A Randomized Pilot Trial for Aggressive Therapeutic Approaches in Aspirin-Resistant Patients Undergoing Percutaneous Coronary Intervention

ABSTRACT: Background. There is great variability among individual patients in platelet inhibition after aspirin intake. Aspirin resistance has been associated with a higher incidence of ischemic events after percutaneous coronary intervention (PCI). The optimal antiplatelet therapy in aspirin-resistant patients undergoing PCI is unknown. The objective of this study was to evaluate whether aggressive antiplatelet therapy would reduce ischemic events in aspirin-resistant patients after PCI. Methods. A total of 330 patients undergoing PCI (with bivalirudin) were screened for aspirin responsiveness. The resulting 36 aspirin-resistant patients were randomized into two arms: 1) conventional strategy patients received 325 mg aspirin orally and a loading dose of 600 mg clopidogrel at the time of the procedure; and 2) aggressive strategy patients received similar amounts of aspirin and clopidogrel, with the addition of an intravenous glycoprotein IIb/IIIa inhibitor bolus intraprocedurally. The primary outcome was an elevation of cardiac enzymes within 24 hours post procedure. The secondary outcome was a composite of major adverse cardiac events including death, myocardial infarction, stent thrombosis and urgent revascularization, and bleeding up to 30 days. Results. Primary outcome occurred in 22% of the conventional strategy group and 11% of the aggressive strategy group (p = 0.36). The secondary outcome was reached in 27.8% of the conventional group and 5.5% of the aggressive strategy group (p = 0.17), which is suggestive of a statistical trend toward more ischemic events with conventional therapy. Importantly, there were 2 cases of definite stent thrombosis in the conventional strategy group. Conclusion. In aspirin-resistant patients, aggressive antiplatelet therapy tended to show better outcomes after PCI, without an increase in bleeding. These findings need validation in a large, randomized study. J INVASIVE CARDIOL 2011;23:9–13 Key words: percutaneous coronary intervention; aspirin resistance ———————————————————— Platelet activation and aggregation play a central role in the pathogenesis of acute coronary syndromes as well as the progression of coronary artery disease.¹ This cascade eventually precipitates acute ischemic syndromes and periprocedural ischemic events during percutaneous coronary interventions (PCI), resulting in significant morbidity and mortality.^2–4 Several antiplatelet agents, i.e.: a) oral antiplatelet drugs, such as aspirin, thienopyridines (ticlopidine, clopidogrel or prasugrel) and cangrelor; and b) intravenous glycoprotein (GP) IIb/IIIa inhibitors (abciximab, eptifibatide and tirofiban), are aimed at improving ischemic outcomes and minimizing thrombotic complications during and after PCI. Aspirin and clopidogrel are a cornerstone in all antiplatelet regimens used for patients undergoing PCI⁵ and have demonstrated a reduction in periprocedural ischemic complications (5% versus 14%).^6,7 Despite the clear benefits of aspirin in the setting of PCI, up to 15% of patients continue to experience recurrent ischemic events including periprocedural myonecrosis, subacute stent thrombosis and sudden death.^8,9 This state of heightened platelet reactivity while on aspirin therapy has been termed “aspirin resistance” and the patients as “aspirin resistant” (non-responders). This condition has been associated with an increased risk of periprocedural myonecrosis¹⁰ as well as a 4- to 5-fold increased risk of thrombotic events.^11–13 The optimal antiplatelet regimen in patients undergoing elective PCI who demonstrate aspirin resistance is not known. The potential of reducing ischemic endpoints with aggressive multipronged antiplatelet therapy with aspirin, clopidogrel and GP IIb/IIIa inhibitors^14–17 has to be weighed against the possibility of an increased risk of bleeding complications with no significant improvement in ischemic endpoints. We prospectively evaluated the effect of an aggressive antiplatelet regimen on cardiovascular events in aspirin-resistant patients undergoing elective PCI.

