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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Adjunctive antithrombotic therapy during primary percutaneous coronary intervention

Giuseppe De Luca*

Division of Cardiology, ‘Maggiore della Carità’ Hospital, Eastern Piedmont University ‘A. Avogadro’, Novara, Italy

* Corresponding author. Tel: +39 0321 3733141; fax: +39 0321 3733407. E-mail address: giuseppe.deluca{at}maggioreosp.novara.it


   Abstract
Top
 Abstract
Rationale for new antithrombotic...
 Anticoagulation beyond...
 Antiplatelet therapy beyond acid...
 Conclusions and future...
 References
 
Even though primary angioplasty for STEMI has significantly improved survival when compared with thrombolysis, there is still room for improvement. In fact, despite restoration of optimal epicardial flow in the vast majority of patients, suboptimal myocardial reperfusion is observed in a relatively large proportion of them. The aim of this article is to provide an update review of adjunctive antithrombotic therapy to primary angioplasty for STEMI.

The Horizons trial has shown a significant reduction in mortality and major bleeding complications, when compared with glycoprotein (Gp) IIb–IIa inhibitors. Thus, bivalirudin may be considered in primary angioplasty as an alternative strategy to heparin + Gp IIb–IIa inhibitors, especially in patients at high risk for bleeding complications. However, despite the negative results of the FINESSE trial, large evidence has been observed in favour of early administration of Gp IIb–IIIa inhibitors that should still be considered the preferred strategy, especially in high.-risk patients and within the first hours from symptom onset.

Non-responsiveness to aspirin and clopidogrel is relatively frequent. However, future trials are needed to evaluate whether its routine assessment and change in therapy (higher dosages or switch to other ADP) may improve clinical outcome. Even though not demonstrated yet, it is conceivable to get the greatest benefits from early administration of clopidogrel as well, which might be considered as part of a facilitation strategy, together with early administration of Gp IIb–IIIa inhibitors. Due to stronger and faster inhibition of platelet aggregation, further benefits might be expected by early administration of new oral ADP-antagonist.

As a consequence of the very low mortality currently achieved by primary angioplasty, additional endpoints, such as infarct size and myocardial perfusion, may be considered to explore the benefits of adjunctive antithrombotic therapies in future randomized trials among patients undergoing mechanical revascularization for STEMI.

Key Words: Antithrombotic therapy • Primary angioplasty • STEMI

A significant mortality reduction has been observed in the last decades in the treatment of ST-segment elevation myocardial infarction (STEMI), mainly due to pharmacological and/or mechanical reperfusion therapies.1–5 Primary angioplasty has provided further survival benefits when compared with thrombolysis, mainly due to a larger proportion of epicardial recanalization.1 Since atherothrombosis plays a pivotal role in the pathogenesis of myocardial infarction (Figure 1),6 great efforts have been done in the last years in order to improve antithrombotic therapies as an essential complement in patients undergoing mechanical reperfusion for STEMI (Figure 2). The aim of this article is to provide a critical and update review of adjunctive antithrombotic therapies to primary angioplasty.


Figure 1
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  		Figure 1 Platelets, procoagulant activity, and coagulation cascade with several key points at which specific drugs may exert their antithombotic activity.

 

Figure 2
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  		Figure 2 Aims of optimal antithrombotic therapy.

 

   Rationale for new antithrombotic therapies and strategies
Top
 Abstract
 Rationale for new antithrombotic...
Anticoagulation beyond...
 Antiplatelet therapy beyond acid...
 Conclusions and future...
 References
 
Time is muscle
A large series of investigations published in the last years have demonstrated that time-to-treatment is a relevant issue in primary angioplasty, with a significant impact on mortality.7–12 Large interests have been focused in the last years on pharmacological facilitation with administration of early antithormbotic therapies aiming at early recanalization. In fact, the vast majority of STEMI patients currently present to non-percutaneous coronary intervention (PCI) hospital, with the need of transportation with subsequent longer delay to treatment. Thus, a pharmaco-invasive approach seems a very attractive strategy in the treatment of STEMI patients, particularly among high-risk patients and within the first hours from symptom onset.13

Re-infarction
Several reports have demonstrated the prognostic impact of re-infarction after STEMI in patients treated with thrombolysis or primary angioplasty.14,15 In-stent thrombosis after coronary stenting in primary angioplasty is not so low as commonly believed. In fact, it seems that a larger unrestricted use of coronary stenting is associated with a poorer outcome in terms of re-infarction, particularly when glycoprotein (GP) IIb–IIIa inhibitors are not administered,16,17 ranging between 5 and 10%.

Distal embolization
Despite successful mechanical revascularization, suboptimal reperfusion may occur, resulting in unfavourable outcome.18–20 In the last years, growing interest has been focused on the role of distal embolization as major determinant of poor reperfusion.

Based on the histological analysis of retrieved debris, the Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris (EMERALD) trial21 showed visible debris in 78% of patients. Henriques et al.22 reported that the incidence of angiographically detectable distal embolization was 16%, and this was associated with poor reperfusion, larger infarct size, and unfavourable 5 years survival, when compared with patients without angiographic signs of distal embolization.

Inter-individual variability in the response to conventional antiplatelet therapies
It has been described a large inter-individual variability in response to antiplatelet therapies.23–29 The percentage of non-responders ranges between 5 and 50% (according to different laboratory tests) for aspirin, and between 20 and 30% for clopidogrel.23–29 Several mechanisms have been proposed.30–45

Limitations of unfractionated heparin
Despite the low costs, several potential disadvantages of unfractionated heparin (UFH) should be remarked: (i) dependency on antithrombin III for inhibition of thrombin activity; (ii) sensitivity to platelet factor 4; (iii) inability to inhibit clot-bound thrombin; (iv) marked inter-individual variability in therapeutic response; (v) the need for frequent aPTT monitoring.

Bleeding complications
Aggressive antithrombotic therapy carries a risk of bleeding and blood transfusion. Although the true incidence of bleeding depends on the population studied (i.e. clinical trial vs. registry) and the definition used,46,47 it is clear that bleeding is associated with an increased risk for adverse outcomes including myocardial infarction and death.46,48 Therefore, therapies that provide an adequate level of anticoagulation to reduce ischaemia while simultaneously minimizing the risk of bleeding and transfusion have the potential to improve outcomes among patients with STEMI, especially in those patients at higher risk for bleeding complications, such as those with low body weight, female gender, and impaired renal function.46–49


   Anticoagulation beyond unfractionated heparin
Top
 Abstract
 Rationale for new antithrombotic...
 Anticoagulation beyond...
Antiplatelet therapy beyond acid...
 Conclusions and future...
 References
 
Direct thrombin inhibitors
Bivalirudin is a 20-amino acid synthetic polypeptide analog of hirudin50 (Table 1). Once bound, bivalirudin is cleaved by thrombin, thereby reducing its antithrombotic activity. Peak bivalirudin concentrations are achieved 15–20 min after intravenous infusion. In patients with normal renal function, the plasma half-life of bivalirudin is 25–36 min. Although it is predominantly eliminated by plasma enzymes (peptidases), approximately 20% of the drug is excreted via the kidneys.51 Unfortunately, there is no antidote for bivalirudin.


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  		Table 1 Characteristics of anticoagulation therapies

 
In the Horizons trial,52 including 3602 STEMI patients undergoing primary angioplasty and randomized to bivalirudin vs. Gp IIb–IIIa inhibitors (Abciximab in 49.9% and Eptifibatide in 44.4%) plus UFH, bivalirudin was associated with a significant reduction in overall net clinical outcome (9.3 vs. 12.2%, P = 0.006), mainly due to a significant reduction of major bleeding complications (5.0 vs. 8.4%, P < 0.0001). Bivalirudin significantly reduced the incidence of cardiac-related mortality by 38% (1.8 vs. 2.9%, P = 0.035), despite a higher rate of 24 h in-stent thrombosis with bivalirudin (1.3 vs. 0.3%, P = 0.0009). Data recently presented at the ACC 2008 annual meeting53 showed that the reduction in the composite endpoint (including bleeding complications) was equally reduced when compared with abciximab or eptifibatide, whereas a slightly higher rate of MACE was observed with bivalirudin when compared with abciximab (5.7 vs. 5.3%) (abciximab strata, n = 1915) but not to eptifibatide (5.2 vs. 5.7%) (eptifibatide strata).

