Contemporary issues on clopidogrel therapy

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1 Intern Emerg Med (2009) 4: DOI /s IM - REVIEW Contemporary issues on clopidogrel therapy Giuseppe Patti Æ Germano Di Sciascio Received: 23 July 2008 / Accepted: 4 December 2008 / Published online: 8 January 2009 Ó SIMI 2008 Abstract In this paper, data from available studies regarding some contemporary issues on clopidogrel therapy are analyzed. In particular, the following clinical questions have been considered and addressed: (a) Is early clopidogrel treatment needed in patients with acute coronary syndromes treated medically or undergoing percutaneous coronary intervention (PCI)? (b) What is the optimal clopidogrel loading dose in patients undergoing PCI? (c) Is pre-treatment with clopidogrel before PCI needed, or can clopidogrel loading be given in the catheter laboratory before intervention, but after coronary anatomy is known? (d) What is the optimal clopidogrel strategy in patients on chronic clopidogrel therapy undergoing PCI? (e) Does the degree of clopidogrel response influence clinical outcome in patients undergoing PCI? Keywords Clopidogrel Percutaneous coronary intervention Acute coronary syndromes Outcome Introduction Dual oral antiplatelet treatment with aspirin plus a thienopyridine has dramatically reduced the occurrence of subacute thrombosis and early adverse events after coronary stenting [1]. Clopidogrel is an antiplatelet agent extensively used in clinical practice; it is a non-reversible inhibitor of the adenosine diphosphate (ADP) receptor and G. Patti (&) G. Di Sciascio Department of Cardiovascular Sciences, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, Rome, Italy g.patti@unicampus.it affects intracellular signaling events that modulate ADPinduced platelet activation. Administration of clopidogrel has been associated with a better safety profile than ticlopidine, as well as with at least similar clinical efficacy [2, 3]. Thus, therapy with aspirin plus clopidogrel for at least 1 month represents the standard of care after percutaneous coronary intervention (PCI). Moreover, the randomized Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial [4] demonstrates that in patients with acute coronary syndromes (ACS) (unstable angina or non- ST-segment elevation myocardial infarction), use of clopidogrel for 1 year is associated with a significant 18% relative risk reduction of cardiovascular death, infarction or stroke and this follow-up clinical benefit is also observed in the subset of patients receiving PCI [5]. Use of clopidogrel also improves clinical outcome in patients with ST-segment elevation myocardial infarction irrespective of the reperfusion strategy [6 8]. However, a number of issues regarding therapy with clopidogrel are growing in the current cardiologic debate; this review has evaluated some of those topics with the aim to analyze contemporary data and to derive evidence-based indications for clinical practice. Is early clopidogrel treatment needed in patients with ACS treated medically or undergoing PCI? Patients with ACS present an enhanced platelet reactivity due to stronger baseline platelet activation and lower inhibition in response to antiplatelet drugs [9, 10]; thus, patients with unstable syndromes are at higher risk of ongoing ischemic complications and get the greatest benefit with an early and aggressive antithrombotic therapy. Post hoc analysis on the overall population of the CURE

2 202 Intern Emerg Med (2009) 4: Fig. 1 Odds reduction in 30-day adverse events by clopidogrel pre-treatment before intervention in PCI-CURE, CREDO and PCI-CLARITY. CV cardiovascular, MI myocardial infarction, PCI percutaneous coronary intervention Trial Clopidogrel pre-treatment in patients undergoing PCI (300 mg loading dose): incidence of adverse events Incidence of MI/CV death after PCI to 1 month OR (95% CI) PCI-CURE CURE (N=2658) 0.65 CREDO (N=1815) 0.83 PCI-CLARITY CLARITY (N=1863) Overall (N=6336) Clopidogrel better Placebo better 29% relative risk reduction P= trial [11] indicate that, in patients with non-st-segment elevation ACS, clinical benefit due to the addition of clopidogrel to aspirin is already observed within 24 h from randomization, with a 34% relative risk reduction of cardiovascular death, myocardial infarction, stroke or recurrence of severe ischemia versus aspirin plus placebo (1.4 vs. 2.1%; P \ 0.003). Clopidogrel benefit is also demonstrated in the CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction) trial [6], which enrolled 3,491 patients with ST-segment elevation acute myocardial infarction treated with thrombolytic therapy and randomized early to receive aspirin plus clopidogrel (300 mg loading dose followed by 75 mg/day) or aspirin plus placebo. The clopidogrel arm shows a lower incidence of the primary end-points including death, recurrent infarction during hospitalization or occluded infarct-related artery at coronary angiography (15 vs. 21.7%; P \ 0.001). In particular, the beneficial effects are essentially driven by a higher patency rate of the culprit coronary artery (68 vs. 61%; P \ 0.001) and this translates into a 20% odds reduction in 30-day cumulative incidence of cardiovascular death, infarction or urgent revascularization (P = 0.03). Interestingly, CLARITY patients who receive clopidogrel loading in the ambulance have higher rates of ST-segment resolution in the electrocardiogram than those treated with clopidogrel upon admission (47 vs. 37%; P = 0.02) [12]. With regard to patients with ACS undergoing PCI, pretreatment with the conventional 300 mg loading dose of clopidogrel is associated with a significant reduction in cardiovascular death or myocardial infarction after PCI at 30 days compared with a 300 mg loading dose given at the time of the procedure (35% relative risk reduction in PCI-CURE and 40% in PCI-CLARITY) [5, 7] (Fig. 1). Indeed, early clinical benefit of clopidogrel therapy in patients with ACS is also confirmed by the events curves of both studies, with early curve diversion of myocardial infarction rates in favor of clopidogrel, leading to a 30% relative risk reduction before intervention in PCI-CURE and 37% in PCI-CLARITY [5, 7]. Of note, in the CREDO (Clopidogrel for the Reduction of Events During Observation) trial, which enrolled patients with a variety of clinical syndromes undergoing PCI, a time dependence in the clinical benefit of 300 mg clopidogrel loading dose has been demonstrated, with at least 15 h of pre-treatment required to significantly decrease adverse events [13, 14]. Furthermore, a recent meta-analysis [15] pooling data from PCI-CURE, PCI-CLARITY and CREDO trials indicate a consistent benefit of clopidogrel pre-treatment in reducing the incidence of cardiovascular death, myocardial infarction or stroke after PCI both in patients who did not receive Glycoprotein IIb/IIIa inhibitors (28% relative risk reduction) and in those who did (31% relative risk reduction). Finally, post hoc analysis from the TARGET trial [16] shows that in patients receiving aspirin and tirofiban/ abciximab, clopidogrel pre-treatment[6 h before the procedure is associated with a significantly lower incidence of death or myocardial infarction at 6 months compared with clopidogrel treatment initiated at the time of PCI (6 vs. 13%; P = 0.001). To note, in this study clopidogrel pre-treatment has no increased risk of major or minor bleeding during index hospitalization. Thus, the abovementioned data strongly support early clopidogrel initiation in patients with ST-segment elevation

3 Intern Emerg Med (2009) 4: myocardial infarction or non-st-segment elevation ACS either treated medically or undergoing coronary revascularization. Optimal clopidogrel loading dose in patients undergoing PCI In 4,160 patients scheduled for PCI [17], pre-treatment with clopidogrel 300 mg, compared with the same loading dose given after intervention, is associated with a lower 1-month incidence of adverse events (1.97 absolute risk reduction; P = 0.02), as well as with significant post-procedural reduction in creatine kinase-mb and troponin elevation [18, 19]. However, the rationale for using the conventional 300 mg loading dose of clopidogrel derives from dose-finding data on healthy volunteers [20]; conversely, patients with coronary artery disease have an enhanced platelet reactivity greater than healthy individuals [21], thus possibly requiring more intense antiplatelet therapies. A higher loading dose with 600 mg of clopidogrel causes an earlier and stronger platelet inhibition than the 300 mg dose; in particular, the higher regimen is associated with about a 30% ADP-induced residual platelet aggregation at 6 h and 25% at 24 h (vs. about 45 and 40% after the conventional