Focus on Adjunctive Pharmacotherapy to Improve Outcomes of Percutaneous Coronary Intervention

From The Christ Hospital Heart and Vascular Center and The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, Cincinnati, Ohio. The author reports no conflicts of interest regarding the content herein. Address for correspondence: Dean J. Kereiakes, MD, FACC, The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, 2123 Auburn Avenue, Suite 424, Cincinnati, OH 45219. E-mail: lindner@fuse.net

J INVASIVE CARDIOL 2009;21:110–113

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The field of adjunctive pharmacotherapy for percutaneous coronary intervention (PCI) is dynamic. Our understanding of basic pathophysiologic mechanisms has evolved in parallel with serial drug and device iterations and has been associated with progressive improvement in clinical outcomes following PCI. Rapid progress in the field of adjunctive pharmacotherapy for both acute coronary syndromes and PCI has necessitated more frequent revision in clinical practice guidelines for patient care. With this background, the Journal of Invasive Cardiology has created two separate focus issues dealing with adjunctive pharmacotherapy for elective and primary PCI. In the present issue, several timely topics have been addressed. New data from the Italian Ravenna registry are presented by Aquilina et al¹ and provide valuable insights into the development of integrated systems for the performance of primary PCI in ST-segment elevation myocardial infarction (STEMI), the pharmacoinvasive therapeutic strategy to optimize early coronary patency as well as the importance of ischemia duration in determining the relative benefit conferred by the “upstream” (preprocedural) administration of platelet glycoprotein (GP) IIb/IIIa receptor blockade (eptifibatide) prior to primary PCI. These data are pertinent to the current practice of STEMI care provided in the United States for several reasons. First, the Ravenna registry STEMI network comprises a “hub” center for the performance of primary PCI and two remote (20–25 km) “spoke” centers for STEMI referral and incorporates prehospital transtelephonic electrocardiographic (ECG) transmission from the point of first patient contact. Second, although both door-to-balloon (D2B) times and in-hospital mortality have gradually declined in the U.S. for patients undergoing primary PCI, those who require transfer in from a non-PCI-capable facility to one capable of performing primary PCI have both longer D2B times and higher hospital mortality.² Indeed, patient presentation to a non-PCI center is a powerful predictor of prolonged door- (spoke hospital) to-balloon (hub hospital) time.³ These observations from the National Registry for Myocardial Infarction (NRMI) underscore the lack of integrated systems for STEMI care in the U.S., where it has been estimated that at least 80% of the adult population lives within 60 minutes ground transportation from a PCI-capable center.⁴ Inexplicably, most U.S. metropolitan areas lack the ability to perform and transmit the prehospital ECG, which has been conclusively demonstrated to expedite subsequent in-hospital treatment (reduced door-to-needle or D2B times).^5–7 Third, controversy exists regarding the role of “upstream” pharmacotherapy prior to the performance of primary PCI. Although the Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial found no apparent clinical benefit of pretreatment with either abciximab GP IIb/IIIa blockade or the combination of reduced dose fibrinolytic plus abciximab (versus in-catheterization laboratory [cath lab] abciximab administration at the time of PCI), upstream adjunctive pharmacotherapy did improve pre-PCI angiographic TIMI flow rates.⁸ Furthermore, close scrutiny of the FINESSE trial data reveals trends for benefit of upstream adjunctive therapy in those patients with the highest risk profile and in those who received enoxaparin (versus unfractionated heparin) on a nonrandomized basis. Indeed, the data provided by Aquilina et al lends support to observations from both the Combined Abciximab RE-teplase Stent Study (CARESS) trial⁹ and the European Registry on Patients with ST-elevation Myocardial Infarction Transferred for Mechanical Reperfusion (PCI) with a Special Focus on Upstream Use of Abciximab (EURO-TRANSFER) registry.