Opinion
EDITORIAL
Direct-Acting Oral Anticoagulants The Brain Gets a Break Robert G. Hart, MD; Janice Pogue, PhD; John W. Eikelboom, MD
About 25% of major hemorrhages occurring in elderly patients during warfarin anticoagulation are intracranial, and most of these bleeds (about 75%) either are fatal or result in severe residual disability.1,2 In contrast, major extracranial Related article page 1486 hemorrhage uncommonly results in death or permanent disability.1 Almost 90% of deaths from warfarin sodium– associated bleeding are due to intracranial bleeding.1 The health consequences of intracranial hemorrhage are so different from those of extracranial major hemorrhage that it begs the question whether these 2 sites of bleeding should be grouped together as “major hemorrhage” when reporting the results of randomized trials of antithrombotic therapies. Intracranial hemorrhage is often the deal breaker in the benefit vs risk decision to use anticoagulation to prevent stroke in elderly patients. After more than 50 years of oral anticoagulation using vitamin K antagonists (warfarin and congeners), orally active alternatives that selectively inhibit factor Xa and thrombin (dabigatran etexilate mesylate, rivaroxaban, apixaban, edoxaban) are now available.3 These agents have been referred to as the “novel oral anticoagulants,” but the first results of phase III trials testing an oral direct thrombin inhibitor were published a decade ago,4 and it is time for “novel” to be replaced. What distinguishes these agents from vitamin K antagonists is that they directly interact with their coagulation protein target, and the term direct-acting oral anticoagulant (DOAC) seems as good a replacement as any. The reduction in intracranial bleeding (both intracerebral and subdural) by DOACs relative to warfarin reported in recent phase III randomized trials was consistent, large, and unexpected. By contrast, reductions in extracranial major bleeding were less consistent and smaller. In JAMA Neurology, Chatterjee et al5 report pooled analyses of 6 randomized trials testing different DOACs in patients with atrial fibrillation using frequentist and Bayesian random-effect models. They demonstrate that the risk of intracranial hemorrhage is halved with DOACs compared with control and, based on indirect comparisons, suggest that there are no important differences between the DOACs. The evidence presented by Chatterjee and colleagues for a reduction in intracranial hemorrhage with the DOACs compared with control is convincing and welcome for patients, but we believe that their conclusion that DOACs are similar should be interpreted with caution. Indirect comparisons are potentially misleading because they can be affected by dif-
ferences among the studies in the types of patients included, cointerventions, and outcomes. 6,7 Compared with welldesigned trials and meta-analyses of such trials, estimates obtained from indirect comparisons have larger standard errors and less precision, reducing our confidence in the results. A head-to-head comparison within a well-designed randomized trial could find important differences between the individual DOACs that did not emerge from the present indirect comparisons. A single estimate of the relative risk of intracranial hemorrhage comparing all DOACs with all comparators is an oversimplification. Simple comparisons of estimates for intracranial hemorrhage across trials suggest that there may be differences among agents and that the risk appears to be dose dependent based on a significant difference in subdural hematoma between 2 dosages of dabigatran.8 We think that one number for all DOACs and all dosages cannot tell the whole story. Intriguingly, intracerebral hemorrhage (about two-thirds of all intracranial hemorrhages) and subdural hematomas (the bulk of the remainder) are both sharply reduced by DOACs relative to warfarin; these represent different types of vessel rupture. The mechanism(s) of reduced intracranial hemorrhage observed with DOACs remains a topic of intensive investigation, but several hypotheses have emerged. The focused single target of the DOACs compared with warfarin, notably their factor VII–sparing effect, supports that vascular bed–specific hemostasis may be important.9 In addition or alternatively, DOACs act as stoichiometric inhibitors (1:1 blockade of thrombin by dabigatran and 1:1 blockade of factor Xa by apixaban or rivaroxaban) such that higher levels of thrombin generation or factor Xa can overwhelm these anticoagulants and thereby maintain physiological hemostasis in the brain, whereas warfarin reduces the substrates required to produce thrombin and thus is much more difficult to overwhelm by a hemostatic response. The importance of the low rate of intracranial hemorrhage associated with the DOACs cannot be overemphasized. The substantial benefits and superior safety of the DOACs compared with warfarin in patients with atrial fibrillation are largely based on their reduction in intracranial hemorrhage to rates approaching those seen with aspirin,10 lowering the threshold for DOAC use to prevent disabling ischemic strokes. Randomized trials remain to be done to define the value of DOACs for stroke prevention outside of patients with atrial fibrillation. Aspirin alone is not the answer,11 leaving a substantial unmet need, and it is clear
jamaneurology.com
JAMA Neurology December 2013 Volume 70, Number 12
Copyright 2013 American Medical Association. All rights reserved.
