Antiplatelet and Antithrombotic Therapy in Diabetic Patients with Acute Coronary Syndrome

Patients with diabetes mellitus (DM) and acute coronary syndrome (ACS) are at particularly high risk for recurrent cardiovascular events and death. The reason for this increased risk is multifactorial, including a higher risk profile, higher platelet reactivity, and underuse of evidence-based medications in these patients. This chapter includes a summary and review of antiplatelet and antithrombotic therapies that are approved in the United States and in Europe for clinical use in patients with ACS.

Platelet Aggregation

Patients with diabetes, particularly those with type 2 diabetes (T2DM), exhibit increased platelet reactivity and a reduced inhibition in response to platelet inhibitors. There is also evidence that platelet activation is directly affected by hyperglycemia and insulin resistance. Platelets are affected by insulin because of the presence of insulin receptor subtypes on the platelet surface. Activation of these receptors leads to suppression of cyclic adenosine monophosphate (cAMP), resulting in inhibition of P2Y12 receptors and decreased calcium influx, thus inhibiting platelet activity. In case of insulin resistance, platelets display increased calcium influx and thereby activation of the P2Y12 receptor. High platelet reactivity (HPR) is well documented in patients with diabetes and may contribute to the high incidence of cardiovascular disease and poor outcomes in this population. Thromboxane A ₂ (TXA ₂ ), the most potent vasoconstrictor that is secreted from platelets after activation, is circulating in higher amounts in patients with T2DM. Another abnormality of platelets in patients with T2DM is an increased platelet expression of P-selectin and of the glycoprotein IIb/IIIa receptor (GP IIb/IIIa) ( Fig. 21-1 ).

Platelet adhesion, activation, and aggregation play a pivotal role in atherothrombosis in patients with and without DM. Intracoronary atherothrombosis is the most common cause of the development of ACS and plays a central role in complications occurring around percutaneous coronary intervention (PCI), including recurrent ACS, procedure-related myocardial infarction (MI), and stent thrombosis. Inhibition of platelet aggregation by medical treatment impairs formation and progression of thrombotic processes and is therefore of great importance in the prevention of complications after ACS or associated with PCI ( Fig. 21-2 ). ^,

Figure 21-2, Targets for antithrombotic treatment.

Platelet Inhibition

Antiplatelet agents include cyclooxygenase (COX) inhibitors such as aspirin, which block the production of TXA ₂ ; GP IIb/IIIa receptor blockers such as abciximab, eptifibatide, and tirofiban, which inhibit fibrin-mediated platelet activation; and thienopyridines such as clopidogrel, prasugrel, cangrelor, ticagrelor, and ticlopidine, which bind to and antagonize P2Y12 receptors. Optimizing dual antiplatelet therapy (DAT) with combinations of agents from these classes may improve cardiovascular disease outcomes in patients with diabetes and ACS events ( Tables 21-1 and 21-2 ).

Table 21-1

Approved Agents for Acute Coronary Syndromes

Agent	Antithrombotic Action	Mechanism of Action	Type or Family	Mode of Administration
Aspirin	Antiplatelet	Cyclooxygenase inhibitor		Oral
Clopidogrel	Antiplatelet	P2Y12 receptor inhibitor	Thienopyridine	Oral
Prasugrel	Antiplatelet	P2Y12 receptor inhibitor	Thienopyridine	Oral
Ticagrelor	Antiplatelet	P2Y12 receptor inhibitor	Cyclopentyl-triazolo-pyrimidine	Oral
Abciximab	Antiplatelet	GP IIb/IIIa inhibitor	Monoclonal antibody	Intravenous
Tirofiban	Antiplatelet	GP IIb/IIIa inhibitor	Peptide	Intravenous
Eptifibatide	Antiplatelet	GP IIb/IIIa inhibitor	Nonpeptide	Intravenous
Unfractionated heparin	Anticoagulant	Antithrombin (IIa) potentiator		Intravenous or subcutaneous
Enoxaparin	Anticoagulant	Xa/IIa (antithrombin) inhibitor		Intravenous or subcutaneous
Fondaparinux	Anticoagulant	Xa inhibitor		Intravenous or subcutaneous
Bivalirudin	Anticoagulant	Thrombin inhibitor		Intravenous
Warfarin	Anticoagulant	Vitamin K antagonist		Oral

