Model guidance for prescribers

Transcription

1 Model guidance for prescribers Dabigatran Etexilate and Rivaroxaban for the Prevention of Stroke and Systemic Embolism in Adults with Non-valvular Atrial Fibrillation This document includes the following materials:- a suggested treatment pathway a checklist to support clinician-patient discussions prescribing information for dabigatran and rivaroxaban an overview of relevant NICE guidance considerations related to dabigatran and rivaroxaban use This document does not replace the necessity to refer to the summary of product characteristics (SPC) and patient information leaflet (PIL) provided by the manufacturer. Reproduced by kind permission of Kent, Surrey and Sussex (KSS) Health Policy Support Unit (HPSU) Page 1

2 Treatment Pathway prevention of Stroke and systemic Embolism in adults with non-valvular atrial fibrillation Use CHA 2 DS 2 -VASc to risk stratify thromboembolic risk in non-valvular AF Use HAS-BLED to stratify bleeding risk (ref: ESC guidelines 2012)* CHA 2 DS 2 -VASc Score? CHA 2 DS 2 -VASc = 0 No thromboembolic treatment CHA 2 DS 2 -VASc = 1** Discuss with patient risk/benefits of aspirin vs. anticoagulation CHA 2 DS 2 -VASc >=2 Recommend anticoagulation NO Patient on warfarin? YES Informed discussion between clinician and patient of risks and benefits of warfarin vs. novel oral anticoagulants (NOAC), taking into account contra-indications, comorbidities, concomitant medicines and concordance*** NO Check concordance Good INR control (TTR >65%)? YES Continue warfarin unless strong patient preference for NOAC or young patient requiring long term anticoagulation CONCORDANCE GOOD informed discussion between clinician and patient of risks and benefits of warfarin vs. NOAC BUT NOAC preferred. CONCORDANCE POOR Warfarin with improved concordance or no anticoagulation preferred *HAS-BLED >=3, high bleeding risk, consider reversible causes for bleeding e.g. aspirin/nsaid use, uncontrolled hypertension, labile INR, and consider risk of bleeding vs. risk of stroke usually the balance remains in favour of stroke prevention. **If female gender is only risk factor, treat as CHA 2DS 2-VASc=0 *** Caution with NOAC in patients with high bleeding risk including: very elderly e.g. age >80, previous bleeding event, HAS-BLED >=3, low body weight, renal impairment (dabigatran contraindicated if egfr<30, rivaroxaban contraindicated if egfr<15, caution if EGFR 15-30) Page 2

3 Section 1: Checklist to support clinician-patient discussions More detail for each issue is provided in Sections 2-4 Issues to discuss with patient Comments Efficacy 1. Comparative efficacy Dabigatran 150mg twice daily (D150) was more clinically effective than warfarin in the RE-LY trial. Dabigatran 110mg twice daily (D110) was equivalent to warfarin in the RE-LY trial. Rivaroxaban was non-inferior to warfarin in the ROCKET-AF trial. Clinical trials showed that when warfarin is used well, it is probably as effective as dabigatran or rivaroxaban. In clinical trials, patients were less likely to continue on dabigatran or rivaroxaban than on warfarin. When dabigatran, rivaroxaban and warfarin were compared indirectly across trials, D150 had the highest probability of being best at reducing stroke or systemic embolism (SEE). However, it is difficult to draw definitive conclusions from indirect comparisons, due to clinical and methodological differences between the trials. Safety 1. Comparative bleeding risks In RE-LY, D150 and warfarin had comparable rates of major bleeding, although the bleeding site differed between the treatment groups. Compared to warfarin, D150 reduced the risk of intracranial bleeding, but increased the risk of major gastrointestinal (GI) bleeding. D110 had a lower rate of major bleeding than warfarin. In ROCKET-AF, the risk of major bleeding was comparable between rivaroxaban and warfarin. Rivaroxaban reduced the risk of intracranial bleeding, but increased the risk of major GI bleeding. 2. No antidote is available for dabigatran or rivaroxaban 3. Risk of myocardial infarction (MI) In RE-LY, dabigatran (both doses) was associated with an increased risk of MI compared to warfarin. Assess bleeding risk using HAS-BLED. Bleeding risk with dabigatran and rivaroxaban is increased in patients aged more than 75 years. Bleeding risk on dabigatran is also increased with impaired renal function or low body weight (less than 50 kg). When dabigatran, rivaroxaban and warfarin were compared indirectly across trials, D110 had the highest probability of being best at reducing major bleeding. However, it is difficult to draw definitive conclusions from indirect comparisons, due to clinical and methodological differences between the trials. There is evidence that the antidotes available for warfarin can arrest serious bleeding. The time to emergency surgery or for control of serious bleeding after trauma is likely to be less with dabigatran or rivaroxaban than with warfarin due to their shorter half-lives. The ability to give antidotes to warfarin does not mean that outcomes such as death from bleeding are better for warfarin than either dabigatran or rivaroxaban. None of these trends reached statistical significance. In ROCKET-AF, rivaroxaban was associated with a reduced risk of MI compared to warfarin Page 3