regimen) [22]. In vitro studies show that a 600 mg clopidogrel loading regimen is associated with maximal platelet inhibition within 2 h after drug administration [23] and post hoc analysis from the ISAR-REACT trial on patients at low-to-intermediate risk undergoing PCI confirms that increasing the pre-treatment interval beyond 2 3 h with 600 mg clopidogrel is not associated with further clinical effect [24]. Thus, as long as a higher antithrombotic status remains the goal of drug therapy in the setting of PCI, a more rapid and intense suppression of platelet reactivity represents the rationale for pre-treatment with a 600 mg clopidogrel loading regimen, with the aim of reducing early ischemic events by decreasing the effects of distal embolization, protecting the microvascular bed, and counterbalancing post-procedural activation of coagulation. The randomized ISAR-REACT trial [25] employed pre-treatment with a 600 mg clopidogrel loading dose before PCI in patients with stable coronary artery disease and demonstrates that this regimen obviates the need for peri-procedural Glycoprotein IIb/IIIa infusion with similar occurrence of the primary end-point (death, myocardial infarction, urgent target vessel revascularization) at 30 days: 4% both in the placebo and abciximab group. However, this trial was not focused on the clinical evaluation of a high clopidogrel loading dose (600 mg) versus a conventional dose (300 mg) and it did not specifically evaluate whether the enhanced antiaggregation due to the 600 mg regimen translates into an independent clinical benefit. The ARMYDA-2 (Antiplatelet therapy for Reduction of Myocardial Damage during Angioplasty) trial [26] was the first randomized study of head-to-head comparison between 6 h pre-treatment with a 600 versus a 300 mg loading dose of clopidogrel before PCI. Primary end-points were the 30-day occurrence of death, myocardial infarction or target vessel revascularization; the primary end-points were detected in 4% of the patients in the high and in 12% of those in the conventional dose group (P = 0.041), and it was entirely due to peri-procedural myocardial infarction. Multivariable analysis indicates that pre-treatment with a 600 mg clopidogrel loading dose is associated with a 52% relative risk reduction of peri-procedural myocardial infarction (P = 0.044). A post hoc analysis of ARMYDA-2 shows a greater benefit in the subgroup of patients of age C70 years, diabetes mellitus, non-st-segment elevation ACS, or those receiving multivessel intervention (80% relative risk reduction) [27] (Fig. 2). Thus, a more rapid and stronger platelet suppression may reduce myocardial injury in patients undergoing PCI by preventing procedural ischemic complications and this effect is higher in patients with an elevated baseline risk profile. More recently, a randomized study [28] has compared outcome after pretreatment with a 600 versus a 300 mg clopidogrel strategy in patients with non-st-segment elevation ACS undergoing PCI within 48 h from admission. This study confirms the ARMYDA-2 results even in this specific clinical setting, showing, in the 600 mg arm, a significantly lower 30-day occurrence of major adverse cardiac and cerebrovascular events (5 vs. 12%), as well as a markedly higher platelet inhibition by light transmittance aggregometry (LTA). Clopidogrel 600 mg pretreatment Clopidogrel 600 mg pre-treatment + statins Clopidogrel 600 mg pretreatment (patients with age >70 yrs, DM, NSTE-ACS, MV intervention) ARMYDA-2 post-hoc analysis Odds ratio for peri-procedural MI ( ) 0.20 ( ) 0.20 ( ) Fig. 2 Post hoc analysis of the ARMYDA-2 trial on benefit due to 600 mg clopidogrel load in the overall study population, in patients who were taking statins at the time of intervention and in those with age C70 years, diabetes mellitus, non-st-segment elevation acute coronary syndrome or multivessel intervention. DM diabetes mellitus, MI myocardial infarction, MV multivessel, NSTE-ACS non-st-segment elevation acute coronary syndrome

