1
Review
Anticoagulation during and after acute coronary syndrome I. Ahrens; C. Bode; A. Zirlik Cardiology and Angiology I, Heart Center Freiburg University
Keywords ACS, activated clotting time, anticoagulation, heparin, enoxaparin, fondaparinux, bivalirudin, pegnivacogin, rivaroxaban
Summary Current antithrombotic therapy in patients with acute coronary syndrome (ACS) comprises antiplatelet and anticoagulant therapy. Dual antiplatelet therapy composed of aspirin plus a third generation P2Y12 inhibitor (prasugrel or ticagrelor) represents the gold standard, while aspirin plus second generation P2Y12 inhibitor (clopidogrel) may be used as an alternative in the presence of contraindications for third generation P2Y12 inhibitors and/or a high risk of bleeding. Unfractionated heparin (UFH) has been the unchallenged mainstay in anticoagulation for ACS for many decades and is still widely used in patients with ACS treated interventionally. Novel alternative parenteral anticoagulant strategies include the low molecular weight heparin enoxaparin and the synthetic pentasaccharide fondaparinux. Both of these agents share advantages over UFH particularly in medically treated patients with ACS not scheduled for PCI. The direct parenteral factor IIa (thrombin) inhibitor bivalirudin, when used as sole anticoagulant in patients with Correspondence to: Priv.-Doz. Dr. Ingo Ahrens, MD Heart Center, University of Freiburg Department of Cardiology and Angiology I Hugstetter Str. 55, 79106 Freiburg, Germany Tel. +49/(0)761/27 03 78 16, Fax +49/(0)761/27 03 78 55 E-mail: [email protected]
ACS is associated with a procoagulant state Acute coronary syndromes (ACS) arise from atherosclerosis of the coronary arteries, known as coronary artery disease (CAD).
ACS undergoing PCI, is as effective as the regimen of UFH plus GPIIb/IIIa inhibitor in NSTEMI and superior to the latter regimen in patients with STEMI. The novel approach of a long-term low dose factor Xa inhibition with rivaroxaban in the post ACS phase even further reduced cardiovascular mortality in a clinical trial but has yet to be established in daily clinical practice in the setting of third generation P2Y12 inhibitors. This review discusses currently clinically established anticoagulants for the treatment of ACS alongside with novel approaches such as rivaroxaban.
Schlüsselwörter Akutes Koronarsyndrom, Antikoagulation, Heparin, Enoxaparin, Fondaparinux, Bivalirudin, Pegnivacogin, Rivaroxaban
Zusammenfassung Die derzeitige antithrombotische Therapie bei Patienten mit akutem Koronarsyndrom umfasst Antiplättchen- und antikoagulative Therapie. Die duale Plättchenhemmung bestehend aus Aspirin sowie einem P2Y12-Inhibitor der dritten Generation (Prasugrel oder Ticagrelor) stellt den Goldstandard dar, während Aspirin zusammen mit einem P2Y12-Inhibitor der Antikoagulation während und nach akutem Koronarsyndrom Hämostaseologie 2014; 34: ••–•• DOI:10.5482/HAMO-13-09-0048 received: September 4, 2013 accepted in revised form: November 29, 2013 prepublished online: December 13, 2013
A plethora of basic as well as clinical evidence identified CAD as a chronic in-flammatory disease governed by a complex cross talk between acellular and cellular immunologic mechanisms on the one side and the vessel wall on the other side (1).
zweiten Generation (Clopidogrel) beim Vorhandensein von Kontraindikationen für P2Y12-Inhibitoren der dritten Generation oder aber bei hohem Blutungsrisiko als Alternative eingesetzt wird. In der klassischen antikoagulativen Therapie gilt unfraktioniertes Heparin nach wie vor als Therapiestandard besonders bei Patienten, die interventionell behandelt werden. Neue alternative parenterale Antikoagulationsstrategien umfassen den Einsatz von niedermolekularen Heparinen, z. B. Enoxaparin, und dem synthetischen Pentasaccharid Fondaparinux. Beide Substanzen teilen Vorteile im Vergleich zum unfraktionierten Heparin, besonders bei Patienten mit akutem Koronarsyndrom, die konservativ behandelt werden. Der direkte parenterale Faktor-IIa(Thrombin)-Inhibitor Bivalirudin ist genauso effektiv wie die Kombination aus unfraktioniertem Heparin plus Glykoprotein-IIb/IIIa-Inhibitor bei Patienten mit NSTEMI und sogar überlegen zu dem genannten Regime bei STEMI-Patienten, sofern Bivalirudin als einziges Antikoagulanz während der PCI genutzt wird. Der neue Ansatz einer Langezeitbehandlung mit einer niedrigen Dosis des oralen Faktor-Xa-Inhibitors Rivaroxaban in der Post-ACS-Phase konnte in der Atlas-II-Studie die kardiovaskuläre Mortalität weiter reduzieren. Allerdings muss sich dieses Konzept in der Klinik in Verbindung mit P2Y12-Inhibitoren der dritten Generation bewähren. Diese Übersichtsarbeit diskutiert ausführlich die etablierten Antikoagulanzien für die Behandlung des akuten Koronarsyndroms sowie neue Ansätze, z. B. Rivaroxaban.
CAD is characterised by the nascence and progress of atherosclerotic plaques ultimately leading to the narrowing of the vessel lumen and at a high degree of stenosis to ischaemic symptoms, typically recognised as angina or chest pain. An acute coronary syndrome develops as a consequence
© Schattauer 2014
Hämostaseologie 1/2014 Downloaded from www.haemostaseologie-online.com on 2014-01-02 | IP: 88.130.206.144 Note: Uncorrected proof, prepublished online For personal or educational use only. No other uses without permission. All rights reserved.
I. Ahrens; C. Bode; A. Zirlik: Anticoagulation during and after ACS
tissue factor
factor VII
factor VIIa factor X
• UFH enoxaparin fondaparinux rivaroxaban
factor Xa prothrombin
UFH enoxaparin bivalirudin
thrombin
factor VIIa
factor VII
pegnivacogin factor Va
factor IXa
VWF
factor XIa factor IX
platelet activation
tenase complex
initiation phase
cells of the vessel wall
factor VIIa
factor Xa
factor IXa
factor Va
pegnivacogin factor X
prothrombinase complex
prothrombin
thrombin
UFH enoxaparin bivalirudin
amplification/propagation phase
2
fondaparinux rivaroxaban
Fig. 1 The cell based coagulation system and the target coagulation factors of anticoagulants that are used in patients with ACS; modified from Ahrens et al. (31).
of superficial erosions or the rupture of an atherosclerotic plaque resulting in local adhesion and aggregation of platelets and the activation of the coagulation cascade (2) (▶ Fig. 1). The latter may lead to intraluminal thrombosis and vessel occlusion causing the clinical correlate, acute myocardial infarction (AMI). Interestingly, approximately 30–40% of ACS arise from previously asymptomatic plaques without haemodynamically relevant stenosis.
Again, the degree of inflammation within the plaque positively correlates with the likelihood of rupture. Local and systemic activation of circulating blood cells relevant for the pathophysiology of atherosclerosis such as pla-
telets and monocytes in the setting of local disruption of the endothelial integrity by superficial erosion of the endothelial layer or rupture of the fibrous cap covering the necrotic core of a plaque causes a measurable increase in circulating tissue factor in patients with ACS (3–5). Tissue factor (TF) initiates the coagulation cascade via conversion of factor VII to factor VIIa (6) contributing to the procoagulant environment observed in patients with ACS (7, 8).
Therapy during ACS Antiplatelets and anticoagulants While antithrombotic therapy is the cornerstone of medical therapy in ACS, it has to be distinguished whether the target of the antithrombotic therapy is
•
the platelet (the cellular phase of the coagulation system) or coagulation factors (the liquid phase of the coagulation system).