Methods

Patients. This pilot study was carried out at Mount Sinai Hospital in New York, New York, between April 2007 and December 2008. The study protocol was reviewed and approved by the Institutional Review Board at our institution. All patients older than 18 years who were scheduled for elective angiography and/or PCI due to symptoms of stable angina and/or a positive stress test and who were taking aspirin orally at doses of at least 81 mg daily for ≥ 7 days prior to presentation and were willing to provide consent were eligible for screening. Inclusion criteria:

• Age > 18 years; • Scheduled for elective or ad-hoc PCI; • Aspirin use daily for ≥ 1 week; • Aspirin-resistant (aspirin reaction units ≥ 550 on VerifyNow™-ASA).

Patients were excluded who had:

• A preprocedural elevation of cardiac biomarkers (CK-MB ≥ 10.4 ng/ml or troponin-I [TnI] ≥ 0.4 ng/ml). • Received any GP IIb/IIIa inhibitors, anticoagulation or lytic therapy in the previous 30 days. • Ongoing bleeding or bleeding diathesis, contraindications for anticoagulation or increased bleeding risk or history of bleeding in the last 8 weeks. • Previous stroke or transient ischemic attack or any intracranial pathology in the last 6 months, major surgery or trauma within the previous 6 weeks. • Platelet count After excluding ineligible patients, response to aspirin was measured in all patients using the point-of-care VerifyNow™ assay (Accumetrics, Inc., San Diego, California). Aspirin resistance was defined as aspirin reaction units (ARU) > 550. A total of 36 aspirin-resistant patients were included for further participation in the study. The protocol encouraged but did not mandate point-of-care screening for clopidogrel response prior to PCI regardless of the results of aspirin testing. Clopidogrel response was tested in 28 of the 36 subjects enrolled. Assessment of aspirin resistance. The Verify Now System is a point-of-care device that is based on integrin aIIb3 (GP IIb/IIIa)-dependant platelet aggregation. It is a turbidimetric-based optical detection system that measures platelet-induced aggregation as an increase in light transmittance. The system consists of an instrument, a disposable assay device and controls. The assay device contains reagents based on microbead agglutination technology as well as a lyophilized preparation of human fibrinogen-coated beads, platelet agonist, preservative and buffer. The patient sample is 3.2% citrated whole blood, which is automatically dispensed from the blood collection tube into the assay device by the instrument, with no blood handling required by the user. ARUs indicate the amount of thromboxane A2-mediated activation of GP IIb/IIIa receptors involved in platelet aggregation. ARU is calculated as a function of the rate and extent of arachidonic acid-induced platelet aggregation. Expected values are in the range of 350–700 ARU. The assay is simple to perform, requires a small sample volume and provides rapid results. Treatment strategies. Conventional strategy: patients received an oral dose of 325 mg aspirin and a loading dose of 600 mg clopidogrel 0–4 hours before the procedure. Bivalirudin 0.75 mg/kg intravenous (IV) bolus followed by a 1.75 mg/kg/hour IV infusion a minimum of 1 hour post PCI was used for procedural anticoagulation. Post procedure, patients were continued on aspirin 325 mg lifelong and clopidogrel 75 mg daily for 1–3 years (Figure 1). Bailout use of GP IIb/IIIa inhibitors was allowed by the protocol. Aggressive strategy: aspirin, clopidogrel and bivalirudin were administered similar to the conventional arm. In addition, an IV GP IIb/IIIa inhibitor (one bolus with abciximab or two boluses with eptifibatide based on published dosing guidelines) was used during the procedure. Post procedure, patients were placed on aspirin 325 mg daily lifelong and clopidogrel 150 mg daily for 1 month and then 75 mg daily for 1–3 years (Figure 1). Sample size. For this pilot study, the total sample size needed for the study to have 80% power to detect a 50% difference in the event rates between the two study groups (event rate of 0.4 in the conventional arm and 0.2 in the aggressive arm) at a 95% confidence level was calculated to be 36 patients. In-hospital course. Following the procedure, blood samples for cardiac biomarkers CK-MB and troponin I (Tn-I) were collected at 6–8 hours and 16–24 hours. Peak CK-MB and Tn-I levels were recorded. The CK-MB was considered elevated when ≥ 10.4 ng/ml. A TnI value of ≥ 0.4 ng/ml was considered elevated. Follow-up. Follow-up was performed weekly by telephone interview on all enrolled patients for the 30-day post-procedure period. Persons performing follow-up interviews were blinded to the aspirin sensitivity status. For those patients who reached the primary endpoint, a comprehensive medical chart review was undertaken to determine whether the event met the definitions of the endpoint described. Study outcome endpoints and definitions. The primary outcome was the incidence of peri-procedural biomarker elevation defined as any elevation above baseline of CK-MB or Tn-I within 24 hours after completion of the procedure. Secondary outcome included: 1) major adverse cardiac events (MACE), defined as the composite of death, MI (CK-MB > 3 times normal), urgent revascularization and definite or probable stent thrombosis (ST) within 30 days. Stent thrombosis was defined according to the new academic research consortium definitions; 2) bleeding complications within 30 days. Major bleeding was defined as intracranial or intraocular bleeding or a drop in hemoglobin > 5 g/dL. Minor bleeding was defined as hemorrhage at the access site requiring intervention, hematoma with a diameter of at least 5 cm, a reduction in hemoglobin levels of at least 4 g/dL without an overt bleeding source or at least 3 g/dL with such a source, reoperation for bleeding or transfusion of a blood product. Bleeding complications were monitored closely on a weekly basis by telephone calls for the 30-day period (Day 7, Day 14, Day 21 and Day 30) after the procedure and the study. Specific signs and symptoms of bleeding that were considered included: 1) bruises/oozing or enlarging mass surrounding puncture site; 2) dizziness and palpitations; headache, weakness and vision problems (symptoms due to occular bleeding); 3) flank, back or abdominal pain and distention (due to retroperitoneal bleed); 4) hematuria; and 5) black stools, bloody vomitus or bright red blood per rectum.

