Possibility of a rebound phenomenon following

0 downloads 0 Views 1MB Size Report
Evidence of a rebound in platelet activity following aspirin withdrawal . ..... thrombosis, administration of extremely low doses of aspirin (in the range of 10− 10 ...
Pharmacology & Therapeutics 123 (2009) 178–186

Contents lists available at ScienceDirect

Pharmacology & Therapeutics j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p h a r m t h e r a

Associate editor: V. Schini-Kerth

Possibility of a rebound phenomenon following antiplatelet therapy withdrawal: A look at the clinical and pharmacological evidence Marie Lordkipanidzé a,c,d, Jean G. Diodati b,c,e, Chantal Pharand a,c,d,⁎ a

Faculty of Pharmacy, Université de Montréal, C.P. 6128, Succursale Centre Ville, Montréal, Québec, Canada H3C 3J7 Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, Québec, Canada H3C 3J7 Research Center, Hôpital du Sacré-Cœur de Montréal, 5400, Boulevard Gouin Ouest, Montréal, Québec, Canada H4J 1C5 d Department of Pharmacy, Hôpital du Sacré-Cœur de Montréal, 5400, Boulevard Gouin Ouest, Montréal, Québec, Canada H4J 1C5 e Division of Cardiology, Hôpital du Sacré-Cœur de Montréal, 5400, Boulevard Gouin Ouest, Montréal, Québec, Canada H4J 1C5 b c

a r t i c l e

i n f o

a b s t r a c t The importance of regular administration of antiplatelet drugs in patients suffering from coronary artery disease stands on firm grounds, as large meta-analyses have shown these therapies to drastically reduce the risk of death. Although the current guidelines published jointly by the American Heart Association, the American College of Cardiology, the Society for Cardiovascular Angiography and Interventions, the American College of Surgeons and the American Dental Association stress the hazards of premature discontinuation of antiplatelet drugs, abrupt withdrawal remains widespread, with potentially catastrophic consequences. In the limited state of knowledge on antiplatelet drug withdrawal, an early sound of alarm has risen from early thromboembolic complications reported after the interruption of treatment in patients who require antiplatelet therapy for prevention of ischemic vascular disease. Acute thrombotic complications are not immediate and usually follow interruption of aspirin or clopidogrel therapy after a mean delay of 8–25 days, a time lapse consistent with normal platelet turnover required to replace the platelet pool in circulation and suggestive of a rebound phenomenon. This review article describes the thrombotic risks associated with discontinuing antiplatelet therapy and the bleeding risks associated with continuing these drugs. By integrating the current understanding of the pharmacology of antiplatelet agents and the kinetics of platelet function recovery, this article unveils the possibility of a pharmacological rebound phenomenon which could lead to adverse ischemic events, and supports the warning against premature discontinuation of antiplatelet drugs issued in current guidelines. © 2009 Elsevier Inc. All rights reserved.

Keywords: Aspirin Clopidogrel Discontinuation Rebound

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Aspirin's pharmacology. . . . . . . . . . . . . . . . . . . . . . . . 4. Clopidogrel's pharmacology. . . . . . . . . . . . . . . . . . . . . . 5. Bleeding risks associated with antiplatelet drugs . . . . . . . . . . . . 6. Evidence of a rebound in platelet activity following aspirin withdrawal . . 7. Evidence of a rebound in platelet activity following clopidogrel withdrawal 8. Potential mechanisms underlying rebound platelet activity . . . . . . . 9. Alternative hypotheses . . . . . . . . . . . . . . . . . . . . . . . . 10. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

179 179 179 179 179 181 181 181 183 181 184 181 184 183 184 183 185

Abbreviations: ADP, adenosine diphosphate; BMS, bare metal stent; CAD, coronary artery disease; COX, cyclooxygenase; CVE, cerebrovascular event; DES, drug-eluting stent; MI, myocardial infraction; PCI, percutaneous coronary intervention; Tx, thromboxane; VASP, vasodilator-stimulated phosphoprotein. ⁎ Corresponding author. Research Center, Hôpital du Sacré-Coeur de 5400, Boulevard Gouin Ouest, Montréal, Québec, Canada H4J 1C5. Tel.: 514 338 2222x2506; fax: 514 338 2694. E-mail address: [email protected] (C. Pharand). 0163-7258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.pharmthera.2009.03.019

M. Lordkipanidzé et al. / Pharmacology & Therapeutics 123 (2009) 178–186

1. Introduction Cardiovascular diseases remain among the leading causes of death in the industrialized world. In the United States, coronary artery disease (CAD) accounts for half of cardiovascular and one fifth of all cause mortality (Thom et al., 2006). In 2006, an estimated 700,000 Americans had a new coronary event and about 500,000 had a recurrent attack, with an additional 175,000 silent first heart attacks estimated to occur each year (Thom et al., 2006). Advances in medical and pharmacological treatment of patients suffering from CAD have improved prognosis in the last decades. It is estimated that stent implantations constitute over 70% of coronary interventions, which have increased by 326% from 1987 to 2003, resulting in an estimated 664,000 procedures being performed in 2003 in the United States alone (Laskey et al., 2000; Thom et al., 2006). In pharmacological breakthroughs, the standard use of antiplatelet agents has considerably reduced cardiovascular mortality (Antithrombotic Trialists' Collaboration, 2002). Current guidelines recommend that all patients suffering from CAD receive daily aspirin therapy, based on aspirin's efficacy to reduce the risk of stroke, myocardial infarction and death by ~25% in patients with cardiovascular disease (Gibbons et al., 2003). Moreover, in patients undergoing stent implantation, addition of clopidogrel to daily aspirin therapy is advocated for at least 1 month in the case of bare metal stents (BMS), 3–6 months for drug-eluting stents (DES), and ideally for up to 1 year (Smith et al., 2006). This combination has been shown to significantly reduce the incidence of ischemic cardiovascular events in patients with stent implantation (Mehta et al., 2001; Steinhubl et al., 2002). Thus, the well established importance of regular administration of antiplatelet drugs stands on firm grounds, as large meta-analyses have shown these therapies to drastically reduce the risk of death (Antithrombotic Trialists' Collaboration, 2002). However, the delicate balance between adequate antithrombotic effect and risk of bleeding remains a sensitive matter, which often influences a patient's or a physician's choice to discontinue daily antiplatelet therapy. Bleeding concerns, mainly in the setting of surgery, are the major reason for abrupt withdrawal of antiplatelet therapy, although other reasons include non compliance, newly diagnosed hemorrhagic disorders, interactions with other drugs and drug intolerance (Collet et al., 2000; Collet et al., 2004; Burger et al., 2005; Ferrari et al., 2005; BiondiZoccai et al., 2006). This review focuses on the risk of prematurely discontinuing antiplatelet agents, with emphasis on clinical and pharmacological key reports suggesting a rebound phenomenon in platelet activity following abrupt cessation of antiplatelet agents. 2. Methodology A literature search was performed using MEDLINE from 1966 to January 2009 with the terms [aspirin AND (withdrawal OR withholding OR cessation OR discontinu*)] and [clopidogrel AND (withdrawal OR withholding OR cessation OR discontinu*)]. The literature search was extended to Web of Science from 1979 to September 2008, as well as to The Cochrane Central Register of Controlled Trials, 3rd quarter 2008, using the terms (aspirin OR clopidogrel) AND withdrawal. Bibliographies of all articles retrieved during the literature search were subsequently studied for articles that might have been missed during the computerized literature search. No language restriction was applied for abstract review; however, only articles written in English or French were examined in detail. 3. Aspirin's pharmacology Aspirin, or acetylsalicylic acid, is the most successful drug ever commercialized, with over 35,000 kg consumed daily in the United