4 4. Long-term treatment data is unavailable for dabigatran and rivaroxaban Patients were only followed up for 2 years in the RE-LY trial and 1.9 years in the ROCKET- AF trial. Dabigatran has only been available at an anticoagulation dose anywhere in the world since October 2010 and rivaroxaban since November There are recent reports from across the world of fatalities and severe bleeding with dabigatran. Current rates are considered to be comparable to rates seen within the trial population but there are concerns about the use of the drug outside of trial conditions (see section 4 for more information). Warfarin has been prescribed for more than 50 years, so there is plenty of experience of its clinical use. 5. Gastrointestinal side effects In RE-LY, dabigatran was associated with a greater risk of major GI bleeding (D150 only) and dyspepsia (both doses) than warfarin. Use of aspirin, clopidogrel or non steroidal antiinflammatory drug (NSAID), as well as the presence of oesophagitis, gastritis or gastroesophageal reflux requiring proton pump inhibitors (PPIs) or histamine 2 (H 2)-blocker treatment increased the risk of GI bleeding. The 110 mg bd dose of dabigatran should be considered for patients at increased risk of GI bleeding. In ROCKET-AF, rivaroxaban was associated with a greater risk of major GI bleeding than warfarin. Patient factors 1. Contraindications Confirm that there are no contraindications to treatment with dabigatran or rivaroxaban. Renal function must be checked prior to treatment with dabigatran. 2. Concomitant medication Confirm that the patient isn t taking any concomitant medication that will interact with dabigatran or rivaroxaban. 3. Concordance issues Dabigatran needs to be taken twice a day. Use of dabigatran in a compliance aid is not recommended. Dabigatran should be kept in its original package until use. Ability to confirm concordance with dabigatran and rivaroxaban is lost as there is no routine monitoring. 4. Current level of international normalised ratio (INR) control See Section 2 for information regarding contraindications and dose adjustments in renal impairment and older age. See Section 2 for drugs that will interact. Check whether the patient is taking St John s wort. Check whether carers are involved in administering medication as this may restrict the dabigatran twice daily regime. Patients with poor concordance may be at a greater risk of thromboembolic complications with dabigatran or rivaroxaban as the shorter half-lives of these agents compared to warfarin will potentially result in more time without any degree of anticoagulation if a dose is missed. The benefits of dabigatran and rivaroxaban over warfarin decline as INR control on warfarin increases. In patients where warfarin is well-controlled (time in therapeutic range [TTR] 65%), the use of dabigatran or rivaroxaban may be less favourable. Page 4

5 5. Switches from warfarin INR must be less than 2 before dabigatran is started. Rivaroxaban should be initiated when INR is less than or equal to Missed doses There is some evidence with warfarin used to prevent stroke in AF, that the period immediately after warfarin is stopped is associated with an increased risk of stroke. In some circumstances bridging with another anticoagulant, such as heparin may be required; seek specialist advice. Dabigatran: A forgotten dose may still be taken up to 6 hours prior to the next due dose. A missed dose should be omitted if the remaining time is below 6 hours prior to the next due dose. Patients should not take a double dose to make up for missed individual doses. Rivaroxaban: If a dose is missed, a dose should be taken immediately, and then patients should continue the following day with the once daily intake as recommended. Patients should not take a double dose to make up for a missed dose. 7. Administration Dabigatran capsules must be swallowed whole, with or without food. Opening dabigatran capsules may increase the bleeding risk. Rivaroxaban tablets are to be taken with food. Costs* 1. Cost estimates for a years treatment with warfarin, including monitoring, range widely depending on local arrangements: per patient. The cost of a years treatment with D110 or D150 is currently 804 per patient. The cost of a years treatment with rivaroxaban is currently 767 per patient. There are minimal opportunities for disinvestment in anticoagulation services in the short term, given the need to maintain people with AF who are stable on warfarin and groups with other indications. *Costs may vary in different settings because of negotiated procurement discounts. Page 5

