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Bleeding Events Associated with Novel Anticoagulants: A Case Series
CLINICAL SPOTLIGHT
Clinical Spotlight
Bleeding Events Associated with Novel Anticoagulants: A Case Series Sam Mirzaee, MD ∗ , Tara Thi Thien Tran, BPharm 1 and John Amerena, FRACP 2 Barwon Health, Geelong Hospital, Victoria, Australia
Until lately warfarin was the only valuable oral anticoagulant in stroke reduction in high risk cases with non valvular atrial fibrillation (NVAF). Although with warfarin the rate of stroke reduced notably, the major concern is the risk of serious bleeding and difficulty of establishing and maintaining the international normalised ratio (INR) within the therapeutic range. With the development of the novel anticoagulants we now have for the first time since the innovation of Warfarin feasible alternatives to it to decrease stroke rates in high risk patients with NVAF. To diminish adverse bleeding events with the novel anticoagulant proper selection of patients prior starting treatment is essential. (Heart, Lung and Circulation 2013;xxx:1–5) Crown Copyright © 2013 Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved. Keywords. Novel anticoagulant; Non valvular atrial fibrilation; Bleeding; Warfarin; Bleeding risk assessment
Introduction
T
he major safety concern with the use of warfarin (and all oral anticoagulants) is the risk of major bleeding. Intracranial bleeding is the most serious complication of anticoagulation with warfarin. The difficulty of establishing and maintaining the international normalised ratio (INR) within the therapeutic range due to genetic differences as well as the associated drug, food and alcohol interactions has encouraged researchers to search for alternatives to warfarin, which has been the only oral anticoagulant available until recently. When considering anticoagulation physicians are often more concerned about the potential for bleeding rather than stroke reduction but this emphasis needs to be changed as although bleeding is problematic, it only sometimes requires hospitalisation and blood transfusion but is rarely fatal or results in long term disability. On the other hand, stroke related to non-valvular atrial fibrillation (NVAF) usually requires hospitalisation, in often fatal and usually is disabling, often with a need for long-term institutional care [1]. Stroke Received 18 December 2012; received in revised form 11 April 2013; accepted 12 April 2013 ∗
Corresponding author at: Geelong Cardiology Research Unit, Level 1 Myer House, Cnr Myer & Bellerine Street, Geelong 3220, Australia. Tel.: +61 03 42151031; fax: +61 03 42151042. E-mail addresses: [email protected] (S. Mirzaee), [email protected] (T.T.T. Tran), [email protected] (J. Amerena). 1 Address: Deakin University, Geelong Clinical School, Kitchen House, Ryrie Street, 3220, Australia. Tel.: +61 03 42155100. 2 Address: Geelong Hospital, Kardinia House, Level 3, Bellerine Street, 3220, Australia. Tel.: +61 03 42151967; fax: +61 03 42151042.
is a devastating complication of NVAF which imposes a massive social and financial burden on patients, their families and the health care system. The total direct and indirect costs of caring for patients over the first year after an index stroke in Australia in 1997 was estimated at $555 million. The lifetime costs of all first-ever stroke cases that occurred in Australia in 1997 were estimated at $1.3 billion or $44,000 per case, expressed in 1997 dollar terms. With the development of the novel anti-coagulants we now have feasible alternatives to warfarin to reduce stroke rates in patients with NVAF. The three new anticoagulants proven in clinical trials are Dabigatran (a direct thrombin inhibitor), Rivaroxaban and Apixaban (factor Xa inhibitors), which all have many advantages over warfarin. Dabigatran is an orally active direct thrombin inhibition with half-life of approximately 12–14 h in adult with normal renal function, as renal excretion of unchanged drug is the predominant elimination pathway (80%). Rivaroxaban is a direct factor Xa inhibitor with a bioavailability of 80% and less renal excretion than dabigatran (33%) and a relatively short half-life of five to 9 h in subjects with normal renal function. Apixiban is another new oral anticoagulant that inhibits factor Xa and that has similar mechanism of action to Rivaroxaban, with rapid absorption, a 12–14 h half-life, and 25% renal excretion [2]. The Randomised Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial in patients with NVAF demonstrated that Dabigatran 110 mg twice a day compared with warfarin was associated with a similar risk of stroke and a lower risk of major bleeding and that Dabigatran 150 mg twice a day was associated with a lower risk of stroke and a similar risk of major bleeding [3].
Crown Copyright © 2013 Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved.
1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2013.04.115 HLC-1358; No. of Pages 5
CLINICAL SPOTLIGHT
2
Mirzaee et al. Bleeding Events Associated with Novel Anticoagulants
In the ROCKET-AF study Rivaroxaban 20 mg once daily was shown to be non-inferior to warfarin in reduction of stroke and systemic embolism in patients with NVAF, with similar bleeding to warfarin, although there was less fatal bleeding. Similarly, Apixaban was shown to reduce both stroke and bleeding compared with warfarin in the Aristotle study [4]. In all these studies, factors associated with higher risk of bleeding were advanced age, hypertension, female gender, concurrent use of antiplatelet agents, as well as associated co morbidities which increase the risk of bleeding such as angiodysplasia or peptic ulceration [5]. With the introduction of these new agents to potentially replace warfarin for stroke prevention in NVAF, post marketing surveillance is essential to monitor the potential adverse effects of these new therapies in the real world outside the highly supervised environment of a clinical trial.
