Downloaded from http://jnis.bmj.com/ on May 25, 2015 - Published by group.bmj.com
Standards
Platelet function inhibitors and platelet function testing in neurointerventional procedures Chirag D Gandhi,1 Ketan R Bulsara,2 Johanna Fifi,3 Tareq Kass-Hout,1 Ryan A Grant,4 Josser E Delgado Almandoz,5 Joey English,6 Philip M Meyers,7 Todd Abruzzo,8 Charles J Prestigiacomo,1 Ciaran James Powers,9 Seon-Kyu Lee,10 Barbara Albani,11 Huy M Do,12 Clifford J Eskey,13 Athos Patsalides,14 Steven Hetts,15 M Shazam Hussain,16 Sameer A Ansari,17 Joshua A Hirsch,18 Michael Kelly,19 Peter Rasmussen,20 William Mack,21 G Lee Pride,22 Michael J Alexander,23 Mahesh V Jayaraman,24 on behalf of the SNIS Standards and Guidelines Committee For numbered affiliations see end of article. Correspondence to Chirag D Gandhi, Department of Neurosurgery, Rutgers University-NJ Medical School, Newark, NJ, USA; [email protected] Accepted 30 June 2014 Published Online First 23 July 2014
To cite: Gandhi CD, Bulsara KR, Fifi J, et al. J NeuroIntervent Surg 2014;6:567–577.
INTRODUCTION Over the past decade there has been a growing use of intracranial stents for the treatment of both ischemic and hemorrhagic cerebrovascular disease, including stents to assist in the remodeling of the neck of aneurysms as well as the use of flow diverting devices for aneurysm treatment. With this increase in stent usage has come a growing need for the neurointerventional (NI) community to understand the pharmacology of medications used for modifying platelet function, as well as the testing methodologies available. Platelet function testing in NI procedures remains controversial. While pre-procedural antiplatelet assays might lead to a reduced rate of thromboembolic complications, little evidence exists to support this as a standard of care practice. Despite the routine use of dual antiplatelet therapy (DAT) with aspirin and a P2Y12 receptor antagonist (such as clopidogrel, prasugrel, or ticagrelor) in most neuroembolization procedures necessitating intraluminal reconstruction devices, thromboembolic complications are still encountered.1–3 Moreover, DAT carries the risk of hemorrhagic complications, with intracerebral hemorrhage (ICH) being the most potentially devastating.4 5 Light transmission aggregometry (LTA) is the gold standard to test for platelet reactivity, but it is usually expensive and may not be easily obtainable at many centers. This has led to the development of pointof-care assays, such as the VerifyNow (Accumetrics, San Diego, California, USA), which correlates strongly with LTA and can reliably measure the degree of P2Y12 receptor inhibition.6–9 VerifyNow results are reported in P2Y12 reaction units (PRUs), with a lower PRU value corresponding to a higher level of P2Y12 receptor inhibition and, presumably, a lower probability of platelet aggregation, and a higher PRU value corresponding to a lower level of P2Y12 receptor inhibition and, hence, a higher chance of platelet activation and aggregation. While aspirin resistance is perhaps less common, clopidogrel resistance may be more challenging as it is reported in the monitoring cohort to be as high as 30–35% and is usually due in part to genetic variation, which is reported to increase thromboembolic complications even with escalating
dosing of clopidogrel.3 4 10 11 Patients who have CYP2C19 allelic variants are highly likely to exhibit clopidogrel resistance. The cardiology literature, representing many large multicenter randomized controlled trials, did not show an overall clinical outcome benefit of antiplatelet therapy modification based on pre-procedural assays.12 13 However, there is evidence in the cardiology literature to suggest that clopidogrel resistance leads to a higher level of thrombotic complications. The validity of extrapolating the cardiology literature to the NI population is questionable, especially since the underlying vessel in the setting of cerebral aneurysm treatment with concomitant stent placement may not be as diseased with atherosclerotic plaque and precedent angioplasty as in the coronary circulation. Furthermore, NI procedures using stents and flow diverters have been associated with perioperative ICH, and some studies indicate that P2Y12 receptor over-inhibition may play a role.4 5 14 Many NI procedures necessitate patient treatment with mono antiplatelet therapy or DAT for variable periods of time, with or without preprocedural loading doses. The purpose of this consensus paper is to develop recommendations for the use of platelet function testing in this unique patient population.