4 204 Intern Emerg Med (2009) 4: Accordingly, guidelines for PCI of the European Society of Cardiology [29] indicate that a 300 mg clopidogrel loading dose should be ideally given the day before planned PCI to achieve an effective platelet inhibition, whereas a 600 mg clopidogrel regimen should be recommended in patients requiring a more rapid platelet inhibition. The recent 2007 focused update of the ACC/AHA/SCAI guideline update for PCI [30] also states that a loading dose of clopidogrel, generally 600 mg, should be administered before or when PCI is performed; a 300 mg clopidogrel loading may be considered in those patients undergoing PCI within h after fibrinolytic therapy. In the context of a 600 mg clopidogrel loading dose, use of abciximab shows clinical benefit in troponin-positive patients with ACS (29% relative risk reduction of adverse events at 30 days vs. placebo) and no beneficial effect in troponin-negative patients with ACS [31]. Randomized studies have also evaluated whether loading with a dose of 900 mg clopidogrel may improve clinical outcome in patients undergoing PCI; indeed, incidence of procedural myonecrosis was similar in patients receiving 600 or 900 mg clopidogrel [32], and the latter dose was not associated with additional suppression of platelet function, because of limited clopidogrel absorption [33]. Moreover, aggregometry data suggest that a repeated 600 mg clopidogrel dose (the day before the procedure and repeated the morning of PCI) provides a significant further platelet inhibition compared with a single 600 mg dose [34]. A recent study [35] has randomized patients undergoing PCI and with impaired response to 600 mg clopidogrel loading (by vasodilator-stimulated phosphoprotein (VASP) index) to a control group and a VASP-guided group, in which up to three additional boluses of 600 mg clopidogrel were given in 24 h increments until a VASP index \50% was obtained. A significantly lower incidence of major adverse cardiac events occurs at 1 month in the latter arm (0 vs. 10%; P = 0.007), without increased risk of bleeding (5 vs. 4%). There is growing evidence indicating that use of a 150 mg/day maintenance dose of clopidogrel is associated with higher inhibition of platelet aggregation as compared to the currently recommended 75 mg/day dose [36, 37]. An inter-individual variability in platelet response has also been observed with the 150 mg dose and a considerable number of patients persist with inadequate platelet inhibition [36]. To date, there are no data demonstrating that the increased antiplatelet effect with the 150 mg dose translates into a significant clinical benefit during follow-up of patients undergoing PCI, especially after drug-eluting stent implantation. However, the ACC/AHA/SCAI 2005 updated PCI guidelines [38] recommend (class IIb indication, level of evidence C) that in patients in whom stent thrombosis may be catastrophic or lethal, platelet aggregation functional tests may be considered, and the maintenance dose increased to 150 mg/day if \50% platelet inhibition is obtained. In the context of a 600 mg loading strategy, is pre-treatment with clopidogrel before PCI needed, or can this loading dose be given in the catheter laborator, before intervention, but after coronary anatomy is known? Bleeding represents a major contemporary concern and it is recognized as a strong predictor of an unfavorable prognosis and mortality in patients with ACS [39, 40]. In particular, pooled data from four randomized trials of patients with ACS [40] indicates a stepwise increase in the risk of death at 1 month according to the bleeding severity (hazard ratios of 1.6, 2.7, 10.6 for mild, moderate and severe bleeding following the GUSTO definition); similar impact on prognosis has been demonstrated in patients undergoing PCI. The hypothetical advantage of a routine use of 600 mg clopidogrel pre-treatment before coronary angiography is the full antiplatelet effect in case of ad hoc PCI after coronary angiography, possibly resulting in increased periprocedural protection and lower ischemic myocardial complications. The disadvantage of this strategy may be a higher risk of peri-procedural bleeding complications, and the need to wait for at least 5 days [41] in patients requiring bypass surgery after diagnostic angiography (with possible enhanced risk of cardiac events waiting for the operation and with elevation of hospital costs and length of stay). Conversely, an approach of in-laboratory loading, after coronary anatomy is known and before ad hoc PCI, allows the administration of the clopidogrel only to patients who are candidates for PCI, thereby limiting peri-procedural bleeding events; the disadvantage may be an increased risk of peri-procedural ischemic