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1483
Opinion Editorial
that we can do better.12 The future of DOACs for secondary prevention of ischemic stroke is promising. Randomized trials testing DOACs in acute brain ischemia13 and cryptoARTICLE INFORMATION Author Affiliations: Department of Medicine, Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada. Corresponding Author: Robert G. Hart, MD, Department of Medicine, McMaster University/Population Health Research Institute, Hamilton General Hospital, DBCVSRI C4-118, 237 Barton St E, Hamilton, ON L8L 2X2, Canada ([email protected]). Published Online: October 28, 2013. doi:10.1001/jamaneurol.2013.4347. Conflict of Interest Disclosures: None reported. REFERENCES 1. Fang MC, Go AS, Chang Y, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med. 2007;120(8):700-705. 2. Granger CB, Alexander JH, McMurray JJV, et al; ARISTOTLE Committees and Investigators. Apixaban vs warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992.
genic ischemic stroke are likely to show superiority to aspirin (currently recommended by most guidelines) with acceptably low rates of intracranial hemorrhage.
3. Eikelboom JW, Weitz JI. New anticoagulants. Circulation. 2010;121(13):1523-1532. 4. Olsson SB; Executive Steering Committee of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximegalatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomized controlled trial. Lancet. 2003;362(9397):1691-1698. 5. Chatterjee S, Sardar P, Biondi-Zoccai G, Kumbhani DJ. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation [published online October 28, 2013]. JAMA Neurol. doi:10.1001/jamaneurol.2013.4021.
8. Hart RG, Diener H-C, Yang S, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke. 2012;43(6):1511-1517. 9. Rosenberg RD, Aird WC. Vascular-bed–specific hemostasis and hypercoagulable states. N Engl J Med. 1999;340(20):1555-1564. 10. Connolly SJ, Eikelboom J, Joyner C, et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-817. 11. Algra A, van Gijn J. Cumulative meta-analysis of aspirin efficacy after cerebral ischaemia of arterial origin. J Neurol Neurosurg Psychiatry. 1999;66(2):255.
6. Donegan S, Williamson P, Gamble C, Tudur-Smith C. Indirect comparisons: a review of reporting and methodological quality. PLoS One. 2010;5(11):e11054. doi:10.1371/journal.pone.0011054.
12. Wang Y, Wang Y, Zhao X, et al; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369(1):11-19.
7. Song F, Loke YK, Walsh T, Glenny AM, Eastwood AJ, Altman DG. Methodological problems in the use of indirect comparisons for evaluating healthcare interventions: survey of published systematic reviews. BMJ. 2009;338:b1147. doi:10.1136 /bmj.b1147.
