**3. Antiplatelet substances**

#### *Acetylic salicylic acid (ASA)*

Of the five main groups of antiplatelet substances **(Tab.1.)**, ASA is probably the most important drug. Its use is considered as the gold standard in primary and secondary prophylaxis of coronary syndromes [18]. However, from the results of collagen and AAinduced aggregation, up to 30% of all patients respond insufficiently to ASA and may profit from a combined (dual) antiplatelet therapy to effectively reduce arterothrombotic events. ASA selectively and irreversibly inhibits COX, an ubiquitous enzyme existing in two isoforms: COX-1 (forms short living prostaglandins (PgG2, PgH2) from which thromboxane synthetase forms TxA2) and COX-2 (forms prostaglandins mainly in leukocytes that are involved in inflammatory and pain processes). After oral administration ASA is rapidly (5- 16 min) and completely absorbed. Due to the hepatic first pass effect the bioavailability drops to about 50% **(Tab.2.)**. Thereafter, COX-1 of all bypassing PLTs is irreversibly acetylated at Ser529. ASA thereby inhibits the production of the potent PLT activator TxA2. However, with stronger agonists than TxA2, especially thrombin, PLT aggregation is not markedly inhibited by ASA. ASA also inhibits synthesis of prostaglandins in endothelial cells (prostacyclin, a potent PLT inhibitor and powerful vasodilatator) and stomach mucosa cells (cytoprotective prostaglandins). Of note, in the absence of protein biosynthesis, COX-1

intact endothelial cells with activated PLTs has the potential to modify chemotactic, proteolytic and adhesive properties inducing increased surface expression of endothelial adhesion receptors (VCAM-1, ICAM-1, vitronectin receptor), which participate in the recruitment of PLTs to the inflamed endothelium. Additionally, the elevated release of endothelial pro-inflammatory substances (MIP-1, IL-6, IL-8) supports chemotaxis, adhesion,

The exposure of sub-endothelial compounds is not required for PLT adhesion in acute inflammatory processes such as ischemia/reperfusion. E.g., p selectin expression of inflamed endothelial cells has been demonstrated to mediate PLT rolling through GP Ib indicating that the vWF receptor mediates both PLT adhesion to the sub-endothelial matrix and to "intact" endothelial cells. Additionally, endothelial adhesion receptors that bridge PLTs via fibrinogen are up-regulated in response to endothelial inflammation (e.g. by IL-1β or CD40L of activated PLTs or thrombin). In this manner, PLTs (if activated or resting) adhere to the vessel wall and promote the recruitment of neutrophils and monocytes by the release of a variety of pro-inflammatory mediators and growth hormones. Furthermore, adhering PLTs can induce up-regulation of NF-κB in endothelial cells leading to further inflammatory changes in the vessel wall. High doses of ASA (≥ 900 mg/d) can influence the NF-κB activation, thus promote the stillstand of atherosclerotic plaque progression [13]. Consequently, cardiac patients with elevated systemic CRP levels benefit especially from antiplatelet therapy with ASA [14]. Another strategy to limit reperfusion injury uses monoclonal antibodies to adhesion receptors such as p selectin (present on endothelial cells and PLTs), CD11/CD18 (present on leukocytes), and the vitronectin receptor (present on endothelial cells). Abciximab not only blocks GP IIb-IIIa on PLTs, but also the vitronectin receptor on endothelial cells explaining its favorable effect on myocardial perfusion,