Results

A total of 330 patients who were scheduled for planned PCI and consented were screened for aspirin resistance. Thirty-six were found to be resistant (incidence of ~10% in our population) and were prospectively included and randomized in the study. The baseline characteristics of patients randomized to both strategies were similar and are listed in Table 1. Both groups were well matched for demographics and common risk factors. All patients underwent successful PCI with thrombolysis in myocardial infarction (TIMI) flow grade 3 after the intervention. There was no bailout use of GP IIb/IIIa inhibitors in the conventional strategy group. Angiographic and procedural characteristics are shown in Table 2 and were not different between the two groups. The patients were clinically followed up to 1 month. The primary outcome of cardiac biomarker release was higher in the conventional arm, although this difference was not significant (22% in the conventional arm and 11% in the aggressive arm; p = 0.36) (Table 3). Similarly, the secondary outcome occurred in 5 patients in the conventional arm (27.7%) versus 1 patient in the aggressive arm (5.5%), favoring a trend toward more ischemic events, particularly ST in the conventional group. In fact, 2 definite cases of ST were identified in the conventional arm (on Day 3 and Day 6) versus none in the aggressive arm (Table 4). Both these patients were clopidogrel responders as per point-of-care testing (platelet aggregation inhibition > 50%). Paradoxically, major and minor bleeding were numerically lower in the aggressive strategy group. Combined primary and secondary outcomes statistically favored the aggressive strategy group (p = 0.03).

