europe. Dabigatran etexilate, a prodrug of the direct thrombin inhibitor dabigatran, was the next new oral anticoagulant drug to complete phase III studies. Several inhibitors of factor Xa are at different stages of development and these include rivaroxaban, apixaban, betrixaban and edoxaban. Dabigatran (Connolly et al, 2009; Schulman et al, 2009) and rivaroxaban (Bauersachs et al, 2010; Patel et al, 2011; Buller et al, 2012) were the first thrombin and X-a inhibitors, respectively, to complete phase III studies of prevention of thromboembolism in patients with non-valvular atrial fibrillation and treatment of acute venous thromboembolism and are now licensed in several countries for routine clinical use. They undoubtedly offer convenience over VKAs and there is some gain in the balance of benefit and risk. The drugs were initially evaluated in patients undergoing lower limb joint replacement and use in this situation is established (Gomez-Outes et al, 2012).

Dabigatran

In the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) study 18 113 patients with atrial fibrillation were randomized to receive either 110 or 150 mg dabigatran twice daily (blinded) or dose-adjusted warfarin to a target INR of 2·5 (unblinded) (Connolly et al, 2009) (Table 1). The mean age of patients was 71 years and the mean CHADS₂ (Congestive heart failure; Hypertension; Age (≥75 years); Diabetes mellitus; prior Stroke, transient ishaemic attack or thromboembolism) score was 2·1. The therapeutic time in range for the warfarin group was 64% (Wallentin et al, 2010). Patients with a creatinine clearance of <30 ml/min were excluded. The primary outcome of stroke or systemic embolism occurred less frequently in patients treated with dabigatran 150 mg twice daily. However, in centres where the centre-time-in-range (cTTR) was above 65%, dabigatran 150 mg twice daily was not superior to warfarin (Schulman & Crowther, 2012). The rate of major bleeding was lower in patients treated with 110 mg twice daily. However, there was an increase in the rate of lower gastrointestinal bleeding in the higher dabigatran dose group. This may be due to the low bioavailability (6·5%) and consequent high concentrations of dabigatran in the faeces causing a local anticoagulant effect at the bowel wall (Blech et al, 2008). Dyspepsia was more common with dabigatran (11·3% and 11·8% in the 150 and 110 mg dabigatran groups) compared to the warfarin group (5·8%). More patients discontinued dabigatran (21%) than warfarin (17%) and discontinuation due to gastrointestinal side effects was more common in patients taking dabigatran. The combination of higher rates of lower gastrointestinal bleeding and drug discontinuation due to dyspepsia may be a reason to choose a different anticoagulant for patients with a history of gastrointestinal disorders (Schulman & Crowther, 2012).

Table 1. Outcomes of clinical trials by intention-to-treat

Diagnosis	Trial	Treatment	Primary outcome (%)	Major haemorrhage (%)	Reference
AF	RE-LY	Dabigatran 150 bd	1·11	3·11	Connolly et al (2009)
		Dabigatran 110 bd	1·53	2·71
		Warfarin	1·69	3·36
	ROCKET-AF	Rivaroxaban 20 od	2·11	3·6	Patel et al (2011)
		Warfarin	2·4	3·4	Patel et al (2011)

DVT & PE	RE-COVER	Dabigatran 150 bd	2·4	1·6	Schulman et al (2009)
	RE-COVER	Warfarin	2·1	1·9	Schulman et al (2009)
	EINSTEIN DVT	Rivaroxaban 20 od	2·1	0·8	Bauersachs et al (2010)
	EINSTEIN DVT	Warfarin	3·0	1·2	Bauersachs et al (2010)
	EINSTEIN PE	Rivaroxaban 20 od	2·1	1·1	Buller et al (2012)
	EINSTEIN PE	Warfarin	1·8	2·2	Buller et al (2012)

Doses of drugs is in mg, od, once daily; bd, twice daily. AF, atrial fibrillation; DVT, deep vein thrombosis; PE, pulmonary embolus.
Statistically significant differences compared to the within-study warfarin group are shown in bold.

In the RE-COVER study, 2539 patients with venous thromboembolism were randomized in a double-blind double-dummy study to receive either 150 mg dabigatran twice daily or adjusted-dose warfarin to a target INR of 2·5 (Schulman et al, 2009). Patients randomized to dabigatran as well as those receiving warfarin received initial standard therapy with low molecular weight heparin (LMWH). The primary outcome of symptomatic recurrent venous thromboembolism in the 6-month treatment period was not significantly different and the rates of major bleeding were similar. The mean age of patients was 55 years, 30% of patients had symptomatic pulmonary embolism (PE) and 5% of patients had cancer. The therapeutic time in range for the warfarin group was 60%. Dyspepsia occurred in 3% of patients taking dabigatran compared to 0·7% in patients taking warfarin. Adverse events leading to discontinuation of drug occurred in 9·0% of patients randomized to dabigatran and 6·8% of patients randomized to warfarin. The difference in rates of dyspepsia and discontinuation of treatment in the RE-LY and RE-COVER studies may be explained by the shorter treatment duration in RE-COVER.