Strong evidence identifies the combination of antiplatelet with anticoagulant therapy as the most efficient antithrombotic treatment strategy in patients with ACS, leading to a reduction of both, all-cause mortality and cardiovascular adverse events. The variety of clinically available antiplatelet and anticoagulant agents allows specific and almost individualized antithrombotic therapy in patients with ACS. However, it also warrants a high degree of clinical expertise in the use of these agents. Particularly, the risk of bleeding needs to be assessed in every case and weighed against the benefit in terms of reduction of ischaemic complications.
Bleeding scores such as the CRUSADE bleeding score are simple tools that facilitate bleeding assessment in the ACS population (▶www.crusadebleedingscore.org). This is of importance since bleeding events clearly correlate with clinical outcome and mortality and may therefore be just as deleterious as ischaemic events (9). Currently, guideline-conform established antiplatelet therapy in ACS consists of aspirin plus a third generation oral P2Y12 inhibitor (prasugrel or ticagrelor).
In case of contraindications for prasugrel or ticagrelor, or if the patient is at very high risk for bleeding events, clopidogrel may be used as an alternative (10). In addition to dual antiplatelet therapy, the use of GP IIb/ IIIa inhibitors may be considered especially if intracoronary thrombi are visible during coronary angiography. However, due to the clinical availability of potent anticoagulants that also affect platelet reactivity such as bivalirudin and fast acting novel platelet inhibitors with high inhibition of platelet activity (IPA) and absence of genetic variability in response, the use of GP IIb/IIIa inhibitors in ACS has declined considerably over the past decade. The anticoagulation on top of antiplatelet therapy in patients with ACS is the
Hämostaseologie 1/2014
© Schattauer 2014 Downloaded from www.haemostaseologie-online.com on 2014-01-02 | IP: 88.130.206.144 Note: Uncorrected proof, prepublished online For personal or educational use only. No other uses without permission. All rights reserved.
I. Ahrens; C. Bode; A. Zirlik: Anticoagulation during and after ACS
focus of this article and will be discussed in detail. During the initial phase of ACS parenteral anticoagulation is the treatment of choice. Unfractionated heparin (UFH), despite its well-known shortcomings, is still the most widely clinically used parenteral anticoagulant. Low molecular weight heparins (LMWH) such as enoxaparin or even the parenteral factor Xa inhibitor fondaparinux are clinically established alternatives for anticoagulation, especially in patients with ACS treated non-invasively. Furthermore, the direct factor IIa (thrombin) inhibitor bivalirudin is an established treatment in patients with ACS undergoing PCI (11–13).
Anticoagulation during ACS State of the Art The routine clinical use of parenteral anticoagulants in patients with acute coronary syndrome dates back several more decades than the introduction of the term acute coronary syndrome itself (14). To date, there is worldwide consensus that anticoagulation reduces cardiovascular adverse events in patients with ACS but we have not yet found the ideal anticoagulant that provides a broad therapeutic window without exposing the patient to an increased risk for bleeding (10, 15). There are currently four clinically approved parenteral anticoagulants for the use in patients with acute coronary syndromes: • UFH, • the LMWH enoxaparin, • fondaparinux, and • bivalirudin. Each of these agents has been investigated in patients with ACS undergoing percutaneous coronary intervention (PCI). Furthermore, UFH, enoxaparin and fondaparinux were also evaluated in large cohorts of patients receiving conservative treatment for ACS. While several large randomized clinical trials suggest superiority of enoxaparin, fondaparinux, or bivalirudin over UFH in patients with ACS, UFH is still widely employed as the anticoagulant of choice in the treatment of patients with ACS for its short half-life, the reversibility of it’s anticoagulant effects with protamine, and the ease in point-of-care control.
Unfractionated heparin (UFH) UFH targets various factors within the coagulation cascade including the major coagulation factors thrombin (IIa), factor Xa, and factor IXa (16). The indirect mode of action via the enhancement of the antithrombin and antifactor Xa activities of plasma antithrombin and the capability of UFH to bind to other plasma proteins (e. g. protein C inhibitor, platelet-factor-4) largely account for the inter- and intraindividual variations in anticoagulant response to intravenously administered UFH. The anticoagulant activity is routinely measured via the activated partial prothrombin time (aPTT). During PCI a rapid bedside test, the activated clotting time (ACT), allows the direct assessment of the anticoagulant activity of intravenously or intraarterially administered UFH. The current dosing recommendation for patients with ACS is 60 U/kg bodyweight administered as a bolus. The systematic measuring of the intraprocedural ACT in the pre-ticagrelor and pre-prasugrel era revealed that an ACT between 350 and 375 seconds provided the best protection from major cardiac adverse events (17). After the clinical introduction of the GPIIb/IIIa antagonists for patients with ACS undergoing PCI, it became evident that a lower ACT between 200 and 250 seconds provides the best net benefit balancing protection from major cardiac adverse events and the risk for major bleeding events associated with the antithrombotic treatment during PCI (18). Until today, UFH during PCI is usually dosed to reach an ACT of at least 200 seconds.
Enoxaparin The low molecular weight heparin enoxaparin has been assessed in a wide spectrum of patients with ACS. The net clinical benefit of enoxaparin as compared to UFH was greatest in patients with ST-elevation myocardial infarction (STEMI) when administered intravenously as a bolus of 0.5mg/kg bodyweight (19, 20). In ACS patients other than STEMI patients, a metaanalysis suggests that anticoagulation with enoxaparin given at a dose of 1 mg/kg bodyweight bid is at least as effective and
safe as UFH for the treatment of ACS (21). Based on the results of clinical trials comparing enoxaparin versus UFH in nonSTEMI patients with ACS it is recommended to administer enoxaparin subcutaneously at a dose of 1.0 mg/kg bodyweight bid (10). For STEMI patients it is currently not entirely clear whether enoxaparin should be preferred over UFH (22). However, if one decides to use enoxaparin as an anticoagulant for the treatment of STEMI patients, the preferred initial dosing regimen should be intravenous injection of 0.5mg/kg bodyweight (23).
Fondaparinux The indirect parenteral factor Xa inhibitor fondaparinux is a synthetic pentasaccharide that exerts its anticoagulant effect via activation of antithrombin. Fondaparinux has been assessed as an anticoagulant in patients with ACS in the OASIS 5&6 clinical trials in comparison to UFH or enoxaparin. If a patient with ACS was treated conservatively without PCI, fondaparinux appeared superior to UFH or enoxaparin in terms of clinical outcome (24). However, in case of an interventional treatment of patients with ACS (which is standard of care in many western countries), adjunctive treatment with UFH is required to prevent catheter-related thrombosis (25, 26). Based on the suspicion of insufficient anticoagulant activity in patients with ACS undergoing PCI, the use of fondaparinux as sole anticoagulant in ACS is limited to conservative treatment. Fondaparinux should be preferred over enoxaparin in conservative treatment of patients with ACS with a recommended dose of 2.5 mg administered subcutaneously (10).
Bivalirudin The direct parenteral factor IIa (thrombin) inhibitor bivalirudin is a peptide derived from its native molecule hirudin, which was originally isolated from leech (11). Bivalirudin has the shortest half-life (approx. 25 minutes) of the anticoagulants currently clinically approved for the treatment of ACS (11, 12). In the ACUITY trial in patients with ACS undergoing PCI, bivaliru-
© Schattauer 2014
Hämostaseologie 1/2014 Downloaded from www.haemostaseologie-online.com on 2014-01-02 | IP: 88.130.206.144 Note: Uncorrected proof, prepublished online For personal or educational use only. No other uses without permission. All rights reserved.