179

States alone (Jack, 1997). Its popularity can be explained by its high efficacy, favourable adverse effect profile and low cost. Indeed, daily aspirin therapy reduces appreciably the risk of acute ischemic events in populations at risk through inhibition of platelet aggregation (Antithrombotic Trialists'Collaboration, 2002). As shown in Fig. 1, the best characterized mechanism by which aspirin inhibits platelets is irreversible acetylation of cyclooxygenase (COX)-1, a key enzyme in prostaglandin formation (Vane, 1971). Inhibition of platelet COX-1 by aspirin blocks the conversion of arachidonic acid to thromboxane (Tx) A2, a platelet activator and vasoconstrictor, thus reducing the formation of thrombi capable of inducing acute ischemic events (Antithrombotic Trialists' Collaboration, 2002). It follows that the pharmacological evaluation of effective COX-1 inhibition by aspirin relies on measurements of TxA2 synthesis or of ensuing TxA2dependent platelet aggregation (Lordkipanidzé et al., 2006). However, protein acetylation by aspirin is not limited to platelet COX-1. Indeed, aspirin can also acetylate fibrinogen, an important player in the final stabilization of the thrombus (Bjornsson et al., 1989). Fibrinogen acetylation results in a molecule more prone to fibrinolysis and less likely to aggregate to fibrin monomers (Bjornsson et al., 1989). This mechanism may also contribute to a reduced propensity to form thrombi in patients taking aspirin daily. 4. Clopidogrel's pharmacology Since its commercialization in 1998, prescription rates for clopidogrel have sky rocketed (Brinker & Swartz, 2006). Although clopidogrel was shown to be at least as effective as aspirin in selected populations, and as such is recommended as a substitute in patients in whom aspirin is contraindicated, clopidogrel is mostly used in combination with aspirin to further reduce the risk of acute ischemic events in high risk individuals, such as those having suffered an acute coronary syndrome, or having undergone coronary stenting (Patrono et al., 2004). As depicted in Fig. 1, clopidogrel inhibits platelet aggregation through a pathway distinct from that targeted by aspirin. Specifically, clopidogrel is an antagonist of the P2Y12 adenosine diphosphate (ADP)-sensitive platelet surface receptor, thus its daily administration hinders ADPinduced platelet aggregation (Geiger et al., 1999). Consequently, the pharmacological evaluation of effective P2Y12 receptor inhibition by clopidogrel relies on measurement of specific downstream signalling events of the P2Y12 receptor (particularly phosphorylation of the vasodilator-stimulated phosphoprotein [VASP]) or assessment of ADPinduced platelet aggregation (Nguyen et al., 2005). 5. Bleeding risks associated with antiplatelet drugs As antiplatelet drugs interfere with primary, and to some extent with secondary hemostasis, their beneficial antithrombotic effects cannot be dissociated from increased risk of bleeding. Indeed, daily aspirin use for primary or secondary prevention of atherothrombotic disease increases the risk of major bleeding, major gastrointestinal bleeding and intracranial bleeding 1.7–2.1-fold (McQuaid & Laine, 2006). However, absolute increase in risk of major bleeding is small, requiring 769 patients to be treated for 1 year to induce one additional major bleeding event (McQuaid & Laine, 2006). Conversely, adding clopidogrel on top of daily aspirin therapy further increases the risk of bleeding, although combined aspirin and clopidogrel therapy has not been associated with increased risk of fatal or intracranial hemorrhage (McQuaid & Laine, 2006). Overall, spontaneous bleeding with either agent alone or in combination is rare, and haemorrhage-induced fatality is exceptional in the primary or secondary CAD prevention population (Chassot et al., 2007). In surgical settings, it is believed that excessive bleeding induced by antiplatelet agents may result in surgical morbidity or mortality. However, a meta-analysis of 41 studies on patients taking aspirin and requiring surgery has shown that, although bleeding risk was

180 M. Lordkipanidzé et al. / Pharmacology & Therapeutics 123 (2009) 178–186 Fig. 1. Pharmacological targets of aspirin and clopidogrel resulting in platelet inhibition. Under basal conditions, arachidonic acid (AA) released from the phospholipid membrane by phospholipase A2 (PLA2) undergoes conversion to prostaglandin H2 (PGH2) by the cyclooxygenase (COX)-1 enzyme. PGH2 is further metabolized to thromboxane A2 (TxA2), a potent vasoconstrictor and pro-aggregant molecule, through the thromboxane synthase (TXAS). By binding the Gαqprotein-coupled thromboxane receptor (TP), TxA2 activates the phospholipase C (PLC), which in turn induces an increase in intraplatelet calcium (Ca2+) and results in platelet shape change as well as degranulation of dense and alpha granules. The release in circulation of pro-aggregant molecules, including adenosine diphosphate (ADP), and of coagulation factors promotes platelet aggregation and thrombus formation. As shown in the left-hand dotted frame, aspirin inhibits platelet aggregation through irreversible acetylation of platelet COX-1 enzyme, which can no longer convert AA to PGH2, and thus abolishes TxA2 formation and ensuing events. Under basal conditions ADP stimulation leads to activation of 2 distinct receptors, i.e. P2Y1 and P2Y12. Gαq-protein-coupled P2Y1 receptor activation leads to similar intracellular events as activation of the TP receptor. The P2Y12 receptor is coupled with the Gαi2 protein. Its activation inhibits adenylate cyclase (AC) and results in reduced formation of cyclic adenosine monophosphate (cAMP), which is required for phosphorylation of the vasodilator-stimulated phosphoprotein (VASP). P2Y12 receptor activation leads to inhibition of VASP phosphorylation, thus facilitating GP IIbIIIa receptor activation. The βγ dimer is responsible for activation of PI-3 kinase (PI-3K) which appears to be the major effector pathway of the P2Y12 receptor, through activation of Rap1b and possibly Akt. As shown in the right-hand dotted frame, clopidogrel inhibits the P2Y12 receptor, thus limiting GPIIbIIIa receptor activation.