Low-molecular-weight heparins
Advantages of low-molecular-weight heparins (LMWHs) include: (i) a stable and reliable anticoagulation effect that obviates the need of frequent monitoring of coagulation parameters; (ii) high bioavailability (90%) that allows subcutaneous administration; (iii) high anti-Xa: antiIIa ratio, producing blockade of the coagulation cascade in an upstream location, results in a marked decrement in thrombin generation (Table 1). It should be remarked that LMWHs are only partially neutralized by protamine sulfate.54

No randomized trial has so far compared LMWHs vs. UFH in primary PCI. However, the STEEPLE trial55 has shown in elective patients a significant reduction in major bleeding complications with 0.5 mg/kg enoxaparin bolus when compared with UFH.

Factor-X inhibitors
Fondaparinux is a synthetic analogue of the pentasaccharide sequence present in UFH and LMWHs that mediate their interaction with antithrombin. However, it selectively inhibits factor Xa (seven-fold higher than that of LMWHs), without specific inhibition of thrombin activity.56 In addition, it was shown that fondaparinux may render the clot more susceptible to fibrinolysis induced by t-PA. Unlike UFH, most factor Xa inhibitors do not have a known antidote.

So far, no randomized trial has investigated the role of Fondaparinux in primary PCI. Among 3768 patients included in the OASIS-6 trial57 and treated with primary angioplasty, there was a trend to harm for fondaparinux in terms of death and reMI at 30 days (6.1 vs. 5.1%, P = 0.19), with higher rate of intracatheter thrombosis (2.2% vs. 0), that were not observed in patients pre-treated with heparin. In addition, fondaparinux was associated with less major bleeding complications, except than in primary PCI patients.

The observed higher rate of intracatheter thrombosis is explained by the fact that UFH is effective in modulating the contact activation pathway by inactivating factor XIa and, to a lesser extent, factor XIIa through an AT-dependent mechanism. In contrast, pentasaccharides are ineffective in blocking these contact activation pathway that contributes to intracatheter thrombosis.58


   Antiplatelet therapy beyond acid acetylsalycilic
Top
 Abstract
 Rationale for new antithrombotic...
 Anticoagulation beyond...
 Antiplatelet therapy beyond acid...
Conclusions and future...
 References
 
P2Y12 antagonists
Non-responsiveness to clopidogrel may be observed in up to 30% of patients, and it is associated with a worse prognosis after coronary stenting.26–29 This issue may be of high clinical relevance particularly in patients receiving drug-eluting stents, due to higher risk of late in-stent thrombosis.27 Due to the impact of SAT on mortality after primary angioplasty,14,15 non-responsiveness to clopidogrel would deserve larger attention. Future randomized trials are certainly needed to identify the optimal strategy to be adopted among these patients, including higher daily dose (150 mg),59 switch to ticlopidine60 or new ADP antagonist, or adjunctive oral anticoagulation therapy. The CURRENT trial61 will hopefully provide important data on the benefits from higher dose of bolus (600 mg) and daily therapy (150 mg) in 14 000 acute coronary syndrome (ACS) patients undergoing early planned coronary intervention, when compared with standard bolus (300 mg) and daily dosage (75 mg) of clopidogrel. A subanalysis of the Horizons trial, recently presented at the ACC 2008 annual meeting,62 showed that 600 mg bolus of clopidogrel was associated with a significant reduction in mortality (1.9 vs. 3.1%, P = 0.03) and re-infarction (1.3 vs. 2.4%, P = 0.02) at 30 days, when compared with standard 300 mg bolus of clopidogrel, and a paradoxically lower incidence of bleeding complications. However, the significant benefits in mortality and re-infarction were not confirmed at multivariate analysis.

Several novel P2Y12 antagonists (Table 2, Figure 3) have been developed and are currently under investigation to determine whether they can provide better or more rapid antithrombotic effects than clopidogrel, without an increase in bleeding complications.


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  		Table 2 Characteristics of intravenous Gp IIb–IIIa inhibitors

 

Figure 3
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  		Figure 3 Chemical structures of major established or emerging antiplatelet agents. Ticlopidine, clopidogrel, and prasugrel are first-, second-, and third-generation thienopyridines, respectively, that irreversibly inhibit the P2Y12 receptor. AZD6140 (Ticangrelor) is a cyclopentyltriazolopyrimidine that reversibly inhibits the P2Y12 receptor, whereas Cangrelor is an ATP analog that reversibly inhibits the P2Y12 receptor.

