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When is it safe to resume anticoagulation in my patient with hemorrhagic stroke?
Balancing risk is critical to decision making
Department of Medicine, Massachusetts General Hospital, Boston
Case
A 75 year-old woman with a history of hypertension, diabetes mellitus, heart failure and nonvalvular atrial fibrillation (CHA2DS2-VASc score, 8) on anticoagulation is admitted with weakness and dysarthria. Exam is notable for hypertension and right-sided hemiparesis. CT of the head shows an intraparenchymal hemorrhage in the left putamen. Her anticoagulation is reversed and blood pressure well controlled. She is discharged 12 days later.
Brief overview of the issue
Intracranial hemorrhage (ICH) is the second most common cause of stroke and is associated with high morbidity and mortality.1 It is estimated that 10%-15% of spontaneous ICH cases occur in patients on therapeutic anticoagulation for atrial fibrillation.2 As our population ages and more people develop atrial fibrillation, anticoagulation for primary or secondary prevention of embolic stroke also will likely increase, placing more people at risk for ICH. Even stringently controlled therapeutic international normalized ratios (INRs) between 2 and 3 may double the risk of ICH.3
Patients with ICH require close monitoring and treatment, including blood pressure control, reversal of anticoagulation, reduction of intracranial pressure and, at times, neurosurgery.4 Although anticoagulation is discontinued and reversed at the onset of ICH, no clear consensus exists as to when it is safe to resume it. Although anticoagulation decreases the risk of stroke/thromboembolism, it may also increase the amount of bleeding associated with the initial ICH or lead to its recurrence.
Factors that may contribute to rebleeding include uncontrolled hypertension, advanced age, time to resumption of anticoagulation, and lobar location of ICH (i.e., in cerebral cortex and/or underlying white matter).5 Traditionally, lobar ICH has high incidence of cerebral amyloid angiopathy and has been associated with higher bleeding rates than has deep ICH (i.e., involving the thalami, basal ganglia, cerebellum, or brainstem) where cerebral amyloid angiopathy is rare and ICH is usually from hypertensive vessel disease. However, in patients with active thromboembolic disease, high-risk atrial fibrillation, and mechanical valves, withholding anticoagulation could place them at high risk of stroke.
Two questions should be addressed in the case presented: Is it safe to restart therapeutic anticoagulation; and if so, what is the optimal time interval between ICH and reinitiation of anticoagulation?
Overview of the data
There is limited guidance from major professional societies regarding the reinitiation of anticoagulation and the optimal timing of safely resuming anticoagulation in patients with prior ICH.
Current European Stroke Organization guidelines provide no specific recommendations for anticoagulation resumption after ICH.7 The American Heart Association/American Stroke Association guideline has a class IIA (weak) recommendation to avoid anticoagulation in spontaneous lobar ICH and a class IIB (very weak) recommendation to consider resuming anticoagulation in nonlobar ICH on a case-by-case basis.4
Two recent meta-analyses have examined outcomes of resuming anticoagulation after ICH. In a meta-analysis of 5,300 patients with nonlobar ICH involving eight retrospective studies, Murthy et al. evaluated the risk of thromboembolic events (described as a composite outcome of MI and stroke) and the risk of recurrent ICH.8 They reported that resumption of therapeutic anticoagulation was associated with a decrease in the rate of thromboembolic events (6.7% vs. 17.6%; risk ratio, 0.35; 95% confidence interval, 0.25-0.45) with no significant change in the rate of repeat ICH (8.7% vs. 7.8%).
A second meta-analysis of three retrospective trials conducted by Biffi et al. examined anticoagulation resumption in 1,012 patients with ICH solely in the setting of thromboprophylaxis for nonvalvular atrial fibrillation.9 Reinitiation of anticoagulation after ICH was associated with decreased mortality (hazard ratio, 0.27; 95% CI, 0.19-0.40; P less than .0001), improved functional outcome (HR, 4.15; 95% CI, 2.92-5.90; P less than .0001), and reduction in all-cause stroke recurrence (HR 0.47; 95% CI, 0.36-0.64; P less than .0001). There was no significant difference in the rate of recurrent ICH when anticoagulation was resumed. Despite the notion that patients with cerebral amyloid angiopathy are at high risk of rebleeding, this positive association still held irrespective of lobar vs. nonlobar location of ICH.
Collectively, these studies suggest that resumption of anticoagulation may be effective in decreasing the rates of thromboembolism, as well as provide a functional and mortality benefit without increasing the risk of rebleeding, irrespective of the location of the bleed.
Less is known about the optimal timing of resumption of therapeutic anticoagulation, with data ranging from 72 hours to 30 weeks.10 The American Heart Association/American Stroke Association has a class IIB (very weak) recommendation to avoid anticoagulation for at least 4 weeks in patients without mechanical heart valves.4 The median time to resumption of therapeutic anticoagulation in aforementioned meta-analyses ranged from 10 to 44 days.8,9
A recent observational study of 2,619 ICH survivors explored the relationship between the timing of reinitiation of anticoagulation and the incidence of thrombotic events (defined as ischemic stroke or death because of MI or systemic arterial thromboembolism) and hemorrhagic events (defined as recurrent ICH or bleeding event leading to death) occurring at least 28 days after initial ICH in patients with atrial fibrillation.11
A decrease in thrombotic events was demonstrated if anticoagulation was started 4-16 weeks after ICH. However, when anticoagulation was started more than 16 weeks after ICH, no benefit was seen. Additionally, there was no significant difference in hemorrhagic events between men and women who resumed anticoagulation. In patients with high venous thromboembolism risk based on CHA2DS2-VASc score, resumption of anticoagulation was associated with a decreased predicted incidence of vascular death and nonfatal stroke, with the greatest benefit observed when anticoagulation was started at 7-8 weeks after ICH.
Unfortunately, published literature to date on anticoagulation after ICH is based entirely on retrospective studies – not randomized, controlled studies – making it more likely that anticoagulation would have been resumed in healthier patients, not those left debilitated by the ICH.
Furthermore, information on the location and size of the hemorrhages – which may serve as another confounding factor – often has not been reported. This is important since patients with smaller hemorrhages in less precarious areas also may be more likely to have resumption of anticoagulation. Another limitation of the current literature is that warfarin is the most common anticoagulant studied, with few studies involving the increasingly prescribed newer direct oral anticoagulants. It is also important to stress that a causal relationship between use of anticoagulants and certain outcomes or adverse effects following ICH may be more difficult to invoke in the absence of randomized controlled study designs.
Application of the data to our patient
Resumption of anticoagulation in our patient with ICH requires balancing the risk of hemorrhage expansion and recurrent ICH with the risk of thromboembolic disease.
Our patient is at higher risk of bleeding because of her advanced age, but adequate control of her blood pressure and nonlobar location of her ICH in the basal ganglia also may decrease her risk of recurrent ICH. Her high CHA2DS2-VASc score places her at high risk of thromboembolic event and stroke, making it more likely for reinitiation of anticoagulation to confer a mortality benefit.
Based on AHA guidelines,4 we should wait at least 4 weeks, or possibly wait until weeks 7-8 after ICH when the greatest benefit may be expected based on prediction models.11
Bottom line
It would likely be safe to resume anticoagulation 4-8 weeks after ICH in our patient.
Dr. Gibson, Dr. Restrepo, Dr. Sasidhara, and Dr. Manian are hospitalists at Massachusetts General Hospital, Boston.
References
1. An SJ et al. Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: An update. J Stroke. 2017 Jan;19:3-10.
2. Horstmann S et al. Intracerebral hemorrhage during anticoagulation with vitamin K antagonists: a consecutive observational study. J Neurol. 2013 Aug;260:2046-51.
3. Rosand J et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004 Apr 26;164:880-4.
4. Hemphill JC et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015 Jul;46:2032-60.
5. Aguillar MI et al. Update in intracerebral hemorrhage. Neurohospitalist. 2011;1:148-59.
6. Hill MD et al. Rate of stroke recurrence in patients with primary intracerebral hemorrhage. Stroke. 2000;31:123-7.
7. Steiner T et al. European Stroke Organization (ESO) guidelines for the management of spontaneous cerebral hemorrhage. Int J Stroke. 2014;9:840-55.
8. Murthy SB et al. Restarting anticoagulation therapy after intracranial hemorrhage: A systematic review and meta-analysis. Stroke. 2017 Jun;48:1594-600.
9. Biffi A et al. Oral anticoagulation and functional outcome after intracerebral hemorrhage. Ann Neurol. 2017 Nov;82:755-65.
10. Witt DM. What to do after the bleed: Resuming anticoagulation after major bleeding. Hematology Am Soc Hematol Educ Program. 2016 Dec 2;206:620-4.
11. Pennlert J et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke. 2017 Feb;48:314-20.
Key Points
- Robust scientific data on when to resume anticoagulation after ICH does not exist.
- Retrospective studies have shown that anticoagulation resumption after 4-8 weeks decreases the risk of thromboembolic events, decreases mortality, and improves functional status following ICH with no significant change in the risk of its recurrence.
- Prospective, randomized controlled trials are needed to explore risks/benefits of anticoagulation resumption and better define its optimal timing in relation to ICH.
Quiz
Which of the following is false regarding ICH?
A. Lobar ICHs are usually associated with cerebral amyloid angiopathy which are prone to bleeding.
B. Randomized, controlled studies have helped guide the decision as to when to resume anticoagulation in patients with ICH.
C. Current guidelines suggest deferring therapeutic anticoagulation for at least 4 weeks following ICH.
D. Resumption of anticoagulation after 4-8 weeks does not lead to increased risk of rebleeding in patients with prior ICH.
The false answer is B: Current recommendations regarding resumption of anticoagulation in patients with ICH are based solely on retrospective observational studies; there are no randomized, control trials to date.
A is true: In contrast to hypertensive vessel disease associated with deep ICH, lobar hemorrhages are usually associated with cerebral amyloid angiopathy, which are more prone to bleeding.
C is true: The AHA/ASA has a class IIB recommendation to avoid anticoagulation for at least 4 weeks after ICH in patients without mechanical heart valves.
D is true: Several studies have shown that resumption of anticoagulation 4-8 weeks after ICH does not increase the risk of rebleeding.
Balancing risk is critical to decision making
Balancing risk is critical to decision making
Department of Medicine, Massachusetts General Hospital, Boston
Case
A 75 year-old woman with a history of hypertension, diabetes mellitus, heart failure and nonvalvular atrial fibrillation (CHA2DS2-VASc score, 8) on anticoagulation is admitted with weakness and dysarthria. Exam is notable for hypertension and right-sided hemiparesis. CT of the head shows an intraparenchymal hemorrhage in the left putamen. Her anticoagulation is reversed and blood pressure well controlled. She is discharged 12 days later.
Brief overview of the issue
Intracranial hemorrhage (ICH) is the second most common cause of stroke and is associated with high morbidity and mortality.1 It is estimated that 10%-15% of spontaneous ICH cases occur in patients on therapeutic anticoagulation for atrial fibrillation.2 As our population ages and more people develop atrial fibrillation, anticoagulation for primary or secondary prevention of embolic stroke also will likely increase, placing more people at risk for ICH. Even stringently controlled therapeutic international normalized ratios (INRs) between 2 and 3 may double the risk of ICH.3
Patients with ICH require close monitoring and treatment, including blood pressure control, reversal of anticoagulation, reduction of intracranial pressure and, at times, neurosurgery.4 Although anticoagulation is discontinued and reversed at the onset of ICH, no clear consensus exists as to when it is safe to resume it. Although anticoagulation decreases the risk of stroke/thromboembolism, it may also increase the amount of bleeding associated with the initial ICH or lead to its recurrence.