complications due to sub-optimal platelet inhibition at the time of intervention. In the PRAGUE-8 study [42], patient candidates for elective coronary angiography were randomized to receive a 600 mg clopidogrel loading dose at a mean time of 20 h prior the procedure versus a 600 mg loading dose given in the catheter laboratory at the time of PCI following angiography. A minority of patients (29% of the initial cohort) received PCI after angiography. A similar 7-day incidence of major adverse cardiac and cerebrovascular events was observed in the two arms (1.3 vs. 2.8%; P = 0.43). To note, sample size of this study was underpowered to detect differences in clinical outcome in the 298 patients undergoing PCI. Rates of major bleeding were similar, whereas the occurrence of minor bleeding was lower in the

5 Intern Emerg Med (2009) 4: ARMYDA-5 trial: preliminary results Individual components of the primary end-point at 30 days % of patients P= In-lab load Preload Death MI TVR Fig. 3 ARMYDA-5 trial: individual components of the primary end-point at 30 days in patients receiving clopidogrel in-lab load or preload. MI myocardial infarction, TVR target vessel revascularization in-laboratory group (0 vs. 6.5%; P = 0.002). However, the bleeding risk in the preload group (6.5%) appears to be excessive considering the elective nature of the procedures. Preliminary results of the ARMYDA-5 trial were presented at the 2007 Transcatheter Cardiovascular Intervention Congress [43] on 350 patients with stable or unstable coronary syndromes randomized to receive a 600 mg dose of clopidogrel 6 h before PCI versus 600 mg given in the catheter laboratory after coronary angiography and before ad hoc PCI. ARMYDA-5 results show that outcomes after in-laboratory load strategy are comparable to that of the pre-treatment approach, with a similar 30-day incidence of adverse events, and, in particular, no significant difference in the rates of peri-procedural myocardial infarction (11 vs. 8%; P = 0.56) (Fig. 3). Thus, the strong and rapid antiplatelet effect following a 600 mg clopidogrel in-laboratory loading dose appears able to 8 counterbalance procedural platelet activation and provide a protection against post-procedural ischemic complications similar to a pre-treatment strategy. Moreover, in ARM- YDA-5, no difference in the bleeding risk by TIMI definition is observed in the two arms (in-lab load: 5%; preload: 4%). According to these data, when needed, in-laboratory clopidogrel administration can be a safe alternative to pretreatment given before knowing the patient s coronary anatomy, and an accurate patient s risk stratification is crucial for choosing an appropriate loading strategy. In particular, clopidogrel pre-treatment might be avoided in patients with stable coronary syndromes: if after coronary angiography PCI is indicated, in-laboratory clopidogrel loading is then applied. Conversely, if bypass surgery is preferred, it may be performed early, without the need to defer operation after clopidogrel withdrawal. Risk of ischemia recurrence is known to be maximal in the early phase of ACS [4]. Thus, unstable patients may benefit from clopidogrel pre-treatment before coronary angiography [44]; in fact, an early platelet suppression is mandatory in such patients due to the elevated thrombotic risk and a full antiplatelet effect in the case of ad hoc PCI is desirable. What is the optimal clopidogrel strategy in patients on chronic clopidogrel therapy undergoing PCI? A number of patients are on chronic therapy with clopidogrel owing to previous ACS, drug-eluting stent implantation, complex, multiple PCI procedures or other atherothrombotic events. In the ARMYDA trial recruiting centers, this proportion of patients constitutes approximately 20% of those receiving PCI and such percentage is Fig. 4 ARMYDA-RELOAD trial: MACE-free survival at 30 days according to clinical presentation on admission. ACS acute coronary syndrome, MACE major adverse cardiac events, PCI percutaneous coronary intervention MACE incidence (%) ARMYDA-RELOAD trial MACE incidence at 30 days and benefit with Clopidogrel reload according to clinical presentation P=0.047 (ACS Placebo vs ACS Reload) ACS Placebo ACS Reload Stable angina Placebo Stable angina Reload Days after intervention (PCI)

