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Duration of Dual Antiplatelet Therapy after Drug-Eluting Stents To the Editor: Mauri et al. (Dec. 4 issue)1 report a significant increase in the risk of cancer-related death in patients receiving a thienopyridine drug, as compared with placebo (0.62% vs. 0.28%, P = 0.02), and a numerical excess in incident cancer (2.03% vs. 1.62%, P = 0.14) (Table S8 in the Supplementary Appendix of the article, available at NEJM.org). Of the two thienopyridines used in this trial, only prasugrel has been associated with a significantly increased risk of incident cancer in a previous trial.2 The association of prasugrel treatment and new cancer diagnosis has also been specifically investigated by the Food and Drug Administration.3 However, whether the signal of excess cancer events observed in the current trial occurred in patients receiving clopidogrel or prasugrel is not reported. Can the authors report the numbers of cancer-related deaths and cancers reported after randomization according to which thienopyridine each patient received? Ilke Sipahi, M.D.
nary-artery stenting. Those patients who received aspirin alone had a higher incidence of stent thrombosis than those who received dual antiplatelet therapy. Most people will buy coated aspirin, unless specifically instructed to use uncoated aspirin. As shown by Grosser et al.,1 49% of people taking coated aspirin do not have effective inhibition of platelet cyclooxygenase-1 and appear to be “aspirin resistant.” The report by Mauri et al. does not indicate how many patients were using coated aspirin, and the activity of platelet cyclooxygenase-1 was apparently not assessed. Is it possible that the apparent benefit of prolonged thienopyridine therapy was due to the use of coated aspirin, with consequent failure of aspirin effect? J. Lawrence Dohan, M.D.
Acibadem University
FitzGerald GA. Drug resistance and pseudoresistance: an unintended consequence of enteric coating aspirin. Circulation 2013; 127:377-85.
Istanbul, Turkey [email protected] Dr. Sipahi reports receiving lecture fees from Bayer. No other potential conflict of interest relevant to this letter was reported.
Marlborough Hospital Hudson, MA [email protected] No potential conflict of interest relevant to this letter was reported. 1. Grosser T, Fries S, Lawson JA, Kapoor SC, Grant GR,
DOI: 10.1056/NEJMc1501195
1. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of
dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155-66. 2. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15. 3. Prasugrel. Silver Spring, MD: Food and Drug Administration (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/ 022307s000_RiskR_P4.pdf). DOI: 10.1056/NEJMc1501195
To the Editor: Mauri et al. report a reduction in vascular events by extending the duration of thienopyridine therapy beyond 1 year after coro-
this week’s letters 1371 Duration of Dual Antiplatelet Therapy after Drug-Eluting Stents 1374 Multiple-System Atrophy 1376 Severe Ebola Virus Infection Complicated by Gram-Negative Septicemia 1377 A Case of Iced-Tea Nephropathy
n engl j med 372;14 nejm.org april 2, 2015
The New England Journal of Medicine Downloaded from nejm.org on April 2, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
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To the Editor: Mauri et al. report a significant reduction in stent thrombosis and major cardiovascular events with dual antiplatelet therapy beyond 12 months after the placement of a drugeluting stent. There was an increased risk of bleeding noted in the group receiving dual antiplatelet therapy for 30 months. In 2010, the American College of Cardiology Foundation, the American College of Gastroenterology, and the American Heart Association updated their expert consensus document on approaches to reduce gastrointestinal risk in persons receiving antiplatelet therapy, with a specific focus on dual antiplatelet therapy.1,2 Both dual antiplatelet therapy and an age of more than 60 years are indications for the use of proton-pump inhibitors (PPIs) in order to reduce the risk of gastrointestinal bleeding. The majority of patients in the study by Mauri et al. were older than 60 years of age and received dual antiplatelet therapy. It would be useful to know the levels of reported PPI use in the study in order to evaluate the safety and efficacy of dual antiplatelet therapy beyond 12 months. Joel C. Marrs, Pharm.D. University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
Aurora, CO [email protected] No potential conflict of interest relevant to this letter was reported. 1. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA
2008 Expert Consensus Document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2008;52: 1502-17. 2. Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation 2010;122:2619-33. DOI: 10.1056/NEJMc1501195
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everolimus and sirolimus, among others.) Therefore, it is questionable whether rebound ischemia is generalizable to all types of stents and thienopyridines. A companion study of dual antiplatelet therapy identified the combination of paclitaxeleluting stents and prasugrel as one in which rebound ischemia was particularly marked.2 This observation is in agreement with findings from a prior multistent trial in which most ischemic events after the discontinuation of clopidogrel occurred with paclitaxel-eluting stents,3 but in contrast to the findings from a recent trial in which there was no such increase with secondgeneration limus-eluting stents after the discontinuation of prasugrel.4 Together, these findings suggest that the increased risk of myocardial infarction after the discontinuation of thienopyridines may not be a general phenomenon but rather may be related to distinct stent–antiplatelet drug interactions, particularly involving paclitaxel-eluting stents. Such a conclusion remains hypothetical, however, pending further analyses of dual antiplatelet therapy regarding limus-eluting and bare-metal stents. Matthias Pfisterer, M.D. Christoph Kaiser, M.D. Raban Jeger, M.D. University Hospital Basel
Basel, Switzerland [email protected] No potential conflict of interest relevant to this letter was reported. 1. Kaiser C, Galatius S, Erne P, et al. Drug-eluting versus bare-
metal stents in large coronary arteries. N Engl J Med 2010;363: 2310-9. 2. Garratt KN, Weaver WD, Jenkins RD, et al. Prasugrel plus aspirin beyond 12 months is associated with improved outcomes after Taxus Liberté paclitaxel-eluting coronary stent placement. Circulation 2015;131:62-73. 3. Valgimigli M, Tebaldi M, Borghesi M, et al. Two-year outcomes after first- or second-generation drug-eluting or baremetal stent implantation in all-comer patients undergoing percutaneous coronary intervention: a pre-specified analysis from the PRODIGY study (PROlonging Dual Antiplatelet Treatment After Grading stent-induced Intimal hyperplasia studY). JACC Cardiovasc Interv 2014;7:20-8. 4. Kaiser C, Galatius S, Jeger R, et al. Long-term efficacy and safety of biodegradable-polymer biolimus-eluting stents: main results of the Basel Stent Kosten-Effektivitäts Trial–PROspective Validation Examination II (BASKET-PROVE II), a randomized, controlled noninferiority 2-year outcome trial. Circulation 2015; 131:74-81.
To the Editor: An intriguing observation of the Dual Antiplatelet Therapy study is the increase in the risk of myocardial infarction after discontinuation of dual antiplatelet therapy. This “rebound ischemia” phenomenon, first described after the discontinuation of clopidogrel in first- DOI: 10.1056/NEJMc1501195 generation drug-eluting stents, was no longer detected with second-generation “limus”-eluting To the Editor: Mauri et al. report that dual anstents.1 (The limus family of drugs includes tiplatelet therapy beyond 1 year after placement 1372
n engl j med 372;14 nejm.org april 2, 2015
The New England Journal of Medicine Downloaded from nejm.org on April 2, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
correspondence
of drug-eluting stents significantly reduced the risk of major adverse cardiovascular and cerebrovascular events. With the introduction of newgeneration drug-eluting stents, accelerated endothelial coverage of struts is attained,1 and the rates of stent thrombosis and myocardial infarction are reduced.2 Thus, recent studies using new-generation drug-eluting stents show no significant difference in adverse-event rates between 6-month and 12-to-24-month dual antiplatelet therapy.3,4 The study by Mauri et al. used a mixture of first-generation drug-eluting stents (mostly paclitaxel-eluting stents) and new-generation devices (mostly everolimus-eluting stents), and the rate of major adverse cardiovascular and cerebrovascular events was 4.3% in the continuedthienopyridine group and 5.9% in the placebo group (P
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
Duration of Dual Antiplatelet Therapy after Drug-Eluting Stents To the Editor: Mauri et al. (Dec. 4 issue)1 report a significant increase in the risk of cancer-related death in patients receiving a thienopyridine drug, as compared with placebo (0.62% vs. 0.28%, P = 0.02), and a numerical excess in incident cancer (2.03% vs. 1.62%, P = 0.14) (Table S8 in the Supplementary Appendix of the article, available at NEJM.org). Of the two thienopyridines used in this trial, only prasugrel has been associated with a significantly increased risk of incident cancer in a previous trial.2 The association of prasugrel treatment and new cancer diagnosis has also been specifically investigated by the Food and Drug Administration.3 However, whether the signal of excess cancer events observed in the current trial occurred in patients receiving clopidogrel or prasugrel is not reported. Can the authors report the numbers of cancer-related deaths and cancers reported after randomization according to which thienopyridine each patient received? Ilke Sipahi, M.D.