3
4
I. Ahrens; C. Bode; A. Zirlik: Anticoagulation during and after ACS
din alone compared to UFH + GPIIb/IIIa inhibitor was as effective in terms of prevention of cardiovascular adverse events while causing less bleeding events (27). In STEMI patients treated with PCI (HORIZONS-AMI trial), bivalirudin was superior compared to the standard regimen composed of UFH + GP IIb/IIIa inhibitor (28) and these results were consistent at the final 3-year analysis of the trial (29). In view of the shortcomings of fondaparinux in ACS patients undergoing PCI and the not yet defined role of enoxaparin in STEMI patients treated with PCI, bivalirudin emerges as the best option for anticoagulation during PCI of patients with ACS. However, the combination of UFH + GPIIb/IIIa inhibitor is still a viable choice (10, 22). In ACS patients undergoing PCI, the recommended dosing of bivalirudin is 0.75 mg/kg bodyweight as intravenous bolus followed by a continuous intravenous infusion during PCI (and up to 4 hours thereafter) of 1.75 mg/kg bodyweight/hour.
Therapy post ACS Long term anticoagulation In long-term treatment and secondary prophylaxis of cardiovascular events after ACS platelet inhibition initially as dual antiplatelet therapy (DAPT) followed by single antiplatelet therapy represent the current gold standard. However, very early data decades ago suggest that anticoagulants may also be effective in this scenario (30). Due to the risks associated with warfarin therapy, its unpredictable individual response, and small therapeutic bandwidth, anticoagulant therapy has not been established in long-term treatment following ACS.
Rivaroxaban Recently, novel oral anticoagulants (NOACs) emerged with dabigatran as factor IIa inhibitor and rivaroxaban and apixaban as factor Xa inhibitors (31). Since these substances overcome several key limitations of warfarin therapy the concept of long-term anticoagulation along with platelet inhibition has been challenged
again in clinical trials. The APPRAISE-2 trial evaluating apixaban two times 5 mg versus placebo on top of dual antiplatelet therapy with aspirin and clopidogrel in high risk ACS patients was prematurely stopped because of significantly increased major bleeding (32). In contrast, the ATLAS ACS 2 TMI 51 trial investigating rivaroxaban either at two times 2.5 mg or two times 5.0 mg versus placebo in the same collective showed very promising data: Rivaroxaban at the 2.5mg dose significantly reduced CV events and overall mortality. This coincided with an increase in major bleeding albeit no increase in fatal bleeding (33). However, these data will have to be validated in patients with ACS receiving the third generation P2Y12 inhibitors ticagrelor and prasugrel that are recommended in patients with ACS by current guidelines.
Future developments The addition of enoxaparin and fondaparinux to the arsenal of parenteral anticoagulants for the treatment ACS was a milestone after decades of restriction to UFH with its well-known shortcomings. However, both agents have a long half-life and although protamine may be used, there are no specific antagonists to reverse their anticoagulant effects. The clinical introduction of bivalirudin, which is actually not a very new substance but was rather rediscovered for anticoagulation in patients with ACS in the beginning of the new millennium (11), provided an anticoagulant agent with a relatively short half-life and therefore better controllability. An ideal anticoagulant drug for the treatment of patients with ACS has yet to be discovered. This drug would have to be efficient in providing steady anticoagulation in all patients with ACS regardless of weight, gender, renal function, and age. In addition there should be no increased risk of bleeding associated with its use. Some approaches of localised anticoagulation centered around single-chain mediated targeting of activated platelets were already successful in animal models (34, 35). However, these have not yet reached the clinical development phase but show a promising
profile in pre-clinical studies. There is currently only one parenteral anticoagulant in late stage clinical development for the treatment of patients with ACS: Pegnivacogin, a member of a new class of drugs, socalled RNA-based aptamers. Pegnivacogin inhibits coagulation factor IXa, which forms the tenase complex on the surface of activated platelets thereby facilitating the formation of the prothrombinase complex (▶ Fig. 1).
Pegnivacogin Pegnivacogin is a direct parenteral inhibitor of factor IXa and a first of its class molecule. It is a RNA aptamer consisting of 34 nucleotides that are conjugated to a 40 kDa polyethylenglycol (PEG) which accounts for its half-life of up to 100 hours (36). If the complimentary RNA nucleotide sequence (anivamersen) is administered, the anticoagulant effect of pegnivacogin is immediately reversed thereby providing ideal controllability of pegnivacogin-mediated anticoagulation. The REG1 anticoagulation system is composed of the two compounds pegnivacogin (the aptamerbased direct factor IXa inhibitor) and its control agent (anivamersen). REG1 has successfully been assessed in the phase IIb RADAR trial in patients with ACS undergoing PCI. In RADAR, patients with ACS undergoing PCI were randomised to anticoagulation with pegnivacogin and post procedural reversal with anivamersen (100, 75, 50, 25% reversal) or to UFH. The 25% reversal arm was closed after accumulation of bleeding events. The trial was stopped early after enrolment of 400 patients due to three allergic-like reactions that were possibly related to the study drug. The analysis of the trial data revealed that at least a 50% reversal dose was necessary to allow safe sheath removal after PCI in the REG1 treated patients, there was no significant difference in the secondary endpoint of ischaemic events between RGE1 and UFH treatment (37). Regado Biosciences, the developer of REG1, is currently planning a major phase III clinical trial (REGULATEPCI) assessing the efficacy of the REG1 system in patients undergoing PCI including patients with ACS (38).
Hämostaseologie 1/2014
© Schattauer 2014 Downloaded from www.haemostaseologie-online.com on 2014-01-02 | IP: 88.130.206.144 Note: Uncorrected proof, prepublished online For personal or educational use only. No other uses without permission. All rights reserved.
I. Ahrens; C. Bode; A. Zirlik: Anticoagulation during and after ACS
Tab. 1
Recommendations according to ESC guidelines modified from (10), (13) and (22)
anticoagulant unfractionated heparin
level of recommendation enoxaparin
level of recommendation fondaparinux level of recommendation bivalirudin
NSTE-ACS interventional
i. v. (target aPTT 50–70 s) if fondaparinux or enoxaparin are not available
i. v. 60 U/kg bolus (+ GPIIb/IIIa inhibitor if patient has a high risk of ischaemia)
i. v. (with or without GP IIb/IIIa inhibitor) must be used in patients not receiving bivalirudin or enoxaparin
IC
IC
IC
1 mg bid s.c. if fondaparinux is not available
30 mg bolus i.v. + 1mg bid s.c.
i. v. (with or without GP IIb/IIIa inhibitor) recommended over UFH + GPIIb/IIIa inhibitor
IB
IIa B
IIa B
2.5 mg od subcutaneously
NA
not recommended
IA
III B
NA
level of recommendation
Conclusion, recommendations & guidelines • It is currently perceived that the LMWH
• •
STEMI
conservative
enoxaparin, but especially the synthetic pentasaccharide fondaparinux are superior parenteral anticoagulants to UFH for patients with ACS that are conservatively managed by medical treatment. For patients with ACS undergoing PCI, UFH plus GPIIb/IIIa inhibitor or bivalirudin are the anticoagulants of choice. In patients with STEMI there is good evidence that bivalirudin is superior to UFH plus GPIIb/IIIa inhibitors mainly due to a lower rate of major bleeding events when bivalirudin is used as the anticoagulant.