Of the five main groups of antiplatelet substances **(Tab.1.)**, ASA is probably the most important drug. Its use is considered as the gold standard in primary and secondary prophylaxis of coronary syndromes [18]. However, from the results of collagen and AAinduced aggregation, up to 30% of all patients respond insufficiently to ASA and may profit from a combined (dual) antiplatelet therapy to effectively reduce arterothrombotic events. ASA selectively and irreversibly inhibits COX, an ubiquitous enzyme existing in two isoforms: COX-1 (forms short living prostaglandins (PgG2, PgH2) from which thromboxane synthetase forms TxA2) and COX-2 (forms prostaglandins mainly in leukocytes that are involved in inflammatory and pain processes). After oral administration ASA is rapidly (5- 16 min) and completely absorbed. Due to the hepatic first pass effect the bioavailability drops to about 50% **(Tab.2.)**. Thereafter, COX-1 of all bypassing PLTs is irreversibly acetylated at Ser529. ASA thereby inhibits the production of the potent PLT activator TxA2. However, with stronger agonists than TxA2, especially thrombin, PLT aggregation is not markedly inhibited by ASA. ASA also inhibits synthesis of prostaglandins in endothelial cells (prostacyclin, a potent PLT inhibitor and powerful vasodilatator) and stomach mucosa cells (cytoprotective prostaglandins). Of note, in the absence of protein biosynthesis, COX-1

microcirculation, and recovery of left ventricular function [14-17].

and transmigration of monocytes.

**3. Antiplatelet substances** 

*Acetylic salicylic acid (ASA)* 

*PLT-mediated inflammation* 


i.v. intravenous; moAB monoclonal antibody;

Table 1. Classification of antiplatelet substances [8]


Impairment of hepatic function can diminish the antiplatelet effect. The onset of action of thienopyridines can be accelerated by higher initial doses. Compared to clopidogrel, prasugrel treatment is associated with more rapid, potent and prolonged PLT inhibition. Preliminary evidence suggests a similar safety profile compared to clopidogrel.

Table 2. Pharmacologic properties of oral antiplatelet drugs [8,23]

inhibition in anucleated PLTs persists for a cellular lifetime compared with nucleated vascular endothelial and stomach mucosa cells, which recover COX-1 activity shortly after exposure to ASA. Daily doses of 30-70 mg ASA are sufficient for complete inhibition of TxA2 synthesis, whereas increasing doses can promote gastrointestinal side effects. The recommended daily dose ranges therefore from 75 to 325 mg. Other side effects include intracerebral hemorrhage (≤ 0.5%), hypersensitivity, respiratory alkalosis, and renal and liver dysfunction (cave Reye's syndrome in children characterized by encephalopathy with liver damage). Higher doses of ASA inhibit the nuclear factor κB (NF-κB) that regulates transcription of many inflammatory cytokines (e.g. MCP-1) and of immunoglobulin adhesion receptors (VCAM-1). Additionally, in ACE-inhibitor-treated patients, ASA should be replaced with thienopyridines, since much of the hemodynamic benefits of ACE inhibitors would be lost by the addition of ASA [19].

#### *Thienopyridines (TPs)*

TPs including drugs under late state development (cangrelor, elinogrel) inhibit PLT adhesion by inhibition of the ADP receptor P2Y12 mediating recruitment and aggregation of further PLTs into the vicinity of a growing plug. After oral administration the antiplatelet effect is exerted by active metabolites formed by cytochrom (CYP) P450 activity upon hepatic metabolism **(Tab.2.)**. Since statins are also metabolized by CPY-P450 (mainly CYP3A4), co-administration is associated with decreased antiplatelet efficacy [20]. While ticlopidine (oral, approved), clopidogrel (oral, approved) and parasugrel (oral, approved) act irreversibly, ticagrelor (oral, approved), cangrelor (intravenous), and elinogrel (oral or intravenous) lead to reversible P2Y12 receptor blockade.

In contrast to ASA, TPs do not influence the COX pathway in endothelial cells (no effect on prostacyclin production) but hinder the rapid degradation of extracellular ADP by impairment of ectoADPse released from the damaged vessel wall. Considerably more than ASA, TPs reduce key factors of arterial thrombosis: shear force-induced PLT activation, PLT-leukocyte formation, and inflammation [21]. Consequently, *ticlopidine*, the first developed TP, was found to be superior to ASA in reducing thrombotic risks (mainly stroke) during different pathological conditions including percutaneous coronary intervention (PCI) [22]. However, due to its unfavorable safety profile (20% diarrhea, 10% skin eruptions, 2.5% neutropenia and thrombotic-thrombocytopenic purpura) and its delayed onset of action (4-7 days), ticlopidine has been replaced by clopidogrel in routine clinical use.

