Review of antithrombotic therapy for percutaneous coronary interventions

Pierre Aubry,MD, Mohamed Majdoub,MD, Antoine Sauguet, MD
Department of Cardiology

Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France.

Address for correspondence:
Dr Pierre Aubry
Département de Cardiologie,
Groupe Hospitalier Bichat-Claude Bernard,
46 rue Henri Huchard, 75018 Paris, France.
Tel : +33-1-40-25-86-65
Fax : +33-1-40-25-88-65
Email: pcaubry@yahoo.fr


Abstract
Antithrombotic therapy is a cornerstone in the management of acute coronary syndromes and plays a major role during percutaneous coronary interventions. Numerous antithrombotic agents are currently available, showing synergistic effects in combination. In considering the physiological basis of thrombosis, platelets and coagulation are seen as interdependent and cannot be dissociated in therapeutic strategies. Nevertheless, new antithrombotic agents and new protocols are emerging.

The use of potent antithrombotic agents may be associated with increased bleeding complications and additional costs.With this in mind, recommendations and expert consensus documents aim to help interventionists in clinical practice. Currently, dual antiplatelet therapy with aspirin and clopidogrel is the standard treatment after stenting, although development of direct thrombin inhibitors may soon change anticoagulation practices. Indications for intravenous GP IIb-IIIa antagonists need to be redefined according to current management of acute coronary syndromes and reliable tests are needed for the monitoring of antiplatelet activity. Insufficient platelet inhibition with standard therapy should be discussed when subacute stent thrombosis occurs. In addition to technological advances with newer devices, further studies must continue to assess antithrombotic strategies in terms of protective effects and bleeding risks.

 Introduction

Percutaneous coronary intervention (PCI) with stent implantation needs appropriate antithrombotic therapy. Thrombosis may influence outcome after PCI, a procedure that produces vessel injury and induces thrombin generation and platelet activation with intertwined pathways. Numerous antithrombotic agents are currently available (Tables 1 and 2).

 Guidelines and expert consensus documents aim to help interventionists to weigh up the benefits and risks of procedures [1,2]. Newer antithrombotic agents are emerging as an alternative to conventional treatments; however, data supporting their use are still limited. Recommendations issued by different organizations are not homogeneous and do not cover all subjects. In addition, burdens and costs of treatments may influence the operator's choices. Finally, individual variability of response to antiplatelet therapy is a recurrent question. This paper summarizes recent recommendations of antithrombotic therapy for PCI and discusses some debated points.

Trends in the evolution of antithrombotic therapy for PCI With the progressive introduction of stents, the need for less aggressive anticoagulation has emerged [3]. Increased use of stents, as well as decreased use of anticoagulation, has been associated with reduced rates of ischaemic and bleeding complications. More recently, a clear benefit of early revascularisation and aggressive antiplatelet therapy has been demonstrated for highrisk patients who should be identified. Risk markers of NSTE-ACS (non-ST-elevation acute coronary syndromes) recognised in ESC guidelines [4] are listed in Table 3.

 Recommendations
Strong clinical recommendations (i.e. evidence that a treatment is beneficial with data derived from multiple randomized clinical trials) are few in number. Recent ESC recommendations on antithrombotic therapy during PCI are summarized in Table 4 and show some differences from the ACCP recommendations [1,2]. Experts recommend against intra-coronary fibrinolytic agents during PCI, ticlopidine beyond 14 days after stenting, and prolonged heparin infusion after PCI.

Aspirin
Studies showing a significant reduction of major vascular events with aspirin were generally performed before the widespread use of PCI. These results have been extrapolated to PCI for which aspirin is considered as the cornerstone of antiplatelet therapy. A daily dose in the range of 75-100 mg is sufficient in association with a thienopyridine [5], while higher doses are associated with increase in bleeding complications without supplementary protective effect.

Thienopyridines
By acting on different platelet proteins (COX-1, ADP receptor P2Y12), aspirin and thienopyridines have synergistic effects for platelet inhibition [5]. This dual antiplatelet therapy has become the standard of care following stent placement [6,7]. Clopidogrel seems to be at least as effective as ticlopidine with fewer side-effects [8]. Consequently, ticlopidine is no longer used in most countries.

Anticoagulation during PCI
PCI without anticoagulation appears unrealistic. However, there are few controlled trials specifically addressing the use of heparin during PCI. The optimal dose of unfractionated heparin (UFH), the most commonly used anticoagulant during PCI, remains unknown [9] - weight-adjusted low doses appear at least as safe as fixed high doses [10]. At the start of PCI, a 50-100 UI/kg bolus of UFH is now recommended. If GP IIb-IIIa inhibitors are given, use of low doses of UFH (50-70 UI/kg) limits bleeding complications [11]. During PCI, the objectives of anticoagulation may differ: treatment of ACS and prevention in clot formation on materials do not necessarily require a similar inhibition of coagulation factors IIa and Xa.

