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{{CMG}}; {{MWT}} | {{CMG}}; {{MWT}} | ||
==Overview== | |||
[[Thrombocytopenia]] is defined as a platelet count of <100,000 cell/mm3. The [[morbidity]] and [[mortality]] associated with percutaneous coronary intervention (PCI) has substantially improved given recent advances in devices and [[pharmacotherapy]].<ref>Singh M, Rihal CS, Gersh BJ, Lennon RJ, Prasad A, Sorajja P, Gullerud RE, Holmes DR Jr. Twenty-five-year trends in in-hospital and long-term outcome after percutaneous coronary intervention: a single-institution experience. Circulation. 2007;115:2835-41. </ref> Increased utilization of [[antiplatelet]] and [[antithrombin]] therapies has been associated with fewer postprocedure [[ischemic]] [[complication]]s. Despite these benefits, there is also an increased risk of [[bleeding]] and [[hematologic]] [[complication]]s. One such [[hematologic]] [[complication]] is [[thrombocytopenia]]. Both [[antiplatelet]] and [[antithrombin]] agents have been associated with a heightened risk of developing [[thrombocytopenia]].<ref>Boersma E, Harrington RA, Moliterno DJ, White H, Théroux P, Van de Werf F, de Torbal A, Armstrong PW, Wallentin LC, Wilcox RG, Simes J, Califf RM, Topol EJ, Simoons ML. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomized clinical trials. Lancet 2002;359:189-98.</ref> Furthermore, patients with pre-PCI [[thrombocytopenia]] are at an increased risk for [[mortality]] and [[hemorrhage]] as compared to patients without [[thrombocytopenia]].<ref>Berkowitz SD, Sane DC, Sigmon KN, Shavender JH, Harrington RA, Tcheng JE, Topol EJ, Califf RM, for the EPIC Study Group. Occurrence and clinical significance of thrombocytopenia in a population undergoing high-risk percutaneous coronary revascularization. J Am Coll Cardiol. 1998;32:387-392.</ref> | |||
==Thrombocytopenia== | ==Thrombocytopenia== | ||
===Epidemiology and Demographics=== | ===Epidemiology and Demographics=== | ||
The [[incidence]] of [[thrombocytopenia]] among patients with [[ischemic heart disease]] exposed to [[antiplatelet]] and [[antithrombin]] [[therapy|therapies]] varies widely and has been reported to be 3% to 16.5%.<ref>Eikelboom JW, Anand SS, Mehta SR, Weitz JI, Yi C, Yusuf S. Prognostic significance of thrombocytopenia during hirudin and heparin therapy in acute coronary syndrome without ST elevation: Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) study. Circulation. 2001;103:643-50.</ref> | The [[incidence]] of [[thrombocytopenia]] among patients with [[ischemic heart disease]] exposed to [[antiplatelet]] and [[antithrombin]] [[therapy|therapies]] varies widely and has been reported to be 3% to 16.5%.<ref>Eikelboom JW, Anand SS, Mehta SR, Weitz JI, Yi C, Yusuf S. Prognostic significance of thrombocytopenia during hirudin and heparin therapy in acute coronary syndrome without ST elevation: Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) study. Circulation. 2001;103:643-50.</ref> | ||
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#[[Platelet]]-rich [[plasma]] aggregation test and the [[antibody test]]ing for anti-[[PF4]] [[antibodies]] are less commonly utilized with poor [[sensitivity (tests)|sensitivities]] reported for both tests. | #[[Platelet]]-rich [[plasma]] aggregation test and the [[antibody test]]ing for anti-[[PF4]] [[antibodies]] are less commonly utilized with poor [[sensitivity (tests)|sensitivities]] reported for both tests. | ||
=== | =====HIT Management===== | ||
#Immediate discontinuation of all heparin-containing compounds. | #Immediate discontinuation of all [[heparin]]-containing compounds. | ||
#Identification of the [[HIT]] subtype. | |||
#Identification of the HIT subtype. | #If [[anticoagulation]] is required (as in the clinical setting of PCI in a patient with a known history of [[HIT]]), one of three commercially available [[direct thrombin inhibitor]]s (DTI)— [[lepirudin]], [[argatroban]], and [[bivalirudin]] should be used. | ||