Table 21-2

Common Oral Antiplatelet Agents and Doses in Patients with Acute Coronary Syndrome (ACS)

Antiplatelet Agent	Loading Dose	When to Give	Regular Dose	Special Situations
Aspirin	300 mg oral; 80-150 mg IV	Before or at cath	75-100 mg daily oral
Clopidogrel	600 mg oral	Before or at cath	75 mg daily oral
Prasugrel	60 mg	After cath for NSTE-ACS Before or at cath for STE-ACS	10 mg daily oral	Only age older than 75, weight < 60 kg (consider 5 mg daily regular dose); contraindicated if history of stroke or TIA
Ticagrelor	180 mg	Before or at cath	90 mg bid oral

cath = Catheterization; NSTE-ACS = non–ST-elevation acute coronary syndrome; STE-ACS = ST-elevation acute coronary syndrome; TIA = transient ischemic attack.

Aspirin

The mechanism of action of aspirin occurs through permanent inactivation of the COX activity of prostaglandin H synthase 1 (PGH ₁ ) and PGH ₂ (also referred to as COX-1 and COX-2) ( Fig. 21-3 ). These isoenzymes catalyze the conversion of arachidonic acid to PGH ₂ . PGH ₂ is in turn a substrate for several tissue-specific isomerases that generate several bioactive prostanoids, including TXA ₂ and prostacyclin (prostaglandin I ₂ [PGI ₂ ]). Low levels of aspirin predominately inhibit COX-1, whereas higher levels are needed to also inhibit COX-2. TXA ₂ is mainly derived from COX-1, and PGE ₁ mainly from COX-2 (see Fig. 21-3 ).

Aspirin has been considered the mainstay of treatment of all patients with ACS and is recommended with a high level of evidence in current international guidelines. ^,

In the setting of ACS, long-term low-dose aspirin treatment (75 to 100 mg/day) is recommended, with support from a meta-analysis. Although a recent small study suggested that more frequent administration would be beneficial in patients with DM, the large Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events—Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7) trial including almost 6000 patients with DM was not able to show that a high dose of aspirin was superior to a low dose. More recent trials have also shown that modifications of clinical care based on the use of platelet function testing for aspirin responsiveness do not improve outcome. The optimal dose of aspirin when used in combination with other platelet inhibitors in the setting of acute and long-term treatment of patients with ACS, with stable coronary artery disease, or after PCI with or without DM has not yet been clearly defined from large randomized controlled trials. Based on published data and tablet availability, the recommended dose should be 75 to 100 mg in patients with or without DM.

ADP Receptor Blockers

An essential part in the platelet activation process is the interaction of adenosine diphosphate (ADP) with the platelet P2Y12 receptor (see also Chapter 16 ). The P2Y12 receptor is the predominant receptor involved in the ADP-stimulated activation of the GP IIb/IIIa receptor. Activation of the GP IIb/IIIa receptor results in enhanced platelet degranulation and thromboxane production and prolonged platelet aggregation. Thienopyridines and non-thienopyridine ADP receptor blockers inhibit the platelet activation and aggregation by antagonizing the thrombocyte P2Y12 receptor. This prevents the binding of ADP to the receptor, which attenuates platelet aggregation and reaction of thrombocytes to stimuli of thrombus aggregation such as thrombin ( Table 21-3 ).

