The
n e w e ng l a n d j o u r na l
of
m e dic i n e
c or r e sp ondence
Cryptogenic Stroke and Atrial Fibrillation To the Editor: The EMBRACE (30-Day Cardiac Event Monitor Belt for Recording Atrial Fibrillation after a Cerebral Ischemic Event) study by Gladstone and colleagues1 and the CRYSTAL AF (Cryptogenic Stroke and Underlying AF) study by Sanna and colleagues2 (both in the June 26 issue) raise the important issue of prolonged monitoring for the detection of atrial fibrillation after stroke. However, because both studies involved monitoring after incident stroke, the direction of causation (i.e., atrial fibrillation leading to stroke versus stroke leading to atrial fibrillation) cannot be determined. Indeed, arrhythmias and increased mortality have been reported after insular infarction, particularly on the right side.3,4 In these studies, further stratification according to location of the lesion might be informative. Brian Silver, M.D. Rhode Island Hospital Providence, RI [email protected] No potential conflict of interest relevant to this letter was reported. 1. Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in
patients with cryptogenic stroke. N Engl J Med 2014;370:246777. 2. Sanna T, Diener H-C, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370:247886. 3. Abboud H, Berroir S, Labreuche J, Orjuela K, Amarenco P. Insular involvement in brain infarction increases risk for cardiac arrhythmia and death. Ann Neurol 2006;59:691-9. 4. Colivicchi F, Bassi A, Santini M, Caltagirone C. Prognostic implications of right-sided insular damage, cardiac autonomic derangement, and arrhythmias after acute ischemic stroke. Stroke 2005;36:1710-5.
monitoring than by means of 24 hours of monitoring in patients with cryptogenic stroke. In the accompanying editorial, Kamel1 recommends that most patients with cryptogenic stroke undergo several weeks of rhythm monitoring. A major limitation of these studies, however, is that they did not involve a control group of patients who had not had a previous stroke. The prevalence of atrial fibrillation is increasing; it occurs in 3.7 to 4.2% of persons 60 to 70 years of age and in 10 to 17% of persons 80 years of age or older.2 Furthermore, in both articles, the prevalences of hypertension and diabetes — risk factors for atrial fibrillation — were similar to those in the U.S. population according to the National Health and Nutrition Examination Survey database.3 Before concluding that the higher prevalence of atrial fibrillation diagnosed by means of prolonged monitoring in patients with previous cryptogenic stroke mandates the use of anticoagulant therapy, we need to know whether the prevalence of atrial fibrillation detected by means of prolonged monitoring is higher than the prevalence among persons who have not had stroke. this week’s letters 1259 Cryptogenic Stroke and Atrial Fibrillation 1262 Prophylaxis against Venous Thromboembolism in Patients with Cancer
DOI: 10.1056/NEJMc1409495
1264 More on Platelet-Rich Plasma Injections in Acute Muscle Injury
To the Editor: The articles by Gladstone et al. and Sanna et al. show a higher prevalence of atrial fibrillation detected by means of prolonged
1265 Pyogenic Granuloma as a Cutaneous Adverse Effect of Vemurafenib
n engl j med 371;13 nejm.org september 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF SUSSEX on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1259
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Stephen D.H. Malnick, M.B., B.S. Marina Somin, M.D. Sorel Goland, M.D. Kaplan Medical Center Rehovot, Israel [email protected] No potential conflict of interest relevant to this letter was reported. 1. Kamel H. Heart-rhythm monitoring for evaluation of crypto-
genic stroke. N Engl J Med 2014;370:2532-3. 2. Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol 2014;6:213-20. 3. Beltrán-Sánchez H, Harhay MO, Harhay MM, McElligott S. Prevalence and trends of metabolic syndrome in the adult U.S. population, 1999-2010. J Am Coll Cardiol 2013;62:697-703. DOI: 10.1056/NEJMc1409495