Methods As part of monitoring patients treated with the new anticoagulants in our hospital we performed an observational retrospective study on all cases on novel anticoagulants to determine the incidence of bleeding events and their management. Data were collected from 67 patient’s electronic medical records in Barwon Health who received the novel anticoagulants Dabigatran and Rivaroxaban for stroke prevention in NVAF between July 2011 and July 2012.
Case Series Patient 1 57 year-old woman, morbidly obese with persistent atrial fibrillation on Dabigatran 110 mg twice a day presented to the emergency department with progressive headache, nausea, vomiting and developed diplopia. On examination, she was hypertensive with BP = 250/130, pulse rate of 110/min and GCS 14. Investigation with non-contrast CT brain followed by MRI brain revealed a small hyper dense lesion left side of the 4th ventricle approximately 12.5 mm × 9.3 mm on axial dimension and 15 mm cephalocaudally suggestive of intra cranial haemorrhage. At the same time her coagulation profile showed INR = 6.8 and APTT = 127 s for which she received 1 mg vitamin K orally and repeated blood test in 5 h time showed decreased INR to 1.3 and APTT = 46. The intracranial bleeding was managed conservatively by ceasing her anticoagulant and serial brain imaging which showed spontaneous resolution of the haemorrhage. Her past medical history was significant for: poliomyelitis syndrome associated with poor mobility due to preexisting right leg weakness, left parietal ischaemic stroke with minimal neurological deficit, Type 2 diabetes mellitus complicated by chronic renal impairment with base line creatinine 180 umol/L (30–90) and eGFR = 25 mL/min. She also had significant ischaemic heart disease with 90% LAD disease treated with a drug eluting stent two years prior to this bleeding event, with a recommendation for infinite dual anti-platelet by her cardiologist due to
Heart, Lung and Circulation 2013;xxx:1–5
severity of her condition and symptoms. Associated clinical conditions were dyslipidaemia, hypertension and morbid obesity BMI = 49. She was on clopidogrel 75 mg, Aspirin 100 mg, in addition to dabigatran as well as labetolol 400 mg daily, amlodipine/atorvastatin 10/20 mg, moxonidine 400 mg, irbesartan 300 mg and frusemide 250 mg daily. Although, she made a partial recovery from intracranial haemorrhage followed by one month admission in the rehabilitation ward, her mobility deteriorated due to multifactorial causes and became wheelchair bound, subsequently discharged to the high level of care nursing home.
Patient 2 81 year-old woman, independent from home, presented with three days history of melaena and an episode of haematemesis associated with intermittent right lower quadrant abdominal pain. She had a past medical history of chronic NVAF on dabigatran 110 mg BD, with a background of hypertension, dilated cardiomyopathy with ejection fraction of 31%, poliomyelitis syndrome with paralysed left leg and scoliosis and permanent pacemaker. On presentation she was haemodynamically stable and her initial blood tests revealed: Hb = 108 g/L and Platelet = 84 10 ˆ 9/L with normal renal function (eGFR > 60 mL/min). There was no coagulation profile ordered on that date. The patient deteriorated but gastroscopy/colonoscopy was not undertaken (for reasons that are not clear) so her further evaluation was limited to a CT abdomen and ultrasound which revealed a hypodense lesion in liver suggestive of a cavernous hemangioma and otherwise was unremarkable for the cause of bleeding. On admission, her concurrent medications were: fish oil, trandolapril, glyceryl nitrate, levodopa–carbidopa and carvidelol, in addition to dabigatran 110 mg. Dabigatran was ceased and she was managed conservatively with proton pump inhibitors and did not have any further bleeding. She had an uneventful recovery and was discharged home. Subsequently she was recommenced on oral anticoagulation (dabigatran) since she did not have any further bleeding and carried high risk of thromboembolic events.