M. Lordkipanidzé et al. / Pharmacology & Therapeutics 123 (2009) 178–186

increased 1.5-fold, there was no detectable increase in surgical morbidity or mortality (Burger et al., 2005). In the case of clopidogrel, the data is sparser, with some reports suggesting a higher perioperative bleeding risk (Kapetanakis et al., 2006; Kang et al., 2007), while others report no increased perioperative bleeding in patients maintained on clopidogrel therapy (Sharma et al., 2004; Song et al., 2008). In recent reviews, it was suggested that surgical bleeding and transfusion rate was increased by ~ 50% when combined clopidogrel and aspirin therapy was continued perioperatively, however morbidity and mortality was unaffected, except in the case of intracranial surgery (Chassot et al., 2007; Pickard et al., 2008). Nevertheless, the practice of withholding antiplatelet agents 7–10 days before surgery to prevent excessive surgical bleeding is widespread (Pass & Simpson, 2004; Dunning et al., 2008). 6. Evidence of a rebound in platelet activity following aspirin withdrawal 6.1. Clinical evidence In the limited state of knowledge on antiplatelet drug withdrawal, an early sound of alarm has risen from early thromboembolic complications reported after the interruption of treatment in patients who required aspirin for prevention of ischemic vascular disease. Among the first cases of major adverse ischemic events following aspirin withdrawal to be reported, five patients suffered transient ischemic events, peripheral emboli, fatal myocardial infraction (MI) and fatal cerebrovascular event (CVE) after discontinuation of aspirin before elective transurethral prostatectomy (Mitchell & Sethia, 1999). Shortly later, 11 cases presenting with acute MI which took place on average 9.4 days after aspirin cessation, were described in a retrospective study (Collet et al., 2000). The occurrence of acute coronary syndromes within 1 month of aspirin discontinuation was further reported in 51 CAD patients; the incidence of acute coronary syndrome was markedly higher in patients who had discontinued aspirin therapy in comparison with patients who had not (Ferrari et al., 2005). Additionally, 5 cases of thrombotic stent occlusions were described several months to years after implantation, 5–14 days following aspirin discontinuation, in patients whose CAD was considered stable (McFadden et al., 2004; Rossi et al., 2007). In parallel, 13 cases of CVE occurring within weeks of aspirin cessation were noted in a prospective fashion (Bachman, 2002). This finding was corroborated by another report of stroke in 13 patients who had discontinued antiplatelet treatment in the previous month (Sibon & Orgogozo, 2004). Moreover, even after adjustment for presence of CAD, interruption of aspirin therapy was found to significantly increase the risk of transient ischemic event or stroke by a factor of 3.4 (Maulaz et al., 2005). Although the data is less extensive in patients suffering from peripheral artery disease, acute lower limb ischemia was observed in 11 patients after discontinuing chronic aspirin therapy (Albaladejo et al., 2004). The abundance of case reports on the risk of discontinuing daily aspirin therapy has prompted two systematic reviews and metaanalyses on the hazards of discontinuing or not adhering to aspirin therapy (Burger et al., 2005; Biondi-Zoccai et al., 2006). Analyzing data obtained from 50,279 patients, the increase in risk of major adverse cardiac events attributed to aspirin withdrawal/non-adherence was approximately three-fold (Biondi-Zoccai et al., 2006). This risk was amplified by a factor of 89 in patients who had undergone stenting, although it should be noted that in this case, co-withdrawal of clopidogrel may have impacted results (Biondi-Zoccai et al., 2006). Moreover, it was found that up to 10.2% of acute coronary syndromes follow interruption of aspirin therapy in a mean delay of ~ 8.5 days, a delay consistent with rebound platelet activity (Burger et al., 2005). The delay is longer for CVE (around 14.3 days) and for peripheral arterial syndromes (about 25.8 days) (Burger et al., 2005).

181

6.2. Pharmacological evidence Little data is available on the recovery of platelet function following abrupt aspirin withdrawal. In a rat model, a rise in thromboembolic complications occurred 8–10 days after the last dose of aspirin, consistent with the delay seen in clinical settings (Aguejouf et al., 1998; Aguejouf et al., 2000). The increased incidence of thromboembolic complications coincided with increased platelet aggregation and subsequent thrombus formation when compared with non treated controls (Aguejouf et al., 1998; Aguejouf et al., 2000). This rebound effect may be attributed to increased platelet COX-1 activity. Because platelet COX-1 acetylation by aspirin is irreversible and platelets have only limited capacity to regenerate active COX-1 following exposure to aspirin, inhibition of platelet activity by aspirin is permanent, lasting through the platelet life-span of ~ 7–10 days (Awtry & Loscalzo, 2000; Evangelista et al., 2006). Thus, the recovery of platelet function following aspirin administration is greatly dependent upon generation of new platelets capable of COX-1 activity from megakaryocytic cells (Patrono et al., 1985; Awtry & Loscalzo, 2000). Upon aspirin discontinuation however, platelet function recovery is not linear; normal hemostasis can occur when as little as 20% of new platelets with unaffected COX-1 activity are present in the circulation, resulting in near normal hemostasis within 48–72 h (Sonksen et al., 1999; Awtry & Loscalzo, 2000; Vilahur et al., 2007). On the other hand, studies examining the ability of platelets to form TxA2 following aspirin discontinuation have reported rebound elevations in COX-1 activity several days after restoration of near normal hemostasis, lasting for several weeks after interruption of therapy. Indeed, when COX-1 activity was assessed by urinary excretion of 11-dehydro-TxB2, a major TxA2 metabolite, the concentration of this molecule was greater in subjects after discontinuing aspirin therapy in comparison with basal levels (Vial et al., 1991). TxA2 synthesis peaked 21 days after cessation, and remained higher than baseline for up to 4 weeks, but was significantly inhibited upon re-administration of aspirin (Vial et al., 1991). Similarly, when TxA2 synthesis was assessed by serum levels of 12-L-5,8,10heptadecatrienoic acid (12-HHT, a marker of platelet TxA2 production) in healthy volunteers, increased TxA2 formation was observed 3 weeks after aspirin discontinuation, a rebound effect that persisted for 6 weeks (Beving et al.,1994). An abnormally high TxA2 formation, suggestive of a rebound effect following interruption of aspirin therapy, was also detected in patients with stable CAD (Beving et al., 1996). In addition to enhanced COX-1 activity, aspirin withdrawal has been associated with increased platelet sensitivity to various agonists. Indeed, prior treatment with aspirin resulted in rebound platelet aggregation in response to ADP and epinephrine in 34 healthy volunteers (Mousa et al., 1993). Similarly, rebound ADP-induced platelet activity was reported following discontinuation of nonsteroidal anti-inflammatory drugs, known to have reversible aspirin-like COX-1 inhibitory effects (Serebruany et al., 2006a). Besides enhancing platelet aggregation, aspirin withdrawal may also increase thrombus stability by improving the efficacy of the fibrin crosslink network. Indeed, the tightness of the fibrin network was more pronounced after aspirin withdrawal than in controls not taking aspirin. This rebound effect was seen 1 week following cessation of aspirin therapy in 18 patients suffering from stable CAD (Fatah et al., 1996). 7. Evidence of a rebound in platelet activity following clopidogrel withdrawal 7.1. Clinical evidence Stent thrombosis is a rare event, occurring in ~ 1–1.5% of patients following effective PCI (Cutlip et al., 2001; Iakovou et al., 2005). However, stent thrombosis has dramatic clinical consequences, with 64% of patients suffering recurrent MI or dying at the time of stent thrombosis. Fatality rate at the time of thrombosis reaches 45% and