Dr. Gladstone and Colleagues Reply: With regard to Silver’s comments: atrial fibrillation detected after a stroke may be causal or incidental, preexisting or of new onset. Our trial was not designed to address this particular question of causation, but rather was aimed at finding a better way of detecting atrial fibrillation in older patients with cryptogenic stroke — a population in which paroxysmal atrial fibrillation is often suspected, especially in those with hypertension, left atrial enlargement, or neuroimaging evidence of emboli within multiple vascular territories of the brain. The idea that some cases of atrial fibrillation may be a consequence rather than a cause of stroke (because of disruption of specific areas of the brain involved in autonomic regulation such as the insula or because of an acute systemic inflammatory response) is an interesting hypothesis that warrants further study.1,2 However, in our trial, insular infarcts were reported in less than 5% of the patients in whom atrial fibrillation was detected. Also, patients underwent randomization a mean (±SD) 75.1±38.6 days after stroke, making it unlikely that the atrial fibrillation was an acute transient phenomenon. Regardless of whether atrial fibrillation occurs before or after a stroke, iden tification of this treatable risk factor provides opportunities to consider anticoagulation for prevention of recurrent stroke. Malnick et al. emphasize the high age-related prevalence of atrial fibrillation, but the statistics cited refer to clinically diagnosed cases that are not relevant to our trial, since we excluded patients with overt atrial fibrillation and then found that an additional 15% of the patients had 1260
of
m e dic i n e
subclinical atrial fibrillation. We agree that it would be of interest to know the prevalence of subclinical atrial fibrillation among age-matched patients who had not had a recent cryptogenic stroke. New Canadian studies are now investigating this question.3 A Swedish study involving twice-daily electrocardiography (ECG) for 2 weeks in healthy persons 75 to 76 years of age showed a 3% prevalence of subclinical atrial fibrillation.4 When atrial fibrillation is detected in patients with stroke, however, it carries greater prognostic significance (a CHADS2 score of 2 points or more on a scale from 0 to 6, with higher scores indicating a greater risk of stroke) and implications for treatment than for lower-risk patients without brain embolism. The aim of prolonged ECG monitoring is to identify patients who have (or will ultimately be found to have) a convincing diagnosis of atrial fibrillation of sufficient duration or frequency to warrant anticoagulant therapy. It may indeed identify patients with only very brief episodes of atrial fibrillation of uncertain significance for which the role of anticoagulation is not yet established; such patients could undergo additional monitoring or randomization in anticoagulant trials. David J. Gladstone, M.D., Ph.D. University of Toronto Toronto, ON, Canada [email protected]
Mukul Sharma, M.D. McMaster University Hamilton, ON, Canada
J. David Spence, M.D. Western University London, ON, Canada
for the EMBRACE Steering Committee and Investigators Since publication of their article, the authors report no further potential conflict of interest. 1. Sposato LA, Riccio PM, Hachinski V. Poststroke atrial fibril-
lation: cause or consequence? Critical review of current views. Neurology 2014;82:1180-6. 2. González Toledo ME, Klein FR, Riccio PM, et al. Atrial fibrillation detected after acute ischemic stroke: evidence supporting the neurogenic hypothesis. J Stroke Cerebrovasc Dis 2013;22: e486-91. 3. Canadian Stroke Prevention Intervention Network (C-SPIN). Ottawa: Canadian Institutes of Health Research (http://www .cihr-irsc.gc.ca/e/48013.html). 4. Svennberg CE, Engdahl J, Frykman-Kull V, Friberg L, Levin LA, Rosenqvist M. Mass screening for silent atrial fibrillation in high risk patients: preliminary results from the STROKETOP trial. Eur Heart J 2013;34:Suppl:809. abstract. DOI: 10.1056/NEJMc1409495
n engl j med 371;13 nejm.org september 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF SUSSEX on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
Dr. Sanna and Colleagues Reply: The Crystal AF trial was designed to compare the rate of detection of atrial fibrillation after cryptogenic stroke among patients randomly assigned to continuous cardiac monitoring by means of insertable cardiac monitors (ICMs) or to routine care. As Silver remarks, our results do not address the direction of causation. Though some patients with stroke may have autonomic alterations that confer a predisposition to atrial fibrillation, studies examining stroke as the cause of the atrial fibrillation are limited by the inability to rule out previously undiagnosed paroxysmal atrial fibrillation that was present before the index event.1,2 Studies that indicate that stroke is a cause of atrial fibrillation show that the arrhythmia resolves during the initial period of hospitalization in nearly all patients.2 In our trial, by 36 months, the median time from randomization to first detection of atrial fibrillation was 8.4 months in patients randomly assigned to continuous monitoring, so it is unlikely that stroke was the cause of atrial fibrillation. We share Silver’s interest in the association between new-onset atrial fibrillation