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ACVC Clinical Decision-Making Toolkit

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Antiplatelets therapy

Antiplatelet therapy in ischemic heart disease



Platelets play an essential role in the pathogenesis of atherothrombotic events, justifying the use of antiplatelet agents in their prevention [1]. The use of antiplatelet agents, especially in secondary prevention of recurrent cardiovascular events is supported by several studies that evaluated their efficacy and safety [2-6]. In primary prevention, the potential benefit of the preventive use of Acetylsalicylic acid (ASA) should be carefully assessed and individualized [7-9]. Advances in understanding the mechanisms by which platelets participate in atherothrombotic processes have led to the search for the development of new drugs capable of consistently inhibiting platelet activity with maximum safety (figure 1).

 

Figure1. Site of action of various antiplatelet drugs.

Different platelet receptors are activated by various agonists and serve as the target of various antiplatelets, which have been evaluated in large randomized clinical trials. AA: arachidonic acid; ADP, adenosine diphosphate; CYP, cytochrome P450; GP indicates glycoprotein; TP, thromboxane receptor; and TxA2, thromboxane A2

Acetylsalicylic acid (ASA)

The beneficial effects of ASA appear to occur at a dose of a minimum of 75 mg daily, with no additional benefit provided using higher doses. Bleeding events are increased by aspirin and seem to be higher at doses of >100 mg. Bleeding events with ASA are more commonly of gastric origin, and occur at a frequency of ≈2% per year. Biochemical ASA resistance is rare in patients who are actually taking and absorbing the agent, and routine testing is not indicated [10]. In patients reacting allergic to ASA (usually with an exanthema), a sensitisation strategy might help to get rid of symptoms within a few days [11].

P2Y12-inhibitors

Given the synergistic importance of the adenosine diphosphate (ADP)-P2Y12 and the human thromboxane (TxA2-TP) pathways in amplifying platelet activation, dual antiplatelet therapy with a P2Y12 inhibitor in combination with aspirin is the most widely used strategy in high-risk patients. The currently available oral P2Y12 receptor blockers are the peroral thienopyridines (clopidogrel, and prasugrel) and ticagrelor.

Thienopyridines are orally administered prodrugs that require metabolic activation by the cytochrome P450 pathway. The active thiolactone metabolite of thienopyridines irreversibly prevents the ADP-induced receptor-mediated signalling and platelet aggregation ‘for the life of platelets” by binding to the ADP receptor P2Y12. Ticagrelor does not prevent ADP binding to P2Y12, but instead reversibly inhibits the ADP-induced receptor conformational change and G-protein activation by binding to a site distinct from the ADP-binding site. Ticagrelor is associated with a more rapid onset of action, a greater level of inhibition and a more rapid offset of pharmacodynamic action compared with clopidogrel.

Vorapaxar

Vorapaxar, a synthetic tricyclic 3-phenylpyridine derived from the natural product himbacine, is a first in class, selective, reversibly binding, orally administered, high-affinity protease-activated receptor-1 antagonist that selectively inhibits thrombin-induced platelet aggregation Its antiplatelet effect is virtually irreversible due to a very slow dissociation constant [12].

 

  Indication Dose Dose Adjustment Comments
acetylsalicylic acid Primary and secondary atherothrombotic prevention LD (if ACS): 150-300 mg oralMD: 75-100 mg once daily   Major contraindications: Gastrointestinal bleeding – active peptic ulcer
clopidogrel ACS + PCI or medical management only (patients who cannot receive ticagrelor or prasugrel) and in ACS patients at high bleeding risk (e.g. patients who require oral anticoagulation) LD: 300-600mg oralMD: 75mg oral once daily     
STEMI + fibrinolysis <75 years of age LD: 300-600 mg oral
MD: 75mg oral once daily
Prasugrel or ticagrelor have not been studied as adjuncts to fibrinolysis    
STEMI + fibrinolysis ≥75 years of age LD: 75 mg oral
MD: 75 mg oral once daily 
     
Secondary prevention > 12 months post coronary stenting  MD: 75 mg oral once daily      
prasugrel ACS with planned PCI  LD: 60 mg oral
MD: 10 mg oral once daily
MD: 5 mg once daily
If weight <60 kg
Major contraindications:
Previous stroke and TIA.
Prasugrel is generally not recommended in elderly, and if positive risk/benefit 5mg is recommended
ticagrelor   ACS (all patients at moderate-to-high risk of ischaemic events) LD: 180 mg oral
MD: 90 mg oral BID
  Major contraindications:
Previous intracerebral haemorrhage
Secondary prevention 1-3 years post Myocardial infarction   MD: 60 mg oral twice daily      
vorapaxar Co-administered with aspirin and, where appropriate, clopidogrel, in patients with a history of myocardial infarction or peripheral artery disease 2.08 mg oral once daily   Initiated at least two weeks after a myocardial infarction and ideally within the first 12 months.
Major contraindications: Active pathologic bleeding, increased bleeding risk, history of stroke/TIA, severe hepatic dysfunction.

LD denotes loading dose; ACS, acute coronary syndromes; MD: maintenance dose; PCI, percutaneous coronary prevention; STEMI, ST-segment elevation myocardial infarction; TIA, transient ischaemic attack.

Adapted from the ACVC Clinical Decision-Making Toolkit chapter 8.

Bleeding avoidance strategy

Gastrointestinal haemorrhage is the most common serious bleeding complication that results from a long-term antiplatelet therapy. The use of a proton pump inhibitor (PPI) is recommended in combination with dual antiplatelet therapy [13-16].

Switching between antiplatelet drugs

When a switch between P2Y12 inhibitors is needed for clinical reasons (i.e. side effects or drug intolerance), switching algorithms based on pharmacodynamics studies should be considered.

Oral anti-platelet therapy, coronary stents and non-cardiac surgery

Management of patients on DAPT who have undergone recent coronary stent treatment and who are referred for surgical procedures involves consideration of: (1) the risk of stent thrombosis (particularly if DAPT needs to be interrupted); (2) the consequences of delaying the surgical procedure; and (3) the increased intra- and peri-procedural bleeding risk and possible consequences of such bleeding if DAPT is continued [17]. Administration of DAPT is recommended for at least 1 month on all patients regardless of the type of implanted stent (i.e. bare-metal stent or newer generation DES), in cases where surgery cannot be delayed for a longer period; however, such surgical procedures should be performed in hospitals where catheterization laboratories are available 24/7, so as to treat patients immediately in case of perioperative thrombotic events.

Single anti-platelet therapy (preferably with aspirin) should be continued independently of the timeframe between stent implantation and surgery. Figure 2 shows two possible bridging protocols that can be used with patients on aspirin plus a P2Y12 receptor inhibitor for (non-cardiac surgery)(adapted from Capodanno et al) [18]. The use of low-molecular-weight heparin for bridging in these patients should be avoided. Dual anti-platelet therapy should be resumed as soon as possible after surgery and, if possible, within 48 hours.

 

Figure 2. For patients requiring surgery within a few days,  the recommendation is to withold clopidogrel and ticagrelor for five days and prasugrel for seven days prior to surgery. For patients with a very high risk of stent thrombosis, bridging therapy with intravenous, reversible glycoprotein inhibitors (e.g. eptifibatide or tirofiban) or cangrelor should be considered.

antiplatelets-figure2A.PNG

 

antiplatelets-figure2B.PNG

Capodanno D, Angiolillo DJ. Management of antiplatelet therapy in patients with coronary artery disease requiring cardiac and noncardiac surgery. Circulation 2013;128(25):2785-98

Antiplatelet agents and nonsteroidal anti-inflammatory drugs

Healthcare professionals should be aware of an interaction between low-dose aspirin and ibuprofen, which might render aspirin less effective when used for its anti-platelet cardioprotective effect [19].

References


[1]. Steg PG, Dorman SH, Amarenco P. Atherothrombosis and the role of antiplatelet therapy. J Thromb Haemost 2011;9 Suppl 1:325-32.

[2]. Faxon DP, Nesto RW. Antiplatelet therapy in populations at high risk of atherothrombosis. J Natl Med Assoc 2006;98(5):711-21.