182 M. Lordkipanidzé et al. / Pharmacology & Therapeutics 123 (2009) 178–186 Fig. 2. Potential mechanisms leading to rebound platelet activity following withdrawal of antiplatelet drugs. A) Increased COX-1 synthesis or activity in response to chronic aspirin therapy predisposes to platelet hyperactivity following aspirin withdrawal. The first panel shows normal platelet activity in the absence of aspirin, where arachidonic acid (AA) is converted to thromboxane A2 (TxA2) via the cyclooxygenase (COX)-1 pathway. Addition of aspirin results in inhibition of COX1 and abolishment of TxA2 formation. Long-term aspirin treatment may result in overabundance of COX-1 in platelets, yet daily aspirin administration is sufficient to palliate this effect, as depicted in the third panel. Finally, upon aspirin discontinuation, AA can be massively converted to TxA2 via uninhibited COX-1 enzymes, as shown in the last panel. B) Increased P2Y12 receptor number or activity, or enhanced coupling with downstream mediators, in response to chronic clopidogrel therapy predisposes to platelet hyperactivity following clopidogrel withdrawal. The first panel shows normal platelet activity in the absence of clopidogrel, where adenosine diphosphate (ADP) stimulation results in activation of both P2Y1 and P2Y12 receptors. Addition of clopidogrel results in inhibition of the P2Y12 receptor, while P2Y1 receptor's function is unaffected. Long-term clopidogrel therapy may result in either overexpression of P2Y12 receptor or enhanced P2Y12 receptor activity, which is masked by daily administration of clopidogrel, as shown in the third panel. Finally, upon clopidogrel discontinuation, available P2Y12 receptors bind ADP and result in marked activation of GPIIbIIIa receptors, and increased platelet aggregation, as depicted in the last panel.

M. Lordkipanidzé et al. / Pharmacology & Therapeutics 123 (2009) 178–186

mortality remains high at 6 months following stent thrombosis, affecting 8.9% of patients (Cutlip et al., 2001; Iakovou et al., 2005). In recent literature, much discussion on the possible prothrombotic effects of DES as compared with BMS has taken place (Newsome et al., 2008). Although this discussion is beyond the scope of this review, where possible, differentiation between DES and BMS has been made. Interruption of clopidogrel treatment often precedes acute stent thromboses. As such, withdrawal of oral antiplatelet agents has been associated with a two-fold increase in 30-day mortality, with 5% of patients admitted for acute coronary syndrome having stopped antiplatelet therapy within 3 weeks before admission (Collet et al., 2004). In a report on the optimal timing of non-cardiac surgery following stenting, six of the seven deaths documented during surgery within 3 weeks of stent implantation occurred in patients having discontinued antiplatelet therapy (Sharma et al., 2004). In a study on 652 patients having undergone successful DES implantation, premature discontinuation of clopidogrel was associated with a 30-fold increase in the risk of stent thrombosis and was found to be the most important risk factor for the development of such an event (Jeremias et al., 2004). A similar finding was reported in a large cohort of 2229 patients followed for 9 months after successful stenting with DES, where premature antiplatelet therapy discontinuation was an independent predictor of stent thrombosis, increasing risk 89 times (Iakovou et al., 2005). Similarly, in 1911 patients with successfully implanted DES, premature cessation of antiplatelet therapy increased the risk of stent thrombosis by a factor of 19 (Park et al., 2006). In the BASKET–LATE trial, which aimed at defining the incidence of late clinical events following clopidogrel discontinuation and relating outcome to stent type, thrombotic events were more frequent among DES- vs. BMS-implanted patients (Pfisterer et al., 2006). Moreover, in a trial on 2006 patients treated with DES implantation, stent thrombosis was shown to occur shortly after clopidogrel was stopped but aspirin was continued, while no cases of stent thrombosis were reported in patients on continuing dual antiplatelet therapy with a mean follow-up of 1.5 years (Ong et al., 2005). The results of the large PREMIER registry are equally worrisome. Almost 1 in 7 patients who received a DES discontinued clopidogrel therapy within 30 days of implantation, thus increasing the risk of dying in the following year by a factor of 9 (Spertus et al., 2006). The median interval from clopidogrel cessation to stent thrombosis in patients with DES was 13.5 days when clopidogrel was discontinued within 6 months of stenting, a delay once again consistent with a role in rebound platelet activation (Airoldi et al., 2007). Increased morbidity and mortality following clopidogrel discontinuation is not restricted to subjects having undergone angioplasty. In a study examining 3137 patients having suffered an acute coronary syndrome, of whom 1568 were not treated by PCI but with medical therapy, discontinuation of clopidogrel therapy led to significantly increased risk of recurrent MI and death within 90 days of cessation (Ho et al., 2008). Rates of MI and death in medically treated patients were in fact higher than in patients having undergone stenting. In both medically and PCI treated patients, discontinuation of clopidogrel was associated with a significantly higher risk of adverse events in the first 90 days following clopidogrel cessation (Ho et al., 2008). The clustering of events in the weeks following clopidogrel withdrawal has led the authors to suggest that the withdrawal of clopidogrel engenders a rebound hyperthrombotic period, possibly due to increased platelet activity (Ho et al., 2008). 7.2. Pharmacological evidence Very few studies have been published examining normalization of platelet function upon abrupt clopidogrel discontinuation. In healthy volunteers, a trend towards increased expression of activation markers in ADP-stimulated platelets was noted 3–5 days after the last clopidogrel dose (Weber et al., 2001). In diabetic patients having undergone stenting and scheduled to discontinue clopidogrel 1 year