#If anticoagulation is required (as in the clinical setting of PCI in a patient with a known history of HIT), one of three commercially available direct thrombin | |||
*Data from REPLACE | *In the setting of PCI, the agent with the most evidence is [[bivalirudin]]. [[Bivalirudin]] is a [[bivalent (chemistry)|bivalent]] DTI with a half-life of 25 minutes, produces consistent profound suppression of [[thrombin]] and has been studied in the setting of PCI, [[NSTEMI|non ST-segment elevation acute coronary syndromes]], and [[STEMI|ST-segment elevation myocardial infarction]]. | ||
*Data from [[REPLACE 2]], [[ACUITY]], [[HORIZON]], and [[ATBAT]] trials suggests that [[bivalirudin]] is a safe and perhaps preferred [[antithrombotic therapy|antithrombin agent]] to use for PCI in the patient with [[HIT]] or HITTS.<ref>Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Jackman JD, Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, Keren G, Carr J, Cohen EA, Betriu A, Desmet W, Kereiakes DJ, Rutsch W, Wilcox RG, de Feyter PJ, Vahanian A, Topol EJ; REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA. 2003;289:853-63.</ref><ref>Stone GW, McLaurin BT, Cox DA, Bertrand ME, Lincoff AM, Moses JW, White HD, Pocock SJ, Ware JH, Feit F, Colombo A, Aylward PE, Cequier AR, Darius H, Desmet W, Ebrahimi R, Hamon M, Rasmussen LH, Rupprecht HJ, Hoekstra J, Mehran R, Ohman EM; ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006;355:2203-16. </ref><ref>Mahaffey KW, Lewis BE, Wildermann NM, Berkowitz SD, Oliverio RM, Turco MA, Shalev Y, Ver Lee P, Traverse JH, Rodriguez AR, Ohman EM, Harrington RA, Califf RM; ATBAT Investigators. The anticoagulant therapy with bivalirudin to assist in the performance of percutaneous coronary intervention in patients with heparin-induced thrombocytopenia (ATBAT) study: main results. J Invasive Cardiol. 2003;15:611-6.</ref> | |||
==Conclusion== | ===Conclusion=== | ||
#Both pharmacological and mechanical interventional strategies can lead to decreased platelet counts in the patient undergoing PCI. | #Both [[pharmacological]] and mechanical [[interventional cardiology|interventional strategies]] can lead to [[low platelet count|decreased platelet counts]] in the patient undergoing PCI. | ||
#Important medication-related causes include thrombotic thrombocytopenic purpura associated with | #Important [[medication]]-related causes include [[TTP|thrombotic thrombocytopenic purpura]] associated with [[thienopyridine]]s, [[antibody]]-related [[platelet]] destruction seen with [[Glycprotein IIb/IIIa inhibitor|GPI]] and [[abciximab]] readministration, and [[HIT]]. | ||
#If HIT is suspected or proven, | #If [[HIT]] is suspected or proven, [[Direct thrombin inhibitor|DTI]]s are the agents of choice, with [[bivalirudin]] having the most supportive evidence. | ||
#Early recognition of thrombocytopenia and rapid assessment of its cause can guide management and improve outcomes among PCI patients with thrombocytopenia. | #Early recognition of [[thrombocytopenia]] and rapid assessment of its cause can guide management and improve outcomes among PCI patients with [[thrombocytopenia]]. | ||
==References== | ==References== | ||
Latest revision as of 15:28, 22 January 2013
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Risk calculators and risk factors for PCI complications: thrombocytopenia |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Template:MWT
Overview
Thrombocytopenia is defined as a platelet count of <100,000 cell/mm3. The morbidity and mortality associated with percutaneous coronary intervention (PCI) has substantially improved given recent advances in devices and pharmacotherapy.[1] Increased utilization of antiplatelet and antithrombin therapies has been associated with fewer postprocedure ischemic complications. Despite these benefits, there is also an increased risk of bleeding and hematologic complications. One such hematologic complication is thrombocytopenia. Both antiplatelet and antithrombin agents have been associated with a heightened risk of developing thrombocytopenia.[2] Furthermore, patients with pre-PCI thrombocytopenia are at an increased risk for mortality and hemorrhage as compared to patients without thrombocytopenia.[3]