METHODS Recommendations were developed based on the existing literature, a robust discussion regarding the interpretation of the literature, and the collective experience of the members of the writing group (table 1). Experts from academic institutions in North America from the specialties of neurosurgery, neurology, and interventional neuroradiology were recruited based on their expertise related to each scenario discussed. A computerized search of the MEDLINE database (PubMed) from 1 January 1991 to 31 November 2013 was performed using the search terms ‘antiplatelet’, ‘treatment’, ‘VerifyNow’, ‘LTA’, ‘PRUs’, ‘endovascular’, ‘neuro-endovascular’, and ‘interventional radiology’ with the purpose of identifying published articles on the utility of antiplatelet function tests in NI procedures. All relevant English language articles published during this period were taken into consideration while writing
Gandhi CD, et al. J NeuroIntervent Surg 2014;6:567–577. doi:10.1136/neurintsurg-2014-011357
567
Downloaded from http://jnis.bmj.com/ on May 25, 2015 - Published by group.bmj.com
Standards Table 1 Consensus agreement on the definitions of levels of evidence Level of evidence A B C
Multiple randomized clinical trials or meta-analyses Single randomized trial or non-randomized studies Expert opinion, case studies or standard of care
this consensus paper. The literature review consisted mostly of case series and non-randomized single-center studies.
MECHANISMS OF INTRAPROCEDURAL THROMBOSIS There are four major platelet function factors which influence potential complications in NI procedures: adherence,15 activation and secretion,16 aggregation,17 and interaction with coagulation factors.18 When a foreign body (eg, aneurysm coil, stent, catheter, or wire) is introduced into the intravascular space, a process of thrombosis and inflammation is initiated.19 Leukocytes are summoned to the foreign body and express tissue factor on exposed monocytes20 that can then activate platelet aggregation. Additionally, released inflammatory mediators can activate platelets, allowing for thrombus formation.19 Furthermore, a number of plasma proteins, including fibrinogen, bind to foreign bodies within minutes, initiating a platelet-induced thrombus cascade.21 22 How much platelet aggregation and thrombosis occurs on neuroendovascular foreign bodies is determined by the composition of the implants/tools, surface charge, endothelial damage, as well as sheer stress.23 Similarly, when detachable coils are detached via a positive charge, negatively charged blood products including platelets and red blood cells may be attracted to this site and this process may induce significant occlusion of aneurysms during coiling.23 Likewise, some authors have theorized that high radial force stents, such as balloon-expandable stents, induce significant endothelial injury and more platelet aggregation and thrombus formation than would be seen with less traumatic low radial force nitinol self-expanding stents.23 While thought provoking, the validity of this theory and its long-term significance remain unknown.
PHARMACOLOGY OF ANTIPLATELET AGENTS Acetylsalicylic acid (aspirin, ASA) Mechanism of action Aspirin is absorbed by the gastrointestinal tract and hydrolyzed to salicylic acid.24 It irreversibly acetylates cyclo-oxygenase COX-1 and COX-2, thereby blocking the conversion of arachidonic acid to prostaglandins and eventually thromboxane A2.25 This equates to a prolonged bleeding time secondary to platelet aggregation being blocked, rather than adhesion.15–17 Platelets lack the ability to regenerate COX, meaning that aspirin is a suicide inhibitor as it lasts for the life of the platelet, which is about 7–10 days.25 Only low doses of aspirin are needed to inhibit COX-1 in healthy subjects,26 whereas higher doses are needed to inhibit COX-2, with the latter providing analgesia and reduction in inflammation.25
Pharmacokinetics The bioavailability of aspirin is approximately 50%,25 with activity noted as early as 5 min after ingestion and peak plasma levels obtained relatively quickly at about 30–60 min.23 This rapid maximal effect has been attributed to acetylation of COX 568
in the portal circulation.27 Enteric-coated preparations have lower bioavailability and a longer time to peak plasma levels of 3–4 h.27 Interestingly, although aspirin has a short half-life of 15–20 min, given that its acetylation is irreversible, its effect is long-acting.25 However, COX activity recovers at about 10% per day, given new platelet synthesis, and it has been shown that as little as 20% of platelets with normal activity can result in normal hemostasis.28
Dosing Platelet prostaglandin synthesis is nearly completely inhibited by 100 mg oral aspirin taken once or by 30 mg taken daily for 7– 10 days.27 28 Doses below 100 mg result in dose-dependent effects on thromboxane A2 production, and repeated daily doses have a cumulative effect.28 To determine the best dose in preventing any serious vascular event (including myocardial infarction and stroke), a meta-analysis of 287 randomized trials, equating to 135 000 patients, found that doses of 75–150 mg resulted in a 32% reduction in vascular events, doses of 160– 325 mg a 26% reduction, and higher doses of 500–1500 mg a 19% reduction, whereas doses 240 predicted thromboembolic events while a PRU value of
Standards
Platelet function inhibitors and platelet function testing in neurointerventional procedures Chirag D Gandhi,1 Ketan R Bulsara,2 Johanna Fifi,3 Tareq Kass-Hout,1 Ryan A Grant,4 Josser E Delgado Almandoz,5 Joey English,6 Philip M Meyers,7 Todd Abruzzo,8 Charles J Prestigiacomo,1 Ciaran James Powers,9 Seon-Kyu Lee,10 Barbara Albani,11 Huy M Do,12 Clifford J Eskey,13 Athos Patsalides,14 Steven Hetts,15 M Shazam Hussain,16 Sameer A Ansari,17 Joshua A Hirsch,18 Michael Kelly,19 Peter Rasmussen,20 William Mack,21 G Lee Pride,22 Michael J Alexander,23 Mahesh V Jayaraman,24 on behalf of the SNIS Standards and Guidelines Committee For numbered affiliations see end of article. Correspondence to Chirag D Gandhi, Department of Neurosurgery, Rutgers University-NJ Medical School, Newark, NJ, USA; [email protected] Accepted 30 June 2014 Published Online First 23 July 2014
To cite: Gandhi CD, Bulsara KR, Fifi J, et al. J NeuroIntervent Surg 2014;6:567–577.
