The Role of Genetics in Acute Coronary Syndrome
Antiplatelet agents are a class of drugs that inhibit the platelets from clumping together and forming blood clots. Many heart attack and stroke patients — and people seeking to avoid these events — are treated with two types of antiplatelet agents to prevent blood clotting. This is called dual antiplatelet therapy (DAPT). As the role and utilization of dual antiplatelet therapy (DAPT) increases, the rate of gastrointestinal (GI) bleeding events are also expected to rise. 1 Gastrointestinal bleeds in patients with coronary artery disease (CAD) are associated with poor prognosis. The need to reduce and prevent these bleeding events is potentially mitigated by the use of proton pump inhibitors (PPIs).
J. Chandrasekhar, R. Mehran, in Cardiovascular Diseases, 2016
Abstract
Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist is standard of care in acute coronary syndrome and is recommended for a period of 12 months regardless of invasive revascularization. The antiplatelet action of these agents is governed by levels of active plasma metabolites, which may be influenced by genetic variations. Recently genotyping has gained considerable attention to identify patients who may demonstrate poor platelet responsiveness, as a potential method to improve long-term outcomes. However whether or not systematic genotyping will prove to be advantageous and cost-effective is the subject of on-going studies. This chapter discusses the current data on the impact of genetic variations with antiplatelet therapy, as well as the potential role of genotyping in prescription of antiplatelet therapies in acute coronary syndrome.
Thrombus formation is a crucial event in acute coronary syndromes,1 bypass occlusion,2 and stent thrombosis.3 In the coronary circulation, platelet activation is an initial event,4 while expression of tissue factor and subsequent activation of the coagulation cascade5 and invading white blood cells6 solidify the evolving clot, an event that often leads to vascular occlusion. Platelets are primarily activated by thromboxane and ADP via thromboxane and P2Y12 receptors on the platelet surface that eventually lead to the expression of the glycoprotein IIB/IIIA receptor that binds fibrin. Twenty-one years ago, the first randomized clinical trial established the superiority of dual antiplatelet therapy over anticoagulant therapy among patients undergoing percutaneous coronary intervention.7 Thus, dual antiplatelet therapy has become a crucial therapeutic intervention in patients with stable or acute coronary artery disease.
However, the duration of dual antiplatelet therapy and its combination with anticoagulants in certain patients remain clinical challenges. Thus, the updated ‘2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS)’, authored by Marco Valgimigli and colleagues from the European Society of Cardiology, is a timely document.8 The authors remind us that based on population estimates, ∼1.4 and 2 .2 million patients per year may have an indication for dual antiplatelet therapy after coronary intervention or a myocardial infarction, respectively. Based on >35 randomized clinical trials, including >225 000 patients, dual antiplatelet therapy is among the most intensively investigated treatments in cardiovascular medicine. Its progressive refinement involved firstly safer drugs, i.e. the move from ticlopidine to clopidogrel, and then more potent and predictable compounds such as ticagrelor or prasugrel. The need to investigate longer dual antiplatelet therapy regimens arose from concerns over late and very late stent thrombosis occurring after first-generation drug-eluting stent implantation as well as late events after an acute coronary syndrome. Yet, the advent of safer newer generation drug-eluting stents and most recent randomized trials have caused major paradigm shifts. Indeed, late and very late stent thrombosis have declined considerably with newer generation drug-eluting stents.9–11 Hence, the risk of bleeding associated with dual antiplatelet therapy prolongation beyond 1 year does not seem to be justified by the small absolute gain in preventing stent thrombosis. Yet, dual antiplatelet therapy seems to reduce the long-term risk of non-stent-related infarction and stroke.12,13 Hence, after 21 years of research, dual antiplatelet therapy has moved from a local, i.e. stent-related, to a systemic treatment strategy, i.e. capable of preventing thrombotic arterial occlusions, conveying global patient protection.
The Guidelines are complemented by ‘Case-based implementation of the 2017 ESC Focused Update on Dual Antiplatelet Therapy in Coronary Artery Disease: The Task Force for the Management of Dual Antiplatelet Therapy in Coronary Artery Disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS)’, where various cases are discussed.14
In a research article entitled ‘Clopidogrel reloading for patients with acute myocardial infarction already on clopidogrel therapy’, Jacob Doll and colleagues from the VA Puget Sound Health Care System in Seattle, Washington, USA sought to determine the association of clopidogrel reloading with in-hospital bleeding and mortality in contemporary practice (Figure 1).15 Among the 12 366 patients on pre-admission clopidogrel therapy who were admitted with ST-segment elevation myocardial infarction, 76% received a loading dose. Of 39 158 patients with non-ST-segment elevation myocardial infarction, 26% were reloaded. Reloaded patients were younger, had fewer co-morbid conditions, and were more likely to be treated with percutaneous coronary intervention. Risks of major bleeding were not significantly different between patients with and without reloading. In ST-segment elevation myocardial infarction, clopidogrel reloading was associated with a 20% lower risk of in-hospital mortality, while no mortality difference was observed in non-ST-segment elevation myocardial infarction. Thus, clopidogrel reloading is frequently practised in patients with myocardial infarction who are on pre-admission clopidogrel therapy, particularly among those with ST-segment elevation myocardial infarction. Reloading appears to be safe and may reduce in-hospital mortality in ST-segment elevation myocardial infarction.