 
Prasugrel is an oral, third generation thienopyridine. Like clopidogrel, it is a prodrug, and thus needs being metabolized via cytochrome P450 in the liver to produce an active metabolites63,64 that irreversibly inhibit the platelet P2Y12 receptor.65 However, there is much more efficient in vivo generation of the active metabolite of prasugrel than of the active metabolite of clopidogrel.64 As a result, a prasugrel 60 mg loading dose results in a much more rapid, potent, and consistent inhibition of platelet function than a clopidogrel loading dose of 300 mg65,66 or 600 mg.67 Furthermore, a maintenance dose of prasugrel 10 mg daily results in a more potent and consistent inhibition of platelet function than the standard clopidogrel maintenance dose of 75 mg daily.68

In fact, recently published data from the Trial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel (TRITON–TIMI) 38 trial69 have shown that among 13 608 ACS patients undergoing coronary angioplasty, 60 mg loading dose and a 10 mg daily maintenance dose of prasugrel, when compared with approved doses of clopidogrel (300 mg loading dose and a 75 mg daily maintenance dose), was better than clopidogrel in reducing the rates of myocardial infarction (7.4 vs. 9.7%, P < 0.001), urgent target-vessel revascularization (2.5 vs. 3.7%, P < 0.001), and stent thrombosis (1.1 vs. 2.4%, P < 0.001), but associated with higher risk of major bleeding complications (2.4 vs. 1.8%, P = 0.03), especially in patients with a history of stroke or transient ischaemic attack, age >75 years, and body weight <60 kg.69 However, it must be remarked that P2Y12 inhibitors were started in the catheterization laboratory or (in the vast majority of patients) soon after PCI. This may have favoured the agent with the fastest onset of action.

AZD6140 is another investigational P2Y12 antagonist (Table 2, Figure 3). To increase oral bioavailability, the structure of AZD6140 was modified from AR-C109318XX. Unlike ticlopidine, clopidogrel, and prasugrel, AZD6140 is not a thienopyridine but an ATP analog, it is a direct (i.e. no metabolism of a prodrug is required), and a reversible P2Y12 antagonist.70

Like prasugrel, AZD6140 results in a more rapid onset of action and greater degree of platelet inhibition than clopidogrel.70 Data from the DISPERSE-2 study71 have shown the safety and a more favourable outcome with the AZD6140 vs. clopidogrel in 990 ACS patients. The ongoing PLATelet inhibition and patient Outcomes (PLATO) trial72 will provide definite data on AZD6140 (90 mg twice daily) vs. clopidogrel in more than 18 000 ACS patients.

Cangrelor is an investigational, direct-acting, reversible P2Y12 antagonist (Figure 3).73 Unlike the above-described orally administered P2Y12 antagonists (ticlopidine, clopidogrel, prasugrel, and AZD6140), cangrelor is administered intravenously—which, together with the rapid reversal of its effects after the end of the infusion, may be potentially advantageous in the PCI setting. Like prasugrel and AZD6140, cangrelor results in a more rapid onset of action and greater degree of platelet inhibition than clopidogrel, and showed no significant increase in bleedings compared with clopidogrel in phase 2 studies.74,75 The STEP-AMI trial did evaluate the use of intravenous P2Y12 platelet receptor inhibition cangrelor as an adjunct to reduced-dose alteplase during acute myocardial infarction in order to evaluate its safety, tolerability, and efficacy in restoring the patency of the infarct-related artery.76 Preliminary results did show that adjuctive cangrelor to thrombolysis (half-dose) did improve epicardial and myocardial reperfusion.

Cangrelor is currently in phase 3 PCI trials: CHAMPION-PCI (Cangrelor Bolus 30 µg/kg followed by infusion 4 µg/kg/h vs. 600 mg clopidogrel)77 and CHAMPION-PLATFORM (Cangrelor Bolus 30 µg/kg followed by infusion 4 µg/kg/h vs. placebo).78

PRT060128 is an investigational, direct-acting, reversible P2Y12 antagonist with a novel structure,79 which can be administered orally or intravenously, has completed phase 1 clinical studies.

Future trials are needed to evaluate whether novel P2Y12 antagonists may further improve outcome of STEMI patients treated by primary angioplasty and whether intravenous P2Y12 antagonists may be considered as an alternative strategy or even add further benefits to Gp IIb–IIIa inhibitors, particularly among patients undergoing transportation for primary angioplasty, when early treatment with both therapies may significantly improve early reperfusion.