¹⁰ In CARESS, patients with STEMI ≤ 12 hours’ duration and age 11 Further analysis of clinical outcomes by patient risk strata and the timecourse of abciximab administration (early versus late, in-lab) in EURO-TRANSFER are pertinent to the Ravenna registry report.¹² Early abciximab (versus late) administration was associated with a reduction in the incidence of death as well as the composite occurrence of death, recurrent MI and urgent revascularization to 30 days’ follow up, even after multivariate and propensity score adjustment. Furthermore, the greatest relative survival benefit of early abciximab administration was observed in those patients within the highest clinical risk strata. Finally, early (versus late) abciximab was associated with improvement in TIMI flow grades both pre- and post-PCI. In this regard, the Ravenna registry confirms and extends the observations of both the Time to Integrilin Therapy in Acute Myocardial Infarction (TITAN-TIMI-34),¹⁴ which randomly assigned STEMI patients to receive early (emergency room) or late (cath lab) eptifibatide prior to planned primary PCI, as well as the Tirofiban Given in the Emergency Room before Primary Angioplasty (TIGER-PA) pilot trial,¹⁴ which employed a similar trial randomization strategy using tirofiban, another small-molecule inhibitor of the platelet GP IIb/IIIa receptor. Both TITAN-TIMI 34 and TIGER PA demonstrated improved pre-PCI TIMI flow grades with earlier (upstream) administration of GP IIb/IIIa blockade therapy. Indeed, a pooled analysis of prior randomized controlled trials comparing early versus late GP IIb/IIIa inhibitor therapy prior to primary PCI for STEMI substantiates the salutary effect of earlier therapy for achieving a higher prevalence of TIMI grade 3 flow rate.¹⁵ However, Aquilina et al provide further insight into the importance of time from symptom onset to GP IIb/IIIa therapy. Platelet GP IIb/IIIa inhibitors, in general, and abciximab in specific, demonstrate a dose-dependent disaggregation of platelet-rich thrombus.^16,17 The putative mechanism for thrombus dissolution is the displacement of fibrinogen, the primary ligand that bridges activated GP IIb/IIIa receptors and thus facilitates platelet aggregation by the high-affinity platelet GP IIb/IIIa receptor inhibitor. As thrombus ages, platelets are crosslinked with fibrin and the thrombus becomes more resistant to disaggregation by GP IIb/IIIa blockers. Prior studies have suggested a direct relationship between the duration of GP IIb/IIIa inhibitor infusion and improvement in TIMI flow grade prior to primary PCI for STEMI. Although a similar relationship is not evident in the study by Aquilina and colleagues, a significant relationship between the duration of ischemia (time from chest pain onset) prior to the initiation of GP IIb/IIIa inhibitor therapy with subsequent improvement in TIMI flow was observed. Those patients who received eptifibatide therapy within 90 minutes of symptom onset derived both angiographic (improved TIMI 2–3 flow grades) as well as clinical (reduction in mortality to 30 days) benefit when compared with those treated beyond 90 minutes of chest pain duration. One plausible explanation for this observation is that early platelet-rich (and fibrin-poor) thrombus is more susceptible to disaggregation by GP IIb/IIIa monotherapy. In this regard, the apparent “gradient” for benefit stratified by time duration of ischemia is intriguing. Indeed, the benefit of early GP IIb/IIIa inhibitor therapy to improve pre-PCI TIMI flow grades that has been observed following several agents (eptifibatide, tirofiban, abciximab) and across multiple trials is remarkable in light of the fact that the major portion of coronary thrombus aspirated prior to primary PCI for STEMI is days-to-weeks old.¹⁸ Several caveats and limitations to the report of Aquilina et al deserve mention. First, the nonrandomized utilization of manual thrombus aspiration across eptifibatide treatment groups (early versus late) may confound both angiographic and clinical endpoint analyses. Indeed, manual aspiration of thrombus prior to primary PCI has been shown to improve both TIMI flow grades as well as late (1 year) survival.