INTRODUCTION Over the past decade there has been a growing use of intracranial stents for the treatment of both ischemic and hemorrhagic cerebrovascular disease, including stents to assist in the remodeling of the neck of aneurysms as well as the use of flow diverting devices for aneurysm treatment. With this increase in stent usage has come a growing need for the neurointerventional (NI) community to understand the pharmacology of medications used for modifying platelet function, as well as the testing methodologies available. Platelet function testing in NI procedures remains controversial. While pre-procedural antiplatelet assays might lead to a reduced rate of thromboembolic complications, little evidence exists to support this as a standard of care practice. Despite the routine use of dual antiplatelet therapy (DAT) with aspirin and a P2Y12 receptor antagonist (such as clopidogrel, prasugrel, or ticagrelor) in most neuroembolization procedures necessitating intraluminal reconstruction devices, thromboembolic complications are still encountered.1–3 Moreover, DAT carries the risk of hemorrhagic complications, with intracerebral hemorrhage (ICH) being the most potentially devastating.4 5 Light transmission aggregometry (LTA) is the gold standard to test for platelet reactivity, but it is usually expensive and may not be easily obtainable at many centers. This has led to the development of pointof-care assays, such as the VerifyNow (Accumetrics, San Diego, California, USA), which correlates strongly with LTA and can reliably measure the degree of P2Y12 receptor inhibition.6–9 VerifyNow results are reported in P2Y12 reaction units (PRUs), with a lower PRU value corresponding to a higher level of P2Y12 receptor inhibition and, presumably, a lower probability of platelet aggregation, and a higher PRU value corresponding to a lower level of P2Y12 receptor inhibition and, hence, a higher chance of platelet activation and aggregation. While aspirin resistance is perhaps less common, clopidogrel resistance may be more challenging as it is reported in the monitoring cohort to be as high as 30–35% and is usually due in part to genetic variation, which is reported to increase thromboembolic complications even with escalating
dosing of clopidogrel.3 4 10 11 Patients who have CYP2C19 allelic variants are highly likely to exhibit clopidogrel resistance. The cardiology literature, representing many large multicenter randomized controlled trials, did not show an overall clinical outcome benefit of antiplatelet therapy modification based on pre-procedural assays.12 13 However, there is evidence in the cardiology literature to suggest that clopidogrel resistance leads to a higher level of thrombotic complications. The validity of extrapolating the cardiology literature to the NI population is questionable, especially since the underlying vessel in the setting of cerebral aneurysm treatment with concomitant stent placement may not be as diseased with atherosclerotic plaque and precedent angioplasty as in the coronary circulation. Furthermore, NI procedures using stents and flow diverters have been associated with perioperative ICH, and some studies indicate that P2Y12 receptor over-inhibition may play a role.4 5 14 Many NI procedures necessitate patient treatment with mono antiplatelet therapy or DAT for variable periods of time, with or without preprocedural loading doses. The purpose of this consensus paper is to develop recommendations for the use of platelet function testing in this unique patient population.