The guidelines of the European Society of Cardiology for the treatment of patients with NSTE-ACS and STEMI have integrated these data (▶ Tab. 1). While the anticoagulant therapy in ACS has made great progress throughout the decades further developments and new drug approaches are still needed to find the best balance of greatest efficacy and least bleeding.
i. v. + provisional GPIIb/IIIa inhibitors particularly in patients with a higher bleeding risk
i. v. (+ GP IIb/IIIa inhibitor for bailout) preferred over UFH + GP IIb/IIIa inhibitor
IB
IB
Conflict of interest
I. A. received speaker’s honoraria from Bayer Healthcare, Lilly and Sanofi Aventis. C. B. received speaker’s honoraria from Bayer Healthcare, Merck, Astra-Zeneca, and Sanofi aventis. A. Z. received speaker’s honoraria from Bayer Healthcare, Astra-Zeneca.
References 1. Gerdes N, Zirlik A. Co-stimulatory molecules in and beyond co-stimulation – tipping the balance in atherosclerosis? Thromb Haemost 2011; 106: 804–813. 2. Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013; 368: 2004–2013. 3. Brambilla M, Camera M, Colnago D et al. Tissue factor in patients with acute coronary syndromes: expression in platelets, leukocytes, and plateletleukocyte aggregates. Arteriosc, Thromb Vasc Biol 2008; 28: 947–953. 4. Viles-Gonzalez JF, Badimon JJ. Atherothrombosis: the role of tissue factor. Int J Biochem Cell Biol 2004; 36: 25–30. 5. Cimmino G, Golino P, Badimon JJ. Pathophysiological role of blood-borne tissue factor: should the old paradigm be revisited? Int Emerg Med 2011; 6: 29–34. 6. Edgington TS, Ruf W, Rehemtulla A, Mackman N. The molecular biology of initiation of coagulation by tissue factor. Current studies in hematology and blood transfusion 1991; 58: 15–21.
7. Kopp CW, Gremmel T, Steiner S et al. Plateletmonocyte cross talk and tissue factor expression in stable angina vs. unstable angina/non ST-elevation myocardial infarction. Platelets 2011; 22: 530–536. 8. Morange PE, Blankenberg S, Alessi MC et al. Prognostic value of plasma tissue factor and tissue factor pathway inhibitor for cardiovascular death in patients with coronary artery disease: the AtheroGene study. J Thromb Haemost 2007; 5: 475–482. 9. Eikelboom JW, Mehta SR, Anand SS et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114: 774–782. 10. Hamm CW, Bassand JP, Agewall S et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2011; 32: 2999–3054. 11. Ahrens I, Smith BK, Bode C, Peter K. Direct thrombin inhibition with bivalirudin as an antithrombotic strategy in general and interventional cardiology. Expert opinion on drug metabolism & toxicology 2007; 3: 609–620. 12. Höchtl T, Farhan S, Wojta J, Huber K. New anticoagulant agents in acute coronary syndromes. Heart 2011; 97: 244–252. 13. Wijns W, Kolh P, Danchin N et al. Guidelines on myocardial revascularization. Eur Heart J 2010; 31: 2501–2555. 14. Chalmers TC, Matta RJ, Smith H Jr, Kunzler AM. Evidence favoring the use of anticoagulants in the hospital phase of acute myocardial infarction. N Engl J Med 1977; 297: 1091–1096. 15. Magee KD, Campbell SG, Moher D, Rowe BH. Heparin versus placebo for acute coronary syndromes. The Cochrane database of systematic reviews 2008: CD003462. 16. Gray E, Hogwood J, Mulloy B. The anticoagulant and antithrombotic mechanisms of heparin.
© Schattauer 2014
Hämostaseologie 1/2014 Downloaded from www.haemostaseologie-online.com on 2014-01-02 | IP: 88.130.206.144 Note: Uncorrected proof, prepublished online For personal or educational use only. No other uses without permission. All rights reserved.
5
6
I. Ahrens; C. Bode; A. Zirlik: Anticoagulation during and after ACS
17.
18.
19.
20.
21.
22.
23.
Handbook of experimental pharmacology 2012; 207: 43–61. Chew DP, Bhatt DL, Lincoff AM et al. Defining the optimal activated clotting time during percutaneous coronary intervention: aggregate results from 6 randomized, controlled trials. Circulation 2001; 103: 961–966. Tolleson TR, O’Shea JC, Bittl JA et al. Relationship between heparin anticoagulation and clinical outcomes in coronary stent intervention: observations from the ESPRIT trial. J Am Coll Cardiol 2003; 41: 386–393. Montalescot G, Zeymer U, Silvain J et al. Intravenous enoxaparin or unfractionated heparin in primary percutaneous coronary intervention for ST-elevation myocardial infarction: the international randomised open-label ATOLL trial. Lancet 2011; 378: 693–703. Navarese EP, De Luca G, Castriota F et al. Lowmolecular-weight heparins vs. unfractionated heparin in the setting of percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis. J Thromb Haemost 2011; 9: 1902–1915. Murphy SA, Gibson CM, Morrow DA et al. Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis. Eur Heart J 2007; 28: 2077–2086. Steg PG, James SK, Atar D et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33: 2569–2619. Silvain J, Beygui F, Barthelemy O et al. Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ 2012; 344: e553.
24. Mehta SR, Boden WE, Eikelboom JW et al. Antithrombotic therapy with fondaparinux in relation to interventional management strategy in patients with ST- and non-ST-segment elevation acute coronary syndromes: an individual patient-level combined analysis of the Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) randomized trials. Circulation 2008; 118: 2038–2046. 25. Montalescot G, Walenga JM. Catheter-related thrombosis: biological and clinical evidence for risk with currently available anticoagulants. Clin Appl Thromb Hemost 2009; 15: 183–196. 26. Steg PG, Jolly SS, Mehta SR et al. Low-dose vs standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux: the FUTURA/OASIS-8 randomized trial. JAMA 2010; 304: 1339–1349. 27. Stone GW, McLaurin BT, Cox DA et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355: 2203–2216. 28. Stone GW, Witzenbichler B, Guagliumi G et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218–2230. 29. Stone GW, Witzenbichler B, Guagliumi G et al. Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial. Lancet 2011; 377: 2193–2204. 30. Meijer A, Verheugt FW, Werter CJ et al. Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT Study. Circulation 1993; 87: 1524–1530.
31. Ahrens I, Lip GY, Peter K. New oral anticoagulant drugs in cardiovascular disease. Thromb Haemost 2010; 104: 49–60. 32. Alexander JH, Lopes RD, James S et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011; 365: 699–708. 33. Mega JL, Braunwald E, Wiviott SD et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366: 9–19. 34. Stoll P, Bassler N, Hagemeyer CE et al. Targeting ligand-induced binding sites on GPIIb/IIIa via single-chain antibody allows effective anticoagulation without bleeding time prolongation. Arterioscl Thromb Vascul Biol 2007; 27: 1206–1212. 35. Schwarz M, Meade G, Stoll P et al. Conformationspecific blockade of the integrin GPIIb/IIIa: a novel antiplatelet strategy that selectively targets activated platelets. Circulation Res 2006; 99: 25–33. 36. Ahrens I, Bode C. New parenteral anticoagulants: focus on factor Xa and thrombin inhibitors. Current drug discovery technologies 2012; 9: 129–136. 37. Povsic TJ, Vavalle JP, Aberle LH et al. A Phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial. Eur Heart J 2013; ::::::::::((VOLUME; SEITEN ODER DOI; AUTOR BITTE ERGÄNZEN)). 38. Regado, Biosciences, press, release. New Investor Leads Round to Fund Phase 3 Development of REG1. wwwregadobiocom/indexphp/2012/12/regado-biosciences-inc-secures-51-million-seriese-financing/. 2012 December 17.
Hämostaseologie 1/2014
© Schattauer 2014 Downloaded from www.haemostaseologie-online.com on 2014-01-02 | IP: 88.130.206.144 Note: Uncorrected proof, prepublished online For personal or educational use only. No other uses without permission. All rights reserved.