13. Eikelboom JW, Hart RG. Anticoagulant therapy in acute brain ischaemia. Lancet Neurol. 2013;12(6):526-527.
Mitochondrial DNA Mutation Load Chance or Destiny? Salvatore DiMauro, MD
It is well known that mitochondrial DNA (mtDNA)–related disorders are clinically heterogeneous, even within the same family.1 This is because in most patients, pathogenic mtDNA mutations are heteroplasmic, that is, a mixture of norRelated article page 1552 mal and mutated mtDNAs. Moreover, applying Mendelian terminology to mitochondrial genetics, heteroplasmic mtDNA mutations are recessive in the sense that very high proportions of a mutation are needed before a clinical phenotype becomes manifest. This threshold effect varies among mutation types and is generally higher for transfer RNA (tRNA) mutations than for protein-coding gene mutations or largescale single deletions. Another common feature of mtDNA-related disorders is that the mutation load (and the clinical phenotype) may vary widely between a mother and each of her children owing to a mitochondrial genetic bottleneck. The mechanism(s) through which the mitochondrial genetic bottleneck operates in humans is still hotly debated and the subject of a vast literature (for review, see article by Folmes et al2). A major factor dictating levels of maternally transmitted mtDNA variants is germline segregation (ie, parceling of mtDNA during the development of primordial germ cells 1484
into oocytes). Germline segregation coupled with reduced numbers of mtDNA molecules per cell produces an undefined germline bottleneck mechanism initially proposed to explain rapid shifts of heteroplasmy within one generation in Holstein cows.3-5 Experiments in mice heteroplasmic for neutral mtDNA variants showed that the physical bottleneck associated with the decrease of mtDNA from the zygote to primordial germ cells and immature oocytes is not accompanied by variations in heteroplasmy, whereas the resumption of mtDNA replication in postnatal oocytes during folliculogenesis rapidly segregates sequence variants and often in a tissue-specific manner. 6 ,7 Although these data were obtained in animal models and did not deal with deleterious mtDNA mutations, they clearly showed the importance of nuclear factors in determining the mitochondrial genetic bottleneck. Nevertheless, human studies also comparing heteroplasmy concordance for a neutral mtDNA trait in monozygotic and dizygotic twins failed to show any nuclear genetic contribution to heteroplasmy.8 It is generally accepted that mature oocytes from normal women contain about 150 000 mtDNAs, and a steep decline in the number of mitochondrial genomes from the zygote to the inner cell mass of the blastocysts allows only a minority of the maternal mtDNA to populate the fetus producing a sec-
JAMA Neurology December 2013 Volume 70, Number 12
Copyright 2013 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/02/2015
jamaneurology.com
EDITORIAL
Direct-Acting Oral Anticoagulants The Brain Gets a Break Robert G. Hart, MD; Janice Pogue, PhD; John W. Eikelboom, MD
About 25% of major hemorrhages occurring in elderly patients during warfarin anticoagulation are intracranial, and most of these bleeds (about 75%) either are fatal or result in severe residual disability.1,2 In contrast, major extracranial Related article page 1486 hemorrhage uncommonly results in death or permanent disability.1 Almost 90% of deaths from warfarin sodium– associated bleeding are due to intracranial bleeding.1 The health consequences of intracranial hemorrhage are so different from those of extracranial major hemorrhage that it begs the question whether these 2 sites of bleeding should be grouped together as “major hemorrhage” when reporting the results of randomized trials of antithrombotic therapies. Intracranial hemorrhage is often the deal breaker in the benefit vs risk decision to use anticoagulation to prevent stroke in elderly patients. After more than 50 years of oral anticoagulation using vitamin K antagonists (warfarin and congeners), orally active alternatives that selectively inhibit factor Xa and thrombin (dabigatran etexilate mesylate, rivaroxaban, apixaban, edoxaban) are now available.3 These agents have been referred to as the “novel oral anticoagulants,” but the first results of phase III trials testing an oral direct thrombin inhibitor were published a decade ago,4 and it is time for “novel” to be replaced. What distinguishes these agents from vitamin K antagonists is that they directly interact with their coagulation protein target, and the term direct-acting oral anticoagulant (DOAC) seems as good a replacement as any. The reduction in intracranial bleeding (both intracerebral and subdural) by DOACs relative to warfarin reported in recent phase III randomized trials was consistent, large, and unexpected. By contrast, reductions in extracranial major bleeding were less consistent and smaller. In JAMA Neurology, Chatterjee et al5 report pooled analyses of 6 randomized trials testing different DOACs in patients with atrial fibrillation using frequentist and Bayesian random-effect models. They demonstrate that the risk of intracranial hemorrhage is halved with DOACs compared with control and, based on indirect comparisons, suggest that there are no important differences between the DOACs. The evidence presented by Chatterjee and colleagues for a reduction in intracranial hemorrhage with the DOACs compared with control is convincing and welcome for patients, but we believe that their conclusion that DOACs are similar should be interpreted with caution. Indirect comparisons are potentially misleading because they can be affected by dif-