[3]. Berger PB, Bhatt DL, Fuster V, Steg PG, Fox KA, Shao M, Brennan DM, Hacke W, Montalescot G, Steinhubl SR, Topol EJ. Bleeding complications with dual antiplatelet therapy among patients with stable vascular disease or risk factors for vascular disease: results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Circulation 2010;121(23):2575-83.

[4]. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361(11):1045-57.

[5]. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357(20):2001-15.

[6]. Tricoci P, Huang Z, Held C, Moliterno DJ, Armstrong PW, Van de Werf F, White HD, Aylward PE, Wallentin L, Chen E, Lokhnygina Y, Pei J, Leonardi S, Rorick TL, Kilian AM, Jennings LH, Ambrosio G, Bode C, Cequier A, Cornel JH, Diaz R, Erkan A, Huber K, Hudson MP, Jiang L, Jukema JW, Lewis BS, Lincoff AM, Montalescot G, Nicolau JC, Ogawa H, Pfisterer M, Prieto JC, Ruzyllo W, Sinnaeve PR, Storey RF, Valgimigli M, Whellan DJ, Widimsky P, Strony J, Harrington RA, Mahaffey KW. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 2012;366(1):20-33.

[7]. Dai Y, Ge J. Clinical use of aspirin in treatment and prevention of cardiovascular disease. Thrombosis 2012;2012:245037.

[8]. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373(9678):1849-60.

[9]. Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 2006;295(3):306-13.

[10]. Kolandaivelu K, Bhatt DL. Overcoming 'resistance' to antiplatelet therapy: targeting the issue of nonadherence. Nat Rev Cardiol 2010;7(8):461-7.

[11]. Tantry US, Gurbel PA. Rapid Desensitization of the Patients with Aspirin Hypersensitivity and Coronary Artery Disease. Circ Cardiovasc Interv 2017;10(2).

[12]. Chackalamannil S. Thrombin receptor (protease activated receptor-1) antagonists as potent antithrombotic agents with strong antiplatelet effects. J Med Chem 2006;49(18):5389-403.

[13]. Agewall S, Cattaneo M, Collet JP, Andreotti F, Lip GY, Verheugt FW, Huber K, Grove EL, Morais J, Husted S, Wassmann S, Rosano G, Atar D, Pathak A, Kjeldsen K, Storey RF. Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy. Eur Heart J 2013;34(23):1708-13, 1713a-1713b.

[14]. Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, Shook TL, Lapuerta P, Goldsmith MA, Laine L, Scirica BM, Murphy SA, Cannon CP. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010;363(20):1909-17.

[15]. Gargiulo G, Costa F, Ariotti S, Biscaglia S, Campo G, Esposito G, Leonardi S, Vranckx P, Windecker S, Valgimigli M. Impact of proton pump inhibitors on clinical outcomes in patients treated with a 6- or 24-month dual-antiplatelet therapy duration: Insights from the PROlonging Dual-antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY trial. Am Heart J 2016;174:95-102.

[16]. Fortuna LA, Pawloski PA, Parker ED, Trower NK, Kottke TE. Proton pump inhibitor use by aspirin-treated coronary artery disease patients is not associated with increased risk of cardiovascular events. Eur Heart J Cardiovasc Pharmacother 2016;2(1):13-9.

[17]. Kristensen SD, Knuuti J, Saraste A, Anker S, Botker HE, Hert SD, Ford I, Gonzalez-Juanatey JR, Gorenek B, Heyndrickx GR, Hoeft A, Huber K, Iung B, Kjeldsen KP, Longrois D, Luscher TF, Pierard L, Pocock S, Price S, Roffi M, Sirnes PA, Sousa-Uva M, Voudris V, Funck-Brentano C. 2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management: The Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). Eur Heart J 2014;35(35):2383-431.

[18]. Capodanno D, Angiolillo DJ. Management of antiplatelet therapy in patients with coronary artery disease requiring cardiac and noncardiac surgery. Circulation 2013;128(25):2785-98.

[19]. Marcus AJ, Broekman MJ, Pinsky DJ. COX inhibitors and thromboregulation. N Engl J Med 2002;347(13):1025-6.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

The ESC Prevention of Cardiovascular Disease programme is supported by AMGEN, AstraZeneca, Ferrer, and Sanofi and Regeneron in the form of educational grants.

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