6 Section 2: Prescribing information for dabigatran and rivaroxaban (Correct at 10 th May 2012) Please see Summary of Product Characteristics for full information at Contraindications Dabigatran Hypersensitivity to the active substance or any of the excipients Creatinine clearance less than 30ml/min (egfr less than 30ml/min/1.73 m 2 ) Pregnancy and breast feeding Liver function tests elevated more than 2 x ULN Active clinically significant bleeding Organic lesion at risk of bleeding Spontaneous or pharmacological impairment of haemostasis Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole and tacrolimus Rivaroxaban Hypersensitivity to the active substance or to any of the excipients Creatinine clearance less than 15 ml/min (egfr < 15 ml/min/1.73 m 2 ) Pregnancy and breast feeding Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C Active clinically significant bleeding Recommended dosing schedule (According to estimated GFR. The manufacturers data sheet is based on CrCl if available, CrCl [ml/min] should be used instead of egfr) Dabigatran* Age/renal function/concomitant medication Adults aged less than 75 years Adults aged years Recommended dose 150 mg bd 150 mg bd Comments Consider 110 mg bd if high bleeding risk or GI irritation If at low thromboembolic risk but high bleding risk consider 110mg bd Adults aged more than 80 years 110 mg bd egfr less than 30 ml/min/1.73 m 2 egfr ml/min/1.73 m 2 egfr ml/min/1.73 m 2 Do not use 150 mg bd 150 mg bd Consider 110 mg bd if high bleeding risk or GI irritation Consider 110mg bd if high bleeding risk or GI irritation + Verapamil 110 mg bd *While on treatment renal function should be assessed at least once a year, or more frequently as needed in certain clinical situations when it is suspected that the renal function could decline or deteriorate. Rivaroxaban Renal function Recommended dose Comments Adults above 18 years of age 20mg once daily This is also the recommended maximum dose egfr less than 15ml/min/1.73 m 2 Do not use egfr ml/min/1.73 m 2 15 mg once daily Limited clinical data; use with caution egfr ml/min/1.73 m 2 15 mg once daily Page 6

7 Drug interactions Dabigatran Interacting Drug St John s wort/ rifampicin/ carbamazepine/ phenytoin Systemic ketoconazole/ cyclosporin/ itraconazole/ tacrolimus Comments May reduce dabigatran blood levels. concomitant use. Use contraindicated with dabigatran. Avoid Posaconazole Dronedarone Ritonavir No data on combined use. Concomitant use not recommended. No data on combined use. Concomitant use not recommended. No data on combined use. Concomitant use not recommended. Verapamil Reduce dabigatran to 110mg bd. Use with caution. Amiodarone/ quinidine/ clarithromycin May increase dabigatran levels. Use with caution. Selective serotonin re-uptake inhibitors (SSRIs) and selective serotonin norepinephrine re-uptake inhibitors (SNRIs) Increased the risk of bleeding in RE-LY in all treatment groups. Anticoagulants Risk of bleeding increased. Avoid concomitant use of other anticoagulants. Detailed instructions for the transitions with warfarin are given below. No parental anticoagulant should be given for 12 hours after last dose of dabigatran. Antiplatelet drugs/ NSAIDs Risk of bleeding increased. This bleeding risk increase is the same as with warfarin, so only use combination where you would with warfarin. Consider 110mg bd. Transition to warfarin: Adjust the starting time of the warfarin based on egfr (CrCl) as follows: egfr greater than or equal to 50 ml/min/1.73 m 2, start warfarin 3 days before discontinuing dabigatran. egfr greater than or equal to 30 less than 50 ml/min/1.73 m 2, start warfarin 2 days before discontinuing dabigatran. Transition from warfarin Warfarin is stopped. Dabigatran can be given as soon as the INR is less than 2.0. Page 7