*Clopidogrel*, a second generation TP, is equally effective as ticlopidine but has a markedly better tolerability profile. Additionally, clopidogrel achieves a significant antiplatelet effect even on the first day of treatment. Bleeding problems are as frequent as under ASA [23]. Clopidogrel, together with ASA, constitutes the current standard of care for high risk patients with cardiovascular diseases and has considerably improved the antithrombotic therapy after coronary stenting. Despite this, a considerable number of patients with recurrent ischemic cardiovascular events remains, which may only in part be attributed to suboptimal PLT inhibition. Less than 60% inhibition of ADP induced PLT aggregation following 75 mg/d clopidogrel in healthy volunteers [24] or 300 mg clopidogrel loading in PCI patients [25] indicates an incomplete P2Y12 receptor blockade. In addition, inhibited ADP induced PLT aggregation < 10% is observed in 10-30% of treated patients [26-31], probably due to poor compliance, drug-drug interactions, genetic receptor polymorphisms, or variability in CYP P450 activity or intestinal absorption. Poor responsiveness to

inhibition in anucleated PLTs persists for a cellular lifetime compared with nucleated vascular endothelial and stomach mucosa cells, which recover COX-1 activity shortly after exposure to ASA. Daily doses of 30-70 mg ASA are sufficient for complete inhibition of TxA2 synthesis, whereas increasing doses can promote gastrointestinal side effects. The recommended daily dose ranges therefore from 75 to 325 mg. Other side effects include intracerebral hemorrhage (≤ 0.5%), hypersensitivity, respiratory alkalosis, and renal and liver dysfunction (cave Reye's syndrome in children characterized by encephalopathy with liver damage). Higher doses of ASA inhibit the nuclear factor κB (NF-κB) that regulates transcription of many inflammatory cytokines (e.g. MCP-1) and of immunoglobulin adhesion receptors (VCAM-1). Additionally, in ACE-inhibitor-treated patients, ASA should be replaced with thienopyridines, since much of the hemodynamic benefits of ACE

TPs including drugs under late state development (cangrelor, elinogrel) inhibit PLT adhesion by inhibition of the ADP receptor P2Y12 mediating recruitment and aggregation of further PLTs into the vicinity of a growing plug. After oral administration the antiplatelet effect is exerted by active metabolites formed by cytochrom (CYP) P450 activity upon hepatic metabolism **(Tab.2.)**. Since statins are also metabolized by CPY-P450 (mainly CYP3A4), co-administration is associated with decreased antiplatelet efficacy [20]. While ticlopidine (oral, approved), clopidogrel (oral, approved) and parasugrel (oral, approved) act irreversibly, ticagrelor (oral, approved), cangrelor (intravenous), and elinogrel (oral or

In contrast to ASA, TPs do not influence the COX pathway in endothelial cells (no effect on prostacyclin production) but hinder the rapid degradation of extracellular ADP by impairment of ectoADPse released from the damaged vessel wall. Considerably more than ASA, TPs reduce key factors of arterial thrombosis: shear force-induced PLT activation, PLT-leukocyte formation, and inflammation [21]. Consequently, *ticlopidine*, the first developed TP, was found to be superior to ASA in reducing thrombotic risks (mainly stroke) during different pathological conditions including percutaneous coronary intervention (PCI) [22]. However, due to its unfavorable safety profile (20% diarrhea, 10% skin eruptions, 2.5% neutropenia and thrombotic-thrombocytopenic purpura) and its delayed onset of action (4-7 days), ticlopidine has been replaced by clopidogrel in routine