Pharmacodynamics and pharmacokinetics

Dabigatran etexilate is an oral prodrug which is hydrolysed by carboxylesterases to the active compound dabigatran after absorption (http://www.medicines.org.uk/emc/medicine/24839). Dabigatran is a direct specific competitive inhibitor of free and fibrin-bound thrombin that binds to the active site of thrombin with high affinity (Kd 7 × 10⁻¹⁰ mol/l). Peak plasma levels are reached 2 h after ingestion, although this may be delayed for up to 6 h after the first post-operative dose. The steady state mean dabigatran peak plasma concentration, measured around 2 h after 150 mg dabigatran etexilate administration twice daily, was 175 ng/ml, with a range of 117–275 ng/ml (25th–75th percentile range). The mean trough concentration, measured 12 h after a 150 mg evening dose was 91 ng/ml, with a range of 61–143 ng/ml (25th–75th percentile range). C_max and the area under the plasma concentration-time curve were dose-dependent. Plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life of 11 h in healthy elderly subjects. After multiple doses a terminal half-life of about 12–14 h was observed. The half-life was independent of dose. Half-life is prolonged if renal function is impaired. With a creatinine clearance (CrCl) of 80 ml/min the half life is 13 h, which increases to 27 h when the CrCl is below 30 ml/min. Renal excretion accounts for 80% of dabigatran clearance and severe renal insufficiency, defined by a CrCl < 30 ml/min is a contraindication to the use of dabigatran.

Drug interactions

The only drugs that interact with dabigatran are inhibitors or inducers of P-glycoprotein (P-gp). CYP3A4 has almost no role in the metabolism of dabigatran and, unlike VKAs, dabigatran is not metabolized by CYP2C9. Use of dabigatran and the following drugs is contra-indicated:

azole antimycotics (ketoconazole, itraconazole, voriconazol, posaconazole);
ciclosporin;
tacrolimus.

It may be necessary to reduce the dose of dabigatran if concomitant use of amiodarone, verapamil or quinidine cannot be avoided. In this situation it may be useful to measure the anticoagulant effect of dabigatran (see 3.7). Clarithromycin slightly increased dabigatran levels in healthy volunteers but not to an extent likely to lead to over-anticoagulation. Protease inhibitors including ritonavir interact with P-gp but their effects on dabigatran have not been studied and they should be avoided in combination with dabigatran. Rifampicin, St John's Wort, carbamazepine and phenytoin are P-gp inducers and may lead to low dabigatran levels. They should be avoided.

Aspirin or clopidogrel should be used with caution or avoided and non-steroidal anti-inflammatory drugs should be avoided because their concomitant use was associated with an increased bleeding risk in the RE-LY study (Connolly et al, 2009). An acid environment is required for dissolution and absorption of dabigatran etexilate and so tartaric acid is included in the formulation. This may contribute to the dyspepsia. Use of proton pump inhibitors and antacids may reduce absorption and so it is advised to take dabigatran 2 h before these medications. No dose adjustment is needed with digoxin. There is no interaction with commonly used antibiotics or statins.

Clinical use

Dabigatran is licensed in Europe for prevention of stroke and systemic embolism (http://www.medicines.org.uk/emc/medicine/24839) in adult patients with one or more of the following risk factors:

previous stroke, transient ischemic attack, or systemic embolism;
left ventricular ejection fraction < 40%;
symptomatic heart failure, ≥New York Heart Association (NYHA) Class 2;
age ≥ 75 years;
age ≥ 65 years associated with one of the following: diabetes mellitus, coronary artery disease, or hypertension.

The recommended dose is 150 mg bd with a dose reduction to 110 mg bd over the age of 80 years. The lower dose can also be used when it is thought that the balance of thromboembolism and bleeding risk is shifted towards bleeding. It is recommended that the CrCl is calculated before starting treatment and this is repeated annually or whenever deterioration in renal function is suspected. A dose reduction is not mandated if the CrCl is >30 ml/min although the lower dose of 110 mg bd might be used when the CrCl is <50 to >30 ml/min. In patients with a CrCl of ≤30 ml/min, dabigatran is not recommended in Europe, although a dose of 75 mg twice daily has been recommended in the United States.

A dose reduction with amiodarone or quinidine may not be necessary but the dose should be reduced to 110 mg bd with verapamil. Measuring peak dabigatran levels may be useful for guiding dose adjustment.

No dose adjustment is required with weight between 50 and 100 kg. No clinical data is available on extremes of body weight and so measurement of peak dabigatran levels and dose adjustment might be considered.

Patients with liver enzymes more than twice the upper limit of normal were excluded from the RE-LY study. However, there is no liver toxicity associated with dabigatran and so the drug might be used as long as there is no coagulopathy associated with liver disease.

Food has no significant effect on absorption of dabigatran etexilate and the capsules should be taken with water with or without food. The capsules should not be opened as this increases absorption unpredictably by up to 75%, which can lead to high dabigatran levels. Only blister packs should be used as the formulation loses potency after exposure and capsules should be discarded after 60 d of exposure.