Factors that may contribute to rebleeding include uncontrolled hypertension, advanced age, time to resumption of anticoagulation, and lobar location of ICH (i.e., in cerebral cortex and/or underlying white matter).5 Traditionally, lobar ICH has high incidence of cerebral amyloid angiopathy and has been associated with higher bleeding rates than has deep ICH (i.e., involving the thalami, basal ganglia, cerebellum, or brainstem) where cerebral amyloid angiopathy is rare and ICH is usually from hypertensive vessel disease. However, in patients with active thromboembolic disease, high-risk atrial fibrillation, and mechanical valves, withholding anticoagulation could place them at high risk of stroke.
Two questions should be addressed in the case presented: Is it safe to restart therapeutic anticoagulation; and if so, what is the optimal time interval between ICH and reinitiation of anticoagulation?
Overview of the data
There is limited guidance from major professional societies regarding the reinitiation of anticoagulation and the optimal timing of safely resuming anticoagulation in patients with prior ICH.
Current European Stroke Organization guidelines provide no specific recommendations for anticoagulation resumption after ICH.7 The American Heart Association/American Stroke Association guideline has a class IIA (weak) recommendation to avoid anticoagulation in spontaneous lobar ICH and a class IIB (very weak) recommendation to consider resuming anticoagulation in nonlobar ICH on a case-by-case basis.4
Two recent meta-analyses have examined outcomes of resuming anticoagulation after ICH. In a meta-analysis of 5,300 patients with nonlobar ICH involving eight retrospective studies, Murthy et al. evaluated the risk of thromboembolic events (described as a composite outcome of MI and stroke) and the risk of recurrent ICH.8 They reported that resumption of therapeutic anticoagulation was associated with a decrease in the rate of thromboembolic events (6.7% vs. 17.6%; risk ratio, 0.35; 95% confidence interval, 0.25-0.45) with no significant change in the rate of repeat ICH (8.7% vs. 7.8%).
A second meta-analysis of three retrospective trials conducted by Biffi et al. examined anticoagulation resumption in 1,012 patients with ICH solely in the setting of thromboprophylaxis for nonvalvular atrial fibrillation.9 Reinitiation of anticoagulation after ICH was associated with decreased mortality (hazard ratio, 0.27; 95% CI, 0.19-0.40; P less than .0001), improved functional outcome (HR, 4.15; 95% CI, 2.92-5.90; P less than .0001), and reduction in all-cause stroke recurrence (HR 0.47; 95% CI, 0.36-0.64; P less than .0001). There was no significant difference in the rate of recurrent ICH when anticoagulation was resumed. Despite the notion that patients with cerebral amyloid angiopathy are at high risk of rebleeding, this positive association still held irrespective of lobar vs. nonlobar location of ICH.
Collectively, these studies suggest that resumption of anticoagulation may be effective in decreasing the rates of thromboembolism, as well as provide a functional and mortality benefit without increasing the risk of rebleeding, irrespective of the location of the bleed.
Less is known about the optimal timing of resumption of therapeutic anticoagulation, with data ranging from 72 hours to 30 weeks.10 The American Heart Association/American Stroke Association has a class IIB (very weak) recommendation to avoid anticoagulation for at least 4 weeks in patients without mechanical heart valves.4 The median time to resumption of therapeutic anticoagulation in aforementioned meta-analyses ranged from 10 to 44 days.8,9
A recent observational study of 2,619 ICH survivors explored the relationship between the timing of reinitiation of anticoagulation and the incidence of thrombotic events (defined as ischemic stroke or death because of MI or systemic arterial thromboembolism) and hemorrhagic events (defined as recurrent ICH or bleeding event leading to death) occurring at least 28 days after initial ICH in patients with atrial fibrillation.11
A decrease in thrombotic events was demonstrated if anticoagulation was started 4-16 weeks after ICH. However, when anticoagulation was started more than 16 weeks after ICH, no benefit was seen. Additionally, there was no significant difference in hemorrhagic events between men and women who resumed anticoagulation. In patients with high venous thromboembolism risk based on CHA2DS2-VASc score, resumption of anticoagulation was associated with a decreased predicted incidence of vascular death and nonfatal stroke, with the greatest benefit observed when anticoagulation was started at 7-8 weeks after ICH.
Unfortunately, published literature to date on anticoagulation after ICH is based entirely on retrospective studies – not randomized, controlled studies – making it more likely that anticoagulation would have been resumed in healthier patients, not those left debilitated by the ICH.
Furthermore, information on the location and size of the hemorrhages – which may serve as another confounding factor – often has not been reported. This is important since patients with smaller hemorrhages in less precarious areas also may be more likely to have resumption of anticoagulation. Another limitation of the current literature is that warfarin is the most common anticoagulant studied, with few studies involving the increasingly prescribed newer direct oral anticoagulants. It is also important to stress that a causal relationship between use of anticoagulants and certain outcomes or adverse effects following ICH may be more difficult to invoke in the absence of randomized controlled study designs.
Application of the data to our patient
Resumption of anticoagulation in our patient with ICH requires balancing the risk of hemorrhage expansion and recurrent ICH with the risk of thromboembolic disease.
Our patient is at higher risk of bleeding because of her advanced age, but adequate control of her blood pressure and nonlobar location of her ICH in the basal ganglia also may decrease her risk of recurrent ICH. Her high CHA2DS2-VASc score places her at high risk of thromboembolic event and stroke, making it more likely for reinitiation of anticoagulation to confer a mortality benefit.
Based on AHA guidelines,4 we should wait at least 4 weeks, or possibly wait until weeks 7-8 after ICH when the greatest benefit may be expected based on prediction models.11
Bottom line
It would likely be safe to resume anticoagulation 4-8 weeks after ICH in our patient.
Dr. Gibson, Dr. Restrepo, Dr. Sasidhara, and Dr. Manian are hospitalists at Massachusetts General Hospital, Boston.
References
1. An SJ et al. Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: An update. J Stroke. 2017 Jan;19:3-10.
2. Horstmann S et al. Intracerebral hemorrhage during anticoagulation with vitamin K antagonists: a consecutive observational study. J Neurol. 2013 Aug;260:2046-51.
3. Rosand J et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004 Apr 26;164:880-4.
4. Hemphill JC et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015 Jul;46:2032-60.
5. Aguillar MI et al. Update in intracerebral hemorrhage. Neurohospitalist. 2011;1:148-59.
6. Hill MD et al. Rate of stroke recurrence in patients with primary intracerebral hemorrhage. Stroke. 2000;31:123-7.
7. Steiner T et al. European Stroke Organization (ESO) guidelines for the management of spontaneous cerebral hemorrhage. Int J Stroke. 2014;9:840-55.
8. Murthy SB et al. Restarting anticoagulation therapy after intracranial hemorrhage: A systematic review and meta-analysis. Stroke. 2017 Jun;48:1594-600.
9. Biffi A et al. Oral anticoagulation and functional outcome after intracerebral hemorrhage. Ann Neurol. 2017 Nov;82:755-65.
10. Witt DM. What to do after the bleed: Resuming anticoagulation after major bleeding. Hematology Am Soc Hematol Educ Program. 2016 Dec 2;206:620-4.
11. Pennlert J et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke. 2017 Feb;48:314-20.
Key Points
- Robust scientific data on when to resume anticoagulation after ICH does not exist.
- Retrospective studies have shown that anticoagulation resumption after 4-8 weeks decreases the risk of thromboembolic events, decreases mortality, and improves functional status following ICH with no significant change in the risk of its recurrence.
- Prospective, randomized controlled trials are needed to explore risks/benefits of anticoagulation resumption and better define its optimal timing in relation to ICH.
Quiz
Which of the following is false regarding ICH?
A. Lobar ICHs are usually associated with cerebral amyloid angiopathy which are prone to bleeding.
B. Randomized, controlled studies have helped guide the decision as to when to resume anticoagulation in patients with ICH.
C. Current guidelines suggest deferring therapeutic anticoagulation for at least 4 weeks following ICH.
D. Resumption of anticoagulation after 4-8 weeks does not lead to increased risk of rebleeding in patients with prior ICH.
The false answer is B: Current recommendations regarding resumption of anticoagulation in patients with ICH are based solely on retrospective observational studies; there are no randomized, control trials to date.
A is true: In contrast to hypertensive vessel disease associated with deep ICH, lobar hemorrhages are usually associated with cerebral amyloid angiopathy, which are more prone to bleeding.
C is true: The AHA/ASA has a class IIB recommendation to avoid anticoagulation for at least 4 weeks after ICH in patients without mechanical heart valves.
D is true: Several studies have shown that resumption of anticoagulation 4-8 weeks after ICH does not increase the risk of rebleeding.
Department of Medicine, Massachusetts General Hospital, Boston
Case
A 75 year-old woman with a history of hypertension, diabetes mellitus, heart failure and nonvalvular atrial fibrillation (CHA2DS2-VASc score, 8) on anticoagulation is admitted with weakness and dysarthria. Exam is notable for hypertension and right-sided hemiparesis. CT of the head shows an intraparenchymal hemorrhage in the left putamen. Her anticoagulation is reversed and blood pressure well controlled. She is discharged 12 days later.
Brief overview of the issue
Intracranial hemorrhage (ICH) is the second most common cause of stroke and is associated with high morbidity and mortality.1 It is estimated that 10%-15% of spontaneous ICH cases occur in patients on therapeutic anticoagulation for atrial fibrillation.2 As our population ages and more people develop atrial fibrillation, anticoagulation for primary or secondary prevention of embolic stroke also will likely increase, placing more people at risk for ICH. Even stringently controlled therapeutic international normalized ratios (INRs) between 2 and 3 may double the risk of ICH.3
Patients with ICH require close monitoring and treatment, including blood pressure control, reversal of anticoagulation, reduction of intracranial pressure and, at times, neurosurgery.4 Although anticoagulation is discontinued and reversed at the onset of ICH, no clear consensus exists as to when it is safe to resume it. Although anticoagulation decreases the risk of stroke/thromboembolism, it may also increase the amount of bleeding associated with the initial ICH or lead to its recurrence.
Factors that may contribute to rebleeding include uncontrolled hypertension, advanced age, time to resumption of anticoagulation, and lobar location of ICH (i.e., in cerebral cortex and/or underlying white matter).5 Traditionally, lobar ICH has high incidence of cerebral amyloid angiopathy and has been associated with higher bleeding rates than has deep ICH (i.e., involving the thalami, basal ganglia, cerebellum, or brainstem) where cerebral amyloid angiopathy is rare and ICH is usually from hypertensive vessel disease. However, in patients with active thromboembolic disease, high-risk atrial fibrillation, and mechanical valves, withholding anticoagulation could place them at high risk of stroke.
Two questions should be addressed in the case presented: Is it safe to restart therapeutic anticoagulation; and if so, what is the optimal time interval between ICH and reinitiation of anticoagulation?
Overview of the data
There is limited guidance from major professional societies regarding the reinitiation of anticoagulation and the optimal timing of safely resuming anticoagulation in patients with prior ICH.
Current European Stroke Organization guidelines provide no specific recommendations for anticoagulation resumption after ICH.7 The American Heart Association/American Stroke Association guideline has a class IIA (weak) recommendation to avoid anticoagulation in spontaneous lobar ICH and a class IIB (very weak) recommendation to consider resuming anticoagulation in nonlobar ICH on a case-by-case basis.4
Two recent meta-analyses have examined outcomes of resuming anticoagulation after ICH. In a meta-analysis of 5,300 patients with nonlobar ICH involving eight retrospective studies, Murthy et al. evaluated the risk of thromboembolic events (described as a composite outcome of MI and stroke) and the risk of recurrent ICH.8 They reported that resumption of therapeutic anticoagulation was associated with a decrease in the rate of thromboembolic events (6.7% vs. 17.6%; risk ratio, 0.35; 95% confidence interval, 0.25-0.45) with no significant change in the rate of repeat ICH (8.7% vs. 7.8%).