ferences among the studies in the types of patients included, cointerventions, and outcomes. 6,7 Compared with welldesigned trials and meta-analyses of such trials, estimates obtained from indirect comparisons have larger standard errors and less precision, reducing our confidence in the results. A head-to-head comparison within a well-designed randomized trial could find important differences between the individual DOACs that did not emerge from the present indirect comparisons. A single estimate of the relative risk of intracranial hemorrhage comparing all DOACs with all comparators is an oversimplification. Simple comparisons of estimates for intracranial hemorrhage across trials suggest that there may be differences among agents and that the risk appears to be dose dependent based on a significant difference in subdural hematoma between 2 dosages of dabigatran.8 We think that one number for all DOACs and all dosages cannot tell the whole story. Intriguingly, intracerebral hemorrhage (about two-thirds of all intracranial hemorrhages) and subdural hematomas (the bulk of the remainder) are both sharply reduced by DOACs relative to warfarin; these represent different types of vessel rupture. The mechanism(s) of reduced intracranial hemorrhage observed with DOACs remains a topic of intensive investigation, but several hypotheses have emerged. The focused single target of the DOACs compared with warfarin, notably their factor VII–sparing effect, supports that vascular bed–specific hemostasis may be important.9 In addition or alternatively, DOACs act as stoichiometric inhibitors (1:1 blockade of thrombin by dabigatran and 1:1 blockade of factor Xa by apixaban or rivaroxaban) such that higher levels of thrombin generation or factor Xa can overwhelm these anticoagulants and thereby maintain physiological hemostasis in the brain, whereas warfarin reduces the substrates required to produce thrombin and thus is much more difficult to overwhelm by a hemostatic response. The importance of the low rate of intracranial hemorrhage associated with the DOACs cannot be overemphasized. The substantial benefits and superior safety of the DOACs compared with warfarin in patients with atrial fibrillation are largely based on their reduction in intracranial hemorrhage to rates approaching those seen with aspirin,10 lowering the threshold for DOAC use to prevent disabling ischemic strokes. Randomized trials remain to be done to define the value of DOACs for stroke prevention outside of patients with atrial fibrillation. Aspirin alone is not the answer,11 leaving a substantial unmet need, and it is clear
jamaneurology.com
JAMA Neurology December 2013 Volume 70, Number 12
Copyright 2013 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/02/2015
1483
Opinion Editorial
that we can do better.12 The future of DOACs for secondary prevention of ischemic stroke is promising. Randomized trials testing DOACs in acute brain ischemia13 and cryptoARTICLE INFORMATION Author Affiliations: Department of Medicine, Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada. Corresponding Author: Robert G. Hart, MD, Department of Medicine, McMaster University/Population Health Research Institute, Hamilton General Hospital, DBCVSRI C4-118, 237 Barton St E, Hamilton, ON L8L 2X2, Canada ([email protected]). Published Online: October 28, 2013. doi:10.1001/jamaneurol.2013.4347. Conflict of Interest Disclosures: None reported. REFERENCES 1. Fang MC, Go AS, Chang Y, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med. 2007;120(8):700-705. 2. Granger CB, Alexander JH, McMurray JJV, et al; ARISTOTLE Committees and Investigators. Apixaban vs warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992.
genic ischemic stroke are likely to show superiority to aspirin (currently recommended by most guidelines) with acceptably low rates of intracranial hemorrhage.
3. Eikelboom JW, Weitz JI. New anticoagulants. Circulation. 2010;121(13):1523-1532. 4. Olsson SB; Executive Steering Committee of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximegalatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomized controlled trial. Lancet. 2003;362(9397):1691-1698. 5. Chatterjee S, Sardar P, Biondi-Zoccai G, Kumbhani DJ. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation [published online October 28, 2013]. JAMA Neurol. doi:10.1001/jamaneurol.2013.4021.