It is recommended to wait 12 h after the last dose of dabigatran when switching to a parenteral anticoagulant, i.e. start when the next dose of dabigatran is due. Dabigatran should be given when the next dose of a parenteral anticoagulant was due when switching to dabigatran.

When switching from a VKA to dabigatran, the VKA should be stopped and the dabigatran started as soon as the INR is <2·0. When switching from dabigatran to a VKA the duration of drug overlap will be determined by the starting dose of VKA (loading or known maintenance dose). Measurement of the INR before the next dose of dabigatran can be used to indicate when the dabigatran can be stopped (when the pre-dabigatran INR > 2·0). Patients with a CrCl <50 ml/min should have a shorter duration of overlap and the dabigatran might be stopped when the INR is >1·5. Point-of-care devices are not recommended for INR measurement when converting from dabigatran to a VKA (Baruch & Sherman, 2011).

Dabigatran should be continued without interruption in patients being cardioverted.

If a dose is missed it may still be taken up to 6 h before the next dose. From 6 h up to the next dose, the missed dose should be omitted.

Surgery may require interruption of anticoagulant therapy. A schedule for interrupting dabigatran is shown in Table 2. Measurement of the anticoagulant effect of dabigatran may be useful in some situations. Ideally, spinal and epidural anaesthesia should not be performed until:

Table 2. Schedules for interruption of dabigatran dosing for surgical procedures (http://www.medicines.org.uk/emc/medicine/24839)

Renal function CrCl (ml/min)	Estimated half-life (h)	Stop dabigatran before surgery (d)
Renal function CrCl (ml/min)	Estimated half-life (h)	High surgical bleeding risk	Low surgical bleeding risk
≥80	13	2	1
≥50 to <80	15	2–3	1–2
≥30 to <50	18	4	2–3

dabigatran is undetectable by quantitative assay;
or the thrombin time is normal;
or, at the very least, the activated partial thromboplastin time (APTT) with a known high sensitivity reagent to dabigatran is not prolonged (see 3.7).

After removal of an epidural catheter there should be an interval of 2 h before the next dose of dabigatran.

Dabigatran should not be prescribed in pregnancy or during breast-feeding and women of child-bearing age should be warned.

In case of suspected overdose it may be useful to measure the anticoagulant effect. Oral activated charcoal may reduce absorption if given in the first few hours after ingestion.

As protein binding is low dabigatran can be dialysed. This may be applicable when there is severe renal failure as the greatly prolonged half-life in the presence of renal failure can result in continued anticoagulation for several days.

Rivaroxaban

In the ROCKET AF study, 14 264 patients were randomized in a double-blind double-dummy study to either rivaroxaban 20 mg daily (15 mg daily in patients with a creatinine clearance of 30–49 ml/min) or dose-adjusted warfarin to a target INR of 2·5 (Patel et al, 2011). The primary outcome of stroke or systemic embolism was not significantly different and the rate of major bleeding was similar (Table 1). There was an increase in the rate of gastrointestinal bleeding in the rivaroxaban group. The mean age of patients was 73 years and the mean CHADS₂ score was 3·5. The therapeutic time in range for the warfarin group was 55%. Patients with a creatinine clearance of <30 ml/min were excluded and those with a clearance of 30–49 ml/min received a reduced dose of 15 mg daily.

In the EINSTEIN Acute deep vein thrombosis (DVT) study, 3449 patients were randomized in an open label study to receive either rivaroxaban 20 mg daily (15 mg twice daily for the first 3 weeks), without a requirement for initial LMWH, or adjusted-dose warfarin to a target INR of 2·5 after initial LMWH (Bauersachs et al, 2010). The primary outcome of symptomatic recurrent venous thromboembolism in the treatment period was not significantly different and the rates of major bleeding were similar. The mean age of patients was 55 years, >99% of patients had DVT without symptomatic PE and 7% of patients had cancer. In the EINSTEIN PE study 4,832 patients were randomized in an open label study to receive either rivaroxaban 20 mg daily (15 mg twice daily for 3 weeks) without necessarily receiving initial LMWH, or adjusted-dose warfarin to a target INR of 2·5 after initial LMWH (Buller et al, 2012). The primary outcome of symptomatic recurrent venous thromboembolism in the treatment period was not significantly different. The rate of major bleeding was lower in the rivaroxaban patients. The mean age of patients was 58 years, 25% had extensive PE (>25% of total pulmonary vasculature) and 5% of patients had cancer.

Pharmacodynamics and pharmacokinetics

Rivaroxaban is a direct competitive inhibitor of factor Xa and limits thrombin generation in a dose-dependent manner (http://www.xarelto.com/html/downloads/Xarelto-Prescribing _Information-Nov-2012.pdf). It binds to the active site of factor Xa with high affinity (Kd 3 × 10⁻¹⁰ mol/l). Absorption of drug is rapid (C_max < 4 h) with a half-life of 7–11 h. The mean rivaroxaban peak plasma concentration, measured 2–4 h after 20 mg, was 215 ng/ml, with a range of 22–535 ng/ml (90% intervals). The mean trough concentration, measured 24 h after a 20 mg evening dose was 32 ng/ml, with a range of 6–239 ng/ml (90% intervals). Two-thirds of rivaroxaban is metabolized in the liver but it can be used in patients with liver disease if there is no coagulopathy. Only about one-third of active rivaroxaban is cleared by the kidneys and there is no accumulation of drug when the CrCl is above 15 ml/min. Rivaroxaban is approved for clinical use in patients with renal insufficiency defined by a CrCl between 15 and 29 ml/min. However, a dose reduction from 20 mg once daily to 15 mg once daily is recommended for patients with moderate to severe renal impairment, indicating the need for periodically monitoring renal function in patients with impaired function.

Drug interactions

Rivaroxaban pharmacokinetics are affected by drugs that affect P-gp and CYP3A4. Unlike VKAs, rivaroxaban is not metabolized by CYP2C9. CYP3A4 plays a pivotal role in the oxidative metabolism of rivaroxaban and drugs that act both as strong inhibitors of both CYP3A4 and of P-gp have been shown to cause important reduction of the clearance of the drug, causing a significant increase in plasma concentrations. These drugs include azole antimycotics and human immunodeficiency virus (HIV) protease inhibitors and they are contraindicated with rivaroxaban. Changes in the bioavailability of the drugs can also be expected when given with other drugs that strongly inhibit only CYP3A4 or only P-gp but these interactions are not considered to be clinically relevant. Nevertheless, co-administration of strong inducers, such as phenytoin, carbamazepine, phenobarbitone and St. John's Wort, should either be avoided or used with caution.

Clinical use

Rivaroxaban is licensed for prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as:

congestive heart failure;
hypertension;
age ≥ 75 years;
diabetes mellitus;
prior stroke or transient ischaemic attack.

The recommended dose is 20 mg once daily.

Rivaroxaban is also licensed for treatment of DVT and PE, and prevention of recurrence in adults. The recommended dose is 15 mg twice daily for 3 weeks followed by 20 mg once daily.

No dose adjustment is required in the elderly.

A dose reduction to 15 mg daily during long term treatment is recommended when the CrCl is <30 ml/min. Rivaroxaban is not recommended when the CrCl is ≤15 ml/min.

Rivaroxaban is not recommended in patients treated with:

Azole antimycotics (ketoconazole, itraconazole, voriconazol, posaconazole);
HIV protease inhibitor, such as Ritonivir.

No dose adjustment is required with weight between 50 and 120 kg. No clinical data is available on extremes of body weight and so measurement of peak rivaroxaban levels and dose adjustment might be considered.

There is no liver toxicity associated with rivaroxaban and so the drug might be used in patients with liver disease as long as there is no associated coagulopathy.

Food increases the absorption of rivaroxaban and it is recommended that the capsules should be taken with food. The formulation contains lactose and patients with lactose intolerance should not be prescribed rivaroxaban.

It is recommended that the first dose of a parenteral anticoagulant is given at the time of the next scheduled dose of rivaroxaban when switching to a parenteral anticoagulant. Rivaroxaban should be given when the next dose of a parenteral anticoagulant was due when switching to rivaroxaban.

When switching from a VKA to rivaroxaban, the VKA should be stopped and the rivaroxaban started as soon as the INR is <2·0. When switching from rivaroxaban to a VKA, the duration of drug overlap will be determined by the starting dose of VKA (loading or known maintenance dose). Measurement of the INR before the next dose of rivaroxaban can be used to indicate when the rivaroxaban can be stopped (when the pre-rivaroxaban INR > 2·5 as the INR is elevated by rivaroxaban). Until further information is available point-of-care devices are not recommended for INR measurement when converting from rivaroxaban to a VKA.

Rivaroxaban should be continued without interruption in patients being cardioverted.

If a dose is missed during the 15 mg twice daily phase of treatment of venous thromboembolism, the dose should be taken immediately to ensure a daily dose of 30 mg daily. In this case two 15 mg tablets may be taken at the same time. If a 20 mg dose is missed it should be taken immediately. It may be preferable not to take it if it is <6 h until the next scheduled dose.

Rivaroxaban should be stopped 24 h before an invasive procedure requiring interruption of anticoagulant therapy. Measurement of the anticoagulant effect of rivaroxaban may be useful in some situations. Ideally, spinal and epidural anaesthesia should not be performed until:

Rivaroxaban is undetectable by quantitative assay;
Or at the very least the prothrombin time (PT) with a known high sensitivity reagent to rivaroxaban is not prolonged (see 3.7).

After removal of an epidural catheter there should be an interval of 2 h before the next dose of rivaroxaban.

Rivaroxaban should not be prescribed in pregnancy or during breast-feeding and women of child bearing age should be warned.

In case of suspected overdose it may be useful to measure the anticoagulant effect. Oral activated charcoal may reduce absorption if given in the first few hours after ingestion.