nary-artery stenting. Those patients who received aspirin alone had a higher incidence of stent thrombosis than those who received dual antiplatelet therapy. Most people will buy coated aspirin, unless specifically instructed to use uncoated aspirin. As shown by Grosser et al.,1 49% of people taking coated aspirin do not have effective inhibition of platelet cyclooxygenase-1 and appear to be “aspirin resistant.” The report by Mauri et al. does not indicate how many patients were using coated aspirin, and the activity of platelet cyclooxygenase-1 was apparently not assessed. Is it possible that the apparent benefit of prolonged thienopyridine therapy was due to the use of coated aspirin, with consequent failure of aspirin effect? J. Lawrence Dohan, M.D.
Acibadem University
FitzGerald GA. Drug resistance and pseudoresistance: an unintended consequence of enteric coating aspirin. Circulation 2013; 127:377-85.
Istanbul, Turkey [email protected] Dr. Sipahi reports receiving lecture fees from Bayer. No other potential conflict of interest relevant to this letter was reported.
Marlborough Hospital Hudson, MA [email protected] No potential conflict of interest relevant to this letter was reported. 1. Grosser T, Fries S, Lawson JA, Kapoor SC, Grant GR,
DOI: 10.1056/NEJMc1501195
1. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of
dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155-66. 2. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15. 3. Prasugrel. Silver Spring, MD: Food and Drug Administration (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/ 022307s000_RiskR_P4.pdf). DOI: 10.1056/NEJMc1501195
To the Editor: Mauri et al. report a reduction in vascular events by extending the duration of thienopyridine therapy beyond 1 year after coro-
this week’s letters 1371 Duration of Dual Antiplatelet Therapy after Drug-Eluting Stents 1374 Multiple-System Atrophy 1376 Severe Ebola Virus Infection Complicated by Gram-Negative Septicemia 1377 A Case of Iced-Tea Nephropathy
n engl j med 372;14 nejm.org april 2, 2015
The New England Journal of Medicine Downloaded from nejm.org on April 2, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
1371
The
n e w e ng l a n d j o u r na l
To the Editor: Mauri et al. report a significant reduction in stent thrombosis and major cardiovascular events with dual antiplatelet therapy beyond 12 months after the placement of a drugeluting stent. There was an increased risk of bleeding noted in the group receiving dual antiplatelet therapy for 30 months. In 2010, the American College of Cardiology Foundation, the American College of Gastroenterology, and the American Heart Association updated their expert consensus document on approaches to reduce gastrointestinal risk in persons receiving antiplatelet therapy, with a specific focus on dual antiplatelet therapy.1,2 Both dual antiplatelet therapy and an age of more than 60 years are indications for the use of proton-pump inhibitors (PPIs) in order to reduce the risk of gastrointestinal bleeding. The majority of patients in the study by Mauri et al. were older than 60 years of age and received dual antiplatelet therapy. It would be useful to know the levels of reported PPI use in the study in order to evaluate the safety and efficacy of dual antiplatelet therapy beyond 12 months. Joel C. Marrs, Pharm.D. University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
Aurora, CO [email protected] No potential conflict of interest relevant to this letter was reported. 1. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA
2008 Expert Consensus Document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2008;52: 1502-17. 2. Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation 2010;122:2619-33. DOI: 10.1056/NEJMc1501195
of
m e dic i n e