Review
Anticoagulation during and after acute coronary syndrome I. Ahrens; C. Bode; A. Zirlik Cardiology and Angiology I, Heart Center Freiburg University
Keywords ACS, activated clotting time, anticoagulation, heparin, enoxaparin, fondaparinux, bivalirudin, pegnivacogin, rivaroxaban
Summary Current antithrombotic therapy in patients with acute coronary syndrome (ACS) comprises antiplatelet and anticoagulant therapy. Dual antiplatelet therapy composed of aspirin plus a third generation P2Y12 inhibitor (prasugrel or ticagrelor) represents the gold standard, while aspirin plus second generation P2Y12 inhibitor (clopidogrel) may be used as an alternative in the presence of contraindications for third generation P2Y12 inhibitors and/or a high risk of bleeding. Unfractionated heparin (UFH) has been the unchallenged mainstay in anticoagulation for ACS for many decades and is still widely used in patients with ACS treated interventionally. Novel alternative parenteral anticoagulant strategies include the low molecular weight heparin enoxaparin and the synthetic pentasaccharide fondaparinux. Both of these agents share advantages over UFH particularly in medically treated patients with ACS not scheduled for PCI. The direct parenteral factor IIa (thrombin) inhibitor bivalirudin, when used as sole anticoagulant in patients with Correspondence to: Priv.-Doz. Dr. Ingo Ahrens, MD Heart Center, University of Freiburg Department of Cardiology and Angiology I Hugstetter Str. 55, 79106 Freiburg, Germany Tel. +49/(0)761/27 03 78 16, Fax +49/(0)761/27 03 78 55 E-mail: [email protected]
ACS is associated with a procoagulant state Acute coronary syndromes (ACS) arise from atherosclerosis of the coronary arteries, known as coronary artery disease (CAD).
ACS undergoing PCI, is as effective as the regimen of UFH plus GPIIb/IIIa inhibitor in NSTEMI and superior to the latter regimen in patients with STEMI. The novel approach of a long-term low dose factor Xa inhibition with rivaroxaban in the post ACS phase even further reduced cardiovascular mortality in a clinical trial but has yet to be established in daily clinical practice in the setting of third generation P2Y12 inhibitors. This review discusses currently clinically established anticoagulants for the treatment of ACS alongside with novel approaches such as rivaroxaban.
Schlüsselwörter Akutes Koronarsyndrom, Antikoagulation, Heparin, Enoxaparin, Fondaparinux, Bivalirudin, Pegnivacogin, Rivaroxaban
Zusammenfassung Die derzeitige antithrombotische Therapie bei Patienten mit akutem Koronarsyndrom umfasst Antiplättchen- und antikoagulative Therapie. Die duale Plättchenhemmung bestehend aus Aspirin sowie einem P2Y12-Inhibitor der dritten Generation (Prasugrel oder Ticagrelor) stellt den Goldstandard dar, während Aspirin zusammen mit einem P2Y12-Inhibitor der Antikoagulation während und nach akutem Koronarsyndrom Hämostaseologie 2014; 34: ••–•• DOI:10.5482/HAMO-13-09-0048 received: September 4, 2013 accepted in revised form: November 29, 2013 prepublished online: December 13, 2013
A plethora of basic as well as clinical evidence identified CAD as a chronic in-flammatory disease governed by a complex cross talk between acellular and cellular immunologic mechanisms on the one side and the vessel wall on the other side (1).
zweiten Generation (Clopidogrel) beim Vorhandensein von Kontraindikationen für P2Y12-Inhibitoren der dritten Generation oder aber bei hohem Blutungsrisiko als Alternative eingesetzt wird. In der klassischen antikoagulativen Therapie gilt unfraktioniertes Heparin nach wie vor als Therapiestandard besonders bei Patienten, die interventionell behandelt werden. Neue alternative parenterale Antikoagulationsstrategien umfassen den Einsatz von niedermolekularen Heparinen, z. B. Enoxaparin, und dem synthetischen Pentasaccharid Fondaparinux. Beide Substanzen teilen Vorteile im Vergleich zum unfraktionierten Heparin, besonders bei Patienten mit akutem Koronarsyndrom, die konservativ behandelt werden. Der direkte parenterale Faktor-IIa(Thrombin)-Inhibitor Bivalirudin ist genauso effektiv wie die Kombination aus unfraktioniertem Heparin plus Glykoprotein-IIb/IIIa-Inhibitor bei Patienten mit NSTEMI und sogar überlegen zu dem genannten Regime bei STEMI-Patienten, sofern Bivalirudin als einziges Antikoagulanz während der PCI genutzt wird. Der neue Ansatz einer Langezeitbehandlung mit einer niedrigen Dosis des oralen Faktor-Xa-Inhibitors Rivaroxaban in der Post-ACS-Phase konnte in der Atlas-II-Studie die kardiovaskuläre Mortalität weiter reduzieren. Allerdings muss sich dieses Konzept in der Klinik in Verbindung mit P2Y12-Inhibitoren der dritten Generation bewähren. Diese Übersichtsarbeit diskutiert ausführlich die etablierten Antikoagulanzien für die Behandlung des akuten Koronarsyndroms sowie neue Ansätze, z. B. Rivaroxaban.
CAD is characterised by the nascence and progress of atherosclerotic plaques ultimately leading to the narrowing of the vessel lumen and at a high degree of stenosis to ischaemic symptoms, typically recognised as angina or chest pain. An acute coronary syndrome develops as a consequence
© Schattauer 2014
Hämostaseologie 1/2014 Downloaded from www.haemostaseologie-online.com on 2014-01-02 | IP: 88.130.206.144 Note: Uncorrected proof, prepublished online For personal or educational use only. No other uses without permission. All rights reserved.
I. Ahrens; C. Bode; A. Zirlik: Anticoagulation during and after ACS
tissue factor
factor VII
factor VIIa factor X
• UFH enoxaparin fondaparinux rivaroxaban
factor Xa prothrombin
UFH enoxaparin bivalirudin
thrombin
factor VIIa
factor VII
pegnivacogin factor Va
factor IXa
VWF
factor XIa factor IX
platelet activation
tenase complex
initiation phase
cells of the vessel wall
factor VIIa
factor Xa
factor IXa
factor Va
pegnivacogin factor X
prothrombinase complex
prothrombin
thrombin
UFH enoxaparin bivalirudin
amplification/propagation phase
2
fondaparinux rivaroxaban
Fig. 1 The cell based coagulation system and the target coagulation factors of anticoagulants that are used in patients with ACS; modified from Ahrens et al. (31).
of superficial erosions or the rupture of an atherosclerotic plaque resulting in local adhesion and aggregation of platelets and the activation of the coagulation cascade (2) (▶ Fig. 1). The latter may lead to intraluminal thrombosis and vessel occlusion causing the clinical correlate, acute myocardial infarction (AMI). Interestingly, approximately 30–40% of ACS arise from previously asymptomatic plaques without haemodynamically relevant stenosis.
Again, the degree of inflammation within the plaque positively correlates with the likelihood of rupture. Local and systemic activation of circulating blood cells relevant for the pathophysiology of atherosclerosis such as pla-
telets and monocytes in the setting of local disruption of the endothelial integrity by superficial erosion of the endothelial layer or rupture of the fibrous cap covering the necrotic core of a plaque causes a measurable increase in circulating tissue factor in patients with ACS (3–5). Tissue factor (TF) initiates the coagulation cascade via conversion of factor VII to factor VIIa (6) contributing to the procoagulant environment observed in patients with ACS (7, 8).
Therapy during ACS Antiplatelets and anticoagulants While antithrombotic therapy is the cornerstone of medical therapy in ACS, it has to be distinguished whether the target of the antithrombotic therapy is
•
the platelet (the cellular phase of the coagulation system) or coagulation factors (the liquid phase of the coagulation system).