Due to a ceiling effect on absorption, no increase in plasma levels are found with doses of rivaroxaban above 50 mg. More than 95% of rivaroxaban is bound to albumin and so it cannot be dialysed.

Practical aspects of treatment with ODIs

Poor compliance with VKA therapy is not necessarily an indication to switch to an ODI as the combination of short half-life and lack of monitoring may make the balance of benefit and risk of an ODI unfavourable in patients with poor compliance. The first sign of non-compliance in a patient taking an ODI may be a thrombotic event. An ODI may be preferred if instability or low therapeutic-time-in-range (TTR) with a VKA is due to drug interactions.

Patients with atrial fibrillation treated with a VKA with a TTR < 65% have a lower rate of stroke if treated with dabigatran 150 mg twice daily (Wallentin et al, 2010). However, careful assessment of the reason for a low TTR is required as non-compliance may make an ODI unfavourable.

For patients with renal impairment rivaroxaban may be the preferred option if the CrCl is <50 ml/min.

Cancer

In the RE-COVER and EINSTEIN studies 5–7% of patients had cancer. Outcomes were similar in cancer and non-cancer patients. Therefore, treatment of patients with cancer with ODIs is likely to be as least as effective as warfarin based on current data. However, in patients with solid tumours, treatment with VKA is inferior to therapeutic dose LMWH (Kearon et al, 2012). Therefore, the decision to use an ODI in preference to LMWH should be made on an individual patient assessment of benefit and risk. Clinical trials directly comparing an ODI with a LMWH would be helpful not only in determining relative treatment benefits in relation to thrombosis and bleeding but also in relation to overall survival (Lee et al, 2005).

Heparin-induced thrombocytopenia and thrombosis (HIT/T)

Oral direct inhibitors are not associated with HIT/T. Clinical trials have not specifically addressed the use of ODIs in patients who develop HIT/T.

Measurement of anticoagulant effect of ODIs

In most circumstances ODIs have predictable bioavailability, pharmacokinetic and pharmacodynamic effects. However, there will be clinical circumstances when assessment of the anticoagulant effect of these drugs will be required. Laboratories should be aware of the sensitivity of their own assays to each drug. This can be achieved using appropriate calibrated plasma samples. Recommendations on measurement of dabigatran and rivaroxaban have been published by the British Committee for Standards in Haematology (BCSH) (Baglin et al, 2012). Assessment of the degree of anticoagulation may be required:

before surgery or an invasive procedure when a patient has taken a drug in the previous 24 h (or longer if CrCl < 50 ml/min on dabigatran);
when a patient is bleeding;
when a patient has taken an overdose;
when a patient has developed renal failure;
in patients with deteriorating renal function;
when establishing the optimal dose in patients taking other drugs that are known to significantly affect pharmacokinetics;
when establishing the optimal dose in patients at extremes of body weight;
when a patient has thrombosis on treatment to assess whether there is failure of therapy or lack of adherence (this may have limited application due to the short half life of ODIs in comparison to VKAs).

The result of a qualitative test, such as the PT or APTT, can indicate whether anticoagulation is supratherapeutic, therapeutic or subtherapeutic but cannot be used to determine the plasma concentration of the drug. The test results are dependent on when the last dose of drug was taken and therefore require interpretation with reference to the dose, anticipated half-life and factors that influence pharmacokinetics. The summary recommendations of the BCSH are:

Each laboratory should be aware of the sensitivity of their own PT and APTT assays to dabigataran and rivaroxaban (and other Xa inhibitors) and this can be achieved appropriately calibrated plasma samples.
The APTT using most reagents can be used for urgent determination of the relative intensity of anticoagulation due to dabigatran. The APTT cannot be used to determine the drug level. A normal thrombin time indicates a very low level of dabigatran.
With an appropriate reagent, the PT (or APTT with some regents) can be used for the urgent determination of the relative intensity of anticoagulation due to rivaroxaban. The PT is usually more sensitive. It cannot be used to determine the drug level.

The Hemoclot^® thrombin inhibitor assay is a sensitive dabigatran-calibrated thrombin clotting time that can be used to determine the drug concentration (Stangier & Feuring, 2012). The Ecarin clotting time (ECT) can also be used to measure dabigatran. Anti-factor Xa assays are sensitive to rivaroxaban (Samama et al, 2010, 2011; Asmis et al, 2011). By using rivaroxaban calibrators and controls, the anti-factor Xa chromogenic method is suitable for measuring a wide range of rivaroxaban plasma concentrations (20–660 ng/ml), which covers the expected rivaroxaban plasma levels after therapeutic doses (Samama et al, 2010, 2011).