^19,20 Of note, the less frequent use of thrombus aspiration in those patients who received upstream eptifibatide suggests a smaller quantitative thrombus burden. Recent observations suggest a direct relationship between both quantitative (thrombus burden)²¹ and qualitative (older age) thrombus characteristics²² with adverse clinical outcomes including stent thrombosis and death following primary PCI. Thus, a lesser thrombus burden in subjects pretreated with eptifibatide should portend better outcomes. Second, the lower frequency of stent deployment in those patients receiving later (cath lab) or no eptifibatide may influence clinical outcomes and may be consistent with the demonstrated salutary effects of stenting (versus balloon only) for primary PCI. Finally, no data regarding the adequacy of microvascular perfusion are provided by Aquilina et al. Although post-PCI TIMI flow grades were improved in eptifibatide pretreated subjects, the potential benefit (or lack thereof) of earlier pretreatment on TIMI myocardial blush grade or the extent (percent) of ST-segment resolution is not reported. Similarly, data on recovery of global or regional infarct zone left ventricular function are omitted. Nevertheless, the Aquilina et al report places focus on the need for integrated systems of care for the provision of primary PCI, the potential benefit of upstream GP IIb/IIIa blockade prior to primary PCI, and the importance of earlier therapy for both pharmacologic and catheter-based treatment of STEMI. The observations of So et al²³ from the Ottawa Heart Institute provide valuable insights into the optimal dose of aspirin when administered in combination with clopidogrel following stent deployment. In a consecutive cohort of patients who underwent PCI and survived to hospital discharge, the occurrence of all-cause mortality and nonfatal MI was analyzed by daily aspirin dose ( 325 mg) to 1-year follow up. Propensity scoring analysis was used to adjust for differences in covariates between the nonrandomly-assigned treatment groups. Current clinical practice guidelines as well as package insert instructions for use (IFU) recommend that aspirin 325 mg daily be administered (in conjunction with clopidogrel) for at least 3 months following Cypher™ (Cordis Corp., Miami Lakes, Florida) and 6 months following Taxus® drug-eluting stent (DES) (Boston Scientific Corp., Natick, Massachusetts) deployment. So et al found no difference in the incidence of death or nonfatal MI or in definite (ARC definition) stent thrombosis between patients treated with aspirin 81 mg versus 325 mg daily. This study confirms and expands prior reports suggesting that no appreciable increment in clinical anti-ischemic event efficacy is achieved by aspirin doses exceeding 81 mg daily.^24–26 Although the aggregate evidence base suggests that a lower dose (27 Similarly, although aspirin resistance has been reported less frequently at higher doses (≥ 300 mg versus ≤ 100 mg), no clinical evidence supports enhanced efficacy.²⁸ Indeed, higher doses of aspirin (> 100 mg) have been associated with increased bleeding risks when administered in conjunction with clopidogrel.^24–26 Finally, as concomitant coumadin therapy was administered to 9.2% of low-dose aspirin-treated patients included in this analysis, the authors may have missed an opportunity to evaluate the relative safety and efficacy of aspirin dose and/or dual antiplatelet therapy in this increasingly important “triple” therapy (coumadin plus aspirin plus thienopyridine) population. Indeed, the safety and efficacy of strategies that combine coumadin (atrial fibrillation, prosthetic heart valves, etc.) to prevent stroke with antiplatelet therapy (aspirin plus thienopyridine) to prevent stent thrombosis have received greater attention in the context of the aging U.S. population. Nevertheless, So et al provide additional support for the premise that “lower is better” with regard to aspirin dosing when used in combination with a thienopyridine to achieve optimal net clinical benefit. The paper by Kammer²⁸ provides a useful and practical algorithm for oral clopidogrel desensitization. As early discontinuation of dual antiplatelet therapy following DES deployment is associated with an increased risk of subacute or early stent thrombosis after either elective or primary PCI,^30,31 all PCI centers should have a clopidogrel desensitization protocol in place. The vast majority of patients who experience rash or urticaria following clopidogrel treatment will tolerate such therapy after undergoing a desensitization protocol.