Strong evidence identifies the combination of antiplatelet with anticoagulant therapy as the most efficient antithrombotic treatment strategy in patients with ACS, leading to a reduction of both, all-cause mortality and cardiovascular adverse events. The variety of clinically available antiplatelet and anticoagulant agents allows specific and almost individualized antithrombotic therapy in patients with ACS. However, it also warrants a high degree of clinical expertise in the use of these agents. Particularly, the risk of bleeding needs to be assessed in every case and weighed against the benefit in terms of reduction of ischaemic complications.
Bleeding scores such as the CRUSADE bleeding score are simple tools that facilitate bleeding assessment in the ACS population (▶www.crusadebleedingscore.org). This is of importance since bleeding events clearly correlate with clinical outcome and mortality and may therefore be just as deleterious as ischaemic events (9). Currently, guideline-conform established antiplatelet therapy in ACS consists of aspirin plus a third generation oral P2Y12 inhibitor (prasugrel or ticagrelor).
In case of contraindications for prasugrel or ticagrelor, or if the patient is at very high risk for bleeding events, clopidogrel may be used as an alternative (10). In addition to dual antiplatelet therapy, the use of GP IIb/ IIIa inhibitors may be considered especially if intracoronary thrombi are visible during coronary angiography. However, due to the clinical availability of potent anticoagulants that also affect platelet reactivity such as bivalirudin and fast acting novel platelet inhibitors with high inhibition of platelet activity (IPA) and absence of genetic variability in response, the use of GP IIb/IIIa inhibitors in ACS has declined considerably over the past decade. The anticoagulation on top of antiplatelet therapy in patients with ACS is the
Hämostaseologie 1/2014
© Schattauer 2014 Downloaded from www.haemostaseologie-online.com on 2014-01-02 | IP: 88.130.206.144 Note: Uncorrected proof, prepublished online For personal or educational use only. No other uses without permission. All rights reserved.
I. Ahrens; C. Bode; A. Zirlik: Anticoagulation during and after ACS
focus of this article and will be discussed in detail. During the initial phase of ACS parenteral anticoagulation is the treatment of choice. Unfractionated heparin (UFH), despite its well-known shortcomings, is still the most widely clinically used parenteral anticoagulant. Low molecular weight heparins (LMWH) such as enoxaparin or even the parenteral factor Xa inhibitor fondaparinux are clinically established alternatives for anticoagulation, especially in patients with ACS treated non-invasively. Furthermore, the direct factor IIa (thrombin) inhibitor bivalirudin is an established treatment in patients with ACS undergoing PCI (11–13).
Anticoagulation during ACS State of the Art The routine clinical use of parenteral anticoagulants in patients with acute coronary syndrome dates back several more decades than the introduction of the term acute coronary syndrome itself (14). To date, there is worldwide consensus that anticoagulation reduces cardiovascular adverse events in patients with ACS but we have not yet found the ideal anticoagulant that provides a broad therapeutic window without exposing the patient to an increased risk for bleeding (10, 15). There are currently four clinically approved parenteral anticoagulants for the use in patients with acute coronary syndromes: • UFH, • the LMWH enoxaparin, • fondaparinux, and • bivalirudin. Each of these agents has been investigated in patients with ACS undergoing percutaneous coronary intervention (PCI). Furthermore, UFH, enoxaparin and fondaparinux were also evaluated in large cohorts of patients receiving conservative treatment for ACS. While several large randomized clinical trials suggest superiority of enoxaparin, fondaparinux, or bivalirudin over UFH in patients with ACS, UFH is still widely employed as the anticoagulant of choice in the treatment of patients with ACS for its short half-life, the reversibility of it’s anticoagulant effects with protamine, and the ease in point-of-care control.
Unfractionated heparin (UFH) UFH targets various factors within the coagulation cascade including the major coagulation factors thrombin (IIa), factor Xa, and factor IXa (16). The indirect mode of action via the enhancement of the antithrombin and antifactor Xa activities of plasma antithrombin and the capability of UFH to bind to other plasma proteins (e. g. protein C inhibitor, platelet-factor-4) largely account for the inter- and intraindividual variations in anticoagulant response to intravenously administered UFH. The anticoagulant activity is routinely measured via the activated partial prothrombin time (aPTT). During PCI a rapid bedside test, the activated clotting time (ACT), allows the direct assessment of the anticoagulant activity of intravenously or intraarterially administered UFH. The current dosing recommendation for patients with ACS is 60 U/kg bodyweight administered as a bolus. The systematic measuring of the intraprocedural ACT in the pre-ticagrelor and pre-prasugrel era revealed that an ACT between 350 and 375 seconds provided the best protection from major cardiac adverse events (17). After the clinical introduction of the GPIIb/IIIa antagonists for patients with ACS undergoing PCI, it became evident that a lower ACT between 200 and 250 seconds provides the best net benefit balancing protection from major cardiac adverse events and the risk for major bleeding events associated with the antithrombotic treatment during PCI (18). Until today, UFH during PCI is usually dosed to reach an ACT of at least 200 seconds.
Enoxaparin The low molecular weight heparin enoxaparin has been assessed in a wide spectrum of patients with ACS. The net clinical benefit of enoxaparin as compared to UFH was greatest in patients with ST-elevation myocardial infarction (STEMI) when administered intravenously as a bolus of 0.5mg/kg bodyweight (19, 20). In ACS patients other than STEMI patients, a metaanalysis suggests that anticoagulation with enoxaparin given at a dose of 1 mg/kg bodyweight bid is at least as effective and
safe as UFH for the treatment of ACS (21). Based on the results of clinical trials comparing enoxaparin versus UFH in nonSTEMI patients with ACS it is recommended to administer enoxaparin subcutaneously at a dose of 1.0 mg/kg bodyweight bid (10). For STEMI patients it is currently not entirely clear whether enoxaparin should be preferred over UFH (22). However, if one decides to use enoxaparin as an anticoagulant for the treatment of STEMI patients, the preferred initial dosing regimen should be intravenous injection of 0.5mg/kg bodyweight (23).
Fondaparinux The indirect parenteral factor Xa inhibitor fondaparinux is a synthetic pentasaccharide that exerts its anticoagulant effect via activation of antithrombin. Fondaparinux has been assessed as an anticoagulant in patients with ACS in the OASIS 5&6 clinical trials in comparison to UFH or enoxaparin. If a patient with ACS was treated conservatively without PCI, fondaparinux appeared superior to UFH or enoxaparin in terms of clinical outcome (24). However, in case of an interventional treatment of patients with ACS (which is standard of care in many western countries), adjunctive treatment with UFH is required to prevent catheter-related thrombosis (25, 26). Based on the suspicion of insufficient anticoagulant activity in patients with ACS undergoing PCI, the use of fondaparinux as sole anticoagulant in ACS is limited to conservative treatment. Fondaparinux should be preferred over enoxaparin in conservative treatment of patients with ACS with a recommended dose of 2.5 mg administered subcutaneously (10).
Bivalirudin The direct parenteral factor IIa (thrombin) inhibitor bivalirudin is a peptide derived from its native molecule hirudin, which was originally isolated from leech (11). Bivalirudin has the shortest half-life (approx. 25 minutes) of the anticoagulants currently clinically approved for the treatment of ACS (11, 12). In the ACUITY trial in patients with ACS undergoing PCI, bivaliru-
© Schattauer 2014
Hämostaseologie 1/2014 Downloaded from www.haemostaseologie-online.com on 2014-01-02 | IP: 88.130.206.144 Note: Uncorrected proof, prepublished online For personal or educational use only. No other uses without permission. All rights reserved.