6 206 Intern Emerg Med (2009) 4: Table 1 Studies evaluating correlation between clopidogrel responsiveness and outcome after PCI Authors Study design No. of patients Clopidogrel dose (mg) Definition of non- responders Follow-up duration Main outcomes Mueller et al. [73] Matetzky et al. [69] Klamroth et al. [74] Ajzenberg et al. [75] Gurbel et al. [58, 72] Gurbel et al. [58, 72] Wenaweser et al. [76] Prospective LD; 75 MD LTA (5 and 20 lmol/l ADP): \10% decrease vs. baseline Prospective LD; 75 MD LTA (5 lmol/l ADP): 1st quartile of reductions (vs. baseline) Case control 20 ST; 20 ctrls 300 LD; 75 MD LTA (20 lmol/l ADP): aggregation [30% 14 days 2 ST in non-responders vs. no ST 6 months 47% MACCE in non-responders (vs. 2%; P \ 0.05) 45% of non-responders in cases (vs. 5% in ctrls; P \ 0.05) Case control 10 ST; 32 ctrls 300 LD; 75 MD % of SIPA SIPA higher in cases (41 vs. 18% in ctrls; P = 0.013) Case control 20 ST; 100 ctrls 300 LD; 75 MD LTA (5 and 20 lmol/l ADP): percentage of PR Prospective or 600 LD; 75 MD LTA (20 lmol/l ADP): 4th quartile of aggregation Case control 23 ST; 50 ctrls 300 LD; 75 MD LTA (5 and 20 lmol/l ADP): \10% decrease vs. baseline Cuisset et al. [65] Prospective LD; 75 MD LTA (10 lmol/l ADP): 4th quartile of aggregation Cuisset et al. [28] Prospective, randomized vs. 600 LD; 75 MD LTA (10 lmol/l ADP): aggregation [70% Geisler et al. [66] Prospective LD; 75 MD LTA (20 lmol/l ADP): aggregation [70% Hochholzer et al. [67] Prospective LD; 75 MD LTA (5 lmol/l ADP): 4th quartile of aggregation Lev et al. [61] Prospective LD; 75 MD LTA (5 and 20 lmol/l ADP): \10% decrease vs. baseline Cuisset et al. [62] Prospective LD; 75 MD LTA (10 lmol/l ADP): aggregation [70% Lev et al. [77] Case control 20 ST; 20 ctrls 300 or 600 LD; 75 MD LTA (5 and 20 lmol/l ADP): percentage of PR Buonamici et al. [78] Prospective LD; 75 MD LTA (10 lmol/l ADP): aggregation C70% PR in cases higher than ctrls (49 65 vs %; P \ 0.001) 6 months 32% MACCE in 4th quartile (vs. 10% in 1st; P = 0.02) 4% of non-responders in cases (vs. 6% in ctrls; P = NS) 1 month 39% MACCE in 4th quartile (vs. 4% in lower 3 quartiles; P = 0.003) 1 month 31% MACCE in non-responders (vs. 3% in responders; P \ ) 3 months 23% MACCE in non-responders (vs. 6% in responders; P = 0.037) 1 month 3.5% MACE in 4th quartile (vs. 0.5% in 1st; P = 0.033) 24 h 32% CK-MB increase after stenting in non-responders (vs. 17% in responders; P = 0.06) 24 h 43% peri-procedural MI in non-responders (vs. 24% in responders; P = 0.014) PR in cases higher than ctrls (50 67 vs %; P B 0.02) 6 months after SES or PES 8.6% ST in non-responders (vs. 2.3% in responders; P \ 0.001)

7 Intern Emerg Med (2009) 4: Table 1 continued Main outcomes Follow-up duration Authors Study design No. of patients Clopidogrel dose (mg) Definition of non- responders 24 h after DES No correlation between PRU and cardiac markers elevation after PCI Buch et al. [63] Prospective or 600 LD; 75 MD PRU by the VerifyNow TM assay 1 year 73% MACCE in non-responders (vs. 9% in responders; P \ ) Bliden et al. [70] Prospective 100 No LD; 75 MD LTA (5 lmol/l ADP): aggregation C50% 6.5% MACE in non-responders (vs. 1% in responders) 6 months after SES 24 h 44% peri-procedural necrosis in non-responders (vs. 15% in responders; P = 0.001) 1 month 20% MACE in the 4th quartile (vs. 3% in 1st; P = 0.034) Price et al. [71] Prospective LD; 75 MD PRU C 235 by the P2Y12 VerifyNow TM assay Cuisset et al. [64] Prospective LD; 75 MD Platelet inhibition\15% by the P2Y12 VerifyNow TM assay Patti et al. [68] Prospective LD; 75 MD PRU in the 4th quartile by the P2Y12 VerifyNow TM assay CK-MB creatine kinase-mb, DES drug-eluting stents, LD loading dose, LTA light transmittance aggregometry, ADP adenosine diphosphate, MACE major adverse cardiac events, MACCE major adverse cardiovascular and cerebrovascular events, MD maintenance dose, PCI percutaneous coronary intervention, PES paclitaxel-eluting stents, PR platelet reactivity, PRU P2Y12 reactivity units; SES sirolimus-eluting stents, SIPA shear-induced platelet aggregation likely to increase because of expanding indications for prolonged dual antiplatelet therapy (aspirin plus clopidogrel) in patients with coronary artery disease. A 75 mg daily dose of clopidogrel has been selected as it provides antiplatelet effects equivalent to those obtained with 500 mg daily dose of ticlopidine, i.e. the first thienopyridine used in clinical practice [45]. Indeed, a platelet inhibition