Thrombocytopenia
Epidemiology and Demographics
The incidence of thrombocytopenia among patients with ischemic heart disease exposed to antiplatelet and antithrombin therapies varies widely and has been reported to be 3% to 16.5%.[4]
Differential Diagnosis of Thrombocytopenia in the Patient Undergoing PCI
- Laboratory Related
- Platelet coagulation with Ethylene diamine tetra acetic acid (EDTA)
- Low specimen temperature
- Decreased Platelet Production
- Viral infections
- Alcohol toxicity
- Chemotherapy
- Vitamin B12 and folate deficiency
- Increased Platelet Destruction
- Thrombotic Thrombocytopenic Purpura (TTP)
- Disseminated Intravascular Coagulation (DIC)
- Cardiopulmonary bypass graft surgery (CABG)
- Intra-aortic balloon pump (IABP) therapy
- Dilutional Thrombocytopenia
- Massive red blood cell transfusion
- Drug-Induced Thrombocytopenia
- Unfractionated heparin, low-molecular-weight heparin (includes heparin associated thrombocytopenia and heparin-induced thrombocytopenia)
- Glycoprotein IIb/IIIa inhibitors: abciximab, tirofiban, eptifibatide
- Thienopyridines: clopidogrel and ticlopidine
- Antibiotics (most commonly agents with a sulfa moiety)
- Thiazide diuretics
The most important clinical entities for the patient undergoing PCI (and the focus of this article) are:
- Pseudothrombocytopenia
- Drug-induced thrombotic thrombocytopenic purpura (TTP)
- Heparin-associated thrombocytopenia
- Heparin-induced thrombocytopenia (HIT) with or without thrombosis
Laboratory Error and Pseudothrombocytopenia
- Benign and spurious, laboratory error and pseudothrombocytopenia are confirmed with repeat blood draw.
- Patients receiving glycoprotein IIb/IIIa inhibitor (GPI) have a reported 1% to 3% incidence of pseudothrombocytopenia. Among patients receiving a GPI who develop low platelet counts, 30% will be found to have pseudothrombocytopenia.[5][6]
- Pseudothrombocytopenia is a benign condition of no clinical significance and is caused by platelet aggregation due to either ethylene diamine tetra acetic acid in the specimen tube or low temperature of the laboratory specimen.
- Diagnosis is confirmed with platelet clumping on a peripheral blood film, or with a repeat, normal platelet count when a citrate-containing specimen tube is utilized.
- Pseudothrombocytopenia is benign and therefore, alterations in management strategies are not recommended.
The importance of diagnosing pseudothrombocytopenia in the PCI patient cannot be overemphasized, as the discontinuation of antiplatelet therapies is inappropriate and may increase the risk for an adverse event.
Thrombotic Thrombocytopenic Purpura (TTP)
- Left untreated, TTP is associated with a 90% mortality rate. Therefore, recognition of the classic pentad of fever, microangiopathic hemolytic anemia, thrombocytopenia, and neurological and renal abnormalities is imperative.[7]
- Diagnosis of TTP is confirmed with the presence of >1% fragmented red blood cells (schistocytes) or microangiopathic hemolysis on the peripheral blood smear in the context of other clinical findings of the pentad.
- Although multiple systemic conditions are associated with the development of TTP, medications are implicated in up to 20% of cases.[8]
TTP occurs in one per every 5,000 patients exposed to thienopyridines and presents as thrombocytopenia usually within 2 to 4 weeks after exposure.[9]
- Clopidogrel-associated TTP commonly presents with ≤2 weeks of thienopyridine therapy, has less severe thrombocytopenia, and often is associated with renal failure.