A second meta-analysis of three retrospective trials conducted by Biffi et al. examined anticoagulation resumption in 1,012 patients with ICH solely in the setting of thromboprophylaxis for nonvalvular atrial fibrillation.9 Reinitiation of anticoagulation after ICH was associated with decreased mortality (hazard ratio, 0.27; 95% CI, 0.19-0.40; P less than .0001), improved functional outcome (HR, 4.15; 95% CI, 2.92-5.90; P less than .0001), and reduction in all-cause stroke recurrence (HR 0.47; 95% CI, 0.36-0.64; P less than .0001). There was no significant difference in the rate of recurrent ICH when anticoagulation was resumed. Despite the notion that patients with cerebral amyloid angiopathy are at high risk of rebleeding, this positive association still held irrespective of lobar vs. nonlobar location of ICH.
Collectively, these studies suggest that resumption of anticoagulation may be effective in decreasing the rates of thromboembolism, as well as provide a functional and mortality benefit without increasing the risk of rebleeding, irrespective of the location of the bleed.
Less is known about the optimal timing of resumption of therapeutic anticoagulation, with data ranging from 72 hours to 30 weeks.10 The American Heart Association/American Stroke Association has a class IIB (very weak) recommendation to avoid anticoagulation for at least 4 weeks in patients without mechanical heart valves.4 The median time to resumption of therapeutic anticoagulation in aforementioned meta-analyses ranged from 10 to 44 days.8,9
A recent observational study of 2,619 ICH survivors explored the relationship between the timing of reinitiation of anticoagulation and the incidence of thrombotic events (defined as ischemic stroke or death because of MI or systemic arterial thromboembolism) and hemorrhagic events (defined as recurrent ICH or bleeding event leading to death) occurring at least 28 days after initial ICH in patients with atrial fibrillation.11
A decrease in thrombotic events was demonstrated if anticoagulation was started 4-16 weeks after ICH. However, when anticoagulation was started more than 16 weeks after ICH, no benefit was seen. Additionally, there was no significant difference in hemorrhagic events between men and women who resumed anticoagulation. In patients with high venous thromboembolism risk based on CHA2DS2-VASc score, resumption of anticoagulation was associated with a decreased predicted incidence of vascular death and nonfatal stroke, with the greatest benefit observed when anticoagulation was started at 7-8 weeks after ICH.
Unfortunately, published literature to date on anticoagulation after ICH is based entirely on retrospective studies – not randomized, controlled studies – making it more likely that anticoagulation would have been resumed in healthier patients, not those left debilitated by the ICH.
Furthermore, information on the location and size of the hemorrhages – which may serve as another confounding factor – often has not been reported. This is important since patients with smaller hemorrhages in less precarious areas also may be more likely to have resumption of anticoagulation. Another limitation of the current literature is that warfarin is the most common anticoagulant studied, with few studies involving the increasingly prescribed newer direct oral anticoagulants. It is also important to stress that a causal relationship between use of anticoagulants and certain outcomes or adverse effects following ICH may be more difficult to invoke in the absence of randomized controlled study designs.
Application of the data to our patient
Resumption of anticoagulation in our patient with ICH requires balancing the risk of hemorrhage expansion and recurrent ICH with the risk of thromboembolic disease.
Our patient is at higher risk of bleeding because of her advanced age, but adequate control of her blood pressure and nonlobar location of her ICH in the basal ganglia also may decrease her risk of recurrent ICH. Her high CHA2DS2-VASc score places her at high risk of thromboembolic event and stroke, making it more likely for reinitiation of anticoagulation to confer a mortality benefit.
Based on AHA guidelines,4 we should wait at least 4 weeks, or possibly wait until weeks 7-8 after ICH when the greatest benefit may be expected based on prediction models.11
Bottom line
It would likely be safe to resume anticoagulation 4-8 weeks after ICH in our patient.
Dr. Gibson, Dr. Restrepo, Dr. Sasidhara, and Dr. Manian are hospitalists at Massachusetts General Hospital, Boston.
References
1. An SJ et al. Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: An update. J Stroke. 2017 Jan;19:3-10.
2. Horstmann S et al. Intracerebral hemorrhage during anticoagulation with vitamin K antagonists: a consecutive observational study. J Neurol. 2013 Aug;260:2046-51.
3. Rosand J et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004 Apr 26;164:880-4.
4. Hemphill JC et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015 Jul;46:2032-60.
5. Aguillar MI et al. Update in intracerebral hemorrhage. Neurohospitalist. 2011;1:148-59.
6. Hill MD et al. Rate of stroke recurrence in patients with primary intracerebral hemorrhage. Stroke. 2000;31:123-7.
7. Steiner T et al. European Stroke Organization (ESO) guidelines for the management of spontaneous cerebral hemorrhage. Int J Stroke. 2014;9:840-55.
8. Murthy SB et al. Restarting anticoagulation therapy after intracranial hemorrhage: A systematic review and meta-analysis. Stroke. 2017 Jun;48:1594-600.
9. Biffi A et al. Oral anticoagulation and functional outcome after intracerebral hemorrhage. Ann Neurol. 2017 Nov;82:755-65.
10. Witt DM. What to do after the bleed: Resuming anticoagulation after major bleeding. Hematology Am Soc Hematol Educ Program. 2016 Dec 2;206:620-4.
11. Pennlert J et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke. 2017 Feb;48:314-20.
Key Points
- Robust scientific data on when to resume anticoagulation after ICH does not exist.
- Retrospective studies have shown that anticoagulation resumption after 4-8 weeks decreases the risk of thromboembolic events, decreases mortality, and improves functional status following ICH with no significant change in the risk of its recurrence.
- Prospective, randomized controlled trials are needed to explore risks/benefits of anticoagulation resumption and better define its optimal timing in relation to ICH.
Quiz
Which of the following is false regarding ICH?
A. Lobar ICHs are usually associated with cerebral amyloid angiopathy which are prone to bleeding.
B. Randomized, controlled studies have helped guide the decision as to when to resume anticoagulation in patients with ICH.
C. Current guidelines suggest deferring therapeutic anticoagulation for at least 4 weeks following ICH.
D. Resumption of anticoagulation after 4-8 weeks does not lead to increased risk of rebleeding in patients with prior ICH.
The false answer is B: Current recommendations regarding resumption of anticoagulation in patients with ICH are based solely on retrospective observational studies; there are no randomized, control trials to date.
A is true: In contrast to hypertensive vessel disease associated with deep ICH, lobar hemorrhages are usually associated with cerebral amyloid angiopathy, which are more prone to bleeding.
C is true: The AHA/ASA has a class IIB recommendation to avoid anticoagulation for at least 4 weeks after ICH in patients without mechanical heart valves.
D is true: Several studies have shown that resumption of anticoagulation 4-8 weeks after ICH does not increase the risk of rebleeding.
New recall for CoaguChek test strips issued
According to a release, the Food and Drug Administration has identified this recall as Class I, which is the most serious type of recall and indicates that “use of these devices may cause serious injuries or death.”
These strips are used by patients taking warfarin to help determine the patients’ international normalized ratio, which doctors and patients then use to decide whether the dose is appropriate. Roche Diagnostics, the strips’ manufacturer, issued a recall in September 2018; the test strips distributed by Terrific Care and Medex, however, were not labeled or authorized for sale in the United States and were therefore not included in that original recall. According to the release, the strips in this recall, which was initiated Dec. 21, 2018, were purchased by Terrific Care and Medex from an unknown source and then distributed in the United States. On Jan. 28, 2019, Terrific Care sent an Urgent Medical Device Recall Notification Letter to customers.
The full recall is described on the FDA website.
According to a release, the Food and Drug Administration has identified this recall as Class I, which is the most serious type of recall and indicates that “use of these devices may cause serious injuries or death.”
These strips are used by patients taking warfarin to help determine the patients’ international normalized ratio, which doctors and patients then use to decide whether the dose is appropriate. Roche Diagnostics, the strips’ manufacturer, issued a recall in September 2018; the test strips distributed by Terrific Care and Medex, however, were not labeled or authorized for sale in the United States and were therefore not included in that original recall. According to the release, the strips in this recall, which was initiated Dec. 21, 2018, were purchased by Terrific Care and Medex from an unknown source and then distributed in the United States. On Jan. 28, 2019, Terrific Care sent an Urgent Medical Device Recall Notification Letter to customers.
The full recall is described on the FDA website.
According to a release, the Food and Drug Administration has identified this recall as Class I, which is the most serious type of recall and indicates that “use of these devices may cause serious injuries or death.”
These strips are used by patients taking warfarin to help determine the patients’ international normalized ratio, which doctors and patients then use to decide whether the dose is appropriate. Roche Diagnostics, the strips’ manufacturer, issued a recall in September 2018; the test strips distributed by Terrific Care and Medex, however, were not labeled or authorized for sale in the United States and were therefore not included in that original recall. According to the release, the strips in this recall, which was initiated Dec. 21, 2018, were purchased by Terrific Care and Medex from an unknown source and then distributed in the United States. On Jan. 28, 2019, Terrific Care sent an Urgent Medical Device Recall Notification Letter to customers.
The full recall is described on the FDA website.
Impaired clot lysis associated with mild bleeding symptoms
Patients with self-reported mild bleeding symptoms may have impaired clot lysis, according to investigators. This finding is remarkable because it contrasts with known bleeding disorders, such as hemophilia, which are associated with enhanced clot lysis, reported lead author Minka J.A. Vries, MD, of the Cardiovascular Research Institute Maastricht (CARIM) at Maastricht (the Netherlands) University and her colleagues.
The observational study, which included 335 patients undergoing elective surgery at Maastricht University Medical Center, was conducted to better understand lysis capacity, which is challenging to assess in a clinical setting. Although the Euglobulin Lysis Time (ELT) is often used in the clinic, it cannot determine the influence of hemostatic proteins or formation of a fibrin clot under physiological conditions.
“In the more recently developed lysis assays,” the investigators wrote in Thrombosis Research, “the turbidity lysis assay and the tissue plasminogen activator–rotational thromboelastometry (tPA-ROTEM) [assay], all plasma proteins are present and fibrin is formed under more physiological conditions for the measurement of fibrinolysis.” These two tests were used in the present study.
Of the 335 adult patients, 240 had self-reported mild bleeding symptoms, and 95 did not. Patients with bleeding disorders, thrombocytopenia, or anemia were excluded, as were pregnant women and those taking blood thinners or NSAIDs. Along with assessing time parameters of fibrinolysis, clot-associated proteins were measured for possible imbalances.
“We hypothesized that clot lysis capacity is enhanced in patients with mild bleeding symptoms,” the investigators wrote, based on other bleeding disorders. Surprisingly, the results told a different story.
After adjusting for sex, BMI, and age, patients with bleeding symptoms had lower tPA-ROTEM lysis speed (beta −0.35; P = .007) and longer tPA-ROTEM lysis time (beta 0.29; P = .022) than did patients without bleeding symptoms. The investigators found that tPA-ROTEM measurements depended on factor II, factor XII, alpha2-antiplasmin, plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), and plasminogen activator inhibitor–1 (PAI-1) level. In contrast, turbidity lysis assay measurements were not significantly different between groups. This latter assay was influenced by alpha2-antiplasmin, TAFI, and PAI-1.
“We did not find evidence for systemic hyperfibrinolytic capacity in patients reporting mild bleeding symptoms in comparison to patients not reporting bleeding symptoms,” the investigators concluded. “tPA-ROTEM even suggested a slower clot lysis in these patients. Though this may appear counterintuitive, our results are in line with two papers assessing systemic clot lysis in mild bleeders.”
While this phenomenon gains supporting evidence, it remains poorly understood.
“We have no good explanation for these findings,” the investigators noted.
This study was funded by the Sint Annadal Foundation Maastricht, Maastricht University Medical Centre, CTMM INCOAG Maastricht, Cardiovascular Research Institute Maastricht, and the British Heart Foundation. No conflicts of interest were reported.
SOURCE: Vries MJA et al. Thromb Res. 2018 Dec 4. doi: 10.1016/j.thromres.2018.12.004.