Patient 3 81 year-old woman, with normal body mass index (BMI = 25) presented to hospital complaining of melaena, severe shortness of breath on minimal exertion and fatigue in the setting of recent commencement of rivaroxaban 10 mg daily for paroxysmal NVAF. Her medical background is significant for severe aortic stenosis with valve area 0.8 cm2 , ischaemic heart disease and NSTEMI for which she was taking aspirin for secondary prevention, hypothyroidism as well as chronic renal impairment with an eGFR = 35 mL/min. Her other medications were: buprenorphin 5 mg patch, frusemide 40 mg daily, amiodarone 200 mg daily, aspirin
100 mg daily, carvidelol 12.5 mg BD, escitalopram 10 mg daily and simvastatin 40 mg daily. On examination, she was haemodynamically unstable with significant postural hypotension of 40 mmHg. Her initial blood tests showed: haemoglobin of 60 g/L, INR = 3.3, APTT = 37 s, renal function: creatinine = 197 umol/L and eGFR = 22 mL/min, and normal liver function tests. She was admitted for the management of acute gastrointestinal bleeding, and rivaroxaban and aspirin were ceased. She was commenced on proton pump inhibitor infusion, 5 mg vitamin k, 1 unit fresh frozen plasma (FFP), 4 units blood transfusion and intravenous fluid to stabilise her condition. Urgent gastroscopy showed evidence of small angiodysplastic lesions in mid duodenum with active bleeding which was treated with a gold probe and injected adrenaline. She had an uneventful recovery and was discharged home for further follow up. She was not recommenced on anticoagulant due to further high risk of bleeding and relatively low risk of stroke
Patient 4 80 year-old woman with complex medical history including persistent atrial fibrillation on 110 mg twice daily dabigatran for a year, had multiple admissions to the hospital with intermittent melaena in addition to symptomatic anaemia. She also had other co morbidities including rectal adenocarcinoma and anterior resection, bioprosthetic aortic valve replacement, Type 2 diabetes mellitus, hypertension and dyslipidaemia. Her other medications included allopurinol 100 mg twice daily, rosuvastatin 10 mg daily, metformin 500 mg daily, ferrogradumet 325 mg daily, irbesartan-hydrochlorothiazide 300 mg/25 mg daily, digoxin 125 mcg daily, atenolol 50 mg daily and pantoprazole 40 mg daily. On presentation, she appeared well and haemodynamically stable. Further investigations revealed her haemoglobin was 73 g/L, coagulation profile INR = 1.5, APTT = 40 along with mildly impaired renal function baseline creatinine of 120 umol/L and eGFR = 40 mL/min. In terms of management, she was treated successfully with withholding of dabigatran, proton pump inhibitor infusion, packed red cell transfusion as well as fluid resuscitation. Urgent and elective gastroscopies and colonoscopies were unremarkable and showed only a Grade 3 haemorrhoid with no evidence of active bleeding. Subsequent examination with pill Cam revealed a small intestinal arteriovenous malformation and inflammation without any obvious bleeding culprit. Small intestinal MRI showed dilated, thickened and fibrous bowel loops consistent with radiation enteritis in the setting of previous radiotherapy for colorectal cancer for which was treated with anterior resection in the past. Consequently no overt cause for her intermittent bleeding was found and since she remained stable, dabigatron 110 mg BD was recommenced.
Mirzaee et al. Bleeding Events Associated with Novel Anticoagulants
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Table 1. Stroke Risk Stratification with CHA2DS2-VASc Score. Condition
Points
C
Congestive heart failure or left ventricular dysfunction
1
H
Hypertension: blood pressure consistently above 140/90 mmHg (or treated hypertension on medication)
1
A
Age ≥ 75 years
2
D
Diabetes mellitus
1
S
Prior stroke or TIA or thromboembolism
2
V
Vascular disease (e.g. peripheral artery disease, myocardial infarction, aortic plaque)
1
A
Age 65–74 years
1
Sc
Sex category (female gender)
1
Discussion Assessment of stroke risk and individual bleeding risk must be hand in hand when considering commencing an anticoagulant. It is essential to determine which patients need to be considered for anti-coagulation therapy with either warfarin or the new agents by using stroke assessment and bleeding risk tools. In the latest European Society of Cardiology Guidelines the CHA2DS2-VASc and HAS-BLED scores have been published in order to provide a more accurate and systematic means of evaluation of stroke and bleeding risk (Tables 1 and 2), to allow the doctors to make a risk: benefit evaluation as to whether anticoagulation should be used and whether dose reduction (particularly for Dabigatran) should be considered [5]. A CHA2DS2-VASc score ≥ 1 can be considered for a novel anticoagulant and a HAS-BLED score ≥ 3 increases the risk of major bleeding, which does not preclude the use of anticoagulation as the overall net benefit is still in favour on anticoagulation [6]. A recently performed audit in New Zealand found that bleeding with dabigatran was due to prescriber errors in approximately 25% of the cases in, with a failure to allow the INR to fall below 2.0 before starting dabigatran and inappropriate patient selection due to severe renal Table 2. Clinical Characteristics Composing the HAS-BLED Bleeding Risk Score. Letter
Clinical Characteristic
Points Awarded
H
Hypertension systolic BP > 160 mmHg
1
A
Abnormal renal and liver function (1 point each)
1 or 2
S
Stroke
1
B
Bleeding
1
L
Labile INRs
1
E
Elderly (age > 65)
1
D
Drugs or alcohol (1 point each)
1 or 2
CLINICAL SPOTLIGHT
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CLINICAL SPOTLIGHT
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Mirzaee et al. Bleeding Events Associated with Novel Anticoagulants
Heart, Lung and Circulation 2013;xxx:1–5
Table 3. Relevant Data in Cases of Bleeding Associated with Novel Anticoagulant. Age
Gender
Renal Function (Creatinine (30–90) and eGFR)
Concomitant Antiplatelets
57 81 81 80
Female Female Female Female
180 umol/L and eGFR = 25 mL/min 64 umol/L and e GFR > 60 mL/min 197 umol/L and eGFR = 22 mL/min 120 umol/L and eGFR = 40 mL/min
Aspirin and Clopidogrel Nil Aspirin Nil