Glycoprotein IIb–44IIIa inhibitors
Several randomized trials have been conducted in primary angioplasty, the vast majority of them on abciximab.3,50,80–91 In the largest trial, the CADILLAC,87 a total of 2082 patients were randomized to stent or balloon with or without periprocedural administration of abciximab. Abciximab did not improve myocardial perfusion as evaluated by myocardial blush grade and ST-segment resolution.90 Some benefits in mortality with abciximab were observed in patients undergoing balloon angioplasty only, whereas no benefits were observed in terms of re-infarction. Abciximab did not increase the risk of bleeding complications. However, a major limitation of this study was the relatively low-risk population. In fact, in trials without strict patient selection, as conducted by Antoniucci and colleagues, abciximab was associated with benefits in terms of death and re-infarction.87 A recent meta-analysis of randomized trials has shown that periprocedural abciximab administration is associated with a significant reduction in mortality and re-infarction, without an increased risk of major bleeding complications.3 However, data from the BRAVE-3 trial92 have shown no benefits in infarct size and 30-day mortality when a clopidogrel loading dose of 600 mg was administrated. Keeping in mind the relationship between the risk profile and mortality benefits from abciximab administration, it may be claimed that the absence of benefits would have been expected in a population with the mortality lower than 3%, as observed in the BRAVE-3 trial.92

Few data have been reported on eptifibatide and tirofiban.91,93–98 Steen et al.91 did show in a small randomized trial (53 patients) a significantly improved epicardial and myocardial perfusion by adjunctive tirofiban. Data from a randomized trial conducted in Zwolle study93 have shown that high-dose tirofiban was associated with a better platelet inhibiton when compared with abciximab or standard dose of tirofiban. In the STRATEGY trial,95 no difference in death and or re-infarction was observed between high-dose tirofiban and abciximab. Data from the MultiSTRATEGY trial96 have shown among 745 STEMI patients undergoing primary angioplasty a similar outcome (non-inferiority) between tirofiban and abciximab, and no difference in major bleeding complications. FATA trial97 will provide further data on the comparison between these two therapies in primary angioplasty.

In the EVA-AMI trial, recently presented at the AHA 2007 annual meeting,98 400 STEMI patients were randomly assigned to periprocedural administration of eptifibatide or abciximab, with similar outcome between the two molecules. The major limitation of the study is that the primary endpoint (ST resolution at 60–90 min) was available in only 50% of patients.

Further benefits may be expected by adjunctive intracoronary administration of Gp IIb–IIIa inhibitors. A small randomized trial99 showed that selective intracoronary administration of abciximab distally to the occlusion (through an over-the-wire balloon) was associated with a significant improvement in myocardial perfusion and smaller infarct size. These data have been confirmed in another small randomized trial,100 showing among 144 STEMI patients that intracatheter administration of abciximab bolus was associated with improved myocardial perfusion and reduced infarct size when compared with intravenous bolus administration.

Pharmacological facilitation
Several randomized trials have been conducted to evaluate the benefits from early Gp IIb–IIIa inhibitors administration in patients undergoing primary angioplasty.85,101–113 In the On-TIME trial,102 a total of 507 STEMI patients transferred to a PCI centre were randomized to early, pre-hospital initiation of tirofiban (early) or to its initiation in the catheterization laboratory (late). Early tirofiban was associated with a better pre-procedural TIMI 2–3 flow (43 vs. 34%, P = 0.04), and myocardial perfusion (myocardial blush grade 2–3: 30 vs. 22%, P = 0.04). However, no benefits were observed in post-procedural TIMI 3 flow, myocardial perfusion, mortality (4.5 vs. 3.7%, P = 0.66), and re-infarction (2.4 vs. 3.7%, P = 0.43) at 1-year follow-up. Similar results have been observed in the TITAN-TIMI 34, where 316 STEMI patients were randomized to early or late eptifibatide.103 Several small randomized trials107,110,111 have been conducted with abciximab, showing benefits in terms of pre-procedural TIMI flow and myocardial perfusion.