Patients with self-reported mild bleeding symptoms may have impaired clot lysis, according to investigators. This finding is remarkable because it contrasts with known bleeding disorders, such as hemophilia, which are associated with enhanced clot lysis, reported lead author Minka J.A. Vries, MD, of the Cardiovascular Research Institute Maastricht (CARIM) at Maastricht (the Netherlands) University and her colleagues.
The observational study, which included 335 patients undergoing elective surgery at Maastricht University Medical Center, was conducted to better understand lysis capacity, which is challenging to assess in a clinical setting. Although the Euglobulin Lysis Time (ELT) is often used in the clinic, it cannot determine the influence of hemostatic proteins or formation of a fibrin clot under physiological conditions.
“In the more recently developed lysis assays,” the investigators wrote in Thrombosis Research, “the turbidity lysis assay and the tissue plasminogen activator–rotational thromboelastometry (tPA-ROTEM) [assay], all plasma proteins are present and fibrin is formed under more physiological conditions for the measurement of fibrinolysis.” These two tests were used in the present study.
Of the 335 adult patients, 240 had self-reported mild bleeding symptoms, and 95 did not. Patients with bleeding disorders, thrombocytopenia, or anemia were excluded, as were pregnant women and those taking blood thinners or NSAIDs. Along with assessing time parameters of fibrinolysis, clot-associated proteins were measured for possible imbalances.
“We hypothesized that clot lysis capacity is enhanced in patients with mild bleeding symptoms,” the investigators wrote, based on other bleeding disorders. Surprisingly, the results told a different story.
After adjusting for sex, BMI, and age, patients with bleeding symptoms had lower tPA-ROTEM lysis speed (beta −0.35; P = .007) and longer tPA-ROTEM lysis time (beta 0.29; P = .022) than did patients without bleeding symptoms. The investigators found that tPA-ROTEM measurements depended on factor II, factor XII, alpha2-antiplasmin, plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), and plasminogen activator inhibitor–1 (PAI-1) level. In contrast, turbidity lysis assay measurements were not significantly different between groups. This latter assay was influenced by alpha2-antiplasmin, TAFI, and PAI-1.
“We did not find evidence for systemic hyperfibrinolytic capacity in patients reporting mild bleeding symptoms in comparison to patients not reporting bleeding symptoms,” the investigators concluded. “tPA-ROTEM even suggested a slower clot lysis in these patients. Though this may appear counterintuitive, our results are in line with two papers assessing systemic clot lysis in mild bleeders.”
While this phenomenon gains supporting evidence, it remains poorly understood.
“We have no good explanation for these findings,” the investigators noted.
This study was funded by the Sint Annadal Foundation Maastricht, Maastricht University Medical Centre, CTMM INCOAG Maastricht, Cardiovascular Research Institute Maastricht, and the British Heart Foundation. No conflicts of interest were reported.
SOURCE: Vries MJA et al. Thromb Res. 2018 Dec 4. doi: 10.1016/j.thromres.2018.12.004.
Patients with self-reported mild bleeding symptoms may have impaired clot lysis, according to investigators. This finding is remarkable because it contrasts with known bleeding disorders, such as hemophilia, which are associated with enhanced clot lysis, reported lead author Minka J.A. Vries, MD, of the Cardiovascular Research Institute Maastricht (CARIM) at Maastricht (the Netherlands) University and her colleagues.
The observational study, which included 335 patients undergoing elective surgery at Maastricht University Medical Center, was conducted to better understand lysis capacity, which is challenging to assess in a clinical setting. Although the Euglobulin Lysis Time (ELT) is often used in the clinic, it cannot determine the influence of hemostatic proteins or formation of a fibrin clot under physiological conditions.
“In the more recently developed lysis assays,” the investigators wrote in Thrombosis Research, “the turbidity lysis assay and the tissue plasminogen activator–rotational thromboelastometry (tPA-ROTEM) [assay], all plasma proteins are present and fibrin is formed under more physiological conditions for the measurement of fibrinolysis.” These two tests were used in the present study.
Of the 335 adult patients, 240 had self-reported mild bleeding symptoms, and 95 did not. Patients with bleeding disorders, thrombocytopenia, or anemia were excluded, as were pregnant women and those taking blood thinners or NSAIDs. Along with assessing time parameters of fibrinolysis, clot-associated proteins were measured for possible imbalances.
“We hypothesized that clot lysis capacity is enhanced in patients with mild bleeding symptoms,” the investigators wrote, based on other bleeding disorders. Surprisingly, the results told a different story.
After adjusting for sex, BMI, and age, patients with bleeding symptoms had lower tPA-ROTEM lysis speed (beta −0.35; P = .007) and longer tPA-ROTEM lysis time (beta 0.29; P = .022) than did patients without bleeding symptoms. The investigators found that tPA-ROTEM measurements depended on factor II, factor XII, alpha2-antiplasmin, plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), and plasminogen activator inhibitor–1 (PAI-1) level. In contrast, turbidity lysis assay measurements were not significantly different between groups. This latter assay was influenced by alpha2-antiplasmin, TAFI, and PAI-1.
“We did not find evidence for systemic hyperfibrinolytic capacity in patients reporting mild bleeding symptoms in comparison to patients not reporting bleeding symptoms,” the investigators concluded. “tPA-ROTEM even suggested a slower clot lysis in these patients. Though this may appear counterintuitive, our results are in line with two papers assessing systemic clot lysis in mild bleeders.”
While this phenomenon gains supporting evidence, it remains poorly understood.
“We have no good explanation for these findings,” the investigators noted.
This study was funded by the Sint Annadal Foundation Maastricht, Maastricht University Medical Centre, CTMM INCOAG Maastricht, Cardiovascular Research Institute Maastricht, and the British Heart Foundation. No conflicts of interest were reported.
SOURCE: Vries MJA et al. Thromb Res. 2018 Dec 4. doi: 10.1016/j.thromres.2018.12.004.
FROM THROMBOSIS RESEARCH
Key clinical point: Patients with self-reported mild bleeding symptoms may have impaired clot lysis, in contrast with known bleeding disorders.
Major finding: Patients with mild bleeding had longer whole blood tissue plasminogen activator-rotational thromboelastometry lysis times (P = .022) than did patients without symptoms.
Study details: An observational study of 335 adult patients undergoing elective surgery.
Disclosures: This study was funded by the Sint Annadal Foundation, Maastricht University Medical Center, CTMM INCOAG Maastricht, Cardiovascular Research Institute Maastricht, and the British Heart Foundation. No conflicts of interest were reported.
Source: Vries MJA et al. Thromb Res. 2018 Dec 4. doi: 10.1016/j.thromres.2018.12.004.
COPD linked to higher in-hospital death rates in patients with PAD
A growing body of evidence suggests that, along with other vascular beds, smoking and chronic obstructive pulmonary disease (COPD) affect the arteries of the lower limbs in terms of the development of peripheral arterial disease (PAD), reported Karsten Keller, MD, of the Johannes Gutenberg-University Mainz (Germany) and his colleagues.
This provided the rationale for their large database analysis of inpatients with concomitant COPD and PAD. They found that the additional presence of COPD was associated with increased in-hospital mortality in patients with PAD.
“Our data suggest that COPD increased the mortality of PAD patients by the factor 1.2-fold,” they wrote in Respiratory Medicine. “Unexpectedly, this increase was not driven by [myocardial infarction] as the life-threatening acute presentation of [coronary artery disease], but rather related to an increased risk for [pulmonary embolism] and a higher coprevalence of cancer.”
Dr. Keller and his colleagues inspected the German inpatient national database based on ICD codes. They identified 5,611,827 adult inpatients (64.8% men) diagnosed with PAD between January 2005 and December 2015, and of those, 13.6% also were coded for COPD. Overall, 277,894 PAD patients (5.0%) died in the hospital, Dr. Keller and his colleagues wrote.
The all-cause, in-hospital mortality was significantly higher in PAD patients with COPD, compared with those without COPD (6.5% vs. 4.7%, respectively; P less than .001), and cardiovascular events comprising pulmonary embolism (PE), deep vein thrombosis (DVT), and myocardial infarction (MI) occurred more often in coprevalence with PAD and COPD than in PAD without COPD.
In PAD patients, COPD was an independent predictor of in-hospital death (odds ratio, 1.16; 95% confidence interval, 1.15-1.17; P less than .001) as well as an independent predictor for PE (OR, 1.44; 95% CI, 1.40-1.49; P less than .001).
Overall, PAD patients with COPD were of similar age as (73 years), but stayed slightly longer in the hospital than (9 vs. 8 days), those without COPD. PAD patients without COPD revealed more often cardiovascular risk factors like essential arterial hypertension and diabetes, but the prevalence of cardiovascular diseases such as coronary artery disease and heart failure were more often found in PAD patients with COPD. In addition, cancer and renal insufficiency also were more common in PAD patients with COPD, according to the authors.
“Remarkably, PAD patients with COPD showed more frequently lower PAD stages than those without COPD. Especially, PAD stage IV was more prevalent in PAD patients without COPD (19.6% vs. 13.8%; P less than 0.001),” the authors stated. In addition, amputations were more often performed in PAD patients without COPD.
Dr. Keller and his colleagues had the following conclusions regarding the clinical implications of their study: “I) PAD patients with long-standing tobacco use might benefit from COPD screening and treatment. II) PAD patients with additional COPD should be monitored more intensively, and the treatment for COPD should be optimized. III) COPD increases the risk for PE, and it is critical not to overlook this life-threatening disease. IV) MI and PE are important causes of in-hospital death in PAD patients with and without COPD.”
The German Federal Ministry of Education and Research funded the study, and the authors reported having no conflicts.
SOURCE: Keller K et al. Respir Med. 2019 Feb;147:1-6.
A growing body of evidence suggests that, along with other vascular beds, smoking and chronic obstructive pulmonary disease (COPD) affect the arteries of the lower limbs in terms of the development of peripheral arterial disease (PAD), reported Karsten Keller, MD, of the Johannes Gutenberg-University Mainz (Germany) and his colleagues.
This provided the rationale for their large database analysis of inpatients with concomitant COPD and PAD. They found that the additional presence of COPD was associated with increased in-hospital mortality in patients with PAD.
“Our data suggest that COPD increased the mortality of PAD patients by the factor 1.2-fold,” they wrote in Respiratory Medicine. “Unexpectedly, this increase was not driven by [myocardial infarction] as the life-threatening acute presentation of [coronary artery disease], but rather related to an increased risk for [pulmonary embolism] and a higher coprevalence of cancer.”
Dr. Keller and his colleagues inspected the German inpatient national database based on ICD codes. They identified 5,611,827 adult inpatients (64.8% men) diagnosed with PAD between January 2005 and December 2015, and of those, 13.6% also were coded for COPD. Overall, 277,894 PAD patients (5.0%) died in the hospital, Dr. Keller and his colleagues wrote.
The all-cause, in-hospital mortality was significantly higher in PAD patients with COPD, compared with those without COPD (6.5% vs. 4.7%, respectively; P less than .001), and cardiovascular events comprising pulmonary embolism (PE), deep vein thrombosis (DVT), and myocardial infarction (MI) occurred more often in coprevalence with PAD and COPD than in PAD without COPD.
In PAD patients, COPD was an independent predictor of in-hospital death (odds ratio, 1.16; 95% confidence interval, 1.15-1.17; P less than .001) as well as an independent predictor for PE (OR, 1.44; 95% CI, 1.40-1.49; P less than .001).
Overall, PAD patients with COPD were of similar age as (73 years), but stayed slightly longer in the hospital than (9 vs. 8 days), those without COPD. PAD patients without COPD revealed more often cardiovascular risk factors like essential arterial hypertension and diabetes, but the prevalence of cardiovascular diseases such as coronary artery disease and heart failure were more often found in PAD patients with COPD. In addition, cancer and renal insufficiency also were more common in PAD patients with COPD, according to the authors.