dysfunction and high dose usage in patients with age above 80 [7]. In our study 32 patients had been taking warfarin while they were switched to novel anticoagulant and none of the bleeding events occurred in this transition period. Triple therapy (oral anticoagulant, aspirin and clopidogrel) is sometimes needed when there is an indication for both antiplatelet and anticoagulant therapy. This is most common when a patient with NVAF or prosthetic valve has an ACS for which stenting is required. Triple therapy increases the risk of major bleeding and recurrent events and mortality. The recently published WOEST study was the first randomised clinical trial that addressed optimal antiplatelet therapy in high risk patients who need oral anticoagulation. The WOEST study has shown that oral anticoagulants plus clopidogrel, without aspirin in the context of coronary stenting is associated with less bleeding and events than triple therapy, but the study had relatively small numbers and the results need to be duplicated before there could be complete confidence in this strategy [8]. Our patients’ sites of bleeding were more related to gastrointestinal tract (75%), contributed with impaired renal function (75%), advanced age of above 80 (75%), coexistent complex medical history (100%)and additional anti-platelet medication (50%; Table 3). These findings are identical to the outcome of previous performed clinical trials; RELY, ROCKET – AF and ARISTOTLE studies. In our study, contributing factors associated with major bleeding and the site of bleeding are comparable to those seen in available literature, despite inappropriate use in some patients with advanced renal impairment. Current data shows that all the novel anticoagulants are associated with lower intracranial bleeding than warfarin but more gastrointestinal bleeding with dabigatran (in the elderly) and rivaroxaban [2–4]. Dabigatran is an orally active direct thrombin inhibitor and renal excretion of unchanged drug is the predominant elimination pathway, therefore dose adjustment is required in patients with renal impairment. The recommended dose for dabigatran in patients with decreased renal function of (30–50 mL/min Cr CL) is 110 mg twice a day versus 150 mg twice a day in patients with normal renal function. Dabigatran is contraindicated in cases of severe renal impairment (CrCL < 30 mL/min). Interestingly, case 3 had severe aortic stenosis associated with gastrointestinal bleeding from duodenal angiodysplasia which is well defined as Heyde’s syndrome. In terms of association between aortic stenosis and gastrointestinal bleeding, a subtle form of von Willebrand disease has been postulated which can resolve rapidly after aortic valve replacement. Proteolysis of von Willebrand factor as
Site of Bleeding Intracranial Gastro intestinal tract Gastro intestinal tract Gastro intestinal tract
it passes through the stenotic valve is one of the proposed causes of the bleeding [9].
Management of Bleeding Associated with Novel Anticoagulant With regard to management of bleeding; there is no antidote at present, although a monoclonal antibody capable of rapidly and completely inhibiting dabigatran is under further development and Prothrombin Complex Concentrate (PCC) reverses the anticoagulant effects of rivaroxaban and apixaban. Due to their short half-life, drug discontinuation is usually sufficient in subjects with normal renal function and also other drugs that may potentiate bleeding should be discontinued. Since dabigatran is approximately 30% protein bound, it can be dialysed in patients with bleeding and significant renal impairment, about 60% of the drug being removed after two to 3 h of dialysis. Charcoal haemofiltration has been suggested as has enhanced diuresis, if tolerated, to hasten renal excretion. The indication of inactivated Prothrombin Complex Concentrates (PCC) due to the risk of precipitating thromboembolism should be reserved for those with life-threatening bleeding. There is no role for administration of vitamin K as new anticoagulant agents do not inhibit vitamin K dependent factors.
Conclusion This review of selected cases of bleeding with the novel anticoagulants in our hospital has limitations but highlights the necessity for proper prescriber education to avoid use of these agents in inappropriate patients, and emphasises the importance of evaluating the risk of bleeding prior to administration of novel anticoagulants. We recommend HAS-BLED score assessment in all cases, particularly those 80 years of age or older with impaired renal function, and those with concomitant antiplatelet as well as multiple comorbidities [5]. All the new agents are at least as good as or better than warfarin in reducing stroke and systemic embolism in patients with non valvular atrial fibrillation, and all have comparable or better rates of bleeding risk. Overall novel anticoagulants are more convenient (no requirement for routine testing of the INR), carry the smaller risk of debilitating intracranial haemorrhage and also have less susceptibility to dietary and drug interactions [2–4]. There are some challenges for clinicians who initiate novel anticoagulants which need to be taken under consideration:
• Renal function needs to be assessed before treatment and monitored regularly during management. • Patients should be selected carefully with risk/benefit evaluated but in general benefits of anticoagulation outweigh risks of bleeding. • Select the correct dose.
References [1] Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham heart study. Circulation 1998;98(September (10)):946–52. [2] Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365(September (11)):981–92. [3] Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139– 51.
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[4] Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365(September (10)): 883–91. [5] Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJGM, Lip GYH. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation. Chest 2010;138(5):1093–100. [6] Lip GY, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: HASBLED score. Journal of the American College of Cardiology 2011;57(January (2)):173–80. [7] John W, Eikelboom, Jeffrey I, Weitz. Bleeding risk with dabigatran in the frail elderly. N Engl J Med 2012;366(March (9)):864. [8] Dewilde W, Oirbans T, Verheugt F, Kelder J, De Smet B, Herrman JP, et al. The WOEST trial: first randomised trial comparing two regimens with and without aspirin in patients on oral anticoagulant therapy undergoing coronary stenting. ESC; 2012, clinicaltrials.gov NCT00769938. [9] Vincentelli A, Susen S, Le Tourneau T, Six I, Fabre O, Juthier F, et al. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med 2003;349(July (10)): 343–9.