183

later, levels of P-selectin, a platelet activation marker, were significantly higher 1 month after clopidogrel cessation when compared to on-clopidogrel values, even though aspirin treatment was continued (Angiolillo et al., 2006). The rebound in platelet activity seems to be more pronounced in subjects with extensive platelet inhibition achieved with clopidogrel, as subjects with insufficient platelet inhibition (commonly referred to as hypo-responders) observe little impact of clopidogrel withdrawal on their platelet response profile (Bernardo et al., 2006). Similarly, non-compliance to combined aspirin and prasugrel, a P2Y12 receptor antagonist like clopidogrel with more pronounced antiplatelet effects, resulted in rebound platelet activation, demonstrated by all platelet aggregation measurements and being particularly high when ADP and collagen were used as agonists, and when platelet activity was measured by activation markers (Serebruany et al., 2006b). In addition to the possible rebound platelet activity, clopidogrel withdrawal was associated with increased levels of inflammatory biomarkers (Angiolillo et al., 2006). Inflammation is currently recognized as an important contributor to the development of atherothrombotic disease by, among other things, promoting plaque erosion and activating the coagulation cascade, thus facilitating thrombosis (Libby, 2001). Although these findings may suggest the presence of a rebound phenomenon, the absence of a baseline measurement before clopidogrel initiation in most studies does not allow differentiation between return to basal levels vs. heightened platelet activation. Nonetheless, these results raise the possibility of a rebound phenomenon following clopidogrel discontinuation that deserves attention. 8. Potential mechanisms underlying rebound platelet activity It is not uncommon to experience rebound activity following longterm antagonism of physiological pathways, as exemplified by rebound elevation in blood pressure following withdrawal of longterm beta-blocker therapy, or rebound anginal symptoms following nitrate discontinuation (Hjemdahl & Olsson, 1982; Ferratini, 1994). Compensatory cellular mechanisms potentially leading to enhanced activity include up-regulation of receptor/enzyme number or activity and enhanced coupling with downstream molecular mediators. Withdrawal of chronically-administered antagonistic drugs in such contexts results in exaggerated cell responses to physiological levels of agonist concentrations. Although these theories may not seem to apply to platelets due to their inability to produce large amounts of protein as a result of a lack of nucleus, the reality may be otherwise. Platelet inability to synthesize protein has been challenged in recent years with the discovery, in platelets, of mRNA coding for a multitude of proteins and of de novo protein synthesis in stimulated platelets (McRedmond et al., 2004; Denis et al., 2005). Most importantly, generation of active COX-1 has been reported in aspirin-treated platelets stimulated with a variety of platelet agonists, resulting in TxA2 generation within 24 h of aspirin administration (Evangelista et al., 2006). Moreover, antiplatelet drug inhibition also affects megakaryocytes, which are nucleated and hence, highly capable of protein synthesis (Cazenave & Gachet, 1997). Therefore, classical mechanisms of rebound activity may well apply to platelets chronically inhibited by aspirin or clopidogrel (Fig. 2). In the case of aspirin, increase in COX-1 synthesis during chronic aspirin administration, either through de novo protein synthesis by platelets or COX-1 overabundance in megakaryocytic platelet precursor cells, may be masked by daily aspirin administration in excess of the minimal dose required to inhibit platelet aggregation. Indeed, it has been shown that 0.45 mg/kg of daily aspirin (equivalent to ~30– 40 mg for an adult weighing 70–90 kg) is sufficient to almost completely abolish TxA2 formation and ensuing platelet aggregation in healthy volunteers and atherosclerotic patients (Patrignani et al.,

184

M. Lordkipanidzé et al. / Pharmacology & Therapeutics 123 (2009) 178–186

1982; FitzGerald et al., 1983; Weksler et al., 1983). Hence, the recommended daily dose of 80–325 mg of aspirin may palliate the increased COX-1 synthesis under chronic aspirin therapy (Antithrombotic Trialists' Collaboration, 2002). Thus, rebound platelet aggregation may only be apparent once aspirin therapy is discontinued, resulting in higher than normal TxA2 production as seen in clinical trials (Fig. 2A). In the case of clopidogrel, a similar phenomenon may occur. While clopidogrel effectively inhibits platelet P2Y12 receptor at usual daily doses, chronic administration may lead to either an increase in expression or sensitivity of the P2Y12 receptor to its natural agonist, ADP (Braun et al., 2007). Alternatively, coupling of the P2Y12 receptor with its G-protein mediator, Gi, may be enhanced (Gachet, 2005; Shankar et al., 2006). As a result, discontinuation of clopidogrel may cause physiological ADP concentrations to activate GPIIbIIIa receptors more efficiently and cause an increase in platelet aggregation, as seen in clinical trials (Fig. 2B). 9. Alternative hypotheses Despite accumulating literature suggesting a possible rebound effect following discontinuation of antiplatelet drugs, it is important to acknowledge that other valid hypotheses may explain the increased incidence of major adverse cardiovascular events in these individuals, particularly as not all trials point toward a rebound in platelet activity markers or ischemic events following early antiplatelet drug cessation. 9.1. Loss of protective antithrombotic effects A number of small trials have failed to see a rebound effect upon discontinuation of antiplatelet agents (Komatsu et al., 2005; Price et al., 2006; Price & Teirstein, 2008). However, in these trials, the follow-up period consisted of 7 days, which may have been insufficient to document a recrudescence in platelet activity. On the other hand, Vanags et al. assessed in 5 healthy volunteers, the initiation and recovery of platelet function as a result of 10-week-long aspirin therapy (Vanags et al., 1990). Within 6 weeks of aspirin cessation, platelet activity and TxB2 formation returned to baseline, with no evident rebound in activity. Still, it should be noted that platelet function measurements were done at 2 week intervals, and thus the rebound may have been missed. Nonetheless, it would appear that antiplatelet drug discontinuation may simply result in loss of antithrombotic effects, not necessarily a rebound phenomenon, which may explain the outbreak of ischemic events. The most noteworthy study negating the likelihood of a rebound in platelet activity following antiplatelet drug discontinuation is the BASKET-LATE trial, which identified 746 patients who were without major adverse events 6 months after stent placement, stopped taking clopidogrel at that time, and were followed up for an additional 12 months (Pfisterer et al., 2006). Although ischemic events were observed during the follow-up period, their occurrence was widespread, ranging from 15 to 362 days after clopidogrel discontinuation; this led the investigators to question a direct relationship between clopidogrel discontinuation and the occurrence of ischemic events (Pfisterer et al., 2006). Hence, the possibility that ischemic events following antiplatelet drug discontinuation are a direct result of the loss of the protective antithrombotic effects of these drugs should not be disregarded. Only adequately-powered, prospectively-designed trials may answer the question whether cessation of antiplatelet therapy results in a rebound phenomenon with an increased propensity to thrombotic events or in the simple withdrawal of the protective effect of these drugs. A number of trials appointing patients to either continued antiplatelet therapy or discontinuation are underway, and may shed more light on this phenomenon.

9.2. Prothrombotic effects of very low-dose aspirin Another interesting hypothesis has been proposed by Aguejouf et al. to explain the increased risk of ischemic events following aspirin withdrawal. According to their studies on animal models of thrombosis, administration of extremely low doses of aspirin (in the range of 10− 10 mg/kg in rats) results in increased thrombotic tendency (Aguejouf et al., 2008). The mechanism remains nebulous, however it would appear to be mediated by the inducible COX-2 enzyme (Doutremepuich et al., 2007). It is therefore not impossible that the very low concentrations of aspirin remaining in circulation as a result of its discontinuation may lead to ischemic events in patients. However, this hypothesis remains to be tested in clinical settings. 10. Conclusion Although no prospective study has been published directly linking rebound platelet activity following antiplatelet drug withdrawal to increased risk of adverse ischemic events, the concordance between rebound in platelet activation markers and occurrence of deleterious cardiovascular events in time suggests a potential causal link. Recognizing this hypothesis as a strong possibility, the American Heart Association, the American College of Cardiology, the Society for Cardiovascular Angiography and Interventions, the American College of Surgeons and the American Dental Association have issued an advisory statement stressing the hazards of premature discontinuation of antiplatelet drugs and promoting sustained antiplatelet treatment, especially following stent implantation (Grines et al., 2007). Large prospective studies are required to assess the mechanisms leading to enhanced risk of thrombotic events following antiplatelet drug discontinuation, as it is among the strongest predictors of major cardiovascular events and death. Several such trials are underway. In an attempt to balance the thrombotic and the bleeding risk of discontinuing aspirin prior to surgery, the Strategy for Managing Antiplatelet Therapy in the Perioperative Period of Non Coronary Surgery (STRATAGEM; NCT00190307) trial will recruit 1500 patients who will receive aspirin or placebo for up to 10 days prior to surgery. A composite endpoint of thrombotic and hemorrhagic events measured 30 days after surgery, reflecting the net clinical benefit of each strategy, will be reported. Scheduled to terminate in July 2009, the Platelet Activity after Clopidogrel Termination (PACT; NCT00619073) trial will determine in a double blind, placebo-controlled and cross-over design, whether clopidogrel discontinuation is associated with increased platelet activity. The study to evaluate the Discontinuation Effect of Clopidogrel After Drug Eluting Stent Implantation in Non-Diabetic Patients (DECADES; NCT00493779) will more specifically assess whether clopidogrel discontinuation results in rebound platelet activation and inflammation in non-diabetic patients. Soon to begin recruitment, the Abrupt Versus Tapered Interruption of Chronic Clopidogrel Therapy After DES Implantation (ISAR-CAUTION; NCT00640679) study will test whether tapering of clopidogrel will be beneficial in avoiding platelet activation in comparison with abrupt withdrawal. Several other smaller studies are also in progress to better understand the pharmacological basis of potentially lethal platelet activation rebound phenomena. Better understanding of the kinetics of platelet function recovery should facilitate management of patients in whom regard must be given to antiplatelet drug discontinuation in a context of high bleeding risk. Until then, clinical judgement should direct conduct, by taking into account both thrombotic burden and bleeding threat in individual patients, to offer therapy best tailored to the needs of each patient. Acknowledgments The authors are thankful to Danielle Binette for graphical assistance. Marie Lordkipanidzé is a recipient of the Fonds de recherche en santé du Québec PhD training award.

M. Lordkipanidzé et al. / Pharmacology & Therapeutics 123 (2009) 178–186

References Aguejouf, O., Belougne-Malfatti, E., Doutremepuich, F., Belon, P., & Doutremepuich, C. (1998). Thromboembolic complications several days after a single-dose administration of aspirin. Thromb Res 89, 123−127. Aguejouf, O., Eizayaga, F., Desplat, V., Belon, P., & Doutremepuich, C. (2008). Prothrombotic and Hemorrhagic Effects of Aspirin. Clin Appl Thromb Hemost. Aguejouf, O., Malfatti, E., Belon, P., & Doutremepuich, C. (2000). Effects of acetyl salicylic acid therapy on an experimental thrombosis induced by laser beam. Thromb Res 99, 595−602. Airoldi, F., Colombo, A., Morici, N., Latib, A., Cosgrave, J., Buellesfeld, L., et al. (2007). Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation 116, 745−754. Albaladejo, P., Geeraerts, T., Francis, F., Castier, Y., Leseche, G., & Marty, J. (2004). Aspirin withdrawal and acute lower limb ischemia. Anesth Analg 99, 440−443. Angiolillo, D. J., Fernandez-Ortiz, A., Bernardo, E., Ramirez, C., Sabate, M., JimenezQuevedo, P., et al. (2006). Clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes and coronary artery disease. Diabetes 55, 780−784. Antithrombotic Trialists' Collaboration. (2002). Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324, 71−86. Awtry, E. H., & Loscalzo, J. (2000). Aspirin. Circulation 101, 1206−1218. Bachman, D. S. (2002). Discontinuing chronic aspirin therapy: another risk factor for stroke? Ann Neurol 51, 137−138. Bernardo, E., Angiolillo, D. J., Ramirez-Guirao, C., Sabate, M., Jimenez-Quevedo, P., Alfonso, F., et al. (2006). Platelet function profiles of clopidogrel hypo-responders identified following drug withdrawal (abstract). Eur Heart J 27(Suppl 1), 785. Beving, H., Eksborg, S., Malmgren, R. S., Nordlander, R., Ryden, L., & Olsson, P. (1994). Inter-individual variations of the effect of low dose aspirin regime on platelet cyclooxygenase activity. Thromb Res 74, 39−51. Beving, H., Zhao, C., Albage, A., & Ivert, T. (1996). Abnormally high platelet activity after discontinuation of acetylsalicylic acid treatment. Blood Coagul Fibrinolysis 7, 80−84. Biondi-Zoccai, G. G., Lotrionte, M., Agostoni, P., Abbate, A., Fusaro, M., Burzotta, F., et al. (2006). A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. Eur Heart J 27, 2667−2674. Bjornsson, T. D., Schneider, D. E., & Berger, H., Jr. (1989). Aspirin acetylates fibrinogen and enhances fibrinolysis. Fibrinolytic effect is independent of changes in plasminogen activator levels. J Pharmacol Exp Ther 250, 154−161. Braun, O. O., Amisten, S., Wihlborg, A. K., Hunting, K., Nilsson, D., & Erlinge, D. (2007). Residual platelet ADP reactivity after clopidogrel treatment is dependent on activation of both the unblocked P2Y(1) and the P2Y (12) receptor and is correlated with protein expression of P2Y (12). Purinergic Signal 3, 195−201. Brinker, A. D., & Swartz, L. (2006). Growth in clopidogrel–aspirin combination therapy. Ann Pharmacother 40, 1212−1213. Burger, W., Chemnitius, J. M., Kneissl, G. D., & Rucker, G. (2005). Low-dose aspirin for secondary cardiovascular prevention—cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation—review and meta-analysis. J Intern Med 257, 399−414. Cazenave, J. P., & Gachet, C. (1997). Anti-platelet drugs: do they affect megakaryocytes? Baillieres Clin Haematol 10, 163−180. Chassot, P. G., Delabays, A., & Spahn, D. R. (2007). Perioperative antiplatelet therapy: the case for continuing therapy in patients at risk of myocardial infarction. Br J Anaesth 99, 316−328. Collet, J. P., Himbet, F., & Steg, P. G. (2000). Myocardial infarction after aspirin cessation in stable coronary artery disease patients. Int J Cardiol 76, 257−258. Collet, J. P., Montalescot, G., Blanchet, B., Tanguy, M. L., Golmard, J. L., Choussat, R., et al. (2004). Impact of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes. Circulation 110, 2361−2367. Cutlip, D. E., Baim, D. S., Ho, K. K., Popma, J. J., Lansky, A. J., Cohen, D. J., et al. (2001). Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation 103, 1967−1971. Denis, M. M., Tolley, N. D., Bunting, M., Schwertz, H., Jiang, H., Lindemann, S., et al. (2005). Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets. Cell 122, 379−391. Doutremepuich, C., Aguejouf, O., Eizayaga, F. X., & Desplat, V. (2007). Reverse effect of aspirin: is the prothrombotic effect after aspirin discontinuation mediated by cyclooxygenase 2 inhibition? Pathophysiol Haemost Thromb 36, 40−44. Dunning, J., Versteegh, M., Fabbri, A., Pavie, A., Kolh, P., Lockowandt, U., et al. (2008). Guideline on antiplatelet and anticoagulation management in cardiac surgery. Eur J Cardiothorac Surg. doi:10.1016/j.ejcts.2008.02.024. Evangelista, V., Manarini, S., Di Santo, A., Capone, M. L., Ricciotti, E., Di Francesco, L., et al. (2006). De novo synthesis of cyclooxygenase-1 counteracts the suppression of platelet thromboxane biosynthesis by aspirin. Circ Res 98, 593−595. Fatah, K., Beving, H., Albage, A., Ivert, T., & Blomback, M. (1996). Acetylsalicylic acid may protect the patient by increasing fibrin gel porosity. Is withdrawing of treatment harmful to the patient? Eur Heart J 17, 1362−1366. Ferrari, E., Benhamou, M., Cerboni, P., & Marcel, B. (2005). Coronary syndromes following aspirin withdrawal: a special risk for late stent thrombosis. J Am Coll Cardiol 45, 456−459. Ferratini, M. (1994). Risk of rebound phenomenon during nitrate withdrawal. Int J Cardiol 45, 89−96. FitzGerald, G. A., Oates, J. A., Hawiger, J., Maas, R. L., Roberts, L. J., Jr., Lawson, J. A., et al. (1983). Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest 71, 676−688.