“Remarkably, PAD patients with COPD showed more frequently lower PAD stages than those without COPD. Especially, PAD stage IV was more prevalent in PAD patients without COPD (19.6% vs. 13.8%; P less than 0.001),” the authors stated. In addition, amputations were more often performed in PAD patients without COPD.
Dr. Keller and his colleagues had the following conclusions regarding the clinical implications of their study: “I) PAD patients with long-standing tobacco use might benefit from COPD screening and treatment. II) PAD patients with additional COPD should be monitored more intensively, and the treatment for COPD should be optimized. III) COPD increases the risk for PE, and it is critical not to overlook this life-threatening disease. IV) MI and PE are important causes of in-hospital death in PAD patients with and without COPD.”
The German Federal Ministry of Education and Research funded the study, and the authors reported having no conflicts.
SOURCE: Keller K et al. Respir Med. 2019 Feb;147:1-6.
A growing body of evidence suggests that, along with other vascular beds, smoking and chronic obstructive pulmonary disease (COPD) affect the arteries of the lower limbs in terms of the development of peripheral arterial disease (PAD), reported Karsten Keller, MD, of the Johannes Gutenberg-University Mainz (Germany) and his colleagues.
This provided the rationale for their large database analysis of inpatients with concomitant COPD and PAD. They found that the additional presence of COPD was associated with increased in-hospital mortality in patients with PAD.
“Our data suggest that COPD increased the mortality of PAD patients by the factor 1.2-fold,” they wrote in Respiratory Medicine. “Unexpectedly, this increase was not driven by [myocardial infarction] as the life-threatening acute presentation of [coronary artery disease], but rather related to an increased risk for [pulmonary embolism] and a higher coprevalence of cancer.”
Dr. Keller and his colleagues inspected the German inpatient national database based on ICD codes. They identified 5,611,827 adult inpatients (64.8% men) diagnosed with PAD between January 2005 and December 2015, and of those, 13.6% also were coded for COPD. Overall, 277,894 PAD patients (5.0%) died in the hospital, Dr. Keller and his colleagues wrote.
The all-cause, in-hospital mortality was significantly higher in PAD patients with COPD, compared with those without COPD (6.5% vs. 4.7%, respectively; P less than .001), and cardiovascular events comprising pulmonary embolism (PE), deep vein thrombosis (DVT), and myocardial infarction (MI) occurred more often in coprevalence with PAD and COPD than in PAD without COPD.
In PAD patients, COPD was an independent predictor of in-hospital death (odds ratio, 1.16; 95% confidence interval, 1.15-1.17; P less than .001) as well as an independent predictor for PE (OR, 1.44; 95% CI, 1.40-1.49; P less than .001).
Overall, PAD patients with COPD were of similar age as (73 years), but stayed slightly longer in the hospital than (9 vs. 8 days), those without COPD. PAD patients without COPD revealed more often cardiovascular risk factors like essential arterial hypertension and diabetes, but the prevalence of cardiovascular diseases such as coronary artery disease and heart failure were more often found in PAD patients with COPD. In addition, cancer and renal insufficiency also were more common in PAD patients with COPD, according to the authors.
“Remarkably, PAD patients with COPD showed more frequently lower PAD stages than those without COPD. Especially, PAD stage IV was more prevalent in PAD patients without COPD (19.6% vs. 13.8%; P less than 0.001),” the authors stated. In addition, amputations were more often performed in PAD patients without COPD.
Dr. Keller and his colleagues had the following conclusions regarding the clinical implications of their study: “I) PAD patients with long-standing tobacco use might benefit from COPD screening and treatment. II) PAD patients with additional COPD should be monitored more intensively, and the treatment for COPD should be optimized. III) COPD increases the risk for PE, and it is critical not to overlook this life-threatening disease. IV) MI and PE are important causes of in-hospital death in PAD patients with and without COPD.”
The German Federal Ministry of Education and Research funded the study, and the authors reported having no conflicts.
SOURCE: Keller K et al. Respir Med. 2019 Feb;147:1-6.
FROM RESPIRATORY MEDICINE
Key clinical point:
Major finding: All-cause, in-hospital mortality was significantly higher in PAD patients with COPD, compared with those without (6.5% vs. 4.7%; P less than 0.001).
Study details: Database analysis of 5.6 million German PAD inpatients stratified for COPD.
Disclosures: The German Federal Ministry of Education and Research funded the study, and the authors reported having no conflicts.
Source: Keller K et al. Respir Med. 2019 Feb;147:1-6.
CTPA may not rule out VTE in high-risk patients
Clinical question: Does a negative computed tomography pulmonary angiography rule out venous thromboembolism (VTE)?
Background: Computed tomography pulmonary angiography (CTPA) is the most common diagnostic modality used to diagnose pulmonary embolism (PE) and has a high negative predictive value in patients with a low 3-month risk of VTE. In patients with higher pretest probability of PE, it is unknown whether CTPA is sufficient to rule out VTE.
Study design: Meta-analysis.
Setting: Published prospective outcome studies of patients with suspected PE using CTPA as a diagnostic strategy.
Synopsis: The authors reviewed 3,143 publications from MEDLINE, EMBASE, and the Cochrane Library and identified 22 prospective outcome studies to include in their meta-analysis. A VTE was diagnosed in 3,923 out of 11,872 participants (33%) using CTPA. Of the 7,863 patients with a negative CTPA, 148 patients had an acute VTE confirmed by venous ultrasound, ventilation/perfusion scan, or angiography, and 74 patients experienced VTE during a 3-month follow-up period, yielding an overall proportion of 2.4% of patients (95% confidence interval, 1.3%-3.8%).
Subgroup analysis showed that cumulative occurrence of VTE was related to pretest prevalence. In the subgroup of patients with a VTE prevalence greater than 40%, VTE was observed in 8.1% of patients with a negative CTPA (95% CI, 3.4%-14.5%).
Bottom line: CTPA may be insufficient to rule out VTE in patients with a high pretest probability of PE.
Citation: Belzile D et al. Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a meta-analysisof the management outcome studies. J Thromb Haemost. 2018 Jun;16(6):1107-20.
Dr. Jenkins is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.
Clinical question: Does a negative computed tomography pulmonary angiography rule out venous thromboembolism (VTE)?
Background: Computed tomography pulmonary angiography (CTPA) is the most common diagnostic modality used to diagnose pulmonary embolism (PE) and has a high negative predictive value in patients with a low 3-month risk of VTE. In patients with higher pretest probability of PE, it is unknown whether CTPA is sufficient to rule out VTE.
Study design: Meta-analysis.
Setting: Published prospective outcome studies of patients with suspected PE using CTPA as a diagnostic strategy.
Synopsis: The authors reviewed 3,143 publications from MEDLINE, EMBASE, and the Cochrane Library and identified 22 prospective outcome studies to include in their meta-analysis. A VTE was diagnosed in 3,923 out of 11,872 participants (33%) using CTPA. Of the 7,863 patients with a negative CTPA, 148 patients had an acute VTE confirmed by venous ultrasound, ventilation/perfusion scan, or angiography, and 74 patients experienced VTE during a 3-month follow-up period, yielding an overall proportion of 2.4% of patients (95% confidence interval, 1.3%-3.8%).
Subgroup analysis showed that cumulative occurrence of VTE was related to pretest prevalence. In the subgroup of patients with a VTE prevalence greater than 40%, VTE was observed in 8.1% of patients with a negative CTPA (95% CI, 3.4%-14.5%).
Bottom line: CTPA may be insufficient to rule out VTE in patients with a high pretest probability of PE.
Citation: Belzile D et al. Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a meta-analysisof the management outcome studies. J Thromb Haemost. 2018 Jun;16(6):1107-20.
Dr. Jenkins is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.
Clinical question: Does a negative computed tomography pulmonary angiography rule out venous thromboembolism (VTE)?
Background: Computed tomography pulmonary angiography (CTPA) is the most common diagnostic modality used to diagnose pulmonary embolism (PE) and has a high negative predictive value in patients with a low 3-month risk of VTE. In patients with higher pretest probability of PE, it is unknown whether CTPA is sufficient to rule out VTE.
Study design: Meta-analysis.
Setting: Published prospective outcome studies of patients with suspected PE using CTPA as a diagnostic strategy.
Synopsis: The authors reviewed 3,143 publications from MEDLINE, EMBASE, and the Cochrane Library and identified 22 prospective outcome studies to include in their meta-analysis. A VTE was diagnosed in 3,923 out of 11,872 participants (33%) using CTPA. Of the 7,863 patients with a negative CTPA, 148 patients had an acute VTE confirmed by venous ultrasound, ventilation/perfusion scan, or angiography, and 74 patients experienced VTE during a 3-month follow-up period, yielding an overall proportion of 2.4% of patients (95% confidence interval, 1.3%-3.8%).
Subgroup analysis showed that cumulative occurrence of VTE was related to pretest prevalence. In the subgroup of patients with a VTE prevalence greater than 40%, VTE was observed in 8.1% of patients with a negative CTPA (95% CI, 3.4%-14.5%).
Bottom line: CTPA may be insufficient to rule out VTE in patients with a high pretest probability of PE.
Citation: Belzile D et al. Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a meta-analysisof the management outcome studies. J Thromb Haemost. 2018 Jun;16(6):1107-20.
Dr. Jenkins is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.
VTE prophylaxis often overused in low-risk patients
Background: Per Chest guidelines, VTE prophylaxis is recommended for hospitalized patients at increased risk for VTE but is not recommended for low-risk patients. Risk stratification can be guided by the Padua Prediction Score to categorize patients.
Study design: Multicenter observational study.
Setting: A total of 52 U.S. hospitals (Michigan Hospital Medicine Safety Consortium database).
Synopsis: Patients admitted during Jan. 1, 2015–Dec. 21, 2016, to 52 non–intensive care medical units for 2 or more days were analyzed and stratified as high or low risk for VTE using the Padua Prediction Score. Excessive VTE prophylaxis was defined as low-risk patients prescribed pharmacologic or mechanical prophylaxis, high-risk patients receiving therapy despite a contraindication to prophylaxis, or any patient who received both mechanical and pharmacologic therapy. Underuse of VTE prophylaxis included high-risk patients who did not receive pharmacologic or mechanical prophylaxis. Of the 44,775 patients included in the study, 32,549 were low risk, and 77.9% (25,369 patients) received excessive VTE prophylaxis. Overtreatment also was present in high-risk patients with and without a contraindication to VTE prophylaxis (26.9% and 32.3%, respectively). Underuse of VTE prophylaxis occurred in 2,693 high-risk patients (22%).
Bottom line: Patients who are at low risk for VTE by Padua Prediction Score often are prescribed pharmacologic or mechanical prophylaxis that may be unnecessary. Overuse of VTE prophylaxis was more common than is underuse.
Citation: Grant PJ et al. Use of venous thromboembolism prophylaxis in hospitalized patients. JAMA Intern Med. 2018 Aug 1;178(8):1122-4. Published online May 21, 2018.
Dr. Marr is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.
Background: Per Chest guidelines, VTE prophylaxis is recommended for hospitalized patients at increased risk for VTE but is not recommended for low-risk patients. Risk stratification can be guided by the Padua Prediction Score to categorize patients.
Study design: Multicenter observational study.
Setting: A total of 52 U.S. hospitals (Michigan Hospital Medicine Safety Consortium database).
Synopsis: Patients admitted during Jan. 1, 2015–Dec. 21, 2016, to 52 non–intensive care medical units for 2 or more days were analyzed and stratified as high or low risk for VTE using the Padua Prediction Score. Excessive VTE prophylaxis was defined as low-risk patients prescribed pharmacologic or mechanical prophylaxis, high-risk patients receiving therapy despite a contraindication to prophylaxis, or any patient who received both mechanical and pharmacologic therapy. Underuse of VTE prophylaxis included high-risk patients who did not receive pharmacologic or mechanical prophylaxis. Of the 44,775 patients included in the study, 32,549 were low risk, and 77.9% (25,369 patients) received excessive VTE prophylaxis. Overtreatment also was present in high-risk patients with and without a contraindication to VTE prophylaxis (26.9% and 32.3%, respectively). Underuse of VTE prophylaxis occurred in 2,693 high-risk patients (22%).