8 Rivaroxaban Interacting Drug Comments Dronedarone Limited data on combined use. Avoid concomitant use. Systemic azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (e.g. ritonavir) Anticoagulants Antiplatelet drugs/ NSAIDs St John s wort/ rifampicin/ carbamazepine/ phenytoin/phenobarbital May increase bleeding risk. Concomitant use with rivaroxaban is not recommended. Risk of bleeding increased. Use with caution. Detailed instructions for the transitions with warfarin are given below. May increase bleeding risk. Use with caution. May reduce rivaroxaban blood levels. Use with caution. Transition to warfarin Warfarin should be given concurrently until the INR is greater than or equal to2.0. For the first two days of the conversion period, standard initial dosing of warfarin should be used followed by dosing guided by INR testing. While patients are on both rivaroxaban and warfarin, the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of rivaroxaban. Transition from Warfarin Warfarin is stopped. Rivaroxaban should be initiated when the INR is less than or equal to 3.0. Measurement of anticoagulation Routine testing is not required during treatment with dabigatran or rivaroxaban. However, testing can guide management in severe bleeding; seek specialist advice. Note that INR is not valid to measure the anticoagulant activity of dabigatran or rivaroxaban and should not be used. Page 8

9 Section 3: Overview of NICE guidance What does NICE recommend? There is no specific guidance from NICE on how to choose between dabigatran and rivaroxaban in preference to warfarin. This is because no head-to-head studies have been conducted comparing them. Instead, NICE assessed both separately versus warfarin and recommended both as options; dabigatran and rivaroxaban are both recommended as options for the prevention of stroke and systemic embolism (SEE) within their licensed indications, that is, in people with non-valvular atrial fibrillation (AF) with one or more of the following risk factors: Dabigatran Prior stroke, TIA or SEE Aged more than or equal to 75 years Aged more than or equal to 65 years with DM, CAD or hypertension Symptomatic heart failure of New York Heart Association class more than or equal to 2 LVEF less than 40% Rivaroxaban Prior stroke or TIA Aged more than or equal to 75 years Hypertension or DM Congestive heart failure The decision about whether to start treatment with dabigatran or rivaroxaban should be made after an informed discussion between the clinician and the person about the risks and benefits compared with warfarin. For people who are taking warfarin, the potential risks and benefits of switching treatment should be considered in light of their level of international normalised ratio (INR) control (1, 2). What evidence is the NICE recommendation based on? Dabigatran NICE based their recommendation on results from the RE-LY trial. NICE considered RE-LY to be a good quality trial with an appropriate study population broadly relevant to UK clinical practice. In RE-LY, dabigatran 150 mg twice daily (D150) reduced the rate of stroke or SEE compared to warfarin with a similar rate of major bleeding, although the rate of major gastrointestinal (GI) bleeding was increased. Dabigatran 110 mg twice daily (D110) was associated with a rate of stroke or SEE comparable to warfarin, but a lower rate of major bleeding. Both doses of dabigatran reduced the rate of intracranial bleeding compared to warfarin. In addition, both doses improved all-cause mortality, but also increased the risk of myocardial infarction (MI) compared to warfarin, although neither trend reached statistical significance. Absolute benefits compared to warfarin, even when statistical significance was achieved were small. Rivaroxaban NICE based their recommendation on results from the ROCKET-AF trial. ROCKET-AF was a good quality trial, but there was uncertainty whether the results were generalisable to UK clinical practice. In ROCKET-AF, rivaroxaban (20 mg once daily) was non-inferior to warfarin in reducing the rate of stroke or SEE, with a comparable rate of major bleeding, although the bleeding site differed between the treatment groups. Compared to warfarin, rivaroxaban reduced the risk of intracranial bleeding, but increased the risk of major GI bleeding. In addition, rivaroxaban reduced the incidence of MI compared to warfarin, although this trend did not reach statistical significance. Absolute benefits compared to warfarin were small, even when statistical significance was achieved. Page 9

10 Section 4: Considerations related to dabigatran and rivaroxaban use Why is there uncertainty about whether the results of the ROCKET-AF trial are generalisable to UK clinical practice? The mean TTR for warfarin during the ROCKET-AF trial was 55%, around the lower end of the level of control that would be expected in UK clinical practice. This may potentially have led to an over-estimation of rivaroxaban benefit. ROCKET-AF excluded patients with a baseline CHADS 2 score of <2. Why can t guidance be issued on how to choose between dabigatran and rivaroxaban? No clinical trial has directly assessed dabigatran and rivaroxaban in a head-to-head comparison. Consequently there is insufficient evidence to draw conclusions regarding their relative safety and efficacy. Indirect comparisons based on results from RE-LY and ROCKET-AF are inappropriate because there were substantial clinical and methodological differences in the way these trials were conducted. In particular, ROCKET-AF participants had a higher baseline risk of stroke and poorer level of INR control (measured as time in therapeutic range; TTR) compared to RE-LY participants. NICE concluded that estimates of clinical effectiveness for dabigatran compared to rivaroxaban obtained from indirect comparisons were unreliable. RE-LY ROCKET-AF Mean CHADS (0 1 in 32%) 3.5 (0 1 in 0.2%) Mean TTR 64% 55% What are the advantages of dabigatran and rivaroxaban compared to warfarin? Unlike warfarin, there is no need for anticoagulant monitoring when using dabigatran or rivaroxaban; the dose regimen is uncomplicated, a more stable level of anticoagulation is achieved with full concordance and there are fewer potential interactions with other medications, alcohol or diet. What are the relative advantages of dabigatran and rivaroxaban? Although not endorsed by NICE, and despite the methodological and clinical variation across studies previously discussed, the Canadian equivalent of NICE undertook an indirect comparison of dabigatran, rivaroxaban and warfarin. 3 They found that: D150 had the highest probability of being best at reducing stroke or SEE D110 had the highest probability of being best at reducing major bleeding Rivaroxaban was associated with the most favourable results regarding MI Dabigatran (dyspepsia) and rivaroxaban (epistaxis, haematuria) have different side effects profiles. Dabigatran and rivaroxaban interact with different medicinal products. Dabigatran is predominantly renally excreted, although both agents require drugspecific dose adjustments in renal impairment and should be used with caution in this group. Page 10

11 There is limited direct trial evidence assessing rivaroxaban among people with a baseline CHADS 2 score of <2. Rivaroxaban is administered once daily; dabigatran twice daily. Dabigatran capsules are not recommended for compliance aids, because they are moisture sensitive and must not be removed from their packaging before administration. Why should dabigatran or rivaroxaban not replace warfarin for all patients? a) Trial data vs. real-life long-term use: There is always a concern about the introduction of new drugs into general prescribing practice. In particular the safe use of dabigatran in real-life settings outside of trial conditions may be more difficult to achieve. This has been demonstrated by recent data from New Zealand 4 where concerns have been raised about the difficulties in ensuring all prescribers are sufficiently informed about this drug to ensure safe use. As with all new drugs, long-term safety has not been established The RE-LY and ROCKET-AF trials reported a median follow-up of about 2 years. On 6 November 2011 a worldwide total of 256 spontaneous case reports of serious bleeding resulting in death were recorded in the EudraVigilance database in association with the use of dabigatran. 5 The company stated that the risk of death is still below the rate reported in the RE-LY trial. There is limited knowledge concerning the use of dabigatran or rivaroxaban in certain patient groups. RE-LY and ROCKET-AF excluded participants with recent strokes, high bleeding risk, liver disease, prosthetic heart valves or severe renal impairment (CrCl less than 30 ml/min). ROCKET-AF also excluded people with a baseline CHADS 2 score of less than 2. There is the suggestion that RE-LY and ROCKET-AF compared dabigatran and rivaroxaban respectively to a poorer standard of anticoagulation control of warfarin than is currently available in the UK. b) Use in severe renal impairment is contraindicated: Both dabigatran and rivaroxaban require drug-specific dose adjustment in renal impairment, and are contra-indicated where there is severe impairment (see Section 2). Following an evaluation of reports of fatal bleeding associated with dabigatran in Japan; the product information was updated in October 2011 to include advice that renal function be assessed in all patients before initiating treatment. While on treatment, renal function should be assessed at least once a year in patients aged more than 75 years and whenever a decline in renal function is suspected in patients of any age. 5 c) Use in hepatic impairment is contraindicated: Check liver function tests before prescribing dabigatran or rivaroxaban (see Section 2). d) Increase in gastrointestinal side effects: In RE-LY, D150 increased the rate of major Gl bleeding compared to warfarin; rates with D110 and warfarin were similar. In ROCKET-AF, rivaroxaban also increased the risk of major GI bleeding compared to warfarin. In RE-LY, dyspepsia was common, and was the only adverse event that occurred Page 11