- Typically, TTP developing >2 weeks after thienopyridine use is associated with an autoimmune pathway and a non immunologic pathway is responsible for TTP developing within 2 weeks of thienopyridine exposure.
Therapy
- Discontinuation of the thienopyridine and plasma exchange.
- Plasma exchange should be performed daily until the platelet count is normal, although the optimal duration of therapy is unknown.
- Whether thienopyridine therapy can be safely reinstituted in patients who have recovered from thienopyridine- associated TTP is unknown.
Drug-Induced Thrombocytopenia
The risk of developing drug-induced thrombocytopenia may be higher in patients undergoing PCI as antiplatelet and antithrombotic therapies have been strongly associated with drug-induced thrombocytopenia.[10]
- Clopidogrel cross-reacts with the platelet Gp IIb/IIIa receptor, signals autoimmune platelet destruction and subsequent thrombocytopenia.
- Diagnosis of Clopidogrel assoicated thrombocytopenia is demonstrated by platelet normalization upon discontinuation of thienopyridine therapy and the absence of the classic findings of TTP (such as schistocytes, fever, etc.).
Caveat for PCI patients with stent placement is that there will be an increased risk for stent thrombosis in the absence of thienopyridine therapy.
Treatment of Clopidogrel associated thrombocytopenia: methylprednisolone and platelet transfusions have demonstrated resolution.[11]
Other Causes of Drug-induced Thrombocytopenia
Glycoprotein IIbIIIa inhibitors (GPIs) and unfractionated or low-molecular-weight heparins.
- GPIs: abciximab, eptifibatide, and tirofiban.
- The reported incidence of thrombocytopenia with abciximab is 2.4% to 9.2%, and the incidence of profound thrombocytopenia (defined as a platelet count < 20,000 cells/mm3) has been reported to be 0.3%.[12]
- The risk of thrombocyopenia with the small-molecule inhibitors tirofiban and eptifibatide appears to be lower than with abciximab (reported rates are 0.5% to 3.2%)[13]
- The onset of GPI associated thrombocytopenia is within hours of initiating therapy.
- The incidence of thrombocytopenia following the readministration of abciximab is no higher than with the first exposure, however, the incidence of profound thrombocytopenia is much higher (approximately 2.4%).[14]
Etiology
GPI-induced thrombocytopenia is analogous to the autoantibody– mediated pathogenesis previously described with thienopyridine- induced thrombocytopenia.
- The [autoantibody|auto-antibodies]] to GPI are typically preformed and account for the acute presentation of thrombocytopenia.
Therapy
- GPIs should be discontinued to reduce the risk for profound thrombocytopenia. Platelet counts can be expected to return to normal 7 to 10 days.
- Platelet transfusion is indicated in patients with profound GPI- associated thrombocytopenia.
- Subsequent administration of GPI in a patient who has previously developed GPI- associated thrombocytopenia may be reasonable provided that another agent is used.[15]
Heparin-Associated and Heparin-Induced Thrombocytopenia
Heparin-associated thrombocytopenia is a benign entity that occurs in approximately 5% of patients within 48 hours to 72 hours of exposure to UFH and results in mild thrombocytopenia that resolves despite continued heparin therapy.
- No specific treatment is warranted.
HIT and its related clinical entity, heparin-induced thrombocytopenia with thrombosis syndrome (HITTS), are less begin as both can result in arterial and venous thrombosis, amputation, and death if not recognized and treated promptly.
- The incidence of HIT in the PCI population is approximately 1% to 5%.
- The pathophysiology of HIT involves heparin binding to the platelet factor 4 receptor (PF-4), which generates an IgG autoantibody. Activated heparin-PF-4 complex autoantibodies then initiate platelet consumption, resulting in a 5% to 7% bleeding rate among HIT patients.[16]
- Thrombotic complications are common and occur in 20% to 50% of HIT patients, with venous events being more common than arterial events.[17]
- HIT should be suspected in a patient who is, or has been, treated with a heparin agent (either UFH or low-molecular-weight heparin) and develops a 50% or greater decrease in platelet count or frank thrombocytopenia (<100,000 cells/m3).