Table 21-3

Major P2Y12 Receptor Inhibitor Trials

Trial	Population	Comparator	Primary Endpoint	Mortality	MI	CVA	Stent Thrombosis	Bleed
Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) (2001)	12,562 NSTE-ACS	Clopidogrel 75 mg (300 mg loading) versus placebo	CV death, MI, CVA Clopidogrel 9.3% Placebo 11.4% ( P < 0.001) ARR 2.1%; RRR 20%; NNT 48	CV death Clopidogrel 5.1% Placebo 5.5% ( P = NS)	Clopidogrel 5.2% Placebo 6.7% ( P not given)	Clopidogrel 1.2% Placebo 1.4% ( P not given)	NA	Major* bleed Clopidogrel 3.7% Placebo 2.7% ( P = 0.001) NNH 100
CURRENT- OASIS (2010)	25,086 (invasive strategy) NSTE-ACS 63% STEMI 37%	Clopidogrel (600 mg loading, 150 mg days 2-7, then 75 mg) versus 150 mg loading, then 75 mg	CV death, MI, CVA (at 30 days) Double 4.2% Standard 4.4% ( P = .30)	CV death Double 2.1% Standard 2.2% All-cause mortality Double 2.3% Standard 2.4%	Double 1.9% Standard 2.2% ( P = 0.09)	Double 0.5% Standard 0.5% ( P = .95)	NA	Major ^† bleed Double 2.5% Standard 2.0% ( P = 0.01) NNH 200
TRITON-TIMI 38 (2007)	13,608 undergoing PCI NSTE-ACS 74% STEMI 26%	Prasugrel 10 mg (60 mg loading) versus clopidogrel 75 mg (300 loading)	CV death, MI, CVA Prasugrel 9.9% Clopidogrel 12.1% ( P < 0.001) ARR 2.2%; RRR 27%; NNT 46	CV death Prasugrel 2.1% Clopidogrel 2.4% ( P = .31) Any cause Prasugrel 3.0% Clopidogrel 3.2% ( P = .64)	Prasugrel 7.3% Clopidogrel 9.5% ( P < 0.001)	Prasugrel 1.0% Clopidogrel 1.0% ( P = 0.93)	Prasugrel 1.1% Clopidogrel 2.4% ( P < 0.001)	Non–CABG-related major ^‡ bleed Prasugrel 2.4% Clopidogrel 1.8% ( P = 0.03) NNH 167 CABG-related major bleed Prasugrel 13.4% Clopidogrel 3.2% ( P < 0.001) NNH 10
TRILOGY (2012)	7243 patients with noninvasive ACS younger than age 75	Prasugrel (10 mg daily) versus clopidogrel (75 mg daily)	CV death, MI, CVA Prasugrel 13.9% and clopidogrel 16.0% ( P = 0.21)	CV death Prasugrel 6.6% Clopidogrel 6.8% ( P = 0.48)	Prasugrel 8.3% Clopidogrel 10.5% ( P = 0.21)	Prasugrel 1.5% Clopidogrel 2.2% ( P = 0.08)	NA	Major ^‡ bleed Prasugrel 2.1% Clopidogrel 1.5% ( P = 0.27)
Study of Platelet Inhibition and Patient Outcomes (PLATO) (2009)	18,624 NSTE-ACS 59% STEMI 38% (invasive and noninvasive)	Ticagrelor 90 mg bid (180 mg loading) versus clopidogrel 75 mg (300-600 mg loading)	Death from vascular causes, MI, CVA Ticagrelor 9.8% Clopidogrel 11.7% ( P < 0.001) ARR 1.9%; RRR 16%; NNT 53	Vascular causes Ticagrelor 4.0% Clopidogrel 5.1% ( P = 0.001) Any cause Ticagrelor 4.5% Clopidogrel 5.9% ( P < 0.001)	Ticagrelor 5.8% Clopidogrel 6.9% ( P = 0.005)	Ticagrelor 1.5% Clopidogrel 1.3% ( P = 0.22)		Major ^§ bleed Ticagrelor 11.6% Clopidogrel 11.2% ( P = 0.43) NNH: NA Non-CABG bleeding Ticagrelor 4.5% Clopidogrel 3.8% ( P = 0.03) NNH 143

ARR = Absolute risk reduction; CABG = coronary artery bypass grafting; CV = cardiovascular; CVA = cerebrovascular accident; NA = not available; NNH = numbers needed to harm; NNT = numbers needed to treat; NS = non significant; RRR = relative risk reduction; STEMI = ST-segment elevation myocardial infarction.

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