and the location of the infarct and are currently evaluating the magnetic resonance imaging data from our trial. Malnick and colleagues question whether the atrial fibrillation detected by means of ICMs in patients with cryptogenic stroke simply reflects the prevalent atrial fibrillation that would also be expected in a matched cohort of patients without stroke. This issue is currently being addressed in the REVEAL AF trial (ClinicalTrials .gov number, NCT01727297), which is using ICMs in patients who have not had stroke or atrial fibrillation but who have two or more risk factors for stroke. Although a causal relationship between cryptogenic stroke and atrial fibrillation cannot be inferred from our study, we believe that the clinical relevance remains unaltered. Studies have consistently shown that a prior thromboembolic event is the single strongest risk factor for recurrent stroke in patients with atrial fibrillation.3,4 In addition, trials of primary and secondary stroke prevention in patients with atrial fibrillation clearly show the superiority of anticoagulation over antiplatelet therapy.3 Thus, the detection of atrial fibrillation in a patient who previously received a diagnosis of cryptogenic stroke should mandate a change in therapy from antiplatelet agents to oral anti-
coagulation therapy, regardless of whether the atrial fibrillation is the cause of the index stroke or a major risk factor for the next one. Tommaso Sanna, M.D. Catholic University of the Sacred Heart Rome, Italy [email protected]
Hans-Christoph Diener, M.D., Ph.D. University Hospital Essen Essen, Germany
Rod S. Passman, M.D., M.S.C.E. Northwestern University Feinberg School of Medicine Chicago, IL
for the Crystal AF Steering Committee Since publication of their article, the authors report no further potential conflict of interest. 1. Vingerhoets F, Bogousslavsky J, Regli F, Van Melle G. Atrial
fibrillation after acute stroke. Stroke 1993;24:26-30.
2. Abboud H, Berroir S, Labreuche J, Orjuela K, Amarenco P.
Insular involvement in brain infarction increases risk for cardiac arrhythmia and death. Ann Neurol 2006;59:691-9. 3. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449-57. [Erratum, Arch Intern Med 1994;154:2254.] 4. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864-70. DOI: 10.1056/NEJMc1409495
The Editorialist Replies: Silver and Malnick and colleagues question whether the episodes of subclinical atrial fibrillation detected by means of continuous heart-rhythm monitoring in the CRYSTAL AF and EMBRACE trials were in fact responsible for the strokes that led to the inclusion of participants in these trials. The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) showed indirect evidence of such a causal association; in that trial, the risk of stroke was higher among participants with subclinical atrial fibrillation than among patients without atrial fibrillation.1 However, few cases of subclinical atrial fibrillation in the ASSERT trial closely preceded a stroke, and many participants with stroke manifested no atrial fibrillation until after their stroke, even though they underwent continuous heart-rhythm monitoring for months beforehand.2 Data are lacking on the precise relationship between subclinical atrial fibrillation and stroke as well as on
n engl j med 371;13 nejm.org september 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF SUSSEX on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
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the best antithrombotic treatment for subclinical atrial fibrillation. In the meantime, however, clinicians who treat patients with stroke need to comprehensively address these patients’ vascular risk factors. In the face of uncertainty about whether or not subclinical atrial fibrillation is directly involved in the pathogenesis of stroke, a prudent evaluation of cryptogenic stroke includes thoroughly ascertaining the presence of atrial fibrillation and, at the very least, following it closely for progression, because subclinical atrial fibrillation frequently progresses to clinically apparent atrial fibrillation,1 which is associated with a high risk of stroke recurrence.3 The CRYSTAL AF and EMBRACE trials, which sought to determine the best strategy for ascertaining
of
m e dic i n e
atrial fibrillation after stroke, showed that several weeks or more of continuous heart-rhythm monitoring detects atrial fibrillation more reliably than routine follow-up. Hooman Kamel, M.D. Weill Cornell Medical College New York, NY Since publication of his article, the author reports no further potential conflict of interest. 1. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fi-
brillation and the risk of stroke. N Engl J Med 2012;366:120-9. 2. Brambatti M, Connolly SJ, Gold MR, et al. Temporal relationship between subclinical atrial fibrillation and embolic events. Circulation 2014;129:2094-9. 3. Kamel H, Johnson DR, Hegde M, et al. Detection of atrial fibrillation after stroke and the risk of recurrent stroke. J Stroke Cerebrovasc Dis 2012;21:726-31. DOI: 10.1056/NEJMc1409495
Prophylaxis against Venous Thromboembolism in Patients with Cancer To the Editor: Connors (June 26 issue)1 focuses on prophylaxis against venous thromboembolism in ambulatory patients with cancer who are receiving chemotherapy.2,3 We proposed a modified Khorana risk-assessment model (the Protecht score), in which we added platinum-based chemotherapy, gemcitabine-based chemotherapy, or both to the predictive variables already taken into account in the Khorana model.4 We compared the Khorana and Protecht models with respect to their ability to identify high-risk patients with cancer among the patients in the control group in the Prophylaxis of Thromboembolism during Chemotherapy (PROTECHT) study. The Protecht score, as compared with the Khorana score, identified more patients at high risk for venous thromboembolism (124 of 378 patients [32.8%] vs. 45 of 378 patients [11.9%]). Among patients at high risk, as defined according to the Protecht score, the rate of venous thromboembolism was 4% (3 of 70 patients) in the prophylaxis group and 11% (5 of 45 patients) in the placebo group, with a number needed to treat of 17. We believe that including chemotherapy as a variable in the Khorana model will improve risk stratification to identify ambulatory patients with cancer who are at risk for venous thromboembolism. Further investigations are needed to
1262
evaluate the clinical benefit of antithrombotic prophylaxis in high-risk patients who are identified with the use of this approach. Melina Verso, M.D. Giancarlo Agnelli, M.D. University of Perugia Perugia, Italy [email protected] No potential conflict of interest relevant to this letter was reported. 1. Connors JM. Prophylaxis against venous thromboembolism in
ambulatory patients with cancer. N Engl J Med 2014;370:2515-9.
2. Agnelli G, Gussoni G, Bianchini C, et al. Nadroparin for the
prevention of thromboembolic events in outpatients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 2009;10:943-9. 3. Agnelli G, George DJ, Kakkar AK, et al. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med 2012;366:601-9. 4. Verso M, Agnelli G, Barni S, Gasparini G, LaBianca R. A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: the Protecht score. Intern Emerg Med 2012;7:291-2. DOI: 10.1056/NEJMc1408866
To the Editor: Although she places particular emphasis on discussing other controversial issues, Connors pays less attention to the debate concerning patients with primary or secondary
n engl j med 371;13 nejm.org september 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF SUSSEX on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
n e w e ng l a n d j o u r na l
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m e dic i n e
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Cryptogenic Stroke and Atrial Fibrillation To the Editor: The EMBRACE (30-Day Cardiac Event Monitor Belt for Recording Atrial Fibrillation after a Cerebral Ischemic Event) study by Gladstone and colleagues1 and the CRYSTAL AF (Cryptogenic Stroke and Underlying AF) study by Sanna and colleagues2 (both in the June 26 issue) raise the important issue of prolonged monitoring for the detection of atrial fibrillation after stroke. However, because both studies involved monitoring after incident stroke, the direction of causation (i.e., atrial fibrillation leading to stroke versus stroke leading to atrial fibrillation) cannot be determined. Indeed, arrhythmias and increased mortality have been reported after insular infarction, particularly on the right side.3,4 In these studies, further stratification according to location of the lesion might be informative. Brian Silver, M.D. Rhode Island Hospital Providence, RI [email protected] No potential conflict of interest relevant to this letter was reported. 1. Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in
patients with cryptogenic stroke. N Engl J Med 2014;370:246777. 2. Sanna T, Diener H-C, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370:247886. 3. Abboud H, Berroir S, Labreuche J, Orjuela K, Amarenco P. Insular involvement in brain infarction increases risk for cardiac arrhythmia and death. Ann Neurol 2006;59:691-9. 4. Colivicchi F, Bassi A, Santini M, Caltagirone C. Prognostic implications of right-sided insular damage, cardiac autonomic derangement, and arrhythmias after acute ischemic stroke. Stroke 2005;36:1710-5.