Recognition is imperative as the 30-day mortality rate among HIT patients is 17% to 30%.[18]
Onset of HIT
- Typical-onset HIT occurs in 65% of reported cases and, in the heparin- naïve patient, develops 5 days to 10 days after heparin exposure.
- Rapid-onset HIT occurs 10 hours to 24 hours after heparin exposure and accounts for 30% of HIT cases.
- Delayed-onset HIT occurs in 2% of HIT patients 10 days to 40 days after the cessation of heparin therapy.
Diagnosis of HIT
- The serotonin release assay is based on the principle that antibodies from the blood of HIT patients will bind to and activate platelets from normal donors and lead to the release of serotonin.
- The heparin-induced platelet aggregation assay uses washed platelets from normal donors and measures platelet aggregation caused by the serum of a HIT patient in the presence of a heparin; this test is one of the most commonly used and is widely available.
- Platelet-rich plasma aggregation test and the antibody testing for anti-PF4 antibodies are less commonly utilized with poor sensitivities reported for both tests.
HIT Management
- Immediate discontinuation of all heparin-containing compounds.
- Identification of the HIT subtype.
- If anticoagulation is required (as in the clinical setting of PCI in a patient with a known history of HIT), one of three commercially available direct thrombin inhibitors (DTI)— lepirudin, argatroban, and bivalirudin should be used.
- In the setting of PCI, the agent with the most evidence is bivalirudin. Bivalirudin is a bivalent DTI with a half-life of 25 minutes, produces consistent profound suppression of thrombin and has been studied in the setting of PCI, non ST-segment elevation acute coronary syndromes, and ST-segment elevation myocardial infarction.
- Data from REPLACE 2, ACUITY, HORIZON, and ATBAT trials suggests that bivalirudin is a safe and perhaps preferred antithrombin agent to use for PCI in the patient with HIT or HITTS.[19][20][21]
Conclusion
- Both pharmacological and mechanical interventional strategies can lead to decreased platelet counts in the patient undergoing PCI.
- Important medication-related causes include thrombotic thrombocytopenic purpura associated with thienopyridines, antibody-related platelet destruction seen with GPI and abciximab readministration, and HIT.
- If HIT is suspected or proven, DTIs are the agents of choice, with bivalirudin having the most supportive evidence.
- Early recognition of thrombocytopenia and rapid assessment of its cause can guide management and improve outcomes among PCI patients with thrombocytopenia.
References
- ↑ Singh M, Rihal CS, Gersh BJ, Lennon RJ, Prasad A, Sorajja P, Gullerud RE, Holmes DR Jr. Twenty-five-year trends in in-hospital and long-term outcome after percutaneous coronary intervention: a single-institution experience. Circulation. 2007;115:2835-41.
- ↑ Boersma E, Harrington RA, Moliterno DJ, White H, Théroux P, Van de Werf F, de Torbal A, Armstrong PW, Wallentin LC, Wilcox RG, Simes J, Califf RM, Topol EJ, Simoons ML. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomized clinical trials. Lancet 2002;359:189-98.
- ↑ Berkowitz SD, Sane DC, Sigmon KN, Shavender JH, Harrington RA, Tcheng JE, Topol EJ, Califf RM, for the EPIC Study Group. Occurrence and clinical significance of thrombocytopenia in a population undergoing high-risk percutaneous coronary revascularization. J Am Coll Cardiol. 1998;32:387-392.
- ↑ Eikelboom JW, Anand SS, Mehta SR, Weitz JI, Yi C, Yusuf S. Prognostic significance of thrombocytopenia during hirudin and heparin therapy in acute coronary syndrome without ST elevation: Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) study. Circulation. 2001;103:643-50.
- ↑ The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. The EPIC Investigation. N Engl J Med. 1994;330:956-61.