It is likely that coagulation tests will be performed on patients taking anticoagulants as part of clinical assessment, e.g. admission to Accident and Emergency. The PT, APTT, Thrombin Time (TT) and fibrinogen level can be affected and recognition of this and interpretation of results requires education of front line clinical staff in many specialties. Thrombin-based measurement of fibrinogen can be significantly affected by dabigatran but with marked variation with different reagents (Lindahl et al, 2011). Some substantially underestimate the fibrinogen concentration whilst others (using higher thrombin concentrations and/or higher dilutions of test plasma) are much less affected. ODIs do not interfere with the D-dimer assay but D-dimer levels are lower in patients treated with anticoagulant drugs. Patients taking dabigatran or rivaroxaban could have a prolonged APTT and/or PT (and a low fibrinogen with dabigatran) and the results might wrongly be interpreted as suggesting disseminated intravascular coagulation (DIC). However, dabigatran and rivaroxaban do not cause thrombocytopenia and the D-dimer level is likely to be low.

Management of bleeding patients treated with ODIs

Management depends on the severity of bleeding. The time of last dose of ODI should be determined and the half-life should be estimated from measurement of serum creatinine and calculation of the CrCl. The anticoagulant activity of the ODI should be determined by the most appropriate laboratory assay.

When bleeding is not severe temporary drug withdrawal may be the only requirement. For more severe bleeding general treatment measures may be required and consideration should be given to:

mechanical compression (e.g. for epistaxis or superficial wounds);
surgical haemostasis (sutures and cautery);
fluid replacement;
correction of anaemia by transfusion of red cells;
correction of additional coagulopathy (e.g. dilutional coagulopathy) with platelet transfusion and appropriate blood products.

Protamine sulphate and vitamin K have no effect on the anticoagulant effects of ODIs. The effect of antifibrinolytics on bleeding due to ODIs is not known but use of tranexamic acid would be reasonable in some patients. Similarly, the general haemostatic effect of desmopressin (DDAVP) independent of thrombin or factor Xa might be beneficial although this is unknown. As yet, specific antidotes to ODIs are not available for clinical use but these are in development as rapid reversal agents (Lu et al, 2013; Schiele et al, 2013).

Fresh frozen plasma does not reverse the anticoagulant effect of ODIs to any appreciable degree and no clinical benefit has been demonstrated.

The effects of prothrombin complex concentrate (PCC) and recombinant factor VIIa (rVIIa) have not been studied in clinical trials in human patients with bleeding. The effect of rivaroxaban on coagulation tests from volunteers is reversed by PCC (50 iu/kg of 4-factor concentrate) but the effect of dabigatran is not (Eerenberg et al, 2011).

In some animals a variable response in bleeding models after exposure to dabigatran has been observed after administration of PCC. However, a dose-dependent reduction of bleeding in a rabbit kidney incision model with normalization of bleeding with a 50 iu/kg dose of Beriplex was observed (Pragst et al, 2012). Beriplex 100 iu/kg was able to prevent haematoma expansion due to dabigatran in a mouse intracranial haematoma model with no effect in response to rVIIa (8 mg/kg) (Zhou et al, 2011). No effect was observed in a mouse tail bleeding model with 14 iu/kg (Lambourne et al, 2012).

A reduction in rabbit ear bleeding time was observed after infusion of 40 u/kg of a PCC to rivaroxaban-treated animals but with no reduction in hepatosplenic incision blood loss (Godier et al, 2012). rVIIa had no effect on bleeding time or blood loss. As observed in humans, prolonged coagulation tests from animals treated with rivaroxaban can be reversed with PCC or rVIIa but as yet there is no strong evidence of a beneficial effect on bleeding. Bleeding times are reduced but major bleeding models have not yet been studied (Gruber et al, 2009).

For patients with life-threatening or intracranial bleeding, administration of 40–50 iu/kg of PCC or a factor eight inhibitor bypassing agent (FEIBA) has been suggested (Schulman & Crowther, 2012; Weitz et al, 2012).

It is not yet known which, if any, coagulation tests might be used as a surrogate marker for reduction of bleeding risk in response to PCCs or rVIIa.

Declaration of interests

TB has received honoraria from Boehringer Ingelheim, Bayer, Pfizer and Daiichi Sankyo for attending advisory boards.