CLINICAL SPOTLIGHT
Heart, Lung and Circulation 2013;xxx:1–5
Clinical Spotlight
Bleeding Events Associated with Novel Anticoagulants: A Case Series Sam Mirzaee, MD ∗ , Tara Thi Thien Tran, BPharm 1 and John Amerena, FRACP 2 Barwon Health, Geelong Hospital, Victoria, Australia
Until lately warfarin was the only valuable oral anticoagulant in stroke reduction in high risk cases with non valvular atrial fibrillation (NVAF). Although with warfarin the rate of stroke reduced notably, the major concern is the risk of serious bleeding and difficulty of establishing and maintaining the international normalised ratio (INR) within the therapeutic range. With the development of the novel anticoagulants we now have for the first time since the innovation of Warfarin feasible alternatives to it to decrease stroke rates in high risk patients with NVAF. To diminish adverse bleeding events with the novel anticoagulant proper selection of patients prior starting treatment is essential. (Heart, Lung and Circulation 2013;xxx:1–5) Crown Copyright © 2013 Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved. Keywords. Novel anticoagulant; Non valvular atrial fibrilation; Bleeding; Warfarin; Bleeding risk assessment
Introduction
T
he major safety concern with the use of warfarin (and all oral anticoagulants) is the risk of major bleeding. Intracranial bleeding is the most serious complication of anticoagulation with warfarin. The difficulty of establishing and maintaining the international normalised ratio (INR) within the therapeutic range due to genetic differences as well as the associated drug, food and alcohol interactions has encouraged researchers to search for alternatives to warfarin, which has been the only oral anticoagulant available until recently. When considering anticoagulation physicians are often more concerned about the potential for bleeding rather than stroke reduction but this emphasis needs to be changed as although bleeding is problematic, it only sometimes requires hospitalisation and blood transfusion but is rarely fatal or results in long term disability. On the other hand, stroke related to non-valvular atrial fibrillation (NVAF) usually requires hospitalisation, in often fatal and usually is disabling, often with a need for long-term institutional care [1]. Stroke Received 18 December 2012; received in revised form 11 April 2013; accepted 12 April 2013 ∗
Corresponding author at: Geelong Cardiology Research Unit, Level 1 Myer House, Cnr Myer & Bellerine Street, Geelong 3220, Australia. Tel.: +61 03 42151031; fax: +61 03 42151042. E-mail addresses: [email protected] (S. Mirzaee), [email protected] (T.T.T. Tran), [email protected] (J. Amerena). 1 Address: Deakin University, Geelong Clinical School, Kitchen House, Ryrie Street, 3220, Australia. Tel.: +61 03 42155100. 2 Address: Geelong Hospital, Kardinia House, Level 3, Bellerine Street, 3220, Australia. Tel.: +61 03 42151967; fax: +61 03 42151042.
is a devastating complication of NVAF which imposes a massive social and financial burden on patients, their families and the health care system. The total direct and indirect costs of caring for patients over the first year after an index stroke in Australia in 1997 was estimated at $555 million. The lifetime costs of all first-ever stroke cases that occurred in Australia in 1997 were estimated at $1.3 billion or $44,000 per case, expressed in 1997 dollar terms. With the development of the novel anti-coagulants we now have feasible alternatives to warfarin to reduce stroke rates in patients with NVAF. The three new anticoagulants proven in clinical trials are Dabigatran (a direct thrombin inhibitor), Rivaroxaban and Apixaban (factor Xa inhibitors), which all have many advantages over warfarin. Dabigatran is an orally active direct thrombin inhibition with half-life of approximately 12–14 h in adult with normal renal function, as renal excretion of unchanged drug is the predominant elimination pathway (80%). Rivaroxaban is a direct factor Xa inhibitor with a bioavailability of 80% and less renal excretion than dabigatran (33%) and a relatively short half-life of five to 9 h in subjects with normal renal function. Apixiban is another new oral anticoagulant that inhibits factor Xa and that has similar mechanism of action to Rivaroxaban, with rapid absorption, a 12–14 h half-life, and 25% renal excretion [2]. The Randomised Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial in patients with NVAF demonstrated that Dabigatran 110 mg twice a day compared with warfarin was associated with a similar risk of stroke and a lower risk of major bleeding and that Dabigatran 150 mg twice a day was associated with a lower risk of stroke and a similar risk of major bleeding [3].
Crown Copyright © 2013 Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved.
1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2013.04.115 HLC-1358; No. of Pages 5
CLINICAL SPOTLIGHT
2
Mirzaee et al. Bleeding Events Associated with Novel Anticoagulants
In the ROCKET-AF study Rivaroxaban 20 mg once daily was shown to be non-inferior to warfarin in reduction of stroke and systemic embolism in patients with NVAF, with similar bleeding to warfarin, although there was less fatal bleeding. Similarly, Apixaban was shown to reduce both stroke and bleeding compared with warfarin in the Aristotle study [4]. In all these studies, factors associated with higher risk of bleeding were advanced age, hypertension, female gender, concurrent use of antiplatelet agents, as well as associated co morbidities which increase the risk of bleeding such as angiodysplasia or peptic ulceration [5]. With the introduction of these new agents to potentially replace warfarin for stroke prevention in NVAF, post marketing surveillance is essential to monitor the potential adverse effects of these new therapies in the real world outside the highly supervised environment of a clinical trial.
