Case Report / Adjunctive Pharmacotherapy

Bivalirudin Use during PCI for Stent Thrombosis in a Patient with Subacute Intracranial Hemorrhage

*,§Gregory R. Giugliano, MD and *Senthil K. Sivalingam, MD
*,§Gregory R. Giugliano, MD and *Senthil K. Sivalingam, MD
From the *Department of Internal Medicine, and the §Division of Cardiology, Baystate Medical Center, The Western Campus of Tufts University School of Medicine, Springfield, Massachusetts. Disclosures: Dr. Giugliano is on the speaker’s bureau of Schering Pharmaceuticals, Merck, Abbott Vascular, The Medicines Company, Pfizer, Radi, CV Therapeutics and Cordis Corp. He is a consultant to Abbott Vascular, Cordis, Medtronic, and the Gerson Lehrman Group. Dr. Giugliano has received research/grant support from The Medicines Co., CV Therapeutics, Medtronic, Boston Scientific Corp., Eli Lilly, Novartis and AstraZeneca. Dr. Senthil K. Sivalingam reports no conflicts of interest regarding the content herein. Address for correspondence: Gregory R. Giugliano, MD, SM, FACC, FSCAI, Associate Director, Cardiac Catheterization Laboratory and Cardiology Research, Baystate Medical Education & Research Foundation, 759 Chestnut St., BMC # S4659, Springfield, MA 01199. E-mail: gregory.giugliano@bhs.org

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ABSTRACT: Caring for patients at high risk is inherent to the practice of interventional cardiology. Recognizing high-risk situations, minimizing risk and employing preventive techniques proactively to avoid complications cannot be over-emphasized within this dynamic field. This case demonstrates real-world concerns and decision-making regarding severe bleeding risk, rescue angioplasty, stent thrombosis, appropriate usage of intravascular ultrasound and differences in stent design. Three take-home messages are identified to reduce complications in similar situations.