adjunctive to that obtained with the currently recommended maintenance dose of clopidogrel might improve clinical outcome in the setting of PCI. Recent aggregometry data have indicated that a further 600 mg clopidogrel dose in patients on chronic therapy is associated with additional, significant attenuation of residual platelet reactivity [46]. The ARMYDA-RELOAD trial was recently presented at the 2008 Scientific Session of the American College of Cardiology [47]. This study first evaluated whether this additional platelet function suppression by clopidogrel reloading translates into a clinical benefit in patients undergoing PCI, primarily in those with unstable syndromes receiving early intervention. Patients on chronic clopidogrel therapy were enrolled and randomized to receive a further 600 mg clopidogrel load ( reload arm) or placebo 6 h before the procedure. In the overall study population, results of ARMYDA- RELOAD show a similar incidence of 30-day adverse events in the two arms (7% in the reload vs. 9% in placebo; P = 0.70); however, analysis of prespecified subgroups (Fig. 4) demonstrates in patients receiving PCI for ACS, a significant 64% relative risk reduction of adverse events in the reload arm (7 vs. 18%; P = 0.035), without increase in the bleeding risk (10% in both arms). In particular, beneficial effect in this subset is essentially driven by peri-procedural protection, with 61% relative risk reduction of procedural myocardial infarction. Conversely, in the subgroup with stable angina on admission, efficacy and safety outcomes at 1 month are similar in the two arms. Thus, patients with stable angina on chronic clopidogrel therapy can safely undergo PCI without need of further reload, whereas in patients with ACS, a reload strategy with 600 mg clopidogrel significantly improves outcome and may be extensively applied in interventional cardiology. A recent study [48] has evaluated, by LTA and a pointof-care assay (VerifyNow TM ), the effects on platelet function of reload with 300, 600 or 900 mg clopidogrel in patients receiving PCI and on chronic clopidogrel therapy 75 mg/day. A significant stepwise increase is demonstrated in the percentage of inhibition of residual platelet aggregation measured at 4 h in patients receiving 300 versus 600 versus 900 mg, and the rates of poor responders are lower in the latter group; however, this study was not powered and designed for clinical end-points.

8 208 Intern Emerg Med (2009) 4: Does the degree of clopidogrel response influence clinical outcome in patients undergoing PCI? Evaluation of clopidogrel responsiveness is an emerging issue in interventional cardiology; wide inter-individual variability in clopidogrel responsiveness has been reported [49, 50] and multiple mechanisms have been invoked: differences in individual drug absorption, variations in biotransformation rate into active metabolite (due to drug drug interactions at the site of cytochrome P or genetic CYP3A/CYP2C19 polymorphisms) [51 54] or P2Y12 receptor polymorphisms affecting receptor number and activity [55], and even non-compliance [56]. Response to clopidogrel is also reduced in the presence of high pretreatment platelet reactivity, as observed in patients with diabetes mellitus [57] and ACS [10] due to accelerated platelet turnover and up-regulation of P2Y-dependent or P2Y-independent pathways for the effect of coagulation agonists (epinephrine, Thromboxane A 2, thrombin) [57]. The reported prevalence of impaired clopidogrel response varies from 4 to 30% [49, 58, 59]. A key question is whether platelet functional tests may provide indications for patient s risk stratification according to degree of platelet inhibition in response to antiplatelet agents. In particular, a variety of methods have been utilized to evaluate clopidogrel response in patients undergoing PCI, with the aim of identifying those at higher risk of adverse events. Table 1 summarizes studies exploring the correlation between clopidogrel responsiveness and outcome after PCI [28, 58, 60 71]. The LTA after ADP stimulation has been the most widely used test, in which low platelet response to clopidogrel is associated with poorer outcome after PCI due to increased incidence of peri-procedural myocardial injury [60 62], as well as of cardiovascular events at short term [28, 65 67] and midterm [58, 69, 70]. Observational data also show