Trends in home P2Y12 inhibitor use among patients presenting with MI. Overall rates of P2Y12 inhibitor use prior to admission changed minimally over the study period for patients presenting with STEMI and NSTEMI. A modest decline in clopidogrel use was accompanied by a corresponding increase in the use of prasugrel and ticagrelor when these agents became clinically available. NSTEMI, non-ST segment elevation myocardial infarction; STEMI, ST segment myocardial infarction (from Doll JA, Li S, Chiswell K, Roe MT, Kosiborod M, Scirica BM, Wang TY. Clopidogrel reloading for patients with acute myocardial infarction already on clopidogrel therapy. See pages 193--200).
Trends in home P2Y12 inhibitor use among patients presenting with MI. Overall rates of P2Y12 inhibitor use prior to admission changed minimally over the study period for patients presenting with STEMI and NSTEMI. A modest decline in clopidogrel use was accompanied by a corresponding increase in the use of prasugrel and ticagrelor when these agents became clinically available. NSTEMI, non-ST segment elevation myocardial infarction; STEMI, ST segment myocardial infarction (from Doll JA, Li S, Chiswell K, Roe MT, Kosiborod M, Scirica BM, Wang TY. Clopidogrel reloading for patients with acute myocardial infarction already on clopidogrel therapy. See pages 193--200).
There are limited data on optimal anti-thrombotic therapy for preventing embolism while minimizing bleeding in patients with first acute myocardial infarction complicated by a left ventricular thrombus. In their paper entitled ‘Appropriate anticoagulation combined with antiplatelet therapy was safe and effective in patients with left ventricular thrombus after first acute myocardial infarction’, Masashi Fujino and colleagues from the National Cerebral and Cardiovascular Center in Suita, Osaka in Japan further examined this issue.16 They studied 1850 patients with first acute myocardial infarction who were discharged alive. Left ventricular thrombus was diagnosed by echocardiography, left ventriculography, or cardiac magnetic resonance imaging in 5% of the patients. During a median follow-up period of 5.4 years, systemic embolism occurred in 3.6% of the 1850 patients or in 16.3% of those with left ventricular thrombus, but in only 2.9% of those without left ventricular thrombus (Figure 2). Multivariate analysis showed that left ventricular thrombus was an independent predictor of systemic embolism. Among the 84 patients with left ventricular thrombus treated with vitamin K antagonists, they compared those with a time within the therapeutic range ≥50% and those with <50%. Only one embolic event developed in those within the therapeutic range ≥50%, but nine embolic events occurred in those with <50%. There was no difference in major bleeding events. Thus, appropriate anticoagulation therapy may decrease the incidence of embolic events without increasing the incidence of bleeding events in patients with first acute myocardial infarction complicated by left ventricular thrombus. These clinically relevant preliminary findings in these underinvestigated patients are further discussed in an Editorial by Robert F. Storey from the University of Sheffield in the UK.17
Kaplan-Meier analysis revealed that there was a significant difference in the incidence of systemic embolism between patients with time in therapeutic range ≥50% and those with <50% in acute myocardial infarction patients complicated with left ventricular thrombus. However, there was no significant difference in the rate of major bleeding events defined as moderate, severe or life-threatening bleeding based on GUSTO bleeding criteria between the groups (from Maniwa N, Fujino M, Nakai M, Nishimura K, Miyamoto Y, Kataoka Y, Asaumi Y, Tahara Y, Nakanishi M, Anzai T, Kusano K, Akasaka T, Goto Y, Noguchi T, Yasuda S. Anticoagulation combined with antiplatelet therapy in patients with left ventricular thrombus after first acute myocardial infarction. See pages 201--208).
Kaplan-Meier analysis revealed that there was a significant difference in the incidence of systemic embolism between patients with time in therapeutic range ≥50% and those with <50% in acute myocardial infarction patients complicated with left ventricular thrombus. However, there was no significant difference in the rate of major bleeding events defined as moderate, severe or life-threatening bleeding based on GUSTO bleeding criteria between the groups (from Maniwa N, Fujino M, Nakai M, Nishimura K, Miyamoto Y, Kataoka Y, Asaumi Y, Tahara Y, Nakanishi M, Anzai T, Kusano K, Akasaka T, Goto Y, Noguchi T, Yasuda S. Anticoagulation combined with antiplatelet therapy in patients with left ventricular thrombus after first acute myocardial infarction. See pages 201--208).
The editors hope that this issue of the European Heart Journal will be of interest to its readers.
References
H
, J
, J
, L
, L
, H
, M
, Y
, S
, E
, H
, S
, B
, IK.
Effective anti-thrombotic therapy without stenting: intravascular optical coherence tomography-based management in plaque erosion (the EROSION study)
. 2017
;:792
–.Z
, TF.
Basic cellular mechanisms of coronary bypass graft disease
. 1993
; Suppl I:193
–.TF
, J
, FR
, M
, G
, FC
, R.
Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications
. 2007
;:1051
–.CY
, YN
, T
, A
, T
, BP
, M
, Y
, JA
, A
, Z
, JR.
Molecular imaging of platelet–endothelial interactions and endothelial von Willebrand factor in early and mid-stage atherosclerosis
. 2015
;:e002765
.J
, TF
, FC.
Tissue factor in cardiovascular diseases: molecular mechanisms and clinical implications
. 2006
;:722
–.G
, N
, L
, X
, N
, G
, G
, P
, C
, G
, G
, E
, R
, O
, T
, A
, S
, L
, C
, P.
Mechanisms of stent thrombosis analysed by optical coherence tomography: insights from the national PESTO French registry
. 2016
;:1208
–.A
, FJ
, A
, H
, R
, M
, H
, EM
, G
, E
, C
, K.
A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents
. 1996
;:1084
–.M
, H
, RA
, JP
, F
, A
, P
, A
, P
, L
, G
, FJ
, M
, M
, PG
, S
, JL
, GN.
2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS)
. 2018
;:213
–.RA
, M
, A.
Stent thrombosis and restenosis: what have we learned and where are we going? The Andreas Gruntzig Lecture ESC 2014
. 2015
;:3320
–.F
, M
, G
, M
, S
, C
, A
, G
, S
, U
, G
, C
, F
, M
, R
, G
, S
, P
, F
, C
, A
, SJ
, A
, D
, M
, F.
Impact of design of coronary stents and length of dual antiplatelet therapies on ischaemic and bleeding events: a network meta-analysis of 64 randomized controlled trials and 102 735 patients
. 2017
;:3160
–.K
, L
, T
, E
, C
, T
, S
, A
, M
, C
, F
, P
, TF
, D
, S.
Ten-year clinical outcomes of first-generation drug-eluting stents: the Sirolimus-Eluting vs. Paclitaxel-Eluting Stents for Coronary Revascularization (SIRTAX) VERY LATE trial
![Dual antiplatelet therapy for tia Dual antiplatelet therapy for tia](/uploads/1/2/5/0/125050830/523476772.png)
2016
;:3386
–.RK
, TF.
Duration of dual antiplatelet therapy after coronary artery stenting: where is the sweet spot between ischaemia and bleeding?
2015
;:1207
–.T
, D
, U
, L
, F
, A
, M
, MC
, M
, MK
, BK
, Y
, HS
, KW
, A
, A
, D
, G
, P
, GD
, M
, J
, DL
, GW.
Three, six, or twelve months of dual antiplatelet therapy after DES implantation in patients with or without acute coronary syndromes: an individual patient data pairwise and network meta-analysis of six randomized trials and 11 473 patients
. 2017
;:1034
–.JP
, M
, RA
, F
, M.
Case-based implementation of the 2017 ESC Focused Update on Dual Antiplatelet Therapy in Coronary Artery Disease: The Task Force for the Management of Dual Antiplatelet Therapy in Coronary Artery Disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS)
. 2018
;:e1
–.JA
, S
, K
, MT
, M
, BM
, TY.
Clopidogrel reloading for patients with acute myocardial infarction already on clopidogrel therapy
. 2018
;:193
–.N
, M
, M
, K
, Y
, Y
, Y
, Y
, M
, T
, K
, T
, Y
, T
, S.
Anticoagulation combined with antiplatelet therapy in patients with left ventricular thrombus after first acute myocardial infarction
. 2018
;:201
–.W
, RF.
The challenges of antithrombotic therapy in patients with left ventricular thrombosis
. 2018
;:209
–.With thanks to Amelia Meier-Batschelet for help with compilation of this article.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions please email: [email protected].
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