T h e N E W E N G L A N D J O U R N A L of M E D I C I N E
Inefficacy o f Platelet Transfusion to Reverse Ticagrelor : Ticagrelor is an antiplatelet agent that is used for the treatment of acute cor onary syndromes.1 It selectively and reversibly binds the P2Y12 receptor. No antidote is currently t o
t h e
e d it o r
available, and the management of severe bleed ing remains challenging. Platelet transfusion, which is usually proposed to reverse the effect of antiplatelet drugs, has been suggested to be inef ficient because circulating ticagrelor and its ac tive metabolite are likely to inhibit the fresh platelets.2 We report a case that shows the inef ficacy of platelet transfusion in reversing the ef fects of ticagrelor. A 65-year-old man was admitted to our emer gency department with hemiplegia and hemispatial neglect. He had been receiving ticagrelor at a dose of 90 mg twice daily and aspirin at a dose of 75 mg per day for a recent acute coronary syndrome that had been treated with two baremetal stents. Magnetic resonance imaging con firmed the diagnosis o f stroke, without hemor rhagic transformation, and thrombolysis was immediately performed with the use of standard doses of recombinant tissue plasminogen activa tor (7-mg bolus, followed by a 67-mg infusion administered over a 60-minute period). Twelve hours later, the patient had a decreased level of consciousness. Computed tomography (CT) re vealed an intracranial hematoma with intraven tricular hemorrhage and acute hydrocephalus requiring an external ventricular drain. Before placement of the external ventricular drain, plate let transfusion was performed with double the conventional dose (17 units of platelets for a man weighing 83 kg, administered in successive transfusions of 8 units and 9 units) in order to reverse the effects of dual antiplatelet therapy. CT performed after the placement surgery re vealed a large intracranial hemorrhage, and the patient died shortly after surgery. F ig u r e 1 . P la t e le t M o n i t o r i n g d u r i n g P la t e le t T r a n s f u s io n .
P latelet tra n s fu s io n was a d m in is te re d as d o u b le th e c o n v e n tio n a l dose (17 u n its o f p la te le ts fo r a m an w e ig h in g 83 kg, a d m in is te re d in successive tra n s fu s io n s o f 8 u n its and 9 u n its; arrow s) to reverse th e e ffe c ts o f a n tip la te le t therapy. M o n ito rin g in clu d e d th e p la te le t c o u n t (Panel A), th e V e rify N o w a s p irin a nd P2Y12 assays, w ith re s u lts s h o w n as th e re s p e c tiv e re a c tio n u n its (Panel B), and th e v a s o d ila to r-s tim u la te d p h o s p h o p ro te in (VASP) a s say, w ith re s u lts s h o w n as th e p la te le t-re a c tiv ity in d e x (P anel C ). T h e d a s h e d lin e s in Panels B an d C s h o w th e p la te le t-re a c tiv ity th re s h o ld s fo r each te s t.
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JA N U A R Y 8, 2015
CORRESPONDENCE
Figure 1 summarizes the results of plateletfunction monitoring during platelet transfusion. Testing was performed with the use of the VerifyNow assay (Accumetrics), a point-of-care device that measures platelet aggregation in whole blood with the use o f two different cartridges, one for aspirin and one for P2Y12 inhibitors,3 and a vaso dilator-stimulated phosphoprotein (VASP) assay to monitor P2Y12-receptor function specifically (CY-QUANT VASP/P2Y12 kit, BioCytex).4 Before platelet transfusion (i.e., 28 hours after the last administration o f antiplatelet therapy), all test results were concordant and showed a good pharmacodynamic response to aspirin and ticagrelor, as evidenced by the fact that the respec tive test values were below the thresholds. The first transfusion o f 8 units of platelets was effec tive in reversing the effect of aspirin, as shown by the results of the aspirin-specific assay. The total 17 units increased the platelet count sub stantially but did not reverse ticagrelor-induced platelet inhibition, as shown by the results of both P2Y12 assays. This observation shows that even high-dose platelet transfusion may not be a potent antidote for ticagrelor.