³² Hopefully, the advent of prasugrel will provide an alternative, safe and effective treatment strategy for these patients. Finally, the case report by Giugliano et al,³³ which suggests the potential utility of bivalirudin during PCI for stent thrombosis in a patient with subacute intracranial hemorrhage, deserves scrutiny. These authors describe a patient with proximal dominant right coronary artery occlusion (STEMI) complicated by complete atrioventricular dissociation and cardiogenic shock. At the time of primary PCI and stenting, thrombus aspiration for a large thrombus burden was performed. An eptifibatide infusion was initiated following the deployment of 3 bare-metal stents (BMS) with segments of stent overlap. Oral clopidogrel 300 mg was administered by nasogastric tube following PCI. Acute stent thrombosis occurred 4 hours later and required re-PCI with thrombus aspiration. Intravascular ultrasound (IVUS) revealed a distal stent marginal dissection and plaque prolapse. An additional stent was deployed followed by infusion of heparin and eptifibatide for 48 hours. On hospital day 8, a small cortical infarct and subdural hematoma were detected and on day 14, recurrent coronary occlusion occurred. The patient was again treated with thrombus aspiration and re-stenting of the entire stented segment with 3 more BMS. Thus, this patient had serial (x 3) thrombus aspiration and repetitive (x 7) BMS stent deployment over a 2-week period from the time of inferior wall STEMI presentation. In addition to the learning points enumerated by Giugliano et al in their report, the following observations can be made. First, thrombus burden at the time of primary PCI is a powerful predictor of adverse outcomes including stent thrombosis.²² Large thrombus burden should be aggressively treated with both catheter-based and pharmacologic techniques. Second, patients who present with stent thrombosis are at high risk for recurrence.³⁴ Third, the occurrence of stent thrombosis (x 2) in-hospital, where compliance with dual antiplatelet therapy should not be an issue, strongly suggests nonresponsiveness/resistance to at least clopidogrel, if not both aspirin and clopidogrel. In this regard, following the initial stent thrombosis, consideration may have been given to either switching from clopidogrel to ticlopidine in combination with aspirin, or to adding cilostazol 100 mg orally twice daily to aspirin plus clopidogrel therapy. Approximately 80% of individuals who are nonresponsive to clopidogrel will respond to ticlopidine, as the pathways for metabolic activation differ.³⁵ In addition, large registry reports in both elective and primary PCI^36,37 demonstrate that triple therapy (aspirin plus thienopyridine plus cilostazol) is associated with a reduction in major adverse cardiovascular events and stent thrombosis compared with dual therapy (aspirin plus thienopyridine). Furthermore, the addition of cilostazol (100 mg twice daily) to aspirin and clopidogrel (75 mg daily) provides significantly greater platelet inhibition than either aspirin and clopidogrel or high-dose (150 mg daily) clopidogrel.³⁸ Specifically, in subjects defined as being clopidogrel-hyporesponsive, the cilostazol-aspirin-clopidogrel (75 mg daily) combination provides significantly greater platelet inhibition than is achieved by double-dose clopidogrel (150 mg daily).³⁹ The patient described by Giugliano et al³³ could have been evaluated for clopidogrel and/or aspirin responsiveness, or conversely, should have been empirically switched to an alternative antiplatelet regimen. Finally, although these authors acknowledge that suboptimal (undersized) stent deployment may be prevented by IVUS at the time of PCI, IVUS was performed during the initial episode of stent thrombosis, and yet 3 additional stents were deployed following re-IVUS for re-thrombosis in less than 2 weeks. Furthermore, optimal stent expansion is unlikely to be achieved, particularly in regions of stent overlap without the performance of high-pressure (≥ 18 atm) postdilatation using a noncompliant balloon catheter. Each of the papers included in the current focus issue in the Journal provides important insights into the many aspects of adjunctive pharmacotherapy. I hope that you find these reports and this discussion to be of value in providing optimal care for your patients.

References

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