monitoring than by means of 24 hours of monitoring in patients with cryptogenic stroke. In the accompanying editorial, Kamel1 recommends that most patients with cryptogenic stroke undergo several weeks of rhythm monitoring. A major limitation of these studies, however, is that they did not involve a control group of patients who had not had a previous stroke. The prevalence of atrial fibrillation is increasing; it occurs in 3.7 to 4.2% of persons 60 to 70 years of age and in 10 to 17% of persons 80 years of age or older.2 Furthermore, in both articles, the prevalences of hypertension and diabetes — risk factors for atrial fibrillation — were similar to those in the U.S. population according to the National Health and Nutrition Examination Survey database.3 Before concluding that the higher prevalence of atrial fibrillation diagnosed by means of prolonged monitoring in patients with previous cryptogenic stroke mandates the use of anticoagulant therapy, we need to know whether the prevalence of atrial fibrillation detected by means of prolonged monitoring is higher than the prevalence among persons who have not had stroke. this week’s letters 1259 Cryptogenic Stroke and Atrial Fibrillation 1262 Prophylaxis against Venous Thromboembolism in Patients with Cancer
DOI: 10.1056/NEJMc1409495
1264 More on Platelet-Rich Plasma Injections in Acute Muscle Injury
To the Editor: The articles by Gladstone et al. and Sanna et al. show a higher prevalence of atrial fibrillation detected by means of prolonged
1265 Pyogenic Granuloma as a Cutaneous Adverse Effect of Vemurafenib
n engl j med 371;13 nejm.org september 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF SUSSEX on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1259
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n e w e ng l a n d j o u r na l
Stephen D.H. Malnick, M.B., B.S. Marina Somin, M.D. Sorel Goland, M.D. Kaplan Medical Center Rehovot, Israel [email protected] No potential conflict of interest relevant to this letter was reported. 1. Kamel H. Heart-rhythm monitoring for evaluation of crypto-
genic stroke. N Engl J Med 2014;370:2532-3. 2. Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol 2014;6:213-20. 3. Beltrán-Sánchez H, Harhay MO, Harhay MM, McElligott S. Prevalence and trends of metabolic syndrome in the adult U.S. population, 1999-2010. J Am Coll Cardiol 2013;62:697-703. DOI: 10.1056/NEJMc1409495
Dr. Gladstone and Colleagues Reply: With regard to Silver’s comments: atrial fibrillation detected after a stroke may be causal or incidental, preexisting or of new onset. Our trial was not designed to address this particular question of causation, but rather was aimed at finding a better way of detecting atrial fibrillation in older patients with cryptogenic stroke — a population in which paroxysmal atrial fibrillation is often suspected, especially in those with hypertension, left atrial enlargement, or neuroimaging evidence of emboli within multiple vascular territories of the brain. The idea that some cases of atrial fibrillation may be a consequence rather than a cause of stroke (because of disruption of specific areas of the brain involved in autonomic regulation such as the insula or because of an acute systemic inflammatory response) is an interesting hypothesis that warrants further study.1,2 However, in our trial, insular infarcts were reported in less than 5% of the patients in whom atrial fibrillation was detected. Also, patients underwent randomization a mean (±SD) 75.1±38.6 days after stroke, making it unlikely that the atrial fibrillation was an acute transient phenomenon. Regardless of whether atrial fibrillation occurs before or after a stroke, iden tification of this treatable risk factor provides opportunities to consider anticoagulation for prevention of recurrent stroke. Malnick et al. emphasize the high age-related prevalence of atrial fibrillation, but the statistics cited refer to clinically diagnosed cases that are not relevant to our trial, since we excluded patients with overt atrial fibrillation and then found that an additional 15% of the patients had 1260
of
m e dic i n e
subclinical atrial fibrillation. We agree that it would be of interest to know the prevalence of subclinical atrial fibrillation among age-matched patients who had not had a recent cryptogenic stroke. New Canadian studies are now investigating this question.3 A Swedish study involving twice-daily electrocardiography (ECG) for 2 weeks in healthy persons 75 to 76 years of age showed a 3% prevalence of subclinical atrial fibrillation.4 When atrial fibrillation is detected in patients with stroke, however, it carries greater prognostic significance (a CHADS2 score of 2 points or more on a scale from 0 to 6, with higher scores indicating a greater risk of stroke) and implications for treatment than for lower-risk patients without brain embolism. The aim of prolonged ECG monitoring is to identify patients who have (or will ultimately be found to have) a convincing diagnosis of atrial fibrillation of sufficient duration or frequency to warrant anticoagulant therapy. It may indeed identify patients with only very brief episodes of atrial fibrillation of uncertain significance for which the role of anticoagulation is not yet established; such patients could undergo additional monitoring or randomization in anticoagulant trials. David J. Gladstone, M.D., Ph.D. University of Toronto Toronto, ON, Canada [email protected]