3
4
I. Ahrens; C. Bode; A. Zirlik: Anticoagulation during and after ACS
din alone compared to UFH + GPIIb/IIIa inhibitor was as effective in terms of prevention of cardiovascular adverse events while causing less bleeding events (27). In STEMI patients treated with PCI (HORIZONS-AMI trial), bivalirudin was superior compared to the standard regimen composed of UFH + GP IIb/IIIa inhibitor (28) and these results were consistent at the final 3-year analysis of the trial (29). In view of the shortcomings of fondaparinux in ACS patients undergoing PCI and the not yet defined role of enoxaparin in STEMI patients treated with PCI, bivalirudin emerges as the best option for anticoagulation during PCI of patients with ACS. However, the combination of UFH + GPIIb/IIIa inhibitor is still a viable choice (10, 22). In ACS patients undergoing PCI, the recommended dosing of bivalirudin is 0.75 mg/kg bodyweight as intravenous bolus followed by a continuous intravenous infusion during PCI (and up to 4 hours thereafter) of 1.75 mg/kg bodyweight/hour.
Therapy post ACS Long term anticoagulation In long-term treatment and secondary prophylaxis of cardiovascular events after ACS platelet inhibition initially as dual antiplatelet therapy (DAPT) followed by single antiplatelet therapy represent the current gold standard. However, very early data decades ago suggest that anticoagulants may also be effective in this scenario (30). Due to the risks associated with warfarin therapy, its unpredictable individual response, and small therapeutic bandwidth, anticoagulant therapy has not been established in long-term treatment following ACS.
Rivaroxaban Recently, novel oral anticoagulants (NOACs) emerged with dabigatran as factor IIa inhibitor and rivaroxaban and apixaban as factor Xa inhibitors (31). Since these substances overcome several key limitations of warfarin therapy the concept of long-term anticoagulation along with platelet inhibition has been challenged
again in clinical trials. The APPRAISE-2 trial evaluating apixaban two times 5 mg versus placebo on top of dual antiplatelet therapy with aspirin and clopidogrel in high risk ACS patients was prematurely stopped because of significantly increased major bleeding (32). In contrast, the ATLAS ACS 2 TMI 51 trial investigating rivaroxaban either at two times 2.5 mg or two times 5.0 mg versus placebo in the same collective showed very promising data: Rivaroxaban at the 2.5mg dose significantly reduced CV events and overall mortality. This coincided with an increase in major bleeding albeit no increase in fatal bleeding (33). However, these data will have to be validated in patients with ACS receiving the third generation P2Y12 inhibitors ticagrelor and prasugrel that are recommended in patients with ACS by current guidelines.
Future developments The addition of enoxaparin and fondaparinux to the arsenal of parenteral anticoagulants for the treatment ACS was a milestone after decades of restriction to UFH with its well-known shortcomings. However, both agents have a long half-life and although protamine may be used, there are no specific antagonists to reverse their anticoagulant effects. The clinical introduction of bivalirudin, which is actually not a very new substance but was rather rediscovered for anticoagulation in patients with ACS in the beginning of the new millennium (11), provided an anticoagulant agent with a relatively short half-life and therefore better controllability. An ideal anticoagulant drug for the treatment of patients with ACS has yet to be discovered. This drug would have to be efficient in providing steady anticoagulation in all patients with ACS regardless of weight, gender, renal function, and age. In addition there should be no increased risk of bleeding associated with its use. Some approaches of localised anticoagulation centered around single-chain mediated targeting of activated platelets were already successful in animal models (34, 35). However, these have not yet reached the clinical development phase but show a promising
profile in pre-clinical studies. There is currently only one parenteral anticoagulant in late stage clinical development for the treatment of patients with ACS: Pegnivacogin, a member of a new class of drugs, socalled RNA-based aptamers. Pegnivacogin inhibits coagulation factor IXa, which forms the tenase complex on the surface of activated platelets thereby facilitating the formation of the prothrombinase complex (▶ Fig. 1).
Pegnivacogin Pegnivacogin is a direct parenteral inhibitor of factor IXa and a first of its class molecule. It is a RNA aptamer consisting of 34 nucleotides that are conjugated to a 40 kDa polyethylenglycol (PEG) which accounts for its half-life of up to 100 hours (36). If the complimentary RNA nucleotide sequence (anivamersen) is administered, the anticoagulant effect of pegnivacogin is immediately reversed thereby providing ideal controllability of pegnivacogin-mediated anticoagulation. The REG1 anticoagulation system is composed of the two compounds pegnivacogin (the aptamerbased direct factor IXa inhibitor) and its control agent (anivamersen). REG1 has successfully been assessed in the phase IIb RADAR trial in patients with ACS undergoing PCI. In RADAR, patients with ACS undergoing PCI were randomised to anticoagulation with pegnivacogin and post procedural reversal with anivamersen (100, 75, 50, 25% reversal) or to UFH. The 25% reversal arm was closed after accumulation of bleeding events. The trial was stopped early after enrolment of 400 patients due to three allergic-like reactions that were possibly related to the study drug. The analysis of the trial data revealed that at least a 50% reversal dose was necessary to allow safe sheath removal after PCI in the REG1 treated patients, there was no significant difference in the secondary endpoint of ischaemic events between RGE1 and UFH treatment (37). Regado Biosciences, the developer of REG1, is currently planning a major phase III clinical trial (REGULATEPCI) assessing the efficacy of the REG1 system in patients undergoing PCI including patients with ACS (38).
Hämostaseologie 1/2014
© Schattauer 2014 Downloaded from www.haemostaseologie-online.com on 2014-01-02 | IP: 88.130.206.144 Note: Uncorrected proof, prepublished online For personal or educational use only. No other uses without permission. All rights reserved.
I. Ahrens; C. Bode; A. Zirlik: Anticoagulation during and after ACS
Tab. 1
Recommendations according to ESC guidelines modified from (10), (13) and (22)
anticoagulant unfractionated heparin
level of recommendation enoxaparin
level of recommendation fondaparinux level of recommendation bivalirudin
NSTE-ACS interventional
i. v. (target aPTT 50–70 s) if fondaparinux or enoxaparin are not available
i. v. 60 U/kg bolus (+ GPIIb/IIIa inhibitor if patient has a high risk of ischaemia)
i. v. (with or without GP IIb/IIIa inhibitor) must be used in patients not receiving bivalirudin or enoxaparin
IC
IC
IC
1 mg bid s.c. if fondaparinux is not available
30 mg bolus i.v. + 1mg bid s.c.
i. v. (with or without GP IIb/IIIa inhibitor) recommended over UFH + GPIIb/IIIa inhibitor
IB
IIa B
IIa B
2.5 mg od subcutaneously
NA
not recommended
IA
III B
NA
level of recommendation
Conclusion, recommendations & guidelines • It is currently perceived that the LMWH
• •
STEMI
conservative
enoxaparin, but especially the synthetic pentasaccharide fondaparinux are superior parenteral anticoagulants to UFH for patients with ACS that are conservatively managed by medical treatment. For patients with ACS undergoing PCI, UFH plus GPIIb/IIIa inhibitor or bivalirudin are the anticoagulants of choice. In patients with STEMI there is good evidence that bivalirudin is superior to UFH plus GPIIb/IIIa inhibitors mainly due to a lower rate of major bleeding events when bivalirudin is used as the anticoagulant.