8. Hart RG, Diener H-C, Yang S, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke. 2012;43(6):1511-1517. 9. Rosenberg RD, Aird WC. Vascular-bed–specific hemostasis and hypercoagulable states. N Engl J Med. 1999;340(20):1555-1564. 10. Connolly SJ, Eikelboom J, Joyner C, et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-817. 11. Algra A, van Gijn J. Cumulative meta-analysis of aspirin efficacy after cerebral ischaemia of arterial origin. J Neurol Neurosurg Psychiatry. 1999;66(2):255.
6. Donegan S, Williamson P, Gamble C, Tudur-Smith C. Indirect comparisons: a review of reporting and methodological quality. PLoS One. 2010;5(11):e11054. doi:10.1371/journal.pone.0011054.
12. Wang Y, Wang Y, Zhao X, et al; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369(1):11-19.
7. Song F, Loke YK, Walsh T, Glenny AM, Eastwood AJ, Altman DG. Methodological problems in the use of indirect comparisons for evaluating healthcare interventions: survey of published systematic reviews. BMJ. 2009;338:b1147. doi:10.1136 /bmj.b1147.
13. Eikelboom JW, Hart RG. Anticoagulant therapy in acute brain ischaemia. Lancet Neurol. 2013;12(6):526-527.
Mitochondrial DNA Mutation Load Chance or Destiny? Salvatore DiMauro, MD
It is well known that mitochondrial DNA (mtDNA)–related disorders are clinically heterogeneous, even within the same family.1 This is because in most patients, pathogenic mtDNA mutations are heteroplasmic, that is, a mixture of norRelated article page 1552 mal and mutated mtDNAs. Moreover, applying Mendelian terminology to mitochondrial genetics, heteroplasmic mtDNA mutations are recessive in the sense that very high proportions of a mutation are needed before a clinical phenotype becomes manifest. This threshold effect varies among mutation types and is generally higher for transfer RNA (tRNA) mutations than for protein-coding gene mutations or largescale single deletions. Another common feature of mtDNA-related disorders is that the mutation load (and the clinical phenotype) may vary widely between a mother and each of her children owing to a mitochondrial genetic bottleneck. The mechanism(s) through which the mitochondrial genetic bottleneck operates in humans is still hotly debated and the subject of a vast literature (for review, see article by Folmes et al2). A major factor dictating levels of maternally transmitted mtDNA variants is germline segregation (ie, parceling of mtDNA during the development of primordial germ cells 1484
into oocytes). Germline segregation coupled with reduced numbers of mtDNA molecules per cell produces an undefined germline bottleneck mechanism initially proposed to explain rapid shifts of heteroplasmy within one generation in Holstein cows.3-5 Experiments in mice heteroplasmic for neutral mtDNA variants showed that the physical bottleneck associated with the decrease of mtDNA from the zygote to primordial germ cells and immature oocytes is not accompanied by variations in heteroplasmy, whereas the resumption of mtDNA replication in postnatal oocytes during folliculogenesis rapidly segregates sequence variants and often in a tissue-specific manner. 6 ,7 Although these data were obtained in animal models and did not deal with deleterious mtDNA mutations, they clearly showed the importance of nuclear factors in determining the mitochondrial genetic bottleneck. Nevertheless, human studies also comparing heteroplasmy concordance for a neutral mtDNA trait in monozygotic and dizygotic twins failed to show any nuclear genetic contribution to heteroplasmy.8 It is generally accepted that mature oocytes from normal women contain about 150 000 mtDNAs, and a steep decline in the number of mitochondrial genomes from the zygote to the inner cell mass of the blastocysts allows only a minority of the maternal mtDNA to populate the fetus producing a sec-
JAMA Neurology December 2013 Volume 70, Number 12
Copyright 2013 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/02/2015
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