12 significantly more with dabigatran compared to warfarin. e) No specific antidote available: There is no proven antidote available for dabigatran or rivaroxaban. The anticoagulant effect of warfarin is easier to measure and reversal can be achieved with vitamin K and prothrombin complex concentrate (PCC). In the event of haemorrhagic complications, treatment with dabigatran or rivaroxaban must be discontinued and the source of bleeding investigated. Since dabigatran is excreted predominantly by the renal route adequate diuresis must be maintained. Appropriate supportive treatment, such as surgical haemostasis and blood volume replacement, should be undertaken at the clinician s discretion. There is some evidence that PCC reverses the anticoagulant effect of rivaroxaban but has no influence on the anticoagulant action of dabigatran. 6 The application of these strategies in clinical practice for managing patients experiencing bleeding is uncertain. f) May not be suitable for patients who have poor concordance: Whilst the lack of the need to routinely monitor dabigatran and rivaroxaban due to their predictable pharmacokinetics has advantages, it also has potential disadvantages since prescribers will not receive any confirmation that the drug is being taken. Patients with poor concordance may be at greater risk of thromboembolic complications with dabigatran or rivaroxaban, as their shorter halflives compared to warfarin will potentially result in more time without any degree of anticoagulation. Consequently, dabigatran and rivaroxaban are not a solution for patients with poor concordance. Dabigatran needs to be taken twice a day. This may be a more difficult regime to manage for some patients, particularly if they are reliant on carers. Inclusion of dabigatran in a compliance aid is not recommended, because it is hygroscopic. Dabigatran can only be included in a compliance aid if the drug is kept in its unopened blister. g) May not be clinically advantageous for patients on warfarin with good INR control i.e. Time in therapeutic range (TTR) more than or equal to 65%: The clinical benefits of dabigatran and rivaroxaban compared to warfarin diminish with improving INR control. In patients where warfarin treatment is well-controlled (TTR greater than or equal to 65%) the use of dabigatran or rivaroxaban may be less favourable. However, NICE concluded that this evidence was insufficient to exclude people with very good INR control from the recommendation of dabigatran or rivaroxaban as treatment options. Nevertheless, NICE emphasise the need to take the level of INR control into consideration when assessing the benefits of a change to dabigatran or rivaroxaban. It is important to investigate the reason for poor INR control, since dabigatran and rivaroxaban are not a solution for patients with poor concordance. As it is not possible to know who will do well with warfarin until it is tried, it may be reasonable to try warfarin first in some circumstances. h) May be less clinically advantageous for older patients (more than or equal to 75 years): The relative risk of bleeding with dabigatran and rivaroxaban compared to warfarin increases with age, such that the absolute risk of major bleeding was similar to the absolute risk of stroke or SEE in patients aged more than or equal to 75 years in clinical trials. 3 However, the relative risk of major bleeding with D110 is comparable to warfarin among patients aged more than or equal to 75 years. Dabigatran requires a dose adjustment in older patients. Page 12

13 References 1. National Institute for Health and Clinical Excellence (2012). Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation. Online: 2. National Institute for Health and Clinical Excellence (2012). Rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation. Online: 3. Canadian Agency for Drugs and Technologies in Health (2012). Safety, effectiveness, and costeffectiveness of new oral anticoagulants compared with warfarin in preventing stroke and other cardiovascular events in patients with atrial fibrillation. Online: (Accessed: 10 May 2012) 4. Harper P, Young L, Merriman E. Bleeding risk with dabigatran in the frail elderly. N Engl J Med 2012; 366: European Medicines Agency (2011). European Medicines Agency updates on safety of Pradaxa. Online: _ jsp&mid=WC0b01ac058004d5c1 (Accessed: 10 May 2012) 6. Eerenberg ES, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124(14): Reproduced by kind permission of Kent, Surrey and Sussex (KSS) Health Policy Support Unit (HPSU) Glossary AF CAD CrCl D110 D150 DM egfr GI INR LVEF MI NICE NSAID PCC PPI SEE SNRI SSRI TIA TTR ULN Atrial fibrillation Coronary artery disease Creatinine clearance Dabigatran 110 mg twice daily Dabigatran 150 mg twice daily Diabetes mellitus Estimated glomerular filtration rate Gastrointestinal International normalised ratio Left ventricular ejection fraction Myocardial infarction National Institute for Health and Clinical Excellence Non-steroidal anti-inflammatory drug Prothrombin complex concentrates Proton pump inhibitors Systemic embolism Selective serotonin norepinephrine re-uptake inhibitors Selective serotonin re-uptake inhibitors Transient ischaemic attack Time in therapeutic range Upper limit of normal Page 13