Methods As part of monitoring patients treated with the new anticoagulants in our hospital we performed an observational retrospective study on all cases on novel anticoagulants to determine the incidence of bleeding events and their management. Data were collected from 67 patient’s electronic medical records in Barwon Health who received the novel anticoagulants Dabigatran and Rivaroxaban for stroke prevention in NVAF between July 2011 and July 2012.
Case Series Patient 1 57 year-old woman, morbidly obese with persistent atrial fibrillation on Dabigatran 110 mg twice a day presented to the emergency department with progressive headache, nausea, vomiting and developed diplopia. On examination, she was hypertensive with BP = 250/130, pulse rate of 110/min and GCS 14. Investigation with non-contrast CT brain followed by MRI brain revealed a small hyper dense lesion left side of the 4th ventricle approximately 12.5 mm × 9.3 mm on axial dimension and 15 mm cephalocaudally suggestive of intra cranial haemorrhage. At the same time her coagulation profile showed INR = 6.8 and APTT = 127 s for which she received 1 mg vitamin K orally and repeated blood test in 5 h time showed decreased INR to 1.3 and APTT = 46. The intracranial bleeding was managed conservatively by ceasing her anticoagulant and serial brain imaging which showed spontaneous resolution of the haemorrhage. Her past medical history was significant for: poliomyelitis syndrome associated with poor mobility due to preexisting right leg weakness, left parietal ischaemic stroke with minimal neurological deficit, Type 2 diabetes mellitus complicated by chronic renal impairment with base line creatinine 180 umol/L (30–90) and eGFR = 25 mL/min. She also had significant ischaemic heart disease with 90% LAD disease treated with a drug eluting stent two years prior to this bleeding event, with a recommendation for infinite dual anti-platelet by her cardiologist due to
Heart, Lung and Circulation 2013;xxx:1–5
severity of her condition and symptoms. Associated clinical conditions were dyslipidaemia, hypertension and morbid obesity BMI = 49. She was on clopidogrel 75 mg, Aspirin 100 mg, in addition to dabigatran as well as labetolol 400 mg daily, amlodipine/atorvastatin 10/20 mg, moxonidine 400 mg, irbesartan 300 mg and frusemide 250 mg daily. Although, she made a partial recovery from intracranial haemorrhage followed by one month admission in the rehabilitation ward, her mobility deteriorated due to multifactorial causes and became wheelchair bound, subsequently discharged to the high level of care nursing home.
Patient 2 81 year-old woman, independent from home, presented with three days history of melaena and an episode of haematemesis associated with intermittent right lower quadrant abdominal pain. She had a past medical history of chronic NVAF on dabigatran 110 mg BD, with a background of hypertension, dilated cardiomyopathy with ejection fraction of 31%, poliomyelitis syndrome with paralysed left leg and scoliosis and permanent pacemaker. On presentation she was haemodynamically stable and her initial blood tests revealed: Hb = 108 g/L and Platelet = 84 10 ˆ 9/L with normal renal function (eGFR > 60 mL/min). There was no coagulation profile ordered on that date. The patient deteriorated but gastroscopy/colonoscopy was not undertaken (for reasons that are not clear) so her further evaluation was limited to a CT abdomen and ultrasound which revealed a hypodense lesion in liver suggestive of a cavernous hemangioma and otherwise was unremarkable for the cause of bleeding. On admission, her concurrent medications were: fish oil, trandolapril, glyceryl nitrate, levodopa–carbidopa and carvidelol, in addition to dabigatran 110 mg. Dabigatran was ceased and she was managed conservatively with proton pump inhibitors and did not have any further bleeding. She had an uneventful recovery and was discharged home. Subsequently she was recommenced on oral anticoagulation (dabigatran) since she did not have any further bleeding and carried high risk of thromboembolic events.