*Clopidogrel*, a second generation TP, is equally effective as ticlopidine but has a markedly better tolerability profile. Additionally, clopidogrel achieves a significant antiplatelet effect even on the first day of treatment. Bleeding problems are as frequent as under ASA [23]. Clopidogrel, together with ASA, constitutes the current standard of care for high risk patients with cardiovascular diseases and has considerably improved the antithrombotic therapy after coronary stenting. Despite this, a considerable number of patients with recurrent ischemic cardiovascular events remains, which may only in part be attributed to suboptimal PLT inhibition. Less than 60% inhibition of ADP induced PLT aggregation following 75 mg/d clopidogrel in healthy volunteers [24] or 300 mg clopidogrel loading in PCI patients [25] indicates an incomplete P2Y12 receptor blockade. In addition, inhibited ADP induced PLT aggregation < 10% is observed in 10-30% of treated patients [26-31], probably due to poor compliance, drug-drug interactions, genetic receptor polymorphisms, or variability in CYP P450 activity or intestinal absorption. Poor responsiveness to

inhibitors would be lost by the addition of ASA [19].

intravenous) lead to reversible P2Y12 receptor blockade.

*Thienopyridines (TPs)* 

clinical use.

clopidogrel was shown to be associated with recurrent cardiovascular events including stent thrombosis [32] and may be overcome by increased clopidogrel doses. This was demonstrated in the CLEAR PLATELETS study, where higher loading doses of clopidogrel prior to PCI acted more rapidly and increased the inhibitory effect on PLTs [25]. During maintenance, however, there was no significant difference in the composite end point (AMI, stroke, vascular death) between the double and the standard dose of clopidogrel [33]. Thus, the search for TPs (third generation) with less response variability is an ongoing feature. Compared to clopidogrel, *cangrelor* exhibits more consistent and greater PLT inhibition as well as short onset and offset of action. The CHAMPION trials, however, were stopped early because of lack of efficiency [34,35]. Cangrelor is still being studied as a bridge for clopidogrel prior to surgery [36]. *Prasugrel* also combines a rapid onset of action (< 30min) with less response variability (0.3%) and a prolonged duration of action (> 3 days). While ticlopidine and clopidogrel require two CYP P450-dependent steps to form active metabolites (mainly CYP 3A4), prasugrel requires only one step (CYP3A4 or CYP2B6). This leads to less CYP P450 dependency and higher amounts of active metabolites [37] translating into a 10-fold (clopidogrel) to 100-fold (ticlopidine) greater potency [38]. As shown in the recent PRINCIPLE-TIMI 44 and TRITON-TIMI 38 studies [39,40], prasugrel increased the efficiency of PCI and improved cardiovascular outcomes (by 20%) but was associated with a significant increase in major bleedings [41]. This was reinforced by the recent CHARISMA trial testing prolonged dual antiplatelet therapy with ASA + prasugrel vs. ASA + clopidogrel [42], although the JUMBO-TIMI 26 trial demonstrated a similar bleeding risk compared to standard clopidogrel [43]. Prasugrel should not be used in adults > 75 years of age or < 60 kg of body weight and in those who have had a recent TIA/stroke or an increased bleeding risk. Like prasugrel*, ticagrelor* acts more potent and rapid but does not significantly increase major bleeding events. Drawbacks, however, are increased incidences of dyspnea and ventricular pauses [36]. The PLATO study demonstrated significantly increased reduction rates of cardiovascular syndromes and mortality vs. clopidogrel (- 16%), while bleeding events were as frequent as under prasugrel [44]. In addition to cangrelor, prasugrel, and ticagrelor *elinogrel* rapidly achieves nearly complete PLT inhibition even in subjects with low responsiveness to clopidogrel [45]. Patients undergoing PCI had greater PLT inhibition under elinogrel (100/150 mg twice daily) than under standard clopidogrel without exhibiting more bleeding events [46]. These results gave promise for further Phase III trials.

#### *Fibrinogen receptor antagonists (FRAs)*

FRAs currently prescribed only during PCI reversibly block one of the final steps of PLT activation irrespective of the stimulus. This is the binding of fibrinogen to GP IIb-IIIa mediating adhesion to the injured vessel wall or interactions with PLTs and other blood cells. Blockade of GP IIb-IIIa further leads to an attenuated formation of pro-coagulant microparticles and inhibits PLT-dependent formation of thrombin. Thus, in addition to inhibition of aggregation, an anticoagulant activity can also be achieved by the administration of FRAs. Side effects include hypotension, vertigo, vomiting, headache, and thrombocytopenia. Bleeding complications must be considered under ongoing therapy (especially in thrombocytopenic, female and elderly patients).

