**4. Antiplatelet therapy and coronary heart disease**

#### *Primary and secondary prophylaxis of cardiac syndromes*

Since > 50 years ASA reduces vascular death by 15% and non-fatal vascular events by 30% as evidenced by meta-analyses of over 100 randomized trials [66,67]. ASA may also be of

antagonists IST (50%) SP: 3 - 4% (mostly catheters)

SP: 1 – 2% (higher plus ASA)

ICH: 0.35% GIT: 0.68% GIT ulcers: 0.68% IOBL: 50% (ASA + clopidogrel) \*

SP: 1 ‰/year ICH: 0.49% GIT: 2.66% GIT ulcers: 1.15% IOBL: 20%\*

**Pharmacological properties Indication (RRR) Bleeding risk** 

IST, recurrent ST (30%)

Sec. prevention (20%)

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

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

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

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.

Since > 50 years ASA reduces vascular death by 15% and non-fatal vascular events by 30% as evidenced by meta-analyses of over 100 randomized trials [66,67]. ASA may also be of

*GP IIb-IIIa antagonists* Fibrinogen receptor

[59]

*Clopidogrel (300 mg LD, 75/d mg MD)*

ADP receptor antagonist AMI in ACS (18%)

COX-1 inhibitor Prim. prevention (40%)

thrombosis averages 35%. The associated mortality reaches 20-40%

**4. Antiplatelet therapy and coronary heart disease** 

*Primary and secondary prophylaxis of cardiac syndromes* 

*Acetylic salicylic acid ASA (100 – 325 mg/d)*

loss; \* without bleeding-related increase in mortality.

benefit in the primary prevention of cardiovascular events but the effect is more modest and its recommendation in this setting is highly debated due to the probably offset of the cardioprotective effect by bleeding complications [68,69]. Additionally, total mortality remains unaffected. Based on these and further data [70-74] daily doses of 160-325 mg ASA are recommended for all subjects > 50 years of age, who are at increased risk of AMI. Higher doses are not more effective in the prevention of cardiovascular events and may be associated with more serious side effects (reduced patient compliance) [33]. Younger subjects should use ASA only, when manifestations of atherosclerotic diseases (e.g. TIA, unstable angina) are present [8].

The CAPRIE study [75] examined the prophylactic efficacy of clopidogrel in comparison to ASA in patients with a history of ischemic stroke, prior AMI or symptomatic peripheral artery disease (PAD). In comparison to ASA (325 mg/d), a significant 8.7% risk reduction of non-fatal and fatal vascular deaths was found for clopidogrel (75 mg/d), which thereby occupies a firm place in secondary prophylaxis of cardiovascular events but is only marginally superior over ASA. Although not significant, ASA showed a trend towards better efficacy after prior AMI, whereas patients with PAD appeared to more profit from clopidogrel than from ASA. Despite this, a large portion of patients remains for whom no satisfactory therapeutic success can be obtained with ASA or clopidogrel monotherapy. Since both antiplatelet drugs have different target receptors and mechanisms of action (COX-1 inhibitor vs. P2Y12 ADP receptor blockade), their combination as dual antiplatelet therapy offers additive effects and provides greater inhibition of PLT aggregation than therapy with either agent alone. As a consequence, the CURE study [76] demonstrated a risk reduction of 20% in patients with unstable angina, when ASA was combined with clopidogrel. The subsequent CREDO trial [77] showed that dual antiplatelet therapy reduced the risk of major adverse cardiovascular events after angioplasty compared with ASA alone. The tolerability profile was good, and major bleedings increased by only 1% as demonstrated in CLARITY-TIMI 28 [78] and COMMIT [79]. In the CHARISMA trial, however, patients with established vascular disease demonstrated a markedly increased bleeding risk, and no additional benefits were achieved with dual antiplatelet therapy over ASA therapy alone (probably due to clopidogrel resistance) [42]. Long-term dual antiplatelet therapy was beneficial only for high-risk patients with clinically evident atherothrombosis, especially for the prevention of stroke in cases with atrial fibrillation [80].