IN S T R U C T IO N S
FO R LE TTE R S T O T H E E D IT O R
Letters to th e Editor are considered fo r publication, subject to editing and abridgm ent, provided they do not contain m aterial th at has been subm itted or published elsewhere. Please note th e following: • Letters in reference to aJournal article m ust not exceed 175 words (excluding references) and m ust be received w ithin
3 weeks after publication o f th e article. • Letters not related to a Journal article m ust not exceed 400 words. • A letter can have no more than five references and one figure or table. • A letter can be signed by no m ore than th ree authors. • Financial associations or other possible conflicts o f interest m ust be disclosed. Disclosures will be published w ith the letters. (For authors o f Journal articles w ho are responding to letters, w e will only publish new relevant relationships th a t have developed since publication o f th e article.) • Include your full m ailing address, telephone num ber, fax num ber, and e-m ail address w ith your letter. • All letters m ust be subm itted at authors.N EJM .org. Letters th a t do not adhere to these instructions will not be considered. W e will notify you w hen w e have m ade a decision about possible publication. Letters regarding a recentJournal article may be shared w ith th e authors o f th a t article. W e are unable to provide prepublication proofs. Subm ission o f a letter constitutes perm ission for th e Massachusetts M edical Society, its licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections,
Anne Godier, M.D., Ph.D. Guillaume Taylor, M.D.
revisions, and any other form or m edium .
F o n d a tio n O p h ta lm o lo g iq u e A d o lp h e de R o th s c h ild P aris, F rance
C O R R EC TIO N S
Pascale Gaussem, Pharm.D., Ph.D. U n iv e r s ity P aris D e s c a rte s P aris, F rance
Supported by grants from INSERM and the Conny-Maeva Charitable Foundation. Disclosure forms provided by the authors are available with the full text o f this letter at NEJM.org. 1. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57. 2. Ticagrelor: product information. London: European Medicines Agency (http://www.ema.europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/001241/WC500100494.pdf). 3. Gurbel PA, Bliden KP, Butler K, et al. Randomized double blind assessment of the ONSET and OFFSET o f the antiplatelet effects o f ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009;120:2577-85. 4. Bonello L, Paganelli F, Arpin-Bornet M, et al. Vasodilatorstimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion o f postproce dural major adverse cardiovascular events. J Thromb Haemost 2007;5:1630-6. DOI: 10.1056/NEJMC1409373 Correspondence C o pyrig ht © 2 01 5 Massachusetts M e d ic a l Society.
N E N G L J M E D 3 7 2 |2
Pandemic Preparedness and Response — Lessons from the H1N1 Influenza o f 2009 (April 3, 2014;370:1335-42). In the “Time Course o f the 2009 H1N1 Pandemic” section, in the first paragraph under “World Health Organization” (page 1337), the third sentence should have begun, “The organization pro vided guidance to inform national influenza-preparedness plans, which were in place in 74% o f countries . . .” rather than, “. . . in 74 countries . . . .” The article is correct at NEJM.org. Abatacept in B7-l-Positive Proteinuric Kidney Disease (March 27, 2014;370:1261-6). The authors’ disclosure statem ent (page 1266) has been updated; it now reads, “Since publication of their article, Drs. Greka and Mundel report anticipated fees from BMS for the planning o f a clinical trial, and Dr. Weins reports participation in negotiations with BMS to initiate a clinical trial. No further potential conflict o f interest relevant to this letter was reported.” The article is correct at NEJM.org. Attention Deficit-Hyperactivity Disorder in Children and Ado lescents (February 27, 2014;370:838-46). In Table 2 (page 842), the inform ation for Quillivant XR was incorrect: the dose should have been “20 mg/day, to a maximum o f 60 m g” rather than “25 mg/5 ml/day, to a maximum o f 60 mg,” and the num ber o f hours under Duration o f Effect should have been 12 rath er than 5. The article is correct at NEJM.org.
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JA N U A R Y 8 , 2015
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Copyright © Massachusetts Medical Society 2015.