Chimeric monoclonal antibodies directed against the vicinity of the fibrinogen recognition (RGD) region (abciximab) can be distinguished from small low molecular mass antagonists (SMAs) including cyclic peptides (eptifibatide) or non-peptide molecules (tirofiban) with a


tyrosine like structure **(Tab.3)**. In contrast to SMAs that bind specifically to the RGD region (competitive inhibition) abciximab binds to a different site, even when the binding pocket is occupied by fibrinogen or vWF (steric inhibirion).

PCI percutaneous coronary intervention; CR cross reaction with the vitronectin (endothelium cells) and the MAC-1 receptor (leukocytes); DD dose dependency; MD maintenance dose

GP IIb-IIIa blockers administered intravenously (i.v.), have proven efficacious in mitigating arterial thrombosis in acute coronary syndromes and coronary interventions such as balloon dilatation and stent implantation but are associated with an increased bleeding risk. Currently, i.v. GP IIb-IIIa blockers are prescribed in high risk patients with acute coronary syndromes immediately before and after coronary intervention (for 24-72 h). Oral GP IIb-IIIa blockers have failed to demonstrate any benefit.

Table 3. Pharmacologic properties of intravenous (i.v.) GP IIb-IIIa antagonists [8]

In order to achieve an effective antithrombotic protection, a receptor blockade of at least 80% should be achieved. A blockade > 90% increases the risk of bleeding. This makes the dosing difficult. The latter is controlled by ADP-induced aggregation that should be carried out in hirudine- or PPACK-anticoagulated blood due to the Ca++ dependency of receptor binding. Unlike abciximab, the function of SMAs depends on the achieved plasma concentration. Excretion modalities are linked directly to body weight and are inversely correlated with age. Unlike SMAs that rapidly dissociate from the receptor, 70% of all GP IIb-IIIa receptors are still inhibited for up to 12 hours after termination of abciximab (PLT bound abciximab even lasts for up to 2 weeks). Thus, receptor blockade with abciximab can be reduced in patients with a strongly elevated PLT count. Due to the fact that internal GP IIb-IIIa receptors cannot adequately be blocked, TRAP-induced aggregation is only very incompletely be inhibited by standard doses of FRAs (in contrast to ADP induced aggregation that must completely be inhibited). Consequently, patients with ACS experience a markedly lower inhibition of aggregation than do patients with stable coronary artery disease. This suggests that higher doses of FRAs are required under conditions of increased PLT activation, especially with thrombin (occurring e.g. during fibrinolysis therapy). Additionally, the release of internal GP IIb-IIIa receptors can lead to a significant residual aggregation and thrombus formation despite the administration of FRAs.

#### *Novel antiplatelet strategies*

Currently, two groups of PLT inhibitors are approved for clinical use in ACS patients: ASA and oral TPs. These agents have shown improved short- and long-term clinical outcomes

tyrosine like structure **(Tab.3)**. In contrast to SMAs that bind specifically to the RGD region (competitive inhibition) abciximab binds to a different site, even when the binding pocket is

**Molecular mass (Dalton)** 45.000 800 495 468 **Receptor specificity** CR no CR no CR no CR **Onset of action (after i.v. bolus)** minutes minutes minutes minutes **Reversibility** slow (> 12 h) rapid (< 6 h) rapid (< 6 h) rapid (< 6 h)

> short long

**expression)** + + + +

250 0.125

the MAC-1 receptor (leukocytes); DD dose dependency; MD maintenance dose

PCI percutaneous coronary intervention; CR cross reaction with the vitronectin (endothelium cells) and