References

Asmis, L.M., Alberio, L., Angelillo-Scherrer, A., Korte, W., Mendez, A., Reber, G., Seifert, B., Stricker, H., Tsakiris, D.A. & Wuillemin, W.A. (2011) Rivaroxaban: Quantification by anti-FXa assay and influence on coagulation tests A study in 9 Swiss laboratories. Thrombosis Research, 129, 492–498.
10.1016/j.thromres.2011.06.031
CASPubMedWeb of Science®Google Scholar
Baglin, T., Keeling, D. & Kitchen, S. (2012) Effects on routine coagulation screens and assessment of anticoagulant intensity in patients taking oral dabigatran or rivaroxaban: Guidance from the British Committee for Standards in Haematology. British Journal of Haematology, 159, 427–429.
10.1111/bjh.12052
CASPubMedWeb of Science®Google Scholar
Baruch, L. & Sherman, O. (2011) Potential inaccuracy of point-of-care INR in dabigatran-treated patients. The Annals of Pharmacotherapy, 45, e40.
10.1345/aph.1Q105
PubMedGoogle Scholar
Bauersachs, R., Berkowitz, S.D., Brenner, B., Buller, H.R., Decousus, H., Gallus, A.S., Lensing, A.W., Misselwitz, F., Prins, M.H., Raskob, G.E., Segers, A., Verhamme, P., Wells, P., Agnelli, G., Bounameaux, H., Cohen, A., Davidson, B.L., Piovella, F. & Schellong, S. (2010) Oral rivaroxaban for symptomatic venous thromboembolism. New England Journal of Medicine, 363, 2499–2510.
10.1056/NEJMoa1007903
CASPubMedWeb of Science®Google Scholar
Blech, S., Ebner, T., Ludwig-Schwellinger, E., Stangier, J. & Roth, W. (2008) The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 36, 386–399.
10.1124/dmd.107.019083
CASPubMedWeb of Science®Google Scholar
Buller, H.R., Prins, M.H., Lensin, A.W., Decousus, H., Jacobson, B.F., Minar, E., Chlumsky, J., Verhamme, P., Wells, P., Agnelli, G., Cohen, A., Berkowitz, S.D., Bounameaux, H., Davidson, B.L., Misselwitz, F., Gallus, A.S., Raskob, G.E., Schellong, S. & Segers, A. (2012) Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. New England Journal of Medicine, 366, 1287–1297.
10.1056/NEJMoa1113572
CASPubMedWeb of Science®Google Scholar
Connolly, S.J., Ezekowitz, M.D., Yusuf, S., Eikelboom, J., Oldgren, J., Parekh, A., Pogue, J., Reilly, P.A., Themeles, E., Varrone, J., Wang, S., Alings, M., Xavier, D., Zhu, J., Diaz, R., Lewis, B.S., Darius, H., Diener, H.C., Joyner, C.D. & Wallentin, L. (2009) Dabigatran versus warfarin in patients with atrial fibrillation. New England Journal of Medicine, 361, 1139–1151.
10.1056/NEJMoa0905561
CASPubMedWeb of Science®Google Scholar
Eerenberg, E.S., Kamphuisen, P.W., Sijpkens, M.K., Meijers, J.C., Buller, H.R. & Levi, M. (2011) Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: A randomized, placebo-controlled, crossover study in healthy subjects. Circulation, 124, 1573–1579.
10.1161/CIRCULATIONAHA.111.029017
CASPubMedWeb of Science®Google Scholar
Godier, A., Miclot, A., Le Bonniec, B., Durand, M., Fischer, A.M., Emmerich, J., Marchand-Leroux, C., Lecompte, T. & Samama, C.M. (2012) Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology, 116, 94–102.
10.1097/ALN.0b013e318238c036
CASPubMedWeb of Science®Google Scholar
Gomez-Outes, A., Terleira-Fernandez, A.I., Suarez-Gea, M.L. & Vargas-Castrillon, E. (2012) Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: Systematic review, meta-analysis, and indirect treatment comparisons. British Medical Journal, 344, e3675.
10.1136/bmj.e3675
PubMedWeb of Science®Google Scholar
Gruber, A., Marzec, U., Buetehorn, U., Hanson, S. & Perzborn, E. (2009) Reversal of the antihaemostatic effects of rivaroxaban by activated factor VII and activated prothrombin complex in primates. Haematologica, 94, 181 Abstract 0449.
Web of Science®Google Scholar
Kearon, C., Akl, E.A., Comerota, A.J., Prandoni, P., Bounameaux, H., Goldhaber, S.Z., Nelson, M.E., Wells, P.S., Gould, M.K., Dentali, F., Crowther, M. & Kahn, S.R. (2012) Antithrombotic therapy for VTE disease: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest, 141, e419S–e494S.
10.1378/chest.11-2301
CASPubMedWeb of Science®Google Scholar
Lambourne, M.D., Eltringham-Smith, L.J., Gataiance, S., Arnold, D.M., Crowther, M.A. & Sheffield, W.P. (2012) Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate. Journal of Thrombosis and Haemostasis, 10, 1830–1840.
10.1111/j.1538-7836.2012.04863.x
CASPubMedWeb of Science®Google Scholar
Lee, A.Y., Rickles, F.R., Julian, J.A., Gent, M., Baker, R.I., Bowden, C., Kakkar, A.K., Prins, M. & Levine, M.N. (2005) Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. Journal of Clinical Oncology, 23, 2123–2129.
10.1200/JCO.2005.03.133
CASPubMedWeb of Science®Google Scholar
Lindahl, T.L., Baghaei, F., Blixter, I.F., Gustafsson, K.M., Stigendal, L., Sten-Linder, M., Strandberg, K. & Hillarp, A. (2011) Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays. Thrombosis and Haemostasis, 105, 371–378.
10.1160/TH10-06-0342
CASPubMedWeb of Science®Google Scholar
Lu, G., DeGuzman, F.R., Hollenbach, S.J., Karbarz, M.J., Abe, K., Lee, G., Luan, P., Hutchaleelaha, A., Inagaki, M., Conley, P.B., Phillips, D.R. & Sinha, U. (2013) A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nature Medicine, 19, 446–451.
10.1038/nm.3102
CASPubMedWeb of Science®Google Scholar
Patel, M.R., Mahaffey, K.W., Garg, J., Pan, G., Singer, D.E., Hacke, W., Breithardt, G., Halperin, J.L., Hankey, G.J., Piccini, J.P., Becker, R.C., Nessel, C.C., Paolini, J.F., Berkowitz, S.D., Fox, K.A. & Califf, R.M. (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New England Journal of Medicine, 365, 883–891.
10.1056/NEJMoa1009638
CASPubMedWeb of Science®Google Scholar
Pragst, I., Zeitler, S.H., Doerr, B., Kaspereit, F.J., Herzog, E., Dickneite, G. & van Ryn, J. (2012) Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. Journal of Thrombosis and Haemostasis, 10, 1841–1848.
10.1111/j.1538-7836.2012.04859.x
CASPubMedWeb of Science®Google Scholar
Samama, M.M., Martinoli, J.L., LeFlem, L., Guinet, C., Plu-Bureau, G., Depasse, F. & Perzborn, E. (2010) Assessment of laboratory assays to measure rivaroxaban–an oral, direct factor Xa inhibitor. Thrombosis and Haemostasis, 103, 815–825.
10.1160/TH09-03-0176
CASPubMedWeb of Science®Google Scholar
Samama, M.M., Contant, G., Spiro, T.E., Perzborn, E., Guinet, C., Gourmelin, Y., Le Flem, L., Rohde, G. & Martinoli, J.L. (2011) Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thrombosis and Haemostasis, 107, 379–387.
10.1160/TH11-06-0391
CASPubMedWeb of Science®Google Scholar
Schiele, F., van Ryn, J., Canada, K., Newsome, C., Sepulveda, E., Park, J., Nar, H. & Litzenburger, T. (2013) A specific antidote for dabigatran: functional and structural characterization. Blood, 121, 3554–3562.
10.1182/blood-2012-11-468207
CASPubMedWeb of Science®Google Scholar
Schulman, S. & Crowther, M.A. (2012) How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood, 119, 3016–3023.
10.1182/blood-2011-10-378950
CASPubMedWeb of Science®Google Scholar
Schulman, S., Kearon, C., Kakkar, A.K., Mismetti, P., Schellong, S., Eriksson, H., Baanstra, D., Schnee, J. & Goldhaber, S.Z. (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. New England Journal of Medicine, 361, 2342–2352.
10.1056/NEJMoa0906598
CASPubMedWeb of Science®Google Scholar
Stangier, J. & Feuring, M. (2012) Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagulation and Fibrinolysis, 23, 138–143.
10.1097/MBC.0b013e32834f1b0c
CASPubMedWeb of Science®Google Scholar
Wallentin, L., Yusuf, S., Ezekowitz, M.D., Alings, M., Flather, M., Franzosi, M.G., Pais, P., Dans, A., Eikelboom, J., Oldgren, J., Pogue, J., Reilly, P.A., Yang, S. & Connolly, S.J. (2010) Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet, 376, 975–983.
10.1016/S0140-6736(10)61194-4
CASPubMedWeb of Science®Google Scholar
Weitz, J.I., Quinlan, D.J. & Eikelboom, J.W. (2012) Periprocedural management and approach to bleeding in patients taking dabigatran. Circulation, 126, 2428–2432.
10.1161/CIRCULATIONAHA.112.123224
PubMedWeb of Science®Google Scholar
Zhou, W., Schwarting, S., Illanes, S., Liesz, A., Middelhoff, M., Zorn, M., Bendszus, M., Heiland, S., van Ryn, J. & Veltkamp, R. (2011) Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke, 42, 3594–3599.
10.1161/STROKEAHA.111.624650
PubMedWeb of Science®Google Scholar