Mukul Sharma, M.D. McMaster University Hamilton, ON, Canada
J. David Spence, M.D. Western University London, ON, Canada
for the EMBRACE Steering Committee and Investigators Since publication of their article, the authors report no further potential conflict of interest. 1. Sposato LA, Riccio PM, Hachinski V. Poststroke atrial fibril-
lation: cause or consequence? Critical review of current views. Neurology 2014;82:1180-6. 2. González Toledo ME, Klein FR, Riccio PM, et al. Atrial fibrillation detected after acute ischemic stroke: evidence supporting the neurogenic hypothesis. J Stroke Cerebrovasc Dis 2013;22: e486-91. 3. Canadian Stroke Prevention Intervention Network (C-SPIN). Ottawa: Canadian Institutes of Health Research (http://www .cihr-irsc.gc.ca/e/48013.html). 4. Svennberg CE, Engdahl J, Frykman-Kull V, Friberg L, Levin LA, Rosenqvist M. Mass screening for silent atrial fibrillation in high risk patients: preliminary results from the STROKETOP trial. Eur Heart J 2013;34:Suppl:809. abstract. DOI: 10.1056/NEJMc1409495
n engl j med 371;13 nejm.org september 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF SUSSEX on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
Dr. Sanna and Colleagues Reply: The Crystal AF trial was designed to compare the rate of detection of atrial fibrillation after cryptogenic stroke among patients randomly assigned to continuous cardiac monitoring by means of insertable cardiac monitors (ICMs) or to routine care. As Silver remarks, our results do not address the direction of causation. Though some patients with stroke may have autonomic alterations that confer a predisposition to atrial fibrillation, studies examining stroke as the cause of the atrial fibrillation are limited by the inability to rule out previously undiagnosed paroxysmal atrial fibrillation that was present before the index event.1,2 Studies that indicate that stroke is a cause of atrial fibrillation show that the arrhythmia resolves during the initial period of hospitalization in nearly all patients.2 In our trial, by 36 months, the median time from randomization to first detection of atrial fibrillation was 8.4 months in patients randomly assigned to continuous monitoring, so it is unlikely that stroke was the cause of atrial fibrillation. We share Silver’s interest in the association between new-onset atrial fibrillation and the location of the infarct and are currently evaluating the magnetic resonance imaging data from our trial. Malnick and colleagues question whether the atrial fibrillation detected by means of ICMs in patients with cryptogenic stroke simply reflects the prevalent atrial fibrillation that would also be expected in a matched cohort of patients without stroke. This issue is currently being addressed in the REVEAL AF trial (ClinicalTrials .gov number, NCT01727297), which is using ICMs in patients who have not had stroke or atrial fibrillation but who have two or more risk factors for stroke. Although a causal relationship between cryptogenic stroke and atrial fibrillation cannot be inferred from our study, we believe that the clinical relevance remains unaltered. Studies have consistently shown that a prior thromboembolic event is the single strongest risk factor for recurrent stroke in patients with atrial fibrillation.3,4 In addition, trials of primary and secondary stroke prevention in patients with atrial fibrillation clearly show the superiority of anticoagulation over antiplatelet therapy.3 Thus, the detection of atrial fibrillation in a patient who previously received a diagnosis of cryptogenic stroke should mandate a change in therapy from antiplatelet agents to oral anti-
coagulation therapy, regardless of whether the atrial fibrillation is the cause of the index stroke or a major risk factor for the next one. Tommaso Sanna, M.D. Catholic University of the Sacred Heart Rome, Italy [email protected]
Hans-Christoph Diener, M.D., Ph.D. University Hospital Essen Essen, Germany
Rod S. Passman, M.D., M.S.C.E. Northwestern University Feinberg School of Medicine Chicago, IL
for the Crystal AF Steering Committee Since publication of their article, the authors report no further potential conflict of interest. 1. Vingerhoets F, Bogousslavsky J, Regli F, Van Melle G. Atrial
fibrillation after acute stroke. Stroke 1993;24:26-30.