In order to achieve an effective antithrombotic protection, a receptor blockade of at least 80% should be achieved. A blockade > 90% increases the risk of bleeding. This makes the dosing difficult. The latter is controlled by ADP-induced aggregation that should be carried out in hirudine- or PPACK-anticoagulated blood due to the Ca++ dependency of receptor binding. Unlike abciximab, the function of SMAs depends on the achieved plasma concentration. Excretion modalities are linked directly to body weight and are inversely correlated with age. Unlike SMAs that rapidly dissociate from the receptor, 70% of all GP IIb-IIIa receptors are still inhibited for up to 12 hours after termination of abciximab (PLT bound abciximab even lasts for up to 2 weeks). Thus, receptor blockade with abciximab can be reduced in patients with a strongly elevated PLT count. Due to the fact that internal GP IIb-IIIa receptors cannot adequately be blocked, TRAP-induced aggregation is only very incompletely be inhibited by standard doses of FRAs (in contrast to ADP induced aggregation that must completely be inhibited). Consequently, patients with ACS experience a markedly lower inhibition of aggregation than do patients with stable coronary artery disease. This suggests that higher doses of FRAs are required under conditions of increased PLT activation, especially with thrombin (occurring e.g. during fibrinolysis therapy). Additionally, the release of internal GP IIb-IIIa receptors can lead to a significant

GP IIb-IIIa blockers administered intravenously (i.v.), have proven efficacious in mitigating arterial thrombosis in acute coronary syndromes and coronary interventions such as balloon dilatation and stent implantation but are associated with an increased bleeding risk. Currently, i.v. GP IIb-IIIa blockers are prescribed in high risk patients with acute coronary syndromes immediately before and after coronary intervention (for 24-72 h). Oral GP IIb-IIIa blockers have failed to demonstrate any benefit.

Table 3. Pharmacologic properties of intravenous (i.v.) GP IIb-IIIa antagonists [8]

residual aggregation and thrombus formation despite the administration of FRAs.

Currently, two groups of PLT inhibitors are approved for clinical use in ACS patients: ASA and oral TPs. These agents have shown improved short- and long-term clinical outcomes

**abciximab eptifibatide tirofiban lamifiban** 

DD DD

0.4 – 10.0 0.10 – 0.15 DD DD


DD DD

90.0 – 180.0 0.5 – 2.0

occupied by fibrinogen or vWF (steric inhibirion).

**Half life** 

**plasma (normally a few hours) receptor (normally a few hours)** 

**Initial bolus (µg/kg) prior to PCI MD (µg/kg/min) for 12-48 (72) h** 

**Intrinsic activity (LIBS** 

*Novel antiplatelet strategies* 

**Recommended dose** 

but are associated with increased bleeding events. Thus, there is a need for new antiplatelet agents with higher PLT inhibition capacity and less bleeding risk.

A new TxA2 receptor antagonist was tested in animals and has demonstrated fast and potent antiplatelet efficacy [47] comparable to that of ASA plus clopidogrel [48]. Additional desired effects were an improved endothelial function [49], an inhibited TxA2-induced vasoconstriction [50], and a favorable bleeding risk profile [48]. *Picotamide*, already marketed in Italy, combines both TxA2 receptor and thromboxane synthetase blockade and, unlike ASA, preserves prostacyclin formation in endothelial cells. Picotamide was shown to reduce atherosclerotic plaque progression, cardiovascular events and mortality without increased bleedings in ASA-refractory patients with peripheral artery disease without [51,52] or with diabetes [53]. Selective inhibition of the thrombin specific PAR-1 receptor *(vorapaxar, atopaxar)* represents a further strategy to reduce ischemic events and was tested in two Phase-II trials (TRA-PCI and LANCELOT-ACS) as secondary prophylaxis of ACS or on the top of standard antithrombotic therapy including ASA, clopidogrel and the heparin of choice. Despite significant dose-dependent increases in abnormal liver function parameters and QT elongation, there was a trend towards lower adverse cardiac events without increased bleeding events in the verum- vs. the placebo treated groups [54,55]. The first developed phosphodiesterase (PDE) inhibitor with an antiplatelet effect was *dipyridamole*. Together with ASA, dipyridamole demonstrated efficacy in the prevention of stroke [56]. However, ASA plus dipyridamole was not superior to clopidogrel in the prevention of recurrent stroke as seen in PRoFESS [57]. *Cilostazol*, a selective PDE III inhibitor, increases cAMP levels in PLTs, endothelial and smooth muscle cells leading to vasodilatatory and antiplatelet properties. Recent studies have shown that the addition of cilostazol to ASA and clopidogrel (triple antiplatelet therapy), particularly in diabetic patients, reduced risk of stent thrombosis (even of drug eluting stents) and increased cardiac outcomes after PCI without increased bleeding complications. However, due to headache, palpitations, and diarrhea, withdrawal of cilostazol approximated 15% [58,59]. Further antiplatelet strategies including blockade of inflammatory substances such as p selectin [60] or collagen receptors [61] are currently under clinical development. An accurate evaluation of the balance between the anti-ischemic effect and the hemorrhagic risk of these new drugs is highly warranted.