185

Gachet, C. (2005). The platelet P2 receptors as molecular targets for old and new antiplatelet drugs. Pharmacol Ther 108, 180−192. Geiger, J., Brich, J., Honig-Liedl, P., Eigenthaler, M., Schanzenbacher, P., Herbert, J. M., et al. (1999). Specific impairment of human platelet P2Y(AC) ADP receptor-mediated signaling by the antiplatelet drug clopidogrel. Arterioscler Thromb Vasc Biol 19, 2007−2011. Gibbons, R. J., Abrams, J., Chatterjee, K., Daley, J., Deedwania, P. C., Douglas, J. S., et al. (2003). ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol 41, 159−168. Grines, C. L., Bonow, R. O., Casey, D. E., Jr., Gardner, T. J., Lockhart, P. B., Moliterno, D. J., et al. (2007). Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation 115, 813−818. Hjemdahl, P., & Olsson, G. (1982). Rebound phenomena following withdrawal of longterm beta-adrenoceptor blockade. Acta Med Scand Suppl 665, 43−47. Ho, P. M., Peterson, E. D., Wang, L., Magid, D. J., Fihn, S. D., Larsen, G. C., et al. (2008). Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA 299, 532−539. Iakovou, I., Schmidt, T., Bonizzoni, E., Ge, L., Sangiorgi, G. M., Stankovic, G., et al. (2005). Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 293, 2126−2130. Jack, D. B. (1997). One hundred years of aspirin. Lancet 350, 437−439. Jeremias, A., Sylvia, B., Bridges, J., Kirtane, A. J., Bigelow, B., Pinto, D. S., et al. (2004). Stent thrombosis after successful sirolimus-eluting stent implantation. Circulation 109, 1930−1932. Kang, W., Theman, T. E., Reed, J. F., III, Stoltzfus, J., & Weger, N. (2007). The effect of preoperative clopidogrel on bleeding after coronary artery bypass surgery. J Surg Educ 64, 88−92. Kapetanakis, E. I., Medlam, D. A., Petro, K. R., Haile, E., Hill, P. C., Dullum, M. K., et al. (2006). Effect of clopidogrel premedication in off-pump cardiac surgery: are we forfeiting the benefits of reduced hemorrhagic sequelae? Circulation 113, 1667−1674. Komatsu, T., Tamai, Y., Takami, H., Yamagata, K., Fukuda, S., & Munakata, A. (2005). Study for determination of the optimal cessation period of therapy with anti-platelet agents prior to invasive endoscopic procedures. J Gastroenterol 40, 698−707. Laskey, W. K., Kimmel, S., & Krone, R. J. (2000). Contemporary trends in coronary intervention: a report from the Registry of the Society for Cardiac Angiography and Interventions. Catheter Cardiovasc Interv 49, 19−22. Libby, P. (2001). Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 104, 365−372. Lordkipanidzé, M., Pharand, C., Palisaitis, D. A., & Diodati, J. G. (2006). Aspirin resistance: Truth or dare. Pharmacol Ther 112, 733−743. Maulaz, A. B., Bezerra, D. C., Michel, P., & Bogousslavsky, J. (2005). Effect of discontinuing aspirin therapy on the risk of brain ischemic stroke. Arch Neurol 62, 1217−1220. McFadden, E. P., Stabile, E., Regar, E., Cheneau, E., Ong, A. T., Kinnaird, T., et al. (2004). Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 364, 1519−1521. McQuaid, K. R., & Laine, L. (2006). Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Am J Med 119, 624−638. McRedmond, J. P., Park, S. D., Reilly, D. F., Coppinger, J. A., Maguire, P. B., Shields, D. C., et al. (2004). Integration of proteomics and genomics in platelets: a profile of platelet proteins and platelet-specific genes. Mol Cell Proteomics 3, 133−144. Mehta, S. R., Yusuf, S., Peters, R. J., Bertrand, M. E., Lewis, B. S., Natarajan, M. K., et al. (2001). Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 358, 527−533. Mitchell, S. M., & Sethia, K. K. (1999). Hazards of aspirin withdrawal before transurethral prostatectomy. BJU Int 84, 530. Mousa, S. A., Forsythe, M. S., Bozarth, J. M., & Reilly, T. M. (1993). Effect of single oral dose of aspirin on human platelet functions and plasma plasminogen activator inhibitor-1. Cardiology 83, 367−373. Newsome, L. T., Kutcher, M. A., & Royster, R. L. (2008). Coronary artery stents: Part I. Evolution of percutaneous coronary intervention. Anesth Analg 107, 552−569. Nguyen, T. A., Diodati, J. G., & Pharand, C. (2005). Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol 45, 1157−1164. Ong, A. T., McFadden, E. P., Regar, E., de Jaegere, P. P., van Domburg, R. T., & Serruys, P. W. (2005). Late angiographic stent thrombosis (LAST) events with drug-eluting stents. J Am Coll Cardiol 45, 2088−2092. Park, D. W., Park, S. W., Park, K. H., Lee, B. K., Kim, Y. H., Lee, C. W., et al. (2006). Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during longterm follow-up. Am J Cardiol 98, 352−356. Pass, S. E., & Simpson, R. W. (2004). Discontinuation and reinstitution of medications during the perioperative period. Am J Health Syst Pharm 61, 899−912. Patrignani, P., Filabozzi, P., & Patrono, C. (1982). Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 69, 1366−1372. Patrono, C., Ciabattoni, G., Patrignani, P., Pugliese, F., Filabozzi, P., Catella, F., et al. (1985). Clinical pharmacology of platelet cyclooxygenase inhibition. Circulation 72, 1177−1184. Patrono, C., Coller, B., FitzGerald, G. A., Hirsh, J., & Roth, G. (2004). Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126, 234S−264S.