J INVASIVE CARDIOL 2009;21:136–138

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Case Report. A 53-year-old male with a past medical history of insulin-dependant diabetes mellitus, hypertension, hyperlipidemia and peripheral vascular disease status post aorto-bifemoral and left femoral-popliteal bypasses initially presented to an outside hospital with an acute inferior ST-segment elevation myocardial infarction. He was initially treated with intravenous (IV) reteplase and IV unfractionated heparin (UFH) without successful reperfusion. His presentation was further complicated by complete heart block and cardiogenic shock. The patient was transferred to our facility for rescue angioplasty. On arrival, the patient was intubated, externally paced and was in cardiogenic shock on a dopamine drip. He was mildly anemic with a hemoglobin of 11.8 and thrombocytopenia of 133. After placing a transvenous pacing wire in the cardiac catheterization laboratory, angiography demonstrated moderate, nonobstructive disease of the left anterior descending and circumflex arteries with faint septal collaterals to the right coronary artery (RCA). The RCA was 100% occluded in the proximal segment with heavy thrombus burden (Figure 1). Additional IV UFH was administered to achieve an activated clotting (ACT) > 300 seconds. The vessel could not be wired using a Patriot Wire™ (Boston Scientific, Natick, Massachusetts), and a Whisper Wire™ (Abbott Vascular, Abbott Park, Illinois) was successfully advanced. The lesion was pre-dilated using a 2.5 mm Opensail balloon™ (Abbott Vascular) which achieved thrombolysis in myocardial infarction (TIMI)-2 flow and identified a large underlying thrombus. The vessel was treated with 3 runs of Angiojet™ (Possis Medical, Minneapolis, Minnesota) which resulted in TIMI-3 flow after a brief period of no-reflow treated with adenosine. The mid-RCA was initially stented with a 4.0 x 30 mm S7™ stent (Medtronic, Inc., Minneapolis, Minnesota) and subsequently 2 additional overlapping S7 stents (4.0 x 9 mm and 3.5 x 15 mm) were deployed at the proximal and distal edges of the first stent, respectively, for dissections at either end. The final angiogram showed TIMI-3 flow with no residual clot or dissection (Figure 2). The transvenous pacer was removed, as the rhythm returned to normal sinus. The patient was transferred to the coronary care unit (CCU) in stable condition after receiving 300 mg of clopidogrel via a nasogastric tube. An eptifibatide drip was started due to transient no-reflow and the large thrombus burden. Four hours later, the patient developed recurrent hypotension, complete heart block and ST elevation in the inferior leads. He was brought back to the cardiac catheterization laboratory and found to have stent thrombosis possibly due to a type-A distal stent edge dissection not apparent in the previous angiograms (Figure 3). The clot was removed with AngioJet thrombectomy (Possis Medical) and the distal edge dissection was stented with a 3.0 x 15 mm S7 stent. Intravascular ultrasound (IVUS) revealed a 4.4 mm vessel with plaque prolapse in the mid-portion of the stent. This was postdilated with a 4.0 NC Ranger™ balloon (Boston Scientific) at 14 atm. Final angiography demonstrated normal flow, no residual clot and no evidence of dissection (Figure 4). The patient was continued on IV heparin and eptifibatide infusion for 48 hours. The patient’s CCU course was complicated by prolonged intubation, pneumonia, uncontrolled diabetes and renal insufficiency. On hospital day 8, he developed a left-sided facial droop and magnetic resonance imaging showed an acute right fronto-parietal infarct and a right parietal subdural hematoma. His oral dual antiplatelet therapy was continued and repeat neuroimaging studies confirmed that the hematoma was stable. Since he was thrombocytopenic, heparin-induced thrombocytopenia (HIT) antibody titers were measured and found to be negative. On hospital day 14 the patient developed acute inferior ST elevation again complicated by complete heart block and hypotension. The patient was taken to the cardiac catheterization laboratory where angiography revealed stent thrombosis in the proximal RCA (Figure 5). A temporary pacing wire was placed. Given the recent intracranial hemorrhage (ICH) and thrombocytopenia (with a question of HIT-antibody titer still pending), anticoagulation with bivalirudin was used for the intervention. The RCA was crossed with a PT-Graphix™ Wire (Boston Scientific). Initial TIMI-2 flow was achieved with repeated short inflations using a 3.5 x 15 mm OpenSail™ balloon (Guidant Corp., Indianapolis, Indiana). Due to the high clot burden, multiple runs with the AngioJet were performed. A distal edge dissection was seen in the stent in the distal RCA. An overlapping 3.0 x 15 mm Zeta™ stent (Abbott Vascular) was then deployed to cover this dissection. IVUS was performed in the RCA and revealed extensive plaque prolapse through the struts of the S7 stents (Figure 6). It became apparent that there had been a dissection from the initial procedure extending from the proximal-distal vessel. A 4.0 x 23 mm and a 4.0 x 38 mm Zeta™ stent were deployed within the S7 stent in the proximal and mid-RCA, respectively, and then postdilated to 4.4 mm for optimal apposition. TIMI-3 flow was achieved with no residual stenosis and no apparent dissection beyond the stented segment (Figure 7). The remainder of the hospital course was event-free. The patient was successfully discharged from the hospital and transferred to a rehabilitation facility for further long-term care. He has been followed closely now for nearly 5 years and suffers from severe pan-vascular disease status post left above-the-knee amputation and chronic renal insufficiency. He has not had any further cardiac events. Discussion. This case represents the successful use of the direct thrombin inhibitor bivalirudin during PCI in a patient at very high risk of hemorrhagic catastrophe due the presence of a recent ICH and recurrent stent thrombosis. There are three major points to be learned from this case: 1. The risk of major bleeding, specifically ICH, when glycoprotein (GP) IIb/IIIa inhibitors are combined with thrombolytic therapy has been explored. Initially, the concept of combined either full- or half-dose thrombolytic therapy with GP IIb/IIIa inhibition was an attractive option to reduce the well-documented risk of ICH with full-dose lytics.1 However, there are now convincing data to put this combination-facilitated strategy to rest.2–4 These data have consistently shown an increase in major bleeding with trends toward increased ICH when thrombolytic therapy and GP IIb/IIIa inhibition are combined. Predictors for major bleeding with combination therapy include older age, shorter time interval from thrombolytic therapy to GP IIb/IIIa inhibitor administration, and use of an intra-aortic balloon pump. This bleeding risk appears to be time-related with less risk of bleeding when the added GP IIb/IIIa occurs more than 24 hours following the thrombolytic administration, although this has not been clearly established.5 The efficacy of combination-facilitated PCI (thrombolytic + GP IIb/IIIa inhibition) versus GP IIb/IIIa inhibition alone confirmed the above increased bleeding risk, with no long-term improvement in outcomes. The ADVANCE MI trial, which compared combination therapy versus eptifibatide alone before primary PCI, showed a two-fold increase in major bleeding events (18/74 vs. 7/74; p = 0.02), but no difference in IC.6 A meta-analysis of randomized clinical trials comparing combination therapy against GP IIb/IIIa inhibitors alone before PCI showed a significantly increased risk of major bleeding with the combination therapy group (40/420 patients [9.5%] vs. 14/299 [4.7%]; relative reduction [RR], 2.2; p = 0.007).7 Conventional guidelines for anticoagulation during rescue PCI in patients who have failed thrombolytic therapy recommend the use of UFH with a goal ACT between 250–350 seconds8 or enoxaparin per the EXTRACT-TIMI-25 protocol, depending on the initial anticoagulant strategy chosen.9 Given the findings in the HORIZONS trial10 with reduced bleeding and improved 30-day outcomes in patients with STEMI undergoing primary PCI who were randomized to bivalirudin compared to UFH + GP IIb/IIIa, the notion of using the direct thrombin inhibitor, bivalirudin, for rescue PCI following failed thrombolytic therapy is appealing. This has become our default strategy in patients with STEMI who have failed thrombolytic therapy and require rescue PCI. However, data are limited on the use of bivalirudin in this population of patients who have failed thrombolytic therapy and need rescue PCI. We are in the process of designing a randomized trial to further assess the safety and efficacy of bivalirudin versus UFH in rescue PCI. 2. When the infarct-related artery is the RCA, initial angiographic assessment of the vessel typically underestimates vessel size. Understanding of this phenomenon and proper use of intra-coronary nitroglycerin may help to avoid stent undersizing, although the routine use of IVUS for proper stent sizing in such cases can also provide important information. IVUS has demonstrated its usefulness in refining appropriate stent deployment by assessing stent geometry, incomplete apposition of the stent to the vessel wall and dissection at the stent margins more accurately than by use of angiography alone.11 The CRUISE trial evaluated IVUS-guided stenting versus conventional stenting in patients undergoing PCI. The IVUS-guided group had a larger minimal lumen diameter (2.9 ± 0.4 vs. 2.7 ± 0.5 mm; p 2; p p 12 Our patient not only had a high thrombus burden, but also developed stent margin dissection and had plaque prolapse through the stent struts in the RCA as seen with IVUS. IVUS guidance during PCI may also be helpful in identifying the exact location of the ruptured plaque as being more distal to the angiographic occlusion13 in certain cases. 3. The initial choice of stent in this case was an S7, which at the time, had the most open-cell architecture of the available stents in the U.S. Although the open-cell design provides increased flexibility, conformability and deliverability, its disadvantages include being prone to plaque prolapse through the struts in the presence of a large atherosclerotic burden. In this case, the initial stents were undersized and required postdilation, which eventually led to overexpansion of the open-cell stent. Additionally, there was a heavy plaque and thrombus burden, which ultimately led to plaque prolapse. Plaque prolapse may increase the risk of stent thrombosis, which clearly was a major problem in this instance. Treating plaque prolapse is definitively accomplished by placing an additional stent within the previously placed stent to adequately scaffold the plaque. Conclusion. In this patient with a high potential of catastrophic IC rebleeding, the use of bivalirudin during PCI provided for a safe antithrombotic regimen despite the presence of a recent ICH and recurrent stent thrombosis. IVUS guidance helped with appropriate stent sizing, detection of edge dissection that was not angiographically apparent and the identification of plaque prolapse. This experience with bivalirudin in high bleeding-risk PCI warrants further evaluation, particularly with respect to its safety and efficacy in patients undergoing rescue PCI.