Bottom line: Patients who are at low risk for VTE by Padua Prediction Score often are prescribed pharmacologic or mechanical prophylaxis that may be unnecessary. Overuse of VTE prophylaxis was more common than is underuse.
Citation: Grant PJ et al. Use of venous thromboembolism prophylaxis in hospitalized patients. JAMA Intern Med. 2018 Aug 1;178(8):1122-4. Published online May 21, 2018.
Dr. Marr is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.
Background: Per Chest guidelines, VTE prophylaxis is recommended for hospitalized patients at increased risk for VTE but is not recommended for low-risk patients. Risk stratification can be guided by the Padua Prediction Score to categorize patients.
Study design: Multicenter observational study.
Setting: A total of 52 U.S. hospitals (Michigan Hospital Medicine Safety Consortium database).
Synopsis: Patients admitted during Jan. 1, 2015–Dec. 21, 2016, to 52 non–intensive care medical units for 2 or more days were analyzed and stratified as high or low risk for VTE using the Padua Prediction Score. Excessive VTE prophylaxis was defined as low-risk patients prescribed pharmacologic or mechanical prophylaxis, high-risk patients receiving therapy despite a contraindication to prophylaxis, or any patient who received both mechanical and pharmacologic therapy. Underuse of VTE prophylaxis included high-risk patients who did not receive pharmacologic or mechanical prophylaxis. Of the 44,775 patients included in the study, 32,549 were low risk, and 77.9% (25,369 patients) received excessive VTE prophylaxis. Overtreatment also was present in high-risk patients with and without a contraindication to VTE prophylaxis (26.9% and 32.3%, respectively). Underuse of VTE prophylaxis occurred in 2,693 high-risk patients (22%).
Bottom line: Patients who are at low risk for VTE by Padua Prediction Score often are prescribed pharmacologic or mechanical prophylaxis that may be unnecessary. Overuse of VTE prophylaxis was more common than is underuse.
Citation: Grant PJ et al. Use of venous thromboembolism prophylaxis in hospitalized patients. JAMA Intern Med. 2018 Aug 1;178(8):1122-4. Published online May 21, 2018.
Dr. Marr is assistant professor of medicine and an academic hospitalist, University of Utah, Salt Lake City.
Ticagrelor holds no edge over aspirin in CABG patients
CHICAGO – Ticagrelor performed about as well as aspirin did as monotherapy for preventing coronary bypass graft failure during the year following surgery in a randomized, multicenter trial with almost 1,900 patients.
Ticagrelor monotherapy also produced about the same number of major bleeding events as did aspirin monotherapy, Heribert Schunkert, MD, said at the American Heart Association scientific sessions. There were two limitations of the trial: The incidence of cardiovascular disease events that served as the efficacy endpoint for the study was less than what Dr. Schunkert and his associates expected, and they enrolled about half the projected number of patients because the study lost industry support and then, a couple of years later, showed a relentlessly neutral result leading to early termination of recruitment, said Dr. Schunkert, professor of cardiology and medical director of the German Heart Center in Munich.
The TiCAB (Study Comparing Ticagrelor With Aspirin for Prevention of Vascular Events in Patients Undergoing CABG) trial randomized 1,893 patients during 2013-2017 who underwent CABG at any of 26 centers in Austria, Germany, or Switzerland. Eligible patients underwent surgery for three-vessel disease, left main disease, or had two-vessel disease plus a left ventricular ejection fraction of less than 50%. About 31% of patients had unstable angina or non-ST elevation MI, with the remaining 69% having stable angina. The study included 931 patients who received 90 mg oral ticagrelor (Brilinta) b.i.d. plus aspirin placebo, and 928 who received 100 mg aspirin once daily plus ticagrelor placebo. The study medications began prior to surgery.
The study’s primary efficacy endpoint was the combined rate of cardiovascular death, MI, stroke, or need for revascularization by 1 year after surgery. This occurred in 9.7% of the ticagrelor patients and in 8.2% of those who received aspirin, a difference that was not statistically significant. Several secondary efficacy endpoints examined also showed a neutral result. The primary safety measure was the incidence of major bleeds by the Bleeding Academic Research Consortium criteria, which occurred in 3.7% of the ticagrelor patients and 3.2% of those on aspirin, not a statistically significant difference. After the year of follow-up about 85% of patients in both treatment arms remained on their assigned regimen, Dr. Schunkert said.
TiCAB received funding from AstraZeneca, which markets ticagrelor (Brilinta). Dr. Schunkert has received honoraria and research support from, and has been a speaker on behalf of, AstraZeneca. He has also received honoraria from Amgen, Bayer Vital, Boehringer Ingelheim, Daiichi Sankyo, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, and Servier.
SOURCE: Schunkert H et al. AHA 2018, Abstract 19561.
Because the TiCAB study was about half the size of the planned study, its power was low and yielded a result with wide confidence intervals. Despite that, I do not believe that a further, larger study is warranted. The TiCAB results are sufficient to show that monotherapy with ticagrelor is not superior to monotherapy with aspirin in patients undergoing coronary artery bypass grafting and during the year following surgery. The TiCAB results add to a larger body of evidence indicating ticagrelor’s noninferiority to and lack of superiority to aspirin as monotherapy for patients with coronary artery disease or a history of ischemic stroke or transient ischemic attack.
How can these two drugs produce similar efficacy outcomes? Aspirin is an effective antiplatelet drug, and evidence also suggests that treatment with opiates such as morphine (Circ Cardiovasc Interv. 2016 Sept;9[9]:e004229) and fentanyl (Circulation. 2018 Jan 16;137[3]:307-9) during and after surgery can interfere with the intestinal absorption of ticagrelor and other oral P2Y12 receptor antagonists, such as clopidogrel and prasugrel.
Another interesting finding in TiCAB was that aspirin and ticagrelor monotherapy produced similar rates of major bleeds. Results from prior studies had raised concerns about ticagrelor’s safety in patients undergoing coronary artery bypass surgery, but the new results show that this may be a problem when patients receive dual antiplatelet therapy but not when they receive ticagrelor monotherapy. Current evidence favors dual antiplatelet therapy to achieve a greater decrease in cardiovascular disease events, but this occurs at the expense of increased bleeding. Larger trials of dual therapy after coronary artery bypass grafting are warranted; further study of monotherapy is not.
Robert F. Storey, MD , is a professor of cardiology at the University of Sheffield (England). He has been a consultant to, and received honoraria and research support from, AstraZeneca, and he has been a consultant to Actelion, Avacta, Bayer, Bristol-Myers Squibb/Pfizer, Haemonetics, Novartis, PlaqueTec, and Thromboserin. He made these comments as designated discussant for the TiCAB report.
Because the TiCAB study was about half the size of the planned study, its power was low and yielded a result with wide confidence intervals. Despite that, I do not believe that a further, larger study is warranted. The TiCAB results are sufficient to show that monotherapy with ticagrelor is not superior to monotherapy with aspirin in patients undergoing coronary artery bypass grafting and during the year following surgery. The TiCAB results add to a larger body of evidence indicating ticagrelor’s noninferiority to and lack of superiority to aspirin as monotherapy for patients with coronary artery disease or a history of ischemic stroke or transient ischemic attack.
How can these two drugs produce similar efficacy outcomes? Aspirin is an effective antiplatelet drug, and evidence also suggests that treatment with opiates such as morphine (Circ Cardiovasc Interv. 2016 Sept;9[9]:e004229) and fentanyl (Circulation. 2018 Jan 16;137[3]:307-9) during and after surgery can interfere with the intestinal absorption of ticagrelor and other oral P2Y12 receptor antagonists, such as clopidogrel and prasugrel.
Another interesting finding in TiCAB was that aspirin and ticagrelor monotherapy produced similar rates of major bleeds. Results from prior studies had raised concerns about ticagrelor’s safety in patients undergoing coronary artery bypass surgery, but the new results show that this may be a problem when patients receive dual antiplatelet therapy but not when they receive ticagrelor monotherapy. Current evidence favors dual antiplatelet therapy to achieve a greater decrease in cardiovascular disease events, but this occurs at the expense of increased bleeding. Larger trials of dual therapy after coronary artery bypass grafting are warranted; further study of monotherapy is not.
Robert F. Storey, MD , is a professor of cardiology at the University of Sheffield (England). He has been a consultant to, and received honoraria and research support from, AstraZeneca, and he has been a consultant to Actelion, Avacta, Bayer, Bristol-Myers Squibb/Pfizer, Haemonetics, Novartis, PlaqueTec, and Thromboserin. He made these comments as designated discussant for the TiCAB report.
Because the TiCAB study was about half the size of the planned study, its power was low and yielded a result with wide confidence intervals. Despite that, I do not believe that a further, larger study is warranted. The TiCAB results are sufficient to show that monotherapy with ticagrelor is not superior to monotherapy with aspirin in patients undergoing coronary artery bypass grafting and during the year following surgery. The TiCAB results add to a larger body of evidence indicating ticagrelor’s noninferiority to and lack of superiority to aspirin as monotherapy for patients with coronary artery disease or a history of ischemic stroke or transient ischemic attack.
How can these two drugs produce similar efficacy outcomes? Aspirin is an effective antiplatelet drug, and evidence also suggests that treatment with opiates such as morphine (Circ Cardiovasc Interv. 2016 Sept;9[9]:e004229) and fentanyl (Circulation. 2018 Jan 16;137[3]:307-9) during and after surgery can interfere with the intestinal absorption of ticagrelor and other oral P2Y12 receptor antagonists, such as clopidogrel and prasugrel.
Another interesting finding in TiCAB was that aspirin and ticagrelor monotherapy produced similar rates of major bleeds. Results from prior studies had raised concerns about ticagrelor’s safety in patients undergoing coronary artery bypass surgery, but the new results show that this may be a problem when patients receive dual antiplatelet therapy but not when they receive ticagrelor monotherapy. Current evidence favors dual antiplatelet therapy to achieve a greater decrease in cardiovascular disease events, but this occurs at the expense of increased bleeding. Larger trials of dual therapy after coronary artery bypass grafting are warranted; further study of monotherapy is not.
Robert F. Storey, MD , is a professor of cardiology at the University of Sheffield (England). He has been a consultant to, and received honoraria and research support from, AstraZeneca, and he has been a consultant to Actelion, Avacta, Bayer, Bristol-Myers Squibb/Pfizer, Haemonetics, Novartis, PlaqueTec, and Thromboserin. He made these comments as designated discussant for the TiCAB report.
CHICAGO – Ticagrelor performed about as well as aspirin did as monotherapy for preventing coronary bypass graft failure during the year following surgery in a randomized, multicenter trial with almost 1,900 patients.
Ticagrelor monotherapy also produced about the same number of major bleeding events as did aspirin monotherapy, Heribert Schunkert, MD, said at the American Heart Association scientific sessions. There were two limitations of the trial: The incidence of cardiovascular disease events that served as the efficacy endpoint for the study was less than what Dr. Schunkert and his associates expected, and they enrolled about half the projected number of patients because the study lost industry support and then, a couple of years later, showed a relentlessly neutral result leading to early termination of recruitment, said Dr. Schunkert, professor of cardiology and medical director of the German Heart Center in Munich.