METHODS Recommendations were developed based on the existing literature, a robust discussion regarding the interpretation of the literature, and the collective experience of the members of the writing group (table 1). Experts from academic institutions in North America from the specialties of neurosurgery, neurology, and interventional neuroradiology were recruited based on their expertise related to each scenario discussed. A computerized search of the MEDLINE database (PubMed) from 1 January 1991 to 31 November 2013 was performed using the search terms ‘antiplatelet’, ‘treatment’, ‘VerifyNow’, ‘LTA’, ‘PRUs’, ‘endovascular’, ‘neuro-endovascular’, and ‘interventional radiology’ with the purpose of identifying published articles on the utility of antiplatelet function tests in NI procedures. All relevant English language articles published during this period were taken into consideration while writing
Gandhi CD, et al. J NeuroIntervent Surg 2014;6:567–577. doi:10.1136/neurintsurg-2014-011357
567
Downloaded from http://jnis.bmj.com/ on May 25, 2015 - Published by group.bmj.com
Standards Table 1 Consensus agreement on the definitions of levels of evidence Level of evidence A B C
Multiple randomized clinical trials or meta-analyses Single randomized trial or non-randomized studies Expert opinion, case studies or standard of care
this consensus paper. The literature review consisted mostly of case series and non-randomized single-center studies.
MECHANISMS OF INTRAPROCEDURAL THROMBOSIS There are four major platelet function factors which influence potential complications in NI procedures: adherence,15 activation and secretion,16 aggregation,17 and interaction with coagulation factors.18 When a foreign body (eg, aneurysm coil, stent, catheter, or wire) is introduced into the intravascular space, a process of thrombosis and inflammation is initiated.19 Leukocytes are summoned to the foreign body and express tissue factor on exposed monocytes20 that can then activate platelet aggregation. Additionally, released inflammatory mediators can activate platelets, allowing for thrombus formation.19 Furthermore, a number of plasma proteins, including fibrinogen, bind to foreign bodies within minutes, initiating a platelet-induced thrombus cascade.21 22 How much platelet aggregation and thrombosis occurs on neuroendovascular foreign bodies is determined by the composition of the implants/tools, surface charge, endothelial damage, as well as sheer stress.23 Similarly, when detachable coils are detached via a positive charge, negatively charged blood products including platelets and red blood cells may be attracted to this site and this process may induce significant occlusion of aneurysms during coiling.23 Likewise, some authors have theorized that high radial force stents, such as balloon-expandable stents, induce significant endothelial injury and more platelet aggregation and thrombus formation than would be seen with less traumatic low radial force nitinol self-expanding stents.23 While thought provoking, the validity of this theory and its long-term significance remain unknown.
PHARMACOLOGY OF ANTIPLATELET AGENTS Acetylsalicylic acid (aspirin, ASA) Mechanism of action Aspirin is absorbed by the gastrointestinal tract and hydrolyzed to salicylic acid.24 It irreversibly acetylates cyclo-oxygenase COX-1 and COX-2, thereby blocking the conversion of arachidonic acid to prostaglandins and eventually thromboxane A2.25 This equates to a prolonged bleeding time secondary to platelet aggregation being blocked, rather than adhesion.15–17 Platelets lack the ability to regenerate COX, meaning that aspirin is a suicide inhibitor as it lasts for the life of the platelet, which is about 7–10 days.25 Only low doses of aspirin are needed to inhibit COX-1 in healthy subjects,26 whereas higher doses are needed to inhibit COX-2, with the latter providing analgesia and reduction in inflammation.25
Pharmacokinetics The bioavailability of aspirin is approximately 50%,25 with activity noted as early as 5 min after ingestion and peak plasma levels obtained relatively quickly at about 30–60 min.23 This rapid maximal effect has been attributed to acetylation of COX 568
in the portal circulation.27 Enteric-coated preparations have lower bioavailability and a longer time to peak plasma levels of 3–4 h.27 Interestingly, although aspirin has a short half-life of 15–20 min, given that its acetylation is irreversible, its effect is long-acting.25 However, COX activity recovers at about 10% per day, given new platelet synthesis, and it has been shown that as little as 20% of platelets with normal activity can result in normal hemostasis.28
Dosing Platelet prostaglandin synthesis is nearly completely inhibited by 100 mg oral aspirin taken once or by 30 mg taken daily for 7– 10 days.27 28 Doses below 100 mg result in dose-dependent effects on thromboxane A2 production, and repeated daily doses have a cumulative effect.28 To determine the best dose in preventing any serious vascular event (including myocardial infarction and stroke), a meta-analysis of 287 randomized trials, equating to 135 000 patients, found that doses of 75–150 mg resulted in a 32% reduction in vascular events, doses of 160– 325 mg a 26% reduction, and higher doses of 500–1500 mg a 19% reduction, whereas doses 240 predicted thromboembolic events while a PRU value of