In the large FINESSE trial,113 up to 2500 STEMI patients were randomized within 6 h from symptom onset to facilitation with half lytic and abciximab, early or periprocedural abciximab administration. When compared with late administration, early abciximab did improve neither pre-procedural TIMI 2–3 flow (26 vs. 25%) nor 90 day mortality (5.5 vs. 4.5%), with a non-significantly higher risk of major bleeding complications (4.1 vs. 2.6%, P = 0.13). Several limitations should be taken into account in the interpretation of the results of this trial. First of all, it was prematurely stopped after 4 years, due to slow recruitment. Thus, the very low enrolment rate per centre per year certainly leaded to a selection bias. In addition, despite the study was focused on facilitation, more than 50% of patients were enrolled in primary PCI centres. However, subgroup analyses have shown some benefits in terms of outcome among patients included within the first 3 h and in high-risk patients.

A recent individual patients' data meta-analysis (including 1662 patients) of randomized trials comparing early vs. late administration of Gp IIb–IIIa inhibitors in primary angioplasty114 has demonstrated significant benefits in pre-procedural TIMI flow with all the molecules. However, only abciximab was associated with significant benefits in post-procedural TIMI flow, myocardial blush, distal embolization, and survival (Figure 4). Of note, facilitation did not significantly increase the risk of major bleeding complications (3.2 vs. 2.9%).


Figure 4
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  		Figure 4 Results of the EGYPT cooperation. Early abciximab was associated in significant benefits in terms of pre- and post-procedural TIMI 3 flow, MBG 3, complete ST-segment resolution, distal embolization, and mortality, when compared with periprocedural administration.

 
Supporting the benefits from early abciximab administration, data from the Eurotransfer registry, recently presented at ESC 2007 annual meeting,115 showed among up to 1000 STEMI patients transferred for primary angioplasty that early abciximab administration improved pre-procedural TIMI 3 flow (17.7 vs. 8.9%, P < 0.05) and was independently associated with better 30 day survival (3.8 vs. 5.8%, P = 0.007) (Figure 5). In addition, in a retrospective analysis from the large APEX-MI trial,116 early Gp IIb–IIIa inhibitors administration was associated with improved pre-procedural TIMI 2–3 flow (27.8 vs. 21%), post-procedural reperfusion (complete ST-resolution: 53.9 vs. 49.5%), and reduced 90 day mortality (3.2 vs. 4.8%), when compared with periprocedural administration (Figure 5).


Figure 5
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  		Figure 5 Mortality benefits with pharmacological facilitation with Gp IIb–IIIa inhibitors in randomized and non-randomized studies. *Abciximab; +Tirofiban.

 
Further evidence of benefits from early Gp IIb–IIIa inhibitors (Tirofiban) has been observed in the On-TIME 2 trial.117 In this study, 984 patients have been randomized to early, pre-hospital administration of high-dose tirofiban (25 µg/kg bolus followed by a 0.15 µg/kg/min maintenance infusion) or placebo. Of note, all patients received early high-dose (600 mg) clopidogrel administration. Early tirofiban was associated with improved pre- and post-procedural reperfusion, with reduced mortality (2.3 vs. 4.0%, P = 0.14) (Figure 5).

Thus, despite the negative results of the FINESSE trial,113 there is evidence of beneficial effects of early Gp IIb–IIIa inhibitors administration (Figure 5) that should still be considered a reasonable strategy, especially in high-risk patients and within the first hours from symptom onset. This is in accordance with ACC/AHA STEMI guidelines that suggest abciximab administration as early as possible (class IIa).5

For years, there have been concerns about the combination of thrombolysis and mechanical reperfusion in STEMI due to the fact that thrombolytic therapy may induce platelet aggregation and impair the results of adjunctive mechanical revascularization.118 However, the results of trials on adjunctive thrombolytic therapy have been negative.119–124 These data may be explained by the higher rates of early reocclusion and re-infarction, potentially due to the low-rate of abciximab administration.

The combination of Gp IIb–IIIa inhibitors with half-dose lysis has been shown to provide a higher rate of reperfusion and may reduce the risk of thrombotic complications. This strategy may be appealing particularly when long-distance transportation to cathlab is needed.125 Few small trials have been so far conducted comparing combination therapy vs. upstream Gp IIb–IIIa inhibitors alone for PCI,126–129 showing no benefits in terms of myocardial salvage106 and clinical outcome, despite the significantly improved pre-procedural epicardial recanalization. Data from the FINESSE trial113 showed that, despite improvement in pre-procedural TIMI flow, combotherapy did not confer any benefit in terms of survival, but was associated with higher risk of major bleeding complications (4.8 vs. 2.6%, P = 0.025).