The TiCAB (Study Comparing Ticagrelor With Aspirin for Prevention of Vascular Events in Patients Undergoing CABG) trial randomized 1,893 patients during 2013-2017 who underwent CABG at any of 26 centers in Austria, Germany, or Switzerland. Eligible patients underwent surgery for three-vessel disease, left main disease, or had two-vessel disease plus a left ventricular ejection fraction of less than 50%. About 31% of patients had unstable angina or non-ST elevation MI, with the remaining 69% having stable angina. The study included 931 patients who received 90 mg oral ticagrelor (Brilinta) b.i.d. plus aspirin placebo, and 928 who received 100 mg aspirin once daily plus ticagrelor placebo. The study medications began prior to surgery.
The study’s primary efficacy endpoint was the combined rate of cardiovascular death, MI, stroke, or need for revascularization by 1 year after surgery. This occurred in 9.7% of the ticagrelor patients and in 8.2% of those who received aspirin, a difference that was not statistically significant. Several secondary efficacy endpoints examined also showed a neutral result. The primary safety measure was the incidence of major bleeds by the Bleeding Academic Research Consortium criteria, which occurred in 3.7% of the ticagrelor patients and 3.2% of those on aspirin, not a statistically significant difference. After the year of follow-up about 85% of patients in both treatment arms remained on their assigned regimen, Dr. Schunkert said.
TiCAB received funding from AstraZeneca, which markets ticagrelor (Brilinta). Dr. Schunkert has received honoraria and research support from, and has been a speaker on behalf of, AstraZeneca. He has also received honoraria from Amgen, Bayer Vital, Boehringer Ingelheim, Daiichi Sankyo, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, and Servier.
SOURCE: Schunkert H et al. AHA 2018, Abstract 19561.
CHICAGO – Ticagrelor performed about as well as aspirin did as monotherapy for preventing coronary bypass graft failure during the year following surgery in a randomized, multicenter trial with almost 1,900 patients.
Ticagrelor monotherapy also produced about the same number of major bleeding events as did aspirin monotherapy, Heribert Schunkert, MD, said at the American Heart Association scientific sessions. There were two limitations of the trial: The incidence of cardiovascular disease events that served as the efficacy endpoint for the study was less than what Dr. Schunkert and his associates expected, and they enrolled about half the projected number of patients because the study lost industry support and then, a couple of years later, showed a relentlessly neutral result leading to early termination of recruitment, said Dr. Schunkert, professor of cardiology and medical director of the German Heart Center in Munich.
The TiCAB (Study Comparing Ticagrelor With Aspirin for Prevention of Vascular Events in Patients Undergoing CABG) trial randomized 1,893 patients during 2013-2017 who underwent CABG at any of 26 centers in Austria, Germany, or Switzerland. Eligible patients underwent surgery for three-vessel disease, left main disease, or had two-vessel disease plus a left ventricular ejection fraction of less than 50%. About 31% of patients had unstable angina or non-ST elevation MI, with the remaining 69% having stable angina. The study included 931 patients who received 90 mg oral ticagrelor (Brilinta) b.i.d. plus aspirin placebo, and 928 who received 100 mg aspirin once daily plus ticagrelor placebo. The study medications began prior to surgery.
The study’s primary efficacy endpoint was the combined rate of cardiovascular death, MI, stroke, or need for revascularization by 1 year after surgery. This occurred in 9.7% of the ticagrelor patients and in 8.2% of those who received aspirin, a difference that was not statistically significant. Several secondary efficacy endpoints examined also showed a neutral result. The primary safety measure was the incidence of major bleeds by the Bleeding Academic Research Consortium criteria, which occurred in 3.7% of the ticagrelor patients and 3.2% of those on aspirin, not a statistically significant difference. After the year of follow-up about 85% of patients in both treatment arms remained on their assigned regimen, Dr. Schunkert said.
TiCAB received funding from AstraZeneca, which markets ticagrelor (Brilinta). Dr. Schunkert has received honoraria and research support from, and has been a speaker on behalf of, AstraZeneca. He has also received honoraria from Amgen, Bayer Vital, Boehringer Ingelheim, Daiichi Sankyo, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, and Servier.
SOURCE: Schunkert H et al. AHA 2018, Abstract 19561.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point: Ticagrelor was similar to aspirin for preventing graft failure in CABG patients.
Major finding: After 1 year, the combined cardiovascular disease endpoint occurred in 9.7% of ticagrelor patients and in 8.2% on aspirin.
Study details: TiCAB, a multicenter, randomized trial with 1,893 patients.
Disclosures: TiCAB received funding from AstraZeneca, which markets ticagrelor (Brilinta). Dr. Schunkert has received honoraria and research support from, and has been a speaker on behalf of, AstraZeneca. He has received honoraria from Amgen, Bayer Vital, Boehringer Ingelheim, Daiichi Sankyo, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, and Servier.
Source: Schunkert H et al. AHA 2018, Abstract 19561.
Reducing heart failure readmissions raises mortality
This week from MDedge Cardiology, the Hospital Readmissions Reduction Program may be doing more harm than good, ticagrelor holds no edge over aspirin in CABG patients, weight-loss apps lack evidence, and the Surgeon General sends out an alarm.
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This week from MDedge Cardiology, the Hospital Readmissions Reduction Program may be doing more harm than good, ticagrelor holds no edge over aspirin in CABG patients, weight-loss apps lack evidence, and the Surgeon General sends out an alarm.
Subscribe to Cardiocast wherever you get your podcasts.
Amazon Alexa
Apple Podcasts
This week from MDedge Cardiology, the Hospital Readmissions Reduction Program may be doing more harm than good, ticagrelor holds no edge over aspirin in CABG patients, weight-loss apps lack evidence, and the Surgeon General sends out an alarm.
Subscribe to Cardiocast wherever you get your podcasts.
Amazon Alexa
Apple Podcasts
Anticoagulation shows promise in concurrent lupus nephritis, thrombotic microangiopathy
The use of anticoagulation in patients with comorbid lupus nephritis and thrombotic microangiopathy was linked with a greater rate of clinical response after 12 months of therapy, according to results from a study published in Annals of the Rheumatic Diseases.
“The purpose of this multicenter retrospective study was to analyze the impact of anticoagulation (vitamin K antagonists and/or heparins), in addition to conventional immunosuppression on kidney outcomes, according to the Kidney Disease: Improving Global Outcomes guidelines,” wrote first author Savino Sciascia, MD, PhD, of the University of Turin (Italy), along with his colleagues.
The researchers analyzed data from 97 patients with biopsy-confirmed lupus nephritis (LN) and thrombotic microangiopathy (TMA) who were diagnosed during 2007-2017. The entire cohort was administered standard immunosuppressive agents, including corticosteroids, cyclophosphamide, and mycophenolate, among others. After 12 months of therapy, the patients were assessed for degree of clinical response, measured using complete, partial, or no response to therapy.
“Sixty-one patients (62.9%) were [antiphospholipid antibody] positive and 37 (38.1%) of these patients received anticoagulation with a vitamin K antagonist and/or heparins,” the investigators wrote. “Mean duration of anticoagulation therapy after TMA and LN diagnosis was 7.7 months,” they added.
After statistical analysis, the researchers found that patients treated with anticoagulation therapy experienced a greater rate of clinical response, compared with those not treated. The investigators saw a complete response to therapy in 22 (59.5%) patients given anticoagulation, compared with 15 (25.0%) patients without anticoagulation. Partial treatment responses were comparable, occurring in 7 (18.9%) with anticoagulation and 15 (25.0%) without. Without anticoagulation, 30 (50%) had no response to therapy, compared with 8 (21.6%) patients given anticoagulation.
“When limiting the analysis to patients with antiphospholipid antibodies, we observed a rate of any response (either complete response [or] partial response) as high as 66% in patients receiving anticoagulant treatment compared with those receiving immunosuppression alone (34%),” they added.
The authors acknowledged a major limitation of the study was the short duration of follow-up, which limited the ability to evaluate relapse rate.
“Despite its limitations, this study represents the largest available multicenter cohort of real-life systemic lupus erythematosus patients,” said Dr. Sciascia and his colleagues. “The use of anticoagulation appeared protective and warrants further investigation as a therapeutic tool,” they concluded.
The authors reported no conflicts of interest, and no specific study funding was declared.
SOURCE: Sciascia S et al. Ann Rheum Dis. 2018 Dec 14. doi: 10.1136/annrheumdis-2018-214559.
The use of anticoagulation in patients with comorbid lupus nephritis and thrombotic microangiopathy was linked with a greater rate of clinical response after 12 months of therapy, according to results from a study published in Annals of the Rheumatic Diseases.
“The purpose of this multicenter retrospective study was to analyze the impact of anticoagulation (vitamin K antagonists and/or heparins), in addition to conventional immunosuppression on kidney outcomes, according to the Kidney Disease: Improving Global Outcomes guidelines,” wrote first author Savino Sciascia, MD, PhD, of the University of Turin (Italy), along with his colleagues.
The researchers analyzed data from 97 patients with biopsy-confirmed lupus nephritis (LN) and thrombotic microangiopathy (TMA) who were diagnosed during 2007-2017. The entire cohort was administered standard immunosuppressive agents, including corticosteroids, cyclophosphamide, and mycophenolate, among others. After 12 months of therapy, the patients were assessed for degree of clinical response, measured using complete, partial, or no response to therapy.
“Sixty-one patients (62.9%) were [antiphospholipid antibody] positive and 37 (38.1%) of these patients received anticoagulation with a vitamin K antagonist and/or heparins,” the investigators wrote. “Mean duration of anticoagulation therapy after TMA and LN diagnosis was 7.7 months,” they added.
After statistical analysis, the researchers found that patients treated with anticoagulation therapy experienced a greater rate of clinical response, compared with those not treated. The investigators saw a complete response to therapy in 22 (59.5%) patients given anticoagulation, compared with 15 (25.0%) patients without anticoagulation. Partial treatment responses were comparable, occurring in 7 (18.9%) with anticoagulation and 15 (25.0%) without. Without anticoagulation, 30 (50%) had no response to therapy, compared with 8 (21.6%) patients given anticoagulation.
“When limiting the analysis to patients with antiphospholipid antibodies, we observed a rate of any response (either complete response [or] partial response) as high as 66% in patients receiving anticoagulant treatment compared with those receiving immunosuppression alone (34%),” they added.
The authors acknowledged a major limitation of the study was the short duration of follow-up, which limited the ability to evaluate relapse rate.
“Despite its limitations, this study represents the largest available multicenter cohort of real-life systemic lupus erythematosus patients,” said Dr. Sciascia and his colleagues. “The use of anticoagulation appeared protective and warrants further investigation as a therapeutic tool,” they concluded.
The authors reported no conflicts of interest, and no specific study funding was declared.
SOURCE: Sciascia S et al. Ann Rheum Dis. 2018 Dec 14. doi: 10.1136/annrheumdis-2018-214559.
The use of anticoagulation in patients with comorbid lupus nephritis and thrombotic microangiopathy was linked with a greater rate of clinical response after 12 months of therapy, according to results from a study published in Annals of the Rheumatic Diseases.
“The purpose of this multicenter retrospective study was to analyze the impact of anticoagulation (vitamin K antagonists and/or heparins), in addition to conventional immunosuppression on kidney outcomes, according to the Kidney Disease: Improving Global Outcomes guidelines,” wrote first author Savino Sciascia, MD, PhD, of the University of Turin (Italy), along with his colleagues.
The researchers analyzed data from 97 patients with biopsy-confirmed lupus nephritis (LN) and thrombotic microangiopathy (TMA) who were diagnosed during 2007-2017. The entire cohort was administered standard immunosuppressive agents, including corticosteroids, cyclophosphamide, and mycophenolate, among others. After 12 months of therapy, the patients were assessed for degree of clinical response, measured using complete, partial, or no response to therapy.
“Sixty-one patients (62.9%) were [antiphospholipid antibody] positive and 37 (38.1%) of these patients received anticoagulation with a vitamin K antagonist and/or heparins,” the investigators wrote. “Mean duration of anticoagulation therapy after TMA and LN diagnosis was 7.7 months,” they added.