2. Abboud H, Berroir S, Labreuche J, Orjuela K, Amarenco P.
Insular involvement in brain infarction increases risk for cardiac arrhythmia and death. Ann Neurol 2006;59:691-9. 3. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449-57. [Erratum, Arch Intern Med 1994;154:2254.] 4. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864-70. DOI: 10.1056/NEJMc1409495
The Editorialist Replies: Silver and Malnick and colleagues question whether the episodes of subclinical atrial fibrillation detected by means of continuous heart-rhythm monitoring in the CRYSTAL AF and EMBRACE trials were in fact responsible for the strokes that led to the inclusion of participants in these trials. The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) showed indirect evidence of such a causal association; in that trial, the risk of stroke was higher among participants with subclinical atrial fibrillation than among patients without atrial fibrillation.1 However, few cases of subclinical atrial fibrillation in the ASSERT trial closely preceded a stroke, and many participants with stroke manifested no atrial fibrillation until after their stroke, even though they underwent continuous heart-rhythm monitoring for months beforehand.2 Data are lacking on the precise relationship between subclinical atrial fibrillation and stroke as well as on
n engl j med 371;13 nejm.org september 25, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF SUSSEX on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1261
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n e w e ng l a n d j o u r na l
the best antithrombotic treatment for subclinical atrial fibrillation. In the meantime, however, clinicians who treat patients with stroke need to comprehensively address these patients’ vascular risk factors. In the face of uncertainty about whether or not subclinical atrial fibrillation is directly involved in the pathogenesis of stroke, a prudent evaluation of cryptogenic stroke includes thoroughly ascertaining the presence of atrial fibrillation and, at the very least, following it closely for progression, because subclinical atrial fibrillation frequently progresses to clinically apparent atrial fibrillation,1 which is associated with a high risk of stroke recurrence.3 The CRYSTAL AF and EMBRACE trials, which sought to determine the best strategy for ascertaining
of
m e dic i n e
atrial fibrillation after stroke, showed that several weeks or more of continuous heart-rhythm monitoring detects atrial fibrillation more reliably than routine follow-up. Hooman Kamel, M.D. Weill Cornell Medical College New York, NY Since publication of his article, the author reports no further potential conflict of interest. 1. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fi-
brillation and the risk of stroke. N Engl J Med 2012;366:120-9. 2. Brambatti M, Connolly SJ, Gold MR, et al. Temporal relationship between subclinical atrial fibrillation and embolic events. Circulation 2014;129:2094-9. 3. Kamel H, Johnson DR, Hegde M, et al. Detection of atrial fibrillation after stroke and the risk of recurrent stroke. J Stroke Cerebrovasc Dis 2012;21:726-31. DOI: 10.1056/NEJMc1409495
Prophylaxis against Venous Thromboembolism in Patients with Cancer To the Editor: Connors (June 26 issue)1 focuses on prophylaxis against venous thromboembolism in ambulatory patients with cancer who are receiving chemotherapy.2,3 We proposed a modified Khorana risk-assessment model (the Protecht score), in which we added platinum-based chemotherapy, gemcitabine-based chemotherapy, or both to the predictive variables already taken into account in the Khorana model.4 We compared the Khorana and Protecht models with respect to their ability to identify high-risk patients with cancer among the patients in the control group in the Prophylaxis of Thromboembolism during Chemotherapy (PROTECHT) study. The Protecht score, as compared with the Khorana score, identified more patients at high risk for venous thromboembolism (124 of 378 patients [32.8%] vs. 45 of 378 patients [11.9%]). Among patients at high risk, as defined according to the Protecht score, the rate of venous thromboembolism was 4% (3 of 70 patients) in the prophylaxis group and 11% (5 of 45 patients) in the placebo group, with a number needed to treat of 17. We believe that including chemotherapy as a variable in the Khorana model will improve risk stratification to identify ambulatory patients with cancer who are at risk for venous thromboembolism. Further investigations are needed to
1262
evaluate the clinical benefit of antithrombotic prophylaxis in high-risk patients who are identified with the use of this approach. Melina Verso, M.D. Giancarlo Agnelli, M.D. University of Perugia Perugia, Italy [email protected] No potential conflict of interest relevant to this letter was reported. 1. Connors JM. Prophylaxis against venous thromboembolism in
ambulatory patients with cancer. N Engl J Med 2014;370:2515-9.
2. Agnelli G, Gussoni G, Bianchini C, et al. Nadroparin for the
prevention of thromboembolic events in outpatients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 2009;10:943-9. 3. Agnelli G, George DJ, Kakkar AK, et al. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med 2012;366:601-9. 4. Verso M, Agnelli G, Barni S, Gasparini G, LaBianca R. A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: the Protecht score. Intern Emerg Med 2012;7:291-2. DOI: 10.1056/NEJMc1408866
To the Editor: Although she places particular emphasis on discussing other controversial issues, Connors pays less attention to the debate concerning patients with primary or secondary
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