Discussion

We conclude from our pilot data that aggressive antiplatelet therapy using a combination of high-dose clopidogrel and GP IIb/IIIa inhibitors may reduce the incidence of ST and ischemic events in general in aspirin-resistant patients. Our study demonstrated the incidence of aspirin resistance to be around 10%, which is in agreement with prior reports. Prior studies have demonstrated that patients deemed to be aspirin nonresponsive using the VerifyNow system are at increased risk of procedural myonecrosis and periprocedural myocardial infarction compared to those who have normal biological responsiveness to aspirin.^10,20,21 These and other studies have shown that pretreatment with thienopyridines and the addition of GP IIb/IIIa inhibitors further improves outcomes in aspirin-resistant patients undergoing PCI.^21,22 In agreement with these studies, with the use of GP IIb/IIIa inhibitors, we found a numerically higher but statistically insignificant, periprocedural cardiac biomarker release in the conventional antiplatelet regimen (p = 0.36). This may be related to the use of bivalirudin in both arms of our study in contrast to the unfractionated heparin previously used. More importantly, and not previously reported, there were 2 cases of definite ST requiring PCI in the conventional arm versus none in the aggressive arm, indicating that aggressive, multipronged antiplatelet therapy may be protective against the potentially catastrophic complication of ST. In agreement with prior studies, there was no significant difference in bleeding complications between both study groups, with a numerically lower incidence in the aggressive group, partly explained by lower ischemic complications.²¹ This may be related to a possibly intrinsic lower risk for bleeding associated with the higher residual platelet reactivity found in patients with poor response to aspirin. Our study is the first United States-based, randomized, double-blind, prospective study using triple antiplatelet therapy and double-dose clopidogrel (maintenance dose in aspirin-resistant patients undergoing elective PCI via femoral access.^21,23 A number of important extrinsic factors, like patient compliance, heterogeneous dosing regimens, drug absorption and drug-drug interactions, as well as genetic polymorphisms and redundancy of cellular pathways, influence the ultimate pharmacologic effect of aspirin on platelet inhibition. In addition, there is a wide array of laboratory tests that are used to provide an estimate of aspirin’s effect on platelet function. We tested aspirin responsiveness in the catheterization suite using the Verify Now system. This offered multiple advantages: it was easy to use, available at the patient’s bedside and required no sample processing or pipetting, thus facilitating rapid decision-making about the antiplatelet regimen to be used. Recent studies have demonstrated that this point-of-care device correlates well with results from more rigorous lab-based assays like arachidonic acid-induced aggregation and urinary 11-dehydro-TXB2 levels (correlation coefficients, approximately 0.7).¹⁹Study limitations. This is a small pilot study with a limited sample size and was not powered to detect differences in individual ischemic endpoints. The small number of patients in the two groups showed a numerical difference, but was not statistically significant. Secondly, our study does not delineate an optimal dose of aspirin, as all patients were treated with 325 mg of aspirin before and after the procedure. Finally, the antiplatelet effect of aspirin may fluctuate in patients at the same dosage. A single baseline measurement may not reflect the extent of platelet inhibition over long periods of time. In addition, the follow-up duration of 30 days may not be sufficient to record all thrombotic events in post-PCI patients, especially with drug-eluting stent use.

Conclusion

Our findings reinforce the need to tailor antiplatelet regimens based on an individual’s responsiveness to various antiplatelet agents. The ongoing Gauging Responsiveness with a VerifyNow Assay — Impact on Thrombosis and Safety (GRAVITAS) trial is expected to provide useful answers to the question of optimal dosing of aspirin and clopidogrel for long-term maintenance in patients with impaired responsiveness to antiplatelet agents. The recent presentation of the multicenter Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7) trial supports the notion of a double dose of clopidogrel in PCI patients by reducing ST and MI. Recent reports have shown significantly higher, faster and more consistent inhibition of platelet aggregation with prasugrel, a novel oral thienopyridine antiplatelet agent.^24,25 Like clopidogrel, prasugrel binds to the P2Y12 receptor on the platelet cell surface, leading to irreversible inhibition of platelet activation and aggregation.²⁵ Among other studies, the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel — Thrombolysis In Myocardial Infarction (TRITON–TIMI 38) demonstrated the safety and efficacy of prasugrel.²⁴ Studies using prasugrel during PCI in aspirin-resistant patients are needed to determine the optimal antiplatelet therapy in this high-risk population.

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———————————————————— From Mount Sinai Hospital, New York, New York. Relevant disclosures: Dr. S. Sharma: honoraria from Abbott Vascular, Boston Scientific, Eli Lilly & Co., DSI, and The Medicines Co., Manuscript submitted June 10, 2010, provisional acceptance given June 29, 2010, final version accepted October 4, 2010. Address for correspondence: Samin Sharma, MD, FSCAI, FACC, Mount Sinai Hospital, One Gustave L. Levy Place, Box 1030, New York, NY 10029. E-mail: samin.sharma@mountsinai.org