References

1. Berkowitz SD, Granger CB, Pieper KS, et al. Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. The Global Utilization of Streptokinase and Tissue Plasminogen activator for Occluded coronary arteries (GUSTO) I Investigators. Circulation 1997;95:2508–2516. 2. Topol EJ. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: The GUSTO V randomised trial. Lancet 2001;357:1905–1914. 3. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: The ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001;358:605–613. 4. Ellis SG, Tendera M, de Belder MA, et al. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med 2008;358:2205–2217. 5. Savonitto S, Armstrong PW, Lincoff AM, et al. Risk of intracranial haemorrhage with combined fibrinolytic and glycoprotein IIb/IIIa inhibitor therapy in acute myocardial infarction. Dichotomous response as a function of age in the GUSTO V trial. Eur Heart J 2003;24:1807–1814. 6. Facilitated percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: Results from the prematurely terminated ADdressing the Value of facilitated ANgioplasty after Combination therapy or Eptifibatide monotherapy in acute Myocardial Infarction (ADVANCE MI) trial. Am Heart J 2005;150:116–122. 7. Sinno MC, Khanal S, Al-Mallah MH, et al. The efficacy and safety of combination glycoprotein IIbIIIa inhibitors and reduced-dose thrombolytic therapy-facilitated percutaneous coronary intervention for ST-elevation myocardial infarction: A meta-analysis of randomized clinical trials. Am Heart J 2007;153:579–586. 8. Popma JJ, Berger P, Ohman EM, et al. Antithrombotic therapy during percutaneous coronary intervention: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:576S–599S. 9. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med 2006;354:1477–1488. 10. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218–2230. 11. Nakamura S, Colombo A, Gaglione A, et al. Intracoronary ultrasound observations during stent implantation. Circulation 1994;89:2026–2034. 12. Fitzgerald PJ, Oshima A, Hayase M, et al. Final results of the Can Routine Ultrasound Influence Stent Expansion (CRUISE) study. Circulation 2000;102:523–530. 13. Komatsu S, Sato Y, Ueda Y, et al. Thrombotic occlusion proximal to plaque rupture in acute myocardial infarction: Evaluation by intravascular ultrasound and coronary angioscopy. Int J Cardiol 2007;123:e12–e14.