The guidelines of the European Society of Cardiology for the treatment of patients with NSTE-ACS and STEMI have integrated these data (▶ Tab. 1). While the anticoagulant therapy in ACS has made great progress throughout the decades further developments and new drug approaches are still needed to find the best balance of greatest efficacy and least bleeding.
i. v. + provisional GPIIb/IIIa inhibitors particularly in patients with a higher bleeding risk
i. v. (+ GP IIb/IIIa inhibitor for bailout) preferred over UFH + GP IIb/IIIa inhibitor
IB
IB
Conflict of interest
I. A. received speaker’s honoraria from Bayer Healthcare, Lilly and Sanofi Aventis. C. B. received speaker’s honoraria from Bayer Healthcare, Merck, Astra-Zeneca, and Sanofi aventis. A. Z. received speaker’s honoraria from Bayer Healthcare, Astra-Zeneca.
References 1. Gerdes N, Zirlik A. Co-stimulatory molecules in and beyond co-stimulation – tipping the balance in atherosclerosis? Thromb Haemost 2011; 106: 804–813. 2. Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013; 368: 2004–2013. 3. Brambilla M, Camera M, Colnago D et al. Tissue factor in patients with acute coronary syndromes: expression in platelets, leukocytes, and plateletleukocyte aggregates. Arteriosc, Thromb Vasc Biol 2008; 28: 947–953. 4. Viles-Gonzalez JF, Badimon JJ. Atherothrombosis: the role of tissue factor. Int J Biochem Cell Biol 2004; 36: 25–30. 5. Cimmino G, Golino P, Badimon JJ. Pathophysiological role of blood-borne tissue factor: should the old paradigm be revisited? Int Emerg Med 2011; 6: 29–34. 6. Edgington TS, Ruf W, Rehemtulla A, Mackman N. The molecular biology of initiation of coagulation by tissue factor. Current studies in hematology and blood transfusion 1991; 58: 15–21.
7. Kopp CW, Gremmel T, Steiner S et al. Plateletmonocyte cross talk and tissue factor expression in stable angina vs. unstable angina/non ST-elevation myocardial infarction. Platelets 2011; 22: 530–536. 8. Morange PE, Blankenberg S, Alessi MC et al. Prognostic value of plasma tissue factor and tissue factor pathway inhibitor for cardiovascular death in patients with coronary artery disease: the AtheroGene study. J Thromb Haemost 2007; 5: 475–482. 9. Eikelboom JW, Mehta SR, Anand SS et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114: 774–782. 10. Hamm CW, Bassand JP, Agewall S et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2011; 32: 2999–3054. 11. Ahrens I, Smith BK, Bode C, Peter K. Direct thrombin inhibition with bivalirudin as an antithrombotic strategy in general and interventional cardiology. Expert opinion on drug metabolism & toxicology 2007; 3: 609–620. 12. Höchtl T, Farhan S, Wojta J, Huber K. New anticoagulant agents in acute coronary syndromes. Heart 2011; 97: 244–252. 13. Wijns W, Kolh P, Danchin N et al. Guidelines on myocardial revascularization. Eur Heart J 2010; 31: 2501–2555. 14. Chalmers TC, Matta RJ, Smith H Jr, Kunzler AM. Evidence favoring the use of anticoagulants in the hospital phase of acute myocardial infarction. N Engl J Med 1977; 297: 1091–1096. 15. Magee KD, Campbell SG, Moher D, Rowe BH. Heparin versus placebo for acute coronary syndromes. The Cochrane database of systematic reviews 2008: CD003462. 16. Gray E, Hogwood J, Mulloy B. The anticoagulant and antithrombotic mechanisms of heparin.
© Schattauer 2014
Hämostaseologie 1/2014 Downloaded from www.haemostaseologie-online.com on 2014-01-02 | IP: 88.130.206.144 Note: Uncorrected proof, prepublished online For personal or educational use only. No other uses without permission. All rights reserved.
5
6
I. Ahrens; C. Bode; A. Zirlik: Anticoagulation during and after ACS
17.
18.
19.
20.
21.
22.
23.
Handbook of experimental pharmacology 2012; 207: 43–61. Chew DP, Bhatt DL, Lincoff AM et al. Defining the optimal activated clotting time during percutaneous coronary intervention: aggregate results from 6 randomized, controlled trials. Circulation 2001; 103: 961–966. Tolleson TR, O’Shea JC, Bittl JA et al. Relationship between heparin anticoagulation and clinical outcomes in coronary stent intervention: observations from the ESPRIT trial. J Am Coll Cardiol 2003; 41: 386–393. Montalescot G, Zeymer U, Silvain J et al. Intravenous enoxaparin or unfractionated heparin in primary percutaneous coronary intervention for ST-elevation myocardial infarction: the international randomised open-label ATOLL trial. Lancet 2011; 378: 693–703. Navarese EP, De Luca G, Castriota F et al. Lowmolecular-weight heparins vs. unfractionated heparin in the setting of percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis. J Thromb Haemost 2011; 9: 1902–1915. Murphy SA, Gibson CM, Morrow DA et al. Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis. Eur Heart J 2007; 28: 2077–2086. Steg PG, James SK, Atar D et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33: 2569–2619. Silvain J, Beygui F, Barthelemy O et al. Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ 2012; 344: e553.
24. Mehta SR, Boden WE, Eikelboom JW et al. Antithrombotic therapy with fondaparinux in relation to interventional management strategy in patients with ST- and non-ST-segment elevation acute coronary syndromes: an individual patient-level combined analysis of the Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) randomized trials. Circulation 2008; 118: 2038–2046. 25. Montalescot G, Walenga JM. Catheter-related thrombosis: biological and clinical evidence for risk with currently available anticoagulants. Clin Appl Thromb Hemost 2009; 15: 183–196. 26. Steg PG, Jolly SS, Mehta SR et al. Low-dose vs standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux: the FUTURA/OASIS-8 randomized trial. JAMA 2010; 304: 1339–1349. 27. Stone GW, McLaurin BT, Cox DA et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355: 2203–2216. 28. Stone GW, Witzenbichler B, Guagliumi G et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218–2230. 29. Stone GW, Witzenbichler B, Guagliumi G et al. Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial. Lancet 2011; 377: 2193–2204. 30. Meijer A, Verheugt FW, Werter CJ et al. Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT Study. Circulation 1993; 87: 1524–1530.
31. Ahrens I, Lip GY, Peter K. New oral anticoagulant drugs in cardiovascular disease. Thromb Haemost 2010; 104: 49–60. 32. Alexander JH, Lopes RD, James S et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011; 365: 699–708. 33. Mega JL, Braunwald E, Wiviott SD et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366: 9–19. 34. Stoll P, Bassler N, Hagemeyer CE et al. Targeting ligand-induced binding sites on GPIIb/IIIa via single-chain antibody allows effective anticoagulation without bleeding time prolongation. Arterioscl Thromb Vascul Biol 2007; 27: 1206–1212. 35. Schwarz M, Meade G, Stoll P et al. Conformationspecific blockade of the integrin GPIIb/IIIa: a novel antiplatelet strategy that selectively targets activated platelets. Circulation Res 2006; 99: 25–33. 36. Ahrens I, Bode C. New parenteral anticoagulants: focus on factor Xa and thrombin inhibitors. Current drug discovery technologies 2012; 9: 129–136. 37. Povsic TJ, Vavalle JP, Aberle LH et al. A Phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial. Eur Heart J 2013; ::::::::::((VOLUME; SEITEN ODER DOI; AUTOR BITTE ERGÄNZEN)). 38. Regado, Biosciences, press, release. New Investor Leads Round to Fund Phase 3 Development of REG1. wwwregadobiocom/indexphp/2012/12/regado-biosciences-inc-secures-51-million-seriese-financing/. 2012 December 17.
Hämostaseologie 1/2014
© Schattauer 2014 Downloaded from www.haemostaseologie-online.com on 2014-01-02 | IP: 88.130.206.144 Note: Uncorrected proof, prepublished online For personal or educational use only. No other uses without permission. All rights reserved.