Unfractionated heparin versus low-molecular-weight heparins (LMWH)
Use of the same anticoagulant agent seems judicious for NSTE-ACS undergoing PCI. The superiority of LMWH over UFH is clear for ACS [12]. The most recent guidelines do not suggest that LMWH may supplant UFH in PCI [1,2]. Registries generally reported a trend towards increased bleeding complications with LMWH in comparison with UFH [13]. If PCI is performed within 8 hours of the last subcutaneous injection of LMWH, no further anticoagulation is needed [14]. Yet, despite its limitations, UFH remains the standard heparin therapy during PCI.

Monitoring of anticoagulation activity
The activated clotting time (ACT) is easily measured in the cath lab and gives a global assessment of the level of anticoagulation for UFH and bivalirudin.With UFH regimen, target ACT values in the range of 250-350 s or 200-250 s (if GP IIb-IIIa antagonists are given), are advocated during PCI [1]. The monitoring of UFH activity by ACT is not systematic if weight-adjusted doses are used. The fact that subcutaneous LMWH slightly modifies the ACT is an issue for the monitoring of anticoagulation activity [9]. On the other hand, ACT may measure anticoagulation activity of LMWH following intravenous administration [15].

Use of intravenous GP IIb-IIIa inhibitors
Based on the results of controlled trials, upstream use of GP IIb-IIIa inhibitors is recommended prior to PCI in moderate-to-high-risk patients with NSTE-ACS [4,5]. Currently, these agents are often started in the cath lab once the coronary anatomy is known and PCI is planned. The burdens and costs of these agents may explain this practice and a multinational registry showed a relatively infrequent use of GP IIb-IIIa inhibitors in the real world [16]. Recommendations for GP IIb-IIIa inhibitors are often derived from non PCI-trials and the position of these agents needs to be redefined using contemporary studies (i.e. planned PCI with stenting in all patients).

New direct thrombin inhibitors
Thrombin, a key modulator of haemostasis, is a potent activator of platelets while bivalirudin, a direct thrombin inhibitor with a short half-life, has shown encouraging results compared with UFH during PCI in terms of bleeding reduction. However, the heparin regimen in the control group was aggressive compared with current practices [17]. More recently, the investigators of REPLACE-2 described similar antithrombotic effects with bivalirudin when compared with heparin in combination with GP IIb-IIIa antagonists during PCI [18]. In addition, bivalirudin appears useful in patients with heparin-induced thrombocytopenia.

Pretreatment with thienopyridines
A loading dose of 300 mg clopidogrel is recommended before PCI [19], although such a pretreatment within 3 hours may not be sufficient. A higher initial dose of 600 mg establishes a greater level of platelet inhibition [20] and can protect against myocardial injury in patients undergoing PCI [21]. It is currently recommended that clopidogrel be administered as soon as possible in patients with NSTE-ACS. The results from NSTE-ACS may be extrapolated to ST-elevation myocardial infarction (STEMI). Immediate administration of clopidogrel (300 mg) appears more effective (CLARITY-TIMI 28 study), as an adjunctive reperfusion therapy when combined with fibrinolytics [22]. Monitoring of antiplatelet activity Numerous methods using flow cytometry or platelet aggregometry are available for evaluation of biological efficiency of antiplatelet regimens. These might prove helpful for monitoring efficacy of the treatment, but there are not currently routinely recommended due to the lack of standardization. In addition, specialised laboratories are usually required. However, these tests have shown important individual variability in the degree of platelet inhibition induced by antiplatelet therapy leading to the concept of 'aspirin or clopidogrel resistance'. One-third of patients treated by clopidogrel appeared to be 'unprotected' [23]. Several mechanisms have been suggested for this observation e.g. higher platelet activity, variability in absorption or metabolism, polymorphism of the P2Y12 platelet receptor.

Hypersensitivity to aspirin
A diagnosis of hypersensitivity to aspirin usually implies complete exclusion of the molecule. Rapid aspirin desensitization has been tested recently with a high rate of success observed in patients with a history of allergy to aspirin [24]. Most of the patients underwent uneventful coronary stenting under dual antiplatelet therapy.

Antithrombotic therapy during primary PCI in patients with STEMI
Aspirin (160-325 mg), UFH (50-70 UI/kg), and clopidogrel (600 mg) should be administered as soon as possible. The use of GP IIb-IIIa inhibitors during primary PCI in patients with STEMI remains under debate. Abciximab has been well investigated with some significant results [25,26] and pre-hospital treatment seems logical in this setting.