- ↑ Sane DC, Damaraju LV, Topol EJ, Cabot CF, Mascelli MA, Harrington RA, Simoons ML, Califf RM. Occurrence and clinical significance of pseudothrombocytopenia during abciximab therapy. J Am Coll Cardiol. 2000;36:75-83.
- ↑ George, JN. Clinical practice. Thrombotic thrombocytopenic Purpura. N Engl J Med. 2006;354:1927-35.
- ↑ Andersohn F, Bronder E, Klimpel A, Garbe E. Proportion of drug-related serious rare blood dyscrasias: estimates from the Berlin Case-Control Surveillance Study.Am J Hematol. 2004;77:316-8.
- ↑ Bennett CL, Connors JM, Carwile JM, Moake JL, Bell WR, Tarantolo SR, McCarthy LJ, Sarode R, Hatfield AJ, Feldman MD, Davidson CJ, Tsai HM. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med. 2000;342:1773–1777.
- ↑ Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med. 200;357:580-7.
- ↑ Best PJ, Berger PB, Davis BR, Grines CL, Sadeghi HM, Williams BA, Willerson JT, Granett JR, Holmes DR Jr; PRESTO Investigators. Impact of mild or moderate chronic kidney disease on the frequency of restenosis: results from the PRESTO trial. J Am Coll Cardiol. 2004;44:1786-91.
- ↑ Topol EJ, Moliterno DJ, Herrmann HC, Powers ER, Grines CL, Cohen DJ, Cohen EA, Bertrand M, Neumann FJ, Stone GW, DiBattiste PM, Demopoulos L; TARGET Investigators. Do Tirofiban and ReoPro Give Similar Efficacy Trial. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med. 344,1888-1894.
- ↑ ESPRIT Investigators. Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. Lancet. 2000;356:2037-44.
- ↑ Tcheng JE, Kereiakes DJ, Lincoff AM, George BS, Kleiman NS, Sane DC, Cines DB, Jordan RE, Mascelli MA, Langrall MA, Damaraju L, Schantz A, Effron MB, Braden GA. Abciximab readministration: results of the ReoPro Readministration Registry. Circulation. 2001;104:870-5.
- ↑ Bougie DW, Wilker PR, Wuitschick ED, Curtis BR, Malik M, Levine S, Lind RN, Pereira J, Aster RH. Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa. Blood. 2002;100:2071-6.
- ↑ Greinacher A, Eichler P, Lubenow N, Kwasny H, Luz M. Heparin induced thrombocytopenia with thromboembolic complications: meta-analysis of 2 prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range. Blood. 2000;96:846-851.
- ↑ Warkentin TE, Kelton JG. A 14-year study of heparin induced thrombocytopenia. Am J Med. 1996;101:502–507.
- ↑ Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med. 2001;344:1286- 92.
- ↑ Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Jackman JD, Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, Keren G, Carr J, Cohen EA, Betriu A, Desmet W, Kereiakes DJ, Rutsch W, Wilcox RG, de Feyter PJ, Vahanian A, Topol EJ; REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA. 2003;289:853-63.
- ↑ Stone GW, McLaurin BT, Cox DA, Bertrand ME, Lincoff AM, Moses JW, White HD, Pocock SJ, Ware JH, Feit F, Colombo A, Aylward PE, Cequier AR, Darius H, Desmet W, Ebrahimi R, Hamon M, Rasmussen LH, Rupprecht HJ, Hoekstra J, Mehran R, Ohman EM; ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006;355:2203-16.
- ↑ Mahaffey KW, Lewis BE, Wildermann NM, Berkowitz SD, Oliverio RM, Turco MA, Shalev Y, Ver Lee P, Traverse JH, Rodriguez AR, Ohman EM, Harrington RA, Califf RM; ATBAT Investigators. The anticoagulant therapy with bivalirudin to assist in the performance of percutaneous coronary intervention in patients with heparin-induced thrombocytopenia (ATBAT) study: main results. J Invasive Cardiol. 2003;15:611-6.