Citing Literature

Volume163, Issue2

October 2013

Pages 160-167

Clinical use of new oral anticoagulant drugs: dabigatran and rivaroxaban

References

Information

Summary

Drug development

Dabigatran

Pharmacodynamics and pharmacokinetics

Drug interactions

Clinical use

Rivaroxaban

Pharmacodynamics and pharmacokinetics

Drug interactions

Clinical use

Practical aspects of treatment with ODIs

Cancer

Heparin-induced thrombocytopenia and thrombosis (HIT/T)

Measurement of anticoagulant effect of ODIs

Management of bleeding patients treated with ODIs

Declaration of interests

References

Citing Literature

References

Information

About Wiley Online Library

Help & Support

Opportunities

Connect with Wiley

Clinical use of new oral anticoagulant drugs: dabigatran and rivaroxaban

References

Related

Information

Summary

Drug development

Dabigatran

Pharmacodynamics and pharmacokinetics

Drug interactions

Clinical use

Rivaroxaban

Pharmacodynamics and pharmacokinetics

Drug interactions

Clinical use

Practical aspects of treatment with ODIs

Cancer

Heparin-induced thrombocytopenia and thrombosis (HIT/T)

Measurement of anticoagulant effect of ODIs

Management of bleeding patients treated with ODIs

Declaration of interests

References

Citing Literature

References

Related

Information