The absence of benefits in terms of survival despite improved pre-procedural recenalization may depend on: (i) relatively late recanalization; (ii) potential haemorrhagic transformation of the infarction zone with lytic therapy.

It must be recognized that even though in several randomized trials, the time window for enrolment has been restricted to the first 6 h from symptoms onset, a large proportion of patients did receive facilitation after the first 3 h, when clinical benefits are certainly low, and the risk of bleeding complications outweights the benefits from early pharmacological reperfusion, due to less myocardium that can be saved and reduced drug effectiveness.

Remarkably, data from CARESS in AMI (including 600 patients)130 and the TRANSFER-AMI (including 1060 patients)131 have recently shown the safety and benefits (in terms of re-infarction and recurrent ischaemia) of early routine angiography (within 6 h) soon after combotherapy (CARESS in AMI) or full-dose lysis (TRANSFER-AMI), without a significant increase in the risk in TIMI major bleeding complications (2.7 vs. 2.3% in the CARESS in AMI, and 4.6 vs. 4.3% in the TRANSFER-AMI). These data will probably contribute to modify current ACC/AHA recommendation5 and hopefully promote future trials in order to address whether the type of pharmacological facilitation should be selected according to the time from symptom onset to the presentation. In fact, complete reperfusion within the first 2 h has a high probability of abortion of myocardial infarction that should still be considered the target in the treatment of STEMI, independently from whether mechanical reperfusion is planned or not.132


   Conclusions and future directions
Top
 Abstract
 Rationale for new antithrombotic...
 Anticoagulation beyond...
 Antiplatelet therapy beyond acid...
 Conclusions and future...
References
 
Great efforts have been done in last years in order to improve adjunctive antithrombotic drugs in patients undergoing primary angioplasty. Thus, aiming at providing an updated overview of this rapidly progressing field, we conclude that:

  1. Early UFH (before transportation or in the CCU) plus additional periprocedural administration should still be regarded as the gold standard in initial antithrombotic therapy. In fact, in addition to very low costs, UFH has some advantages when compared with new anticoagulants. The first is that the anticoagulant effects of UFH can be rapidly and completely neutralized by protamine. This is essential to face intraprocedural mechanical complications, such as coronary rupture. Second, UFH is not cleared by the kidneys and therefore is potentially safer than LMWH or fondaparinux in patients with renal insufficiency. The third advantage is that UFH is effective in modulating the contact activation pathway.
  2. Due to undeniable practical advantages, post-procedural initiation of LMWHs or fondaparinux may be considered instead of continuous IV infusion of UFH.
  3. ASA and clopidogrel still represent the cornerstone of oral antiplatelet therapy. Even though not demonstrated yet, it is conceivable to get the greatest benefits from early administration of clopidogrel as well, that might be considered as part of a facilitation strategy, together with early administration of Gp IIb–IIIa inhibitors. Due to stronger and faster inhibition of platelet aggregation, further benefits might be expected by early administration of new oral ADP-antagonist.
  4. Non-responsiveness to aspirin and clopidogrel is relatively frequent. However, future trials are needed to evaluate whether its routine assessment and change in therapy (higher dosages or switch to other ADP) may improve clinical outcome, before monitoring antiplatelet therapy can be recommended in the clinical practice.
  5. Due to the positive results observed in the Horizons trial,52 bivalirudin may be considered as alternative strategy to heparin+Gp IIb–IIIa inhibitors, especially in patients at high risk for bleeding complications.
  6. Despite the negative results of the FINESSE trial,113 early abciximab administration should still be considered the preferred strategy, especially in high-risk patients and within the first hours from symptom onset.
  7. Future trials are certainly needed to further explore the advantages of new anticoagulation and antithrombotic therapies among primary PCI patients in terms of both efficacy and safety (bleeding complications). Due to the very low mortality currently observed with primary angioplasty, additional endpoints, such as infarct size and myocardial perfusion, may be considered as major endpoints in future randomized trials among patients undergoing mechanical revascularization for STEMI.

Conflict of interest: none declared.


   References
Top
 Abstract
 Rationale for new antithrombotic...
 Anticoagulation beyond...
 Antiplatelet therapy beyond acid...
 Conclusions and future...
 References
 

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