Facilitated PCI during STEMI
Facilitated PCI is defined as planned intervention within 12 hours following the onset of symptoms and soon after the administration of potent antithrombotic agents (fibrinolytic agents and GPIIb-IIIa inhibitors) alone or in association. So far, there is no evidence for the recommendation of facilitated PCI. However, the results of ongoing trials (FINESSE, ASSENT-4) may change the current indications.

PCI after thrombolysis If thrombolysis is preferred in patients with STEMI, it should not be considered as the final treatment. Rescue PCI after failed thrombolysis appears superior to conservative treatment [27]. ESC guidelines recommend routine coronary angiography and - if needed - PCI early (< 24 hours) post thrombolysis [2]. Adequate regimens are still to be defined in this setting where too low or too high a degree of anticoagulation may increase the risks of thrombotic and bleeding complications.

Effects of contrast media on coagulation
Contrast media have anticoagulant properties of varying intensity, depending on their chemical structure. In vitro anticoagulant effects are more marked with ionic agents [28]. However, large multicentre randomised trials showed that non-ionic contrast media do not increase the risk of thromboembolic complications [29,30]. Costs of antithrombotic therapy during PCI Interventionists must take the cost and cost-effectiveness of antithrombotic treatments into consideration, including possible additional costs resulting from any bleeding complications [31]. Increased use of the radial approach and development of arterial closure devices has led to minimized risks of bleeding at the access site. Economic evaluations can provide substantial information supporting the choices between agents with similar clinical impact.

Antithrombotic therapy and sheath removal
Use of low doses of heparin represents a major advance in the last decade for the management of femoral vascular access following PCI with stent placement. Late sheath removal is associated with a higher rate of bleeding and vascular events [32]. Less aggressive anticoagulation allows early and even immediate sheath withdrawal after PCI performed via the femoral route [33].

Stent thrombosis Despite the use of dual antiplatelet therapy and better interventional techniques optimising stent implantation, stent thrombosis has not been abolished (~1%). The one-month incidence of subacute stent thrombosis appears similar following the use of bare-metal stents and drug-eluting stents in the real world [34]. Biological variations in the response to antiplatelet therapy are potential causes of subacute stent thrombosis. An increased platelet reactivity, which cannot be overcome by ordinary antiplatelet therapy, has been described in patients who suffered subacute stent thrombosis [35].

Non-responders to antiplatelet treatment
The strategy for patients with insufficient platelet inhibition with standard therapy remains unclear. An increase in doses of clopidogrel (150 mg daily) or use of another thienopyridine (ticlopidine) is the general practice. An association between inadequate platelet inhibition ex vivo and the risks of thrombotic complications has yet to be demonstrated. Prasugrel, a new molecule of the thienopyridine family currently undergoing a Phase III clinical trial (TRITON TIMI-38), seems more effective in vitro at inhibiting platelet aggregation than clopidogrel.36

Conclusion
As well as the meticulous intravascular techniques necessary to minimize thromboembolic events, an effective and safe antithrombotic therapy is needed during PCI. Understanding of the roles of coagulation and platelets in the complex process of thrombosis has only evolved recently. Data supporting superior benefits of new antithrombotic agents in the setting of PCI may soon change the practices of interventionists. Moreover, new management of ACS with earlier PCI leads to the redefinition of most antithrombotic strategies.

The issue of non-responders to standard antiplatelet therapy has probably been underestimated: simple and reliable tests are needed to identify patients insufficiently protected by antiplatelet therapy. In the future, economic implications of ischaemic and bleeding complications will guide the choice of antithrombotic treatments for PCI. However, the implementation of guidelines in antithrombotic therapy for PCI have yet to be evaluated by contemporary surveys.
Key Learning
  • PCI needs adequate antithrombotic therapy to limit thrombin generation and platelet activation
  • Recently published recommendations on antithrombotic strategies during PCI are not homogeneous
  • During PCI, use of LMWH remains debated and direct thrombin inhibitors are emerging
  • Synergistic action of aspirin and thienopyridines has proved its efficiency after stent implantation
  • Use of GP IIb-IIIa inhibitors in the real world conflicts with current recommendations
  • Biological evaluation shows a large inter-individual variability in response to standard antiplatelet therapy
  • Abolition of subacute stent thrombosis remains a major challenge
  • Some antithrombotic strategies should be redefined using contemporary practices
  • Cost and cost-effectiveness of antithrombotic treatments will guide the interventionist's choices during PC

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07-2005 BUY1137946/JB1538/MB001367/OS 7th edition