Patient 3 81 year-old woman, with normal body mass index (BMI = 25) presented to hospital complaining of melaena, severe shortness of breath on minimal exertion and fatigue in the setting of recent commencement of rivaroxaban 10 mg daily for paroxysmal NVAF. Her medical background is significant for severe aortic stenosis with valve area 0.8 cm2 , ischaemic heart disease and NSTEMI for which she was taking aspirin for secondary prevention, hypothyroidism as well as chronic renal impairment with an eGFR = 35 mL/min. Her other medications were: buprenorphin 5 mg patch, frusemide 40 mg daily, amiodarone 200 mg daily, aspirin
100 mg daily, carvidelol 12.5 mg BD, escitalopram 10 mg daily and simvastatin 40 mg daily. On examination, she was haemodynamically unstable with significant postural hypotension of 40 mmHg. Her initial blood tests showed: haemoglobin of 60 g/L, INR = 3.3, APTT = 37 s, renal function: creatinine = 197 umol/L and eGFR = 22 mL/min, and normal liver function tests. She was admitted for the management of acute gastrointestinal bleeding, and rivaroxaban and aspirin were ceased. She was commenced on proton pump inhibitor infusion, 5 mg vitamin k, 1 unit fresh frozen plasma (FFP), 4 units blood transfusion and intravenous fluid to stabilise her condition. Urgent gastroscopy showed evidence of small angiodysplastic lesions in mid duodenum with active bleeding which was treated with a gold probe and injected adrenaline. She had an uneventful recovery and was discharged home for further follow up. She was not recommenced on anticoagulant due to further high risk of bleeding and relatively low risk of stroke
Patient 4 80 year-old woman with complex medical history including persistent atrial fibrillation on 110 mg twice daily dabigatran for a year, had multiple admissions to the hospital with intermittent melaena in addition to symptomatic anaemia. She also had other co morbidities including rectal adenocarcinoma and anterior resection, bioprosthetic aortic valve replacement, Type 2 diabetes mellitus, hypertension and dyslipidaemia. Her other medications included allopurinol 100 mg twice daily, rosuvastatin 10 mg daily, metformin 500 mg daily, ferrogradumet 325 mg daily, irbesartan-hydrochlorothiazide 300 mg/25 mg daily, digoxin 125 mcg daily, atenolol 50 mg daily and pantoprazole 40 mg daily. On presentation, she appeared well and haemodynamically stable. Further investigations revealed her haemoglobin was 73 g/L, coagulation profile INR = 1.5, APTT = 40 along with mildly impaired renal function baseline creatinine of 120 umol/L and eGFR = 40 mL/min. In terms of management, she was treated successfully with withholding of dabigatran, proton pump inhibitor infusion, packed red cell transfusion as well as fluid resuscitation. Urgent and elective gastroscopies and colonoscopies were unremarkable and showed only a Grade 3 haemorrhoid with no evidence of active bleeding. Subsequent examination with pill Cam revealed a small intestinal arteriovenous malformation and inflammation without any obvious bleeding culprit. Small intestinal MRI showed dilated, thickened and fibrous bowel loops consistent with radiation enteritis in the setting of previous radiotherapy for colorectal cancer for which was treated with anterior resection in the past. Consequently no overt cause for her intermittent bleeding was found and since she remained stable, dabigatron 110 mg BD was recommenced.
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Table 1. Stroke Risk Stratification with CHA2DS2-VASc Score. Condition
Points
C
Congestive heart failure or left ventricular dysfunction
1
H
Hypertension: blood pressure consistently above 140/90 mmHg (or treated hypertension on medication)
1
A
Age ≥ 75 years
2
D
Diabetes mellitus
1
S
Prior stroke or TIA or thromboembolism
2
V
Vascular disease (e.g. peripheral artery disease, myocardial infarction, aortic plaque)
1
A
Age 65–74 years
1
Sc
Sex category (female gender)
1
Discussion Assessment of stroke risk and individual bleeding risk must be hand in hand when considering commencing an anticoagulant. It is essential to determine which patients need to be considered for anti-coagulation therapy with either warfarin or the new agents by using stroke assessment and bleeding risk tools. In the latest European Society of Cardiology Guidelines the CHA2DS2-VASc and HAS-BLED scores have been published in order to provide a more accurate and systematic means of evaluation of stroke and bleeding risk (Tables 1 and 2), to allow the doctors to make a risk: benefit evaluation as to whether anticoagulation should be used and whether dose reduction (particularly for Dabigatran) should be considered [5]. A CHA2DS2-VASc score ≥ 1 can be considered for a novel anticoagulant and a HAS-BLED score ≥ 3 increases the risk of major bleeding, which does not preclude the use of anticoagulation as the overall net benefit is still in favour on anticoagulation [6]. A recently performed audit in New Zealand found that bleeding with dabigatran was due to prescriber errors in approximately 25% of the cases in, with a failure to allow the INR to fall below 2.0 before starting dabigatran and inappropriate patient selection due to severe renal Table 2. Clinical Characteristics Composing the HAS-BLED Bleeding Risk Score. Letter
Clinical Characteristic
Points Awarded
H
Hypertension systolic BP > 160 mmHg
1
A
Abnormal renal and liver function (1 point each)
1 or 2
S
Stroke
1
B
Bleeding
1
L
Labile INRs
1
E
Elderly (age > 65)
1
D
Drugs or alcohol (1 point each)
1 or 2
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Mirzaee et al. Bleeding Events Associated with Novel Anticoagulants
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Table 3. Relevant Data in Cases of Bleeding Associated with Novel Anticoagulant. Age
Gender
Renal Function (Creatinine (30–90) and eGFR)
Concomitant Antiplatelets
57 81 81 80
Female Female Female Female
180 umol/L and eGFR = 25 mL/min 64 umol/L and e GFR > 60 mL/min 197 umol/L and eGFR = 22 mL/min 120 umol/L and eGFR = 40 mL/min
Aspirin and Clopidogrel Nil Aspirin Nil