Inefficacy o f Platelet Transfusion to Reverse Ticagrelor : Ticagrelor is an antiplatelet agent that is used for the treatment of acute cor onary syndromes.1 It selectively and reversibly binds the P2Y12 receptor. No antidote is currently t o
t h e
e d it o r
available, and the management of severe bleed ing remains challenging. Platelet transfusion, which is usually proposed to reverse the effect of antiplatelet drugs, has been suggested to be inef ficient because circulating ticagrelor and its ac tive metabolite are likely to inhibit the fresh platelets.2 We report a case that shows the inef ficacy of platelet transfusion in reversing the ef fects of ticagrelor. A 65-year-old man was admitted to our emer gency department with hemiplegia and hemispatial neglect. He had been receiving ticagrelor at a dose of 90 mg twice daily and aspirin at a dose of 75 mg per day for a recent acute coronary syndrome that had been treated with two baremetal stents. Magnetic resonance imaging con firmed the diagnosis o f stroke, without hemor rhagic transformation, and thrombolysis was immediately performed with the use of standard doses of recombinant tissue plasminogen activa tor (7-mg bolus, followed by a 67-mg infusion administered over a 60-minute period). Twelve hours later, the patient had a decreased level of consciousness. Computed tomography (CT) re vealed an intracranial hematoma with intraven tricular hemorrhage and acute hydrocephalus requiring an external ventricular drain. Before placement of the external ventricular drain, plate let transfusion was performed with double the conventional dose (17 units of platelets for a man weighing 83 kg, administered in successive transfusions of 8 units and 9 units) in order to reverse the effects of dual antiplatelet therapy. CT performed after the placement surgery re vealed a large intracranial hemorrhage, and the patient died shortly after surgery. F ig u r e 1 . P la t e le t M o n i t o r i n g d u r i n g P la t e le t T r a n s f u s io n .
P latelet tra n s fu s io n was a d m in is te re d as d o u b le th e c o n v e n tio n a l dose (17 u n its o f p la te le ts fo r a m an w e ig h in g 83 kg, a d m in is te re d in successive tra n s fu s io n s o f 8 u n its and 9 u n its; arrow s) to reverse th e e ffe c ts o f a n tip la te le t therapy. M o n ito rin g in clu d e d th e p la te le t c o u n t (Panel A), th e V e rify N o w a s p irin a nd P2Y12 assays, w ith re s u lts s h o w n as th e re s p e c tiv e re a c tio n u n its (Panel B), and th e v a s o d ila to r-s tim u la te d p h o s p h o p ro te in (VASP) a s say, w ith re s u lts s h o w n as th e p la te le t-re a c tiv ity in d e x (P anel C ). T h e d a s h e d lin e s in Panels B an d C s h o w th e p la te le t-re a c tiv ity th re s h o ld s fo r each te s t.
196
N
ENG LJ
M E D 3 7 2 |2
N E J M .O R G
JA N U A R Y 8, 2015
CORRESPONDENCE
Figure 1 summarizes the results of plateletfunction monitoring during platelet transfusion. Testing was performed with the use of the VerifyNow assay (Accumetrics), a point-of-care device that measures platelet aggregation in whole blood with the use o f two different cartridges, one for aspirin and one for P2Y12 inhibitors,3 and a vaso dilator-stimulated phosphoprotein (VASP) assay to monitor P2Y12-receptor function specifically (CY-QUANT VASP/P2Y12 kit, BioCytex).4 Before platelet transfusion (i.e., 28 hours after the last administration o f antiplatelet therapy), all test results were concordant and showed a good pharmacodynamic response to aspirin and ticagrelor, as evidenced by the fact that the respec tive test values were below the thresholds. The first transfusion o f 8 units of platelets was effec tive in reversing the effect of aspirin, as shown by the results of the aspirin-specific assay. The total 17 units increased the platelet count sub stantially but did not reverse ticagrelor-induced platelet inhibition, as shown by the results of both P2Y12 assays. This observation shows that even high-dose platelet transfusion may not be a potent antidote for ticagrelor.