#### *Fibrinolysis*

Thrombin liberation in the region of the lysed thrombus may promote increased activation of circulating PLTs [81]. Moreover, due to high amounts of PAI-1, the PLT-rich core (white) thrombus is practically resistant to fibrinolytic agents. For these reasons, a successful reperfusion upon fibrinolysis can be achieved in only 50% of AMI and a TIMI-3 flow, which is a decisive survival parameter, is only insufficiently restored. For these reasons, antiplatelet drugs have been administered together with fibrinolytics: full dose fibrinolytics plus partial dose FRAs [82] or reduced-dose fibrinolytics plus full dose FRAs [83]. Pooled results from these studies and equivalent data suggest that FRAs together with ASA significantly increase the efficacy of fibrinolytics, reduce fatal and non fatal re-infarctions and the need for urgent revascularization [84-86]. Drawbacks, however, were increased intracranial bleeding and unaffected re-infarction rates after 30 days asking for safety and long-term efficacy of this combination [87].

#### *Percutaneous transluminal coronary angioplasty (PTCA)*

Pretreatment with ASA as well as with TPs significantly lower (up to 70%) the incidence of early acute thrombotic occlusions after PTCA [8]. Since the additional administration of FRAs to ASA and/or clopidogrel as well as to standard therapy including anticoagulants, nitrates, and beta-blockers, further reduce (40%) early cardiac incidents (partly, however, at cost of increased bleeding events [88-105]), the ACC/AHA guidelines recommend the addition of a FRA to ASA and heparin to patients in whom catheterization and coronary intervention are planned [106]. Furthermore, eptifibatide or tirofiban together with ASA and heparin should be given to patients with continuing ischemia or elevated troponin levels, in whom invasive management is not planned. Clopidogrel administered before cardiac catheterization enhances perioperative bleeding, if angiography reveals that bypass grafting is required rather than percutaneous coronary intervention. Thus, the American College of Chest Physicians (ACCP) guidelines recommend withholding clopidogrel until the coronary anatomy is determined [107]. Despite the efficacy of antiplatelet therapy concerning early thrombotic occlusions after PTCA, studies on the prevention of later re-stenosis (> 6 month) were disappointing [108,109]. Due to an excessive fibroproliferative response, up to 30% of PTCA patients developed recurrent ischemia and re-stenosis [110]. Only the results of the TACTICS study [104] showed that in patients with ACS early invasive strategy combined with immediate administration of FRAs was significantly better concerning late vascular deaths than the "wait and see" approach. Patients with elevated troponin levels had the greatest benefit from this strategy [8].

#### *Coronary stenting*

2 million patients of Western Countries undergo coronary dilatation each year [77], and coronary stents are placed in over 90% of these patients [111]. One of the greatest fears is subacute stent thrombosis triggered within minutes to hours after coronary intervention by activated PLTs. Predictors for increased risk of re-thrombosis are elevated GP IIb-IIIa expression or PLT degranulation markers prior to PCI as well as high post-interventional PLT reactivity to ADP [112]. Thus, long-term antiplatelet therapy is mandatory for the success of coronary stenting.

One of the first trials on stent thrombosis showed that ticlopidine (vs. anticoagulants) reduced the risk [113]. Thereafter, numerous clinical trials have demonstrated the superiority of dual antiplatelet therapy [114-116]. Based on these data, the American Heart Association/American College of Cardiology guidelines recommend ASA plus a 300 mg or 600 mg (better PLT inhibition) clopidogrel loading, followed by a 75 mg clopidogrel maintenance for 12 months for all patients undergoing PCI and/or stenting [117]. Recently, prasugrel demonstrated even higher efficiency than clopidogrel (plus 52%) irrespective of the clopidogrel loading dose: 300 mg [40] or 600 mg [39], however at cost of increased bleeding (2.4% vs. 1.8%, p=0.03) [40]. Moreover, the additional application of FRAs prior to PCI has significantly increased clinical outcomes as seen by improvements in early and late TIMI 3 flow rate, global left ventricular function, early re-stenosis, and recurrent ischemia [89,91,92,105,118,119] in spite of bleeding complications [92]. Abciximab could promote the re-establishment of the microcirculation, thus the functional recovery of the infarcted heart region. From the STOP-AMI trial [120] stenting + abciximab + dual antiplatelet therapy was superior over fibrinolysis with respect to myocardial salvage and the accumulation of death and thromboembolic complications for up to 6 months (p=0.02) and resulted in superior inhibition of inflammation [28]. In the ERASER study [121], however, the rate of late reinfarction (> 6 month) remained unaffected.