#### *Antiplatelet-therapy-inherited bleeding risk*

Sufficient hemostasis requires normal PLT function in at least 20% of circulating PLTs [62]. As the effects of antiplatelet drugs are not reversible by other drugs, PLT transfusions are the only manner to rapidly restore normal hemostasis. Today, prevention of cardiac events, especially stent thrombosis, is considered as being highly dependent on antiplatelet therapy during the first year after coronary intervention. In this period, however, up to 5% of patients have to undergo surgery for non cardiac reasons, whereby elderly patients, women, patients with anemia, renal dysfunction, and hypertension are at especially increased risk for perioperative bleeding. Not only does bleeding constitute an immediate threat, but is also associated with increased re-infarction and cardiac morbidity (5-fold/year) both in the short as well as the long term [63]. For this reason, the inherited bleeding risk of all antiplatelet drugs has to be outweighed against the concomitant cardioprotective effect **(Tab.4.)**. Of note, antiplatelet replacement by heparin does not provide protection against the risk of coronary artery or stent thrombosis. Based on a retrospective evaluation, we recommended discontinuation of antiplatelet therapy for at least 2 days prior to elective


PCI percutaneous coronary intervention; LD loading dose; MD maintenance dose; AMI acute myocardial infarction; ACS acute coronary syndrome; ST stent thrombosis; IST immediate stent thrombosis; SP spontaneous; ICH intracranial hemorrhage; GIT gastrointestinal; intraoperative blood loss; \* without bleeding-related increase in mortality.

The risk of cardiac events is maximal (increased up to 5-10-fold) in malignancy, diabetes mellitus, the early postoperative state and during stent re-endothelialization, especially of high risk stents (proximal, multiple, or overlapping stents, small vessels, bifurcated lesions). In these settings, the risk for stent thrombosis averages 35%. The associated mortality reaches 20-40%

Table 4. Relative risk reduction (RRR) and bleeding risk of common antiplatelet substances [59]

surgery [64]. However, since antiplatelet agents are maximally helpful when the thrombotic risk is highest, long-term dual antiplatelet therapy should be pursued until surgery, especially during stent re-endothelialization (4 – 6 weeks after bare metal stents, 12 months after drug-eluting stents). Due to the rise in fibrinogen, CRP and PAI-1, the risk of plaque rupture and consecutive thrombosis is maximal (2-4-fold higher) in the early postoperative setting. Here, the mortality rate due to stent thrombosis is estimated to about 20-40% [65]. After withdrawal of ASA, the cardiac complication rate increases 3-fold, and ASA should never be stopped when prescribed for secondary prophylaxis of ACS or in patients with stents. When prescribed for primary prevention, there is no evidence that ASA withdrawal 7 days prior to surgery is harmful. Clopidogrel withdrawal during the first month after coronary intervention makes patients 10 times more likely to die. When necessary, ADP receptor blockers could be bridged with short acting GP IIb-IIIa antagonists like eptifibatide. After surgery, both drugs ASA and clopidogrel should be resumed within 12-24 hours.