a higher residual platelet reactivity after clopidogrel treatment in patients with stent thrombosis [72 77] and this has been confirmed in a prospective study [78] demonstrating [3-fold increased risk of drug-eluting stent thrombosis at 6 months in the presence of impaired clopidogrel response. However, LTA presents a number of limitations, such as need for highly trained personnel, repeated centrifugations, large sample volume, length of assay time, and sub-optimal reproducibility. VASP phosphorylation by flow cytometry is a more specific test for evaluating antiplatelet effects of clopidogrel, as it directly measures effects of the drug on the target receptor. In observational studies, a lower degree of platelet inhibition, as assessed by VASP phosphorylation, has been observed in patients with stent thrombosis [72]. Cost and need for long sample preparation and skilled personnel limit a widespread use of this test. We have recently investigated in a prospective protocol (ARMYDA-PRO study), the correlation between clopidogrel responsiveness with clinical outcome after PCI using a rapid, point-of-care assay (VerifyNow TM )[68]. This test is specific for detecting the extent of ADP-induced adenylyl cyclase inhibition, which is mediated uniquely by action of clopidogrel on the P2Y12 receptor, and residual platelet reactivity is expressed by P2Y12 reaction units (PRU). The predictive value for adverse events of the 4th PRU quartile before intervention is independent of possible confounding factors with sixfold increased risk of peri-procedural myocardial infarction versus the 1st quartile (20 vs. 3%; P = 0.034) (Fig. 5). Multivariable analysis reveals that pre-pci PRU levels in the 4th quartile are independently associated with higher risk of adverse events at 30 days (OR 6.1, 95% CI ; P = 0.033). Age[70 years and use of Glycoprotein IIb/IIIa inhibitors are also predictors of increased risk (OR 4.2 and 7.3, respectively). Moreover, Fig. 5 ARMYDA-PRO (Antiplatelet Therapy for Reduction of MYocardial Damage During Angioplasty- Platelet Reactivity Predicts Outcome) study. Panel a Distribution of pre-intervention PRU levels in patients with post-procedural normal CK-MB values and post-procedural myocardial infarction ([3 times CK-MB elevation). Panel b Receiver-operating characteristic (ROC) curve analysis for the VerifyNow TM assay. Area under the curve was 0.69 (95% CI ; P = 0.016). CK-MB creatine kinase-mb, PRU platelet (P2Y12) reaction units A PRU values Normal CK-MB P=0.030 ARMYDA-PRO study B CK-MB 3x Sensitivity 1-Specificity

9 Intern Emerg Med (2009) 4: ROC analysis demonstrates that this point-of-care assay is able to significantly predict outcome at 30 days: the optimal cut-off point to discriminate patients at higher risk of events is PRU C240 with a positive predictive value of 81%. This threshold for clinical outcome is similar to that observed in a recent study by Price et al. [71], in which a cut-off C235 PRU is correlated to 6-month events, including stent thrombosis, in patients undergoing PCI with sirolimus-eluting stent implantation. However, the following considerations may be raised with regard to use of platelet function assays in patients on clopidogrel therapy and undergoing PCI: (a) impaired clopidogrel response should be considered as a continuum, rather than an on/off phenomenon; (b) the large variability in the reported prevalence of impaired clopidogrel response also depends on different assays used, variable definitions empirically applied and presence of potential confounders; (c) standardized definition of reduced clopidogrel response resulting from correlation between results of laboratory assays and clinical outcome has yet to be developed; (d) it may be difficult to evaluate the relationship between results of platelet function tests and clinical outcome due to inter-individual and intra-patient response variability; (e) no studies have extensively addressed the issue of whether individual clinical outcome may be modified when treatment is addressed according to results of platelet function assays; (f) at present, a systematic use of platelet function tests is not recommended in clinical practice; (g) those tests may represent a very useful research tool, but in the individual patient their results should be referred to the clinical context. 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