IN S T R U C T IO N S
FO R LE TTE R S T O T H E E D IT O R
Letters to th e Editor are considered fo r publication, subject to editing and abridgm ent, provided they do not contain m aterial th at has been subm itted or published elsewhere. Please note th e following: • Letters in reference to aJournal article m ust not exceed 175 words (excluding references) and m ust be received w ithin
3 weeks after publication o f th e article. • Letters not related to a Journal article m ust not exceed 400 words. • A letter can have no more than five references and one figure or table. • A letter can be signed by no m ore than th ree authors. • Financial associations or other possible conflicts o f interest m ust be disclosed. Disclosures will be published w ith the letters. (For authors o f Journal articles w ho are responding to letters, w e will only publish new relevant relationships th a t have developed since publication o f th e article.) • Include your full m ailing address, telephone num ber, fax num ber, and e-m ail address w ith your letter. • All letters m ust be subm itted at authors.N EJM .org. Letters th a t do not adhere to these instructions will not be considered. W e will notify you w hen w e have m ade a decision about possible publication. Letters regarding a recentJournal article may be shared w ith th e authors o f th a t article. W e are unable to provide prepublication proofs. Subm ission o f a letter constitutes perm ission for th e Massachusetts M edical Society, its licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections,
Anne Godier, M.D., Ph.D. Guillaume Taylor, M.D.
revisions, and any other form or m edium .
F o n d a tio n O p h ta lm o lo g iq u e A d o lp h e de R o th s c h ild P aris, F rance
C O R R EC TIO N S
Pascale Gaussem, Pharm.D., Ph.D. U n iv e r s ity P aris D e s c a rte s P aris, F rance
Supported by grants from INSERM and the Conny-Maeva Charitable Foundation. Disclosure forms provided by the authors are available with the full text o f this letter at NEJM.org. 1. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57. 2. Ticagrelor: product information. London: European Medicines Agency (http://www.ema.europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/001241/WC500100494.pdf). 3. Gurbel PA, Bliden KP, Butler K, et al. Randomized double blind assessment of the ONSET and OFFSET o f the antiplatelet effects o f ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009;120:2577-85. 4. Bonello L, Paganelli F, Arpin-Bornet M, et al. Vasodilatorstimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion o f postproce dural major adverse cardiovascular events. J Thromb Haemost 2007;5:1630-6. DOI: 10.1056/NEJMC1409373 Correspondence C o pyrig ht © 2 01 5 Massachusetts M e d ic a l Society.
N E N G L J M E D 3 7 2 |2
Pandemic Preparedness and Response — Lessons from the H1N1 Influenza o f 2009 (April 3, 2014;370:1335-42). In the “Time Course o f the 2009 H1N1 Pandemic” section, in the first paragraph under “World Health Organization” (page 1337), the third sentence should have begun, “The organization pro vided guidance to inform national influenza-preparedness plans, which were in place in 74% o f countries . . .” rather than, “. . . in 74 countries . . . .” The article is correct at NEJM.org. Abatacept in B7-l-Positive Proteinuric Kidney Disease (March 27, 2014;370:1261-6). The authors’ disclosure statem ent (page 1266) has been updated; it now reads, “Since publication of their article, Drs. Greka and Mundel report anticipated fees from BMS for the planning o f a clinical trial, and Dr. Weins reports participation in negotiations with BMS to initiate a clinical trial. No further potential conflict o f interest relevant to this letter was reported.” The article is correct at NEJM.org. Attention Deficit-Hyperactivity Disorder in Children and Ado lescents (February 27, 2014;370:838-46). In Table 2 (page 842), the inform ation for Quillivant XR was incorrect: the dose should have been “20 mg/day, to a maximum o f 60 m g” rather than “25 mg/5 ml/day, to a maximum o f 60 mg,” and the num ber o f hours under Duration o f Effect should have been 12 rath er than 5. The article is correct at NEJM.org.
N E J M .O R G
JA N U A R Y 8 , 2015
197
Copyright © Massachusetts Medical Society 2015.