After statistical analysis, the researchers found that patients treated with anticoagulation therapy experienced a greater rate of clinical response, compared with those not treated. The investigators saw a complete response to therapy in 22 (59.5%) patients given anticoagulation, compared with 15 (25.0%) patients without anticoagulation. Partial treatment responses were comparable, occurring in 7 (18.9%) with anticoagulation and 15 (25.0%) without. Without anticoagulation, 30 (50%) had no response to therapy, compared with 8 (21.6%) patients given anticoagulation.
“When limiting the analysis to patients with antiphospholipid antibodies, we observed a rate of any response (either complete response [or] partial response) as high as 66% in patients receiving anticoagulant treatment compared with those receiving immunosuppression alone (34%),” they added.
The authors acknowledged a major limitation of the study was the short duration of follow-up, which limited the ability to evaluate relapse rate.
“Despite its limitations, this study represents the largest available multicenter cohort of real-life systemic lupus erythematosus patients,” said Dr. Sciascia and his colleagues. “The use of anticoagulation appeared protective and warrants further investigation as a therapeutic tool,” they concluded.
The authors reported no conflicts of interest, and no specific study funding was declared.
SOURCE: Sciascia S et al. Ann Rheum Dis. 2018 Dec 14. doi: 10.1136/annrheumdis-2018-214559.
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point:
Major finding: A greater proportion of patients given anticoagulation achieved partial or complete response (78.4%) versus those not given anticoagulation (50.0%).
Study details: A retrospective analysis of 97 patients with biopsy-confirmed lupus nephritis and thrombotic microangiopathy.
Disclosures: The authors reported no conflicts of interest, and no specific study funding was declared.
Source: Sciascia S et al. Ann Rheum Dis. 2018 Dec 14. doi: 10.1136/annrheumdis-2018-214559.
FDA approves ravulizumab for PNH
The U.S. Food and Drug Administration (FDA) has approved ravulizumab-cwvz (Ultomiris) to treat adults with paroxysmal nocturnal hemoglobinuria (PNH).
Ravulizumab is a long-acting C5 complement inhibitor, administered every 8 weeks, that has been shown to prevent hemolysis.
The prescribing information for ravulizumab includes a boxed warning stating that meningococcal infections/sepsis have occurred in patients treated with the drug, and these adverse effects can become life-threatening or fatal if not recognized and treated early.
Ravulizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy.
The FDA previously granted the application for ravulizumab priority review, and the product received orphan drug designation from the FDA.
The FDA granted the approval of ravulizumab to Alexion Pharmaceuticals.
The FDA’s approval of ravulizumab is based on results from two phase 3 studies, one in patients who had previously received treatment with a complement inhibitor and one in patients who were complement-inhibitor-naïve. Both studies were recently published in Blood.
Efficacy in inhibitor-experienced patients
In one study (NCT03056040), researchers compared ravulizumab administered every 8 weeks to eculizumab administered every 2 weeks in complement-inhibitor-experienced patients.
The trial included 195 PNH patients who were taking eculizumab for more than 6 months. They were randomized to switch to ravulizumab (n=97) or continue on eculizumab (n=98).
Ravulizumab proved noninferior to eculizumab for all endpoints studied (P<0.0006), including:
- Percentage change in lactate dehydrogenase (LDH): difference, 9.21% (95% CI: -0.42 to 18.84; P=0.058 for superiority)
- Breakthrough hemolysis: difference, 5.1 (95% CI: -8.89 to 18.99)
- Change in FACIT-Fatigue score: difference, 1.47 (95% CI: -0.21 to 3.15)
- Transfusion avoidance: difference, 5.5 (95% CI: -4.27 to 15.68)
- Stabilized hemoglobin: difference, 1.4 (95% CI: -10.41 to 13.31).
Efficacy in inhibitor-naïve patients
In another study (NCT02946463), researchers compared ravulizumab and eculizumab in 246 PNH patients who had not previously received a complement inhibitor.
Ravulizumab was noninferior to eculizumab for all endpoints (P<0.0001), including:
- Transfusion avoidance: 73.6% vs 66.1%; difference of 6.8% (95% CI: -4.66 to 18.14)
- LDH normalization: 53.6% vs 49.4%; odds ratio=1.19 (95% CI: 0.80 to 1.77)
- Percent reduction in LDH: -76.8% vs -76.0%; difference of -0.83% (95% CI: -5.21 to 3.56)
- Change in FACIT-Fatigue score: 7.07 vs 6.40; difference of 0.67 (95% CI: -1.21 to 2.55)
- Breakthrough hemolysis: 4.0% vs 10.7%; difference of -6.7% (95% CI: -14.21 to 0.18)
- Stabilized hemoglobin: 68.0% vs 64.5%; difference of 2.9 (95% CI: -8.80 to 14.64).
Safety in both trials
The safety data from both trials included 441 adults who received ravulizumab (n=222) or eculizumab (n=219) for a median of 6 months.
The most frequent adverse events in both arms (ravulizumab and eculizumab, respectively) were upper respiratory tract infection (39% and 39%) and headache (32% and 26%).
Serious adverse events occurred in 15 (6.8%) patients treated with ravulizumab. These events included hyperthermia and pyrexia.
There was one fatal case of sepsis in a patient treated with ravulizumab.
The U.S. Food and Drug Administration (FDA) has approved ravulizumab-cwvz (Ultomiris) to treat adults with paroxysmal nocturnal hemoglobinuria (PNH).
Ravulizumab is a long-acting C5 complement inhibitor, administered every 8 weeks, that has been shown to prevent hemolysis.
The prescribing information for ravulizumab includes a boxed warning stating that meningococcal infections/sepsis have occurred in patients treated with the drug, and these adverse effects can become life-threatening or fatal if not recognized and treated early.
Ravulizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy.
The FDA previously granted the application for ravulizumab priority review, and the product received orphan drug designation from the FDA.
The FDA granted the approval of ravulizumab to Alexion Pharmaceuticals.
The FDA’s approval of ravulizumab is based on results from two phase 3 studies, one in patients who had previously received treatment with a complement inhibitor and one in patients who were complement-inhibitor-naïve. Both studies were recently published in Blood.
Efficacy in inhibitor-experienced patients
In one study (NCT03056040), researchers compared ravulizumab administered every 8 weeks to eculizumab administered every 2 weeks in complement-inhibitor-experienced patients.
The trial included 195 PNH patients who were taking eculizumab for more than 6 months. They were randomized to switch to ravulizumab (n=97) or continue on eculizumab (n=98).
Ravulizumab proved noninferior to eculizumab for all endpoints studied (P<0.0006), including:
- Percentage change in lactate dehydrogenase (LDH): difference, 9.21% (95% CI: -0.42 to 18.84; P=0.058 for superiority)
- Breakthrough hemolysis: difference, 5.1 (95% CI: -8.89 to 18.99)
- Change in FACIT-Fatigue score: difference, 1.47 (95% CI: -0.21 to 3.15)
- Transfusion avoidance: difference, 5.5 (95% CI: -4.27 to 15.68)
- Stabilized hemoglobin: difference, 1.4 (95% CI: -10.41 to 13.31).
Efficacy in inhibitor-naïve patients
In another study (NCT02946463), researchers compared ravulizumab and eculizumab in 246 PNH patients who had not previously received a complement inhibitor.
Ravulizumab was noninferior to eculizumab for all endpoints (P<0.0001), including:
- Transfusion avoidance: 73.6% vs 66.1%; difference of 6.8% (95% CI: -4.66 to 18.14)
- LDH normalization: 53.6% vs 49.4%; odds ratio=1.19 (95% CI: 0.80 to 1.77)
- Percent reduction in LDH: -76.8% vs -76.0%; difference of -0.83% (95% CI: -5.21 to 3.56)
- Change in FACIT-Fatigue score: 7.07 vs 6.40; difference of 0.67 (95% CI: -1.21 to 2.55)
- Breakthrough hemolysis: 4.0% vs 10.7%; difference of -6.7% (95% CI: -14.21 to 0.18)
- Stabilized hemoglobin: 68.0% vs 64.5%; difference of 2.9 (95% CI: -8.80 to 14.64).
Safety in both trials
The safety data from both trials included 441 adults who received ravulizumab (n=222) or eculizumab (n=219) for a median of 6 months.
The most frequent adverse events in both arms (ravulizumab and eculizumab, respectively) were upper respiratory tract infection (39% and 39%) and headache (32% and 26%).
Serious adverse events occurred in 15 (6.8%) patients treated with ravulizumab. These events included hyperthermia and pyrexia.
There was one fatal case of sepsis in a patient treated with ravulizumab.
The U.S. Food and Drug Administration (FDA) has approved ravulizumab-cwvz (Ultomiris) to treat adults with paroxysmal nocturnal hemoglobinuria (PNH).
Ravulizumab is a long-acting C5 complement inhibitor, administered every 8 weeks, that has been shown to prevent hemolysis.
The prescribing information for ravulizumab includes a boxed warning stating that meningococcal infections/sepsis have occurred in patients treated with the drug, and these adverse effects can become life-threatening or fatal if not recognized and treated early.
Ravulizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy.
The FDA previously granted the application for ravulizumab priority review, and the product received orphan drug designation from the FDA.
The FDA granted the approval of ravulizumab to Alexion Pharmaceuticals.
The FDA’s approval of ravulizumab is based on results from two phase 3 studies, one in patients who had previously received treatment with a complement inhibitor and one in patients who were complement-inhibitor-naïve. Both studies were recently published in Blood.
Efficacy in inhibitor-experienced patients
In one study (NCT03056040), researchers compared ravulizumab administered every 8 weeks to eculizumab administered every 2 weeks in complement-inhibitor-experienced patients.
The trial included 195 PNH patients who were taking eculizumab for more than 6 months. They were randomized to switch to ravulizumab (n=97) or continue on eculizumab (n=98).
Ravulizumab proved noninferior to eculizumab for all endpoints studied (P<0.0006), including:
- Percentage change in lactate dehydrogenase (LDH): difference, 9.21% (95% CI: -0.42 to 18.84; P=0.058 for superiority)
- Breakthrough hemolysis: difference, 5.1 (95% CI: -8.89 to 18.99)
- Change in FACIT-Fatigue score: difference, 1.47 (95% CI: -0.21 to 3.15)
- Transfusion avoidance: difference, 5.5 (95% CI: -4.27 to 15.68)
- Stabilized hemoglobin: difference, 1.4 (95% CI: -10.41 to 13.31).
Efficacy in inhibitor-naïve patients
In another study (NCT02946463), researchers compared ravulizumab and eculizumab in 246 PNH patients who had not previously received a complement inhibitor.
Ravulizumab was noninferior to eculizumab for all endpoints (P<0.0001), including:
- Transfusion avoidance: 73.6% vs 66.1%; difference of 6.8% (95% CI: -4.66 to 18.14)
- LDH normalization: 53.6% vs 49.4%; odds ratio=1.19 (95% CI: 0.80 to 1.77)
- Percent reduction in LDH: -76.8% vs -76.0%; difference of -0.83% (95% CI: -5.21 to 3.56)
- Change in FACIT-Fatigue score: 7.07 vs 6.40; difference of 0.67 (95% CI: -1.21 to 2.55)
- Breakthrough hemolysis: 4.0% vs 10.7%; difference of -6.7% (95% CI: -14.21 to 0.18)
- Stabilized hemoglobin: 68.0% vs 64.5%; difference of 2.9 (95% CI: -8.80 to 14.64).
Safety in both trials
The safety data from both trials included 441 adults who received ravulizumab (n=222) or eculizumab (n=219) for a median of 6 months.
The most frequent adverse events in both arms (ravulizumab and eculizumab, respectively) were upper respiratory tract infection (39% and 39%) and headache (32% and 26%).
Serious adverse events occurred in 15 (6.8%) patients treated with ravulizumab. These events included hyperthermia and pyrexia.
There was one fatal case of sepsis in a patient treated with ravulizumab.