everolimus and sirolimus, among others.) Therefore, it is questionable whether rebound ischemia is generalizable to all types of stents and thienopyridines. A companion study of dual antiplatelet therapy identified the combination of paclitaxeleluting stents and prasugrel as one in which rebound ischemia was particularly marked.2 This observation is in agreement with findings from a prior multistent trial in which most ischemic events after the discontinuation of clopidogrel occurred with paclitaxel-eluting stents,3 but in contrast to the findings from a recent trial in which there was no such increase with secondgeneration limus-eluting stents after the discontinuation of prasugrel.4 Together, these findings suggest that the increased risk of myocardial infarction after the discontinuation of thienopyridines may not be a general phenomenon but rather may be related to distinct stent–antiplatelet drug interactions, particularly involving paclitaxel-eluting stents. Such a conclusion remains hypothetical, however, pending further analyses of dual antiplatelet therapy regarding limus-eluting and bare-metal stents. Matthias Pfisterer, M.D. Christoph Kaiser, M.D. Raban Jeger, M.D. University Hospital Basel
Basel, Switzerland [email protected] No potential conflict of interest relevant to this letter was reported. 1. Kaiser C, Galatius S, Erne P, et al. Drug-eluting versus bare-
metal stents in large coronary arteries. N Engl J Med 2010;363: 2310-9. 2. Garratt KN, Weaver WD, Jenkins RD, et al. Prasugrel plus aspirin beyond 12 months is associated with improved outcomes after Taxus Liberté paclitaxel-eluting coronary stent placement. Circulation 2015;131:62-73. 3. Valgimigli M, Tebaldi M, Borghesi M, et al. Two-year outcomes after first- or second-generation drug-eluting or baremetal stent implantation in all-comer patients undergoing percutaneous coronary intervention: a pre-specified analysis from the PRODIGY study (PROlonging Dual Antiplatelet Treatment After Grading stent-induced Intimal hyperplasia studY). JACC Cardiovasc Interv 2014;7:20-8. 4. Kaiser C, Galatius S, Jeger R, et al. Long-term efficacy and safety of biodegradable-polymer biolimus-eluting stents: main results of the Basel Stent Kosten-Effektivitäts Trial–PROspective Validation Examination II (BASKET-PROVE II), a randomized, controlled noninferiority 2-year outcome trial. Circulation 2015; 131:74-81.
To the Editor: An intriguing observation of the Dual Antiplatelet Therapy study is the increase in the risk of myocardial infarction after discontinuation of dual antiplatelet therapy. This “rebound ischemia” phenomenon, first described after the discontinuation of clopidogrel in first- DOI: 10.1056/NEJMc1501195 generation drug-eluting stents, was no longer detected with second-generation “limus”-eluting To the Editor: Mauri et al. report that dual anstents.1 (The limus family of drugs includes tiplatelet therapy beyond 1 year after placement 1372
n engl j med 372;14 nejm.org april 2, 2015
The New England Journal of Medicine Downloaded from nejm.org on April 2, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
correspondence
of drug-eluting stents significantly reduced the risk of major adverse cardiovascular and cerebrovascular events. With the introduction of newgeneration drug-eluting stents, accelerated endothelial coverage of struts is attained,1 and the rates of stent thrombosis and myocardial infarction are reduced.2 Thus, recent studies using new-generation drug-eluting stents show no significant difference in adverse-event rates between 6-month and 12-to-24-month dual antiplatelet therapy.3,4 The study by Mauri et al. used a mixture of first-generation drug-eluting stents (mostly paclitaxel-eluting stents) and new-generation devices (mostly everolimus-eluting stents), and the rate of major adverse cardiovascular and cerebrovascular events was 4.3% in the continuedthienopyridine group and 5.9% in the placebo group (P