186

M. Lordkipanidzé et al. / Pharmacology & Therapeutics 123 (2009) 178–186

Pfisterer, M., Brunner-La Rocca, H. P., Buser, P. T., Rickenbacher, P., Hunziker, P., Mueller, C., et al. (2006). Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drugeluting versus bare-metal stents. J Am Coll Cardiol 48, 2584−2591. Pickard, A. S., Becker, R. C., Schumock, G. T., & Frye, C. B. (2008). Clopidogrel-associated bleeding and related complications in patients undergoing coronary artery bypass grafting. Pharmacotherapy 28, 376−392. Price, M. J., Coleman, J. L., Steinhubl, S. R., Wong, G. B., Cannon, C. P., & Teirstein, P. S. (2006). Onset and offset of platelet inhibition after high-dose clopidogrel loading and standard daily therapy measured by a point-of-care assay in healthy volunteers. Am J Cardiol 98, 681−684. Price, M. J., & Teirstein, P. S. (2008). Dynamics of platelet functional recovery following a clopidogrel loading dose in healthy volunteers. Am J Cardiol 102, 790−795. Rossi, M. L., Zavalloni, D., Gasparini, G. L., & Presbitero, P. (2007). Very late multivessel thrombosis of bare metal stents with concomitant patent drug-eluting stents after withdrawal of aspirin. Int J Cardiol. doi:10.1016/j.ijcard.2007.06.144. Serebruany, V. L., Malinin, A. I., & Bhatt, D. L. (2006). Paradoxical rebound platelet activation after painkillers cessation: missing risk for vascular events? Am J Med 119, 707 e11−6. Serebruany, V. L., Midei, M. G., Meilman, H., Malinin, A. I., & Lowry, D. R. (2006). Rebound platelet activation after termination of prasugrel and aspirin therapy due to confirmed non-compliance in patient enrolled in the JUMBO Trial. Int J Clin Pract 60, 863−866. Shankar, H., Kahner, B., & Kunapuli, S. P. (2006). G-protein dependent platelet signaling— perspectives for therapy. Curr Drug Targets 7, 1253−1263. Sharma, A. K., Ajani, A. E., Hamwi, S. M., Maniar, P., Lakhani, S. V., Waksman, R., et al. (2004). Major noncardiac surgery following coronary stenting: when is it safe to operate? Catheter Cardiovasc Interv 63, 141−145. Sibon, I., & Orgogozo, J. M. (2004). Antiplatelet drug discontinuation is a risk factor for ischemic stroke. Neurology 62, 1187−1189. Smith, S. C., Jr., Feldman, T. E., Hirshfeld, J. W., Jr., Jacobs, A. K., Kern, M. J., King, S. B., III, et al. (2006). ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention). Circulation 113, e166−286.

Song, S. W., Youn, Y. N., Yi, G., Lee, S., & Yoo, K. J. (2008). Effects of continuous administration of clopidogrel before off-pump coronary artery bypass grafting in patients with acute coronary syndrome. Circ J 72, 626−632. Sonksen, J. R., Kong, K. L., & Holder, R. (1999). Magnitude and time course of impaired primary haemostasis after stopping chronic low and medium dose aspirin in healthy volunteers. Br J Anaesth 82, 360−365. Spertus, J. A., Kettelkamp, R., Vance, C., Decker, C., Jones, P. G., Rumsfeld, J. S., et al. (2006). Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry. Circulation 113, 2803−2809. Steinhubl, S. R., Berger, P. B., Mann, J. T., 3rd, Fry, E. T., DeLago, A., Wilmer, C., et al. (2002). Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 288, 2411−2420. Thom, T., Haase, N., Rosamond, W., Howard, V. J., Rumsfeld, J., Manolio, T., et al. (2006). Heart disease and stroke statistics—2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 113, e85−151. Vanags, D., Rodgers, S. E., Lloyd, J. V., & Bochner, F. (1990). The antiplatelet effect of daily low dose enteric-coated aspirin in man: a time course of onset and recovery. Thromb Res 59, 995−1005. Vane, J. R. (1971). Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 231, 232−235. Vial, J. H., McLeod, L. J., & Roberts, M. S. (1991). Rebound elevation in urinary thromboxane B2 and 6-keto-PGF1 alpha excretion after aspirin withdrawal. Adv Prostaglandin Thromboxane Leukot Res 21A, 157−160. Vilahur, G., Choi, B. G., Zafar, M. U., Viles-Gonzalez, J. F., Vorchheimer, D. A., Fuster, V., et al. (2007). Normalization of platelet reactivity in clopidogrel-treated subjects. J Thromb Haemost 5, 82−90. Weber, A. A., Braun, M., Hohlfeld, T., Schwippert, B., Tschope, D., & Schror, K. (2001). Recovery of platelet function after discontinuation of clopidogrel treatment in healthy volunteers. Br J Clin Pharmacol 52, 333−336. Weksler, B. B., Pett, S. B., Alonso, D., Richter, R. C., Stelzer, P., Subramanian, V., et al. (1983). Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients. N Engl J Med 308, 800−805.