dysfunction and high dose usage in patients with age above 80 [7]. In our study 32 patients had been taking warfarin while they were switched to novel anticoagulant and none of the bleeding events occurred in this transition period. Triple therapy (oral anticoagulant, aspirin and clopidogrel) is sometimes needed when there is an indication for both antiplatelet and anticoagulant therapy. This is most common when a patient with NVAF or prosthetic valve has an ACS for which stenting is required. Triple therapy increases the risk of major bleeding and recurrent events and mortality. The recently published WOEST study was the first randomised clinical trial that addressed optimal antiplatelet therapy in high risk patients who need oral anticoagulation. The WOEST study has shown that oral anticoagulants plus clopidogrel, without aspirin in the context of coronary stenting is associated with less bleeding and events than triple therapy, but the study had relatively small numbers and the results need to be duplicated before there could be complete confidence in this strategy [8]. Our patients’ sites of bleeding were more related to gastrointestinal tract (75%), contributed with impaired renal function (75%), advanced age of above 80 (75%), coexistent complex medical history (100%)and additional anti-platelet medication (50%; Table 3). These findings are identical to the outcome of previous performed clinical trials; RELY, ROCKET – AF and ARISTOTLE studies. In our study, contributing factors associated with major bleeding and the site of bleeding are comparable to those seen in available literature, despite inappropriate use in some patients with advanced renal impairment. Current data shows that all the novel anticoagulants are associated with lower intracranial bleeding than warfarin but more gastrointestinal bleeding with dabigatran (in the elderly) and rivaroxaban [2–4]. Dabigatran is an orally active direct thrombin inhibitor and renal excretion of unchanged drug is the predominant elimination pathway, therefore dose adjustment is required in patients with renal impairment. The recommended dose for dabigatran in patients with decreased renal function of (30–50 mL/min Cr CL) is 110 mg twice a day versus 150 mg twice a day in patients with normal renal function. Dabigatran is contraindicated in cases of severe renal impairment (CrCL < 30 mL/min). Interestingly, case 3 had severe aortic stenosis associated with gastrointestinal bleeding from duodenal angiodysplasia which is well defined as Heyde’s syndrome. In terms of association between aortic stenosis and gastrointestinal bleeding, a subtle form of von Willebrand disease has been postulated which can resolve rapidly after aortic valve replacement. Proteolysis of von Willebrand factor as
Site of Bleeding Intracranial Gastro intestinal tract Gastro intestinal tract Gastro intestinal tract
it passes through the stenotic valve is one of the proposed causes of the bleeding [9].
Management of Bleeding Associated with Novel Anticoagulant With regard to management of bleeding; there is no antidote at present, although a monoclonal antibody capable of rapidly and completely inhibiting dabigatran is under further development and Prothrombin Complex Concentrate (PCC) reverses the anticoagulant effects of rivaroxaban and apixaban. Due to their short half-life, drug discontinuation is usually sufficient in subjects with normal renal function and also other drugs that may potentiate bleeding should be discontinued. Since dabigatran is approximately 30% protein bound, it can be dialysed in patients with bleeding and significant renal impairment, about 60% of the drug being removed after two to 3 h of dialysis. Charcoal haemofiltration has been suggested as has enhanced diuresis, if tolerated, to hasten renal excretion. The indication of inactivated Prothrombin Complex Concentrates (PCC) due to the risk of precipitating thromboembolism should be reserved for those with life-threatening bleeding. There is no role for administration of vitamin K as new anticoagulant agents do not inhibit vitamin K dependent factors.
Conclusion This review of selected cases of bleeding with the novel anticoagulants in our hospital has limitations but highlights the necessity for proper prescriber education to avoid use of these agents in inappropriate patients, and emphasises the importance of evaluating the risk of bleeding prior to administration of novel anticoagulants. We recommend HAS-BLED score assessment in all cases, particularly those 80 years of age or older with impaired renal function, and those with concomitant antiplatelet as well as multiple comorbidities [5]. All the new agents are at least as good as or better than warfarin in reducing stroke and systemic embolism in patients with non valvular atrial fibrillation, and all have comparable or better rates of bleeding risk. Overall novel anticoagulants are more convenient (no requirement for routine testing of the INR), carry the smaller risk of debilitating intracranial haemorrhage and also have less susceptibility to dietary and drug interactions [2–4]. There are some challenges for clinicians who initiate novel anticoagulants which need to be taken under consideration:
• Renal function needs to be assessed before treatment and monitored regularly during management. • Patients should be selected carefully with risk/benefit evaluated but in general benefits of anticoagulation outweigh risks of bleeding. • Select the correct dose.
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[4] Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365(September (10)): 883–91. [5] Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJGM, Lip GYH. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation. Chest 2010;138(5):1093–100. [6] Lip GY, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: HASBLED score. Journal of the American College of Cardiology 2011;57(January (2)):173–80. [7] John W, Eikelboom, Jeffrey I, Weitz. Bleeding risk with dabigatran in the frail elderly. N Engl J Med 2012;366(March (9)):864. [8] Dewilde W, Oirbans T, Verheugt F, Kelder J, De Smet B, Herrman JP, et al. The WOEST trial: first randomised trial comparing two regimens with and without aspirin in patients on oral anticoagulant therapy undergoing coronary stenting. ESC; 2012, clinicaltrials.gov NCT00769938. [9] Vincentelli A, Susen S, Le Tourneau T, Six I, Fabre O, Juthier F, et al. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med 2003;349(July (10)): 343–9.
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