The safe and effective use of dabigatran and warfarin in primary care

Dabigatran was the first direct oral anticoagulant (DOAC) subsidised on the New Zealand Pharmaceutical Schedule. Other DOACs available in New Zealand are rivaroxaban, which is subsidised with Special Authority approval for the short-term prevention of venous thromboembolism following major joint/orthopaedic surgery and apixaban, which is not subsidised.

Dabigatran etexilate is a prodrug which is converted to dabigatran after it is absorbed.⁶ The active compound prevents platelet aggregation by binding directly to thrombin.^{6, 8} Anticoagulation with dabigatran occurs rapidly compared to warfarin.⁸ Peak plasma concentrations are achieved within two hours of an oral dose, followed by a decrease in concentration over the next four to six hours.⁸ With twice-daily dosing the elimination half-life of dabigatran is 12 – 17 hours.⁸ Two to three days of treatment is required for patients to achieve steady-state levels of dabigatran.⁸

Indications and contraindications for dabigatran

Indications for dabigatran have widened and it is now indicated in New Zealand for the:^{4, 9}

• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation with one or more of the following risk factors: previous stroke, transient ischaemic attack or systemic embolism, left ventricular ejection fraction < 40%, symptomatic heart failure, age ≥ 75 years, age ≥ 65 years with coronary artery disease, hypertension or diabetes. N.B. all of these risk factors, with the exception of left ventricular ejection fraction, are assessed as part of calculation of the CHA₂DS₂-VASc score^* to determine whether anticoagulation is required in patients with atrial fibrillation.
• Prophylaxis of venous thromboembolism following major orthopaedic surgery
• Treatment of deep-vein thrombosis or pulmonary embolism following at least five days of parenteral anticoagulant treatment
• Prevention of recurrent deep-vein thrombosis or pulmonary embolism

Dabigatran is contraindicated in patients with active bleeding or at significant risk of major bleeding, a prosthetic heart valve or severe renal impairment, i.e. a creatinine clearance less than 30 mL/min.⁴ Dabigatran is not recommended in patients with mitral stenosis, e.g. following rheumatic heart disease, as the safety and efficacy of treatment is unknown.¹

* For further information on CHA₂DS₂-VASc , see: bpac.org.nz/2017/af.aspx

Assess renal function before starting dabigatran

Renal function should be assessed before prescribing dabigatran because the majority of the medicine (85%) is excreted unchanged by the kidneys and bleeding is more likely in patients with reduced renal function.⁸ For example, in patients with moderately impaired renal function, i.e. creatinine clearance of 30 – 50 mL/min, the exposure to dabigatran is approximately 2.7 fold higher compared to patients with normal renal function.⁴

Use the Cockcroft-Gault equation for patients with reduced renal function

The Cockcroft-Gault equation is used to calculate creatinine clearance (in mL/min) and guide dabigatran dosing in preference to the estimated glomerular filtration rate (eGFR – mL/min/1.73m²) supplied by the laboratory. This is because the Cockcroft-Gault equation was used in the original Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study and therefore dabigatran dosing has only been validated using these calculations.^{4, 5} Significant variations can occur between estimates of renal function provided by Cockcroft-Gault and eGFR in people who are obese or very slim or in older people with reduced muscle mass. It is therefore good practice to confirm the correct dosing of dabigatran using the Cockcroft-Gault equation, particularly in patients with borderline eGFR values or in older patients.

A creatinine clearance calculator is available from the NZF: http://nzf.org.nz/nzf/resource/Creatinine%20Clearance%20Calculator.htm

Dabigatran dosing is determined by indication

The recommended dose of dabigatran differs depending on the indication, due to the different doses used in the original trials where safety and efficacy were established (Table 2). There are two standard doses for the prevention of stroke and systemic embolism: 150 mg, twice daily and 110 mg, twice daily, with the lower dose preferred for patients at increased risk of bleeding.

Regular monitoring of renal function is required

Patients taking dabigatran should have their renal function assessed every six to 12 months.^{1, 10} More frequent monitoring is recommended in patients with reduced renal function, i.e. a creatinine clearance less than 50 mL/min, or in situations where renal function may decline rapidly e.g. dehydrating illness, initiation of a diuretic or hypovolaemia.¹⁰ Decreasing renal function or increasing age may require a dose reduction or a switch to warfarin (see below).¹⁰

Table 2: Recommended dosing regimens for dabigatran by indication.^{* 9}

* In practice lower doses may be prescribed according to clinical experience and patient factors such as age, renal function and frailty

Managing dyspepsia associated with dabigatran use

Dyspepsia is reported by 3% to 12% of patients taking dabigatran, depending on the dose and the length of treatment.⁶ Gastrointestinal symptoms are often transient and patients can be encouraged to persist with treatment.¹¹ Taking dabigatran with food and a glass of water can prevent the onset of dyspepsia, which in turn reduces the risk of rare complications such as contact ulceration of the oesophagus.^{11, 12} A trial of treatment with a proton pump inhibitor (PPI) or an H2-receptor antagonist should be considered in patients with persistent dyspepsia.¹¹ Gastrointestinal bleeding is increased in patients taking dabigatran, in a dose-dependent manner.¹³ The use of PPIs reduces this risk and prophylactic treatment with a PPI may be appropriate in patients taking dabigatran who have a history of peptic ulcers or gastrointestinal bleeds.¹³ A switch to warfarin may be appropriate if the patient finds the adverse effects of dabigatran to be intolerable (see below).

Dabigatran is currently listed on Medsafe’s M² Medicines Monitoring programme and prescribers are encouraged to report any adverse reactions to the Centre for Adverse Reactions Monitoring (CARM): https://nzphvc.otago.ac.nz/report

Managing bleeding in patients taking dabigatran

The risk of bleeding in patients taking dabigatran is reduced by appropriate dosing and monitoring.

Patients with minor cuts and abrasions can be treated in primary care with mechanical compression. Oral tranexamic acid 15 mg/kg, four times daily, may be appropriate in some cases to increase clotting and prevent excessive blood loss.¹⁴ Adequate fluid intake should be encouraged to ensure continued excretion of dabigatran in the urine.¹⁴ Treatment of spontaneous bleeding in a patient taking dabigatran generally requires consultation with a haematology service.

A reversal agent for dabigatran, idarucizumab, has been subsidised for use in hospitals since September, 2016, although it may not be stocked in all hospitals. Idarucizumab is able to rapidly inhibit dabigatran in patients who have uncontrolled bleeding or who need to undergo urgent surgery.¹⁵

Medicine interactions with dabigatran

There are a number of medicines that have clinically significant interactions with dabigatran. For example, the combination of amiodarone or verapamil with dabigatran increases the amount of dabigatran absorbed, therefore increasing the risk of bleeding. This combination should be avoided or the dose of dabigatran reduced and the patient monitored for signs of bleeding.¹⁶ The risk of bleeding is also increased in patients who are concurrently taking dabigatran and selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors or NSAIDs.¹⁶

The NZF interactions checker provides details on medicines that interact with dabigatran and their clinical significance. The interactions between dabigatran and amiodarone, verapamil, SSRIs, SNRIs and NSAIDs are all “orange category”, which means that dose adjustment or close monitoring is required. Available from: www.nzf.org.nz

Changing from dabigatran to warfarin

Declining renal function or adverse effects, e.g. persistent dyspepsia, may require a change from dabigatran to warfarin. The patient’s renal function determines when warfarin should be started:⁴

1. Creatinine clearance ≥ 50 mL/min – start warfarin three days before stopping dabigatran
2. Creatinine clearance 30 – 49 mL/min – start warfarin two days before stopping dabigatran

Warfarin is commenced as per the usual protocol, with the dose depending on risk of thrombosis (see below).

Indications and contraindications for warfarin

Warfarin is indicated for the:⁹

• Prevention and treatment of venous thrombosis and pulmonary embolism
• Prevention of stroke following myocardial infarction in patients with increased embolic risk
• Prevention of thromboembolism in patients with atrial fibrillation
• Prevention of thromboembolism in patients with prosthetic heart valves

Warfarin is contraindicated in patients with a history of haemorrhagic stroke, clinically significant bleeding (e.g. GI bleed) or risk of bleeding, or after recent child birth.⁹

Managing warfarin in primary care

The monitoring of warfarin treatment requires a systematic and practice-wide process to ensure consistent and optimal care. The target INR for patients treated with warfarin is 2.5, with a clinically acceptable range of 2.0 – 3.0, or 2.5 – 3.5 for patients with mechanical heart valves.¹⁸ A “time in therapeutic range” of ≥ 70% is the goal of treatment,¹ however, this may be difficult to achieve for many patients. Variations in INR should be discussed with the patient to find out what has changed before adjusting the dose of warfarin.

Warfarin treatment may be monitored by a pharmacist as part of the Community Pharmacy-Based Anticoagulation Management Service (CPAMS), or using a home testing device.

Initiating warfarin

The regimen for initiating warfarin varies according to the indication and the patient’s clinical characteristics. There are numerous protocols for warfarin initiation and monitoring; it is suggested that clinicians select one that they prefer and use it consistently. A protocol from Queensland Health for initiating patients with atrial fibrillation on warfarin is given as an example in Table 3. Bestpractice decision support has a warfarin initiation module and some DHBs have their own protocols.

In general:¹⁸

• For patients with a lower risk of thrombosis, e.g. with atrial fibrillation, begin treatment with warfarin 3 mg, daily, with baseline and then weekly INR testing for the first two weeks, with subsequent dose adjustments as appropriate
• For patients with a higher risk of thrombosis, e.g. prophylaxis or treatment of deep vein thrombosis, begin treatment with warfarin 5 mg, daily and concurrent subcutaneous LMWH (enoxaparin), with daily INR testing for the first five days (the higher frequency of INR testing is required due to the greater risk of bleeding and concurrent treatment with LMWH)
• Dose adjustments should be at least four days apart to allow for changes in steady state and older patients are more likely to have a slower response
• A system needs to be in place for the patient to record their current dose, any dose adjustment and their next required INR. Prescribing 1 mg tablets may make it easier for the patient to adjust the dose, e.g. from 3 mg to 2 mg.
• A small number of patients may be resistant or hypersensitive to warfarin due to genetic variations
• Once maintenance dosing begins, the frequency of INR testing and any dose adjustments are determined by the proximity of the patient’s INR to target and the stability of results. Patients with stable results only require testing every four to six weeks, or possibly every eight weeks. Testing INR more frequently than every three days is unnecessary for dosing but may occasionally be done for safety reasons.

Table 3: Example of a protocol for initiating and monitoring warfarin treatment in patients at low risk of thrombosis, e.g. with atrial fibrillation, adapted from Queensland Health (2016).¹⁸

* A major bleed in the last four weeks or major surgery in the last two weeks, liver disease, concurrent antiplatelet treatment, thrombocytopaenia with platelets < 50 × 10⁹/L

† For oral administration use the injection preparation orally