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Antiplatelet Therapy in Cardiovascular Medicine


The evolution of cardiovascular (CV) medicine has flourished with advancements in our understanding of vascular biology, hemostasis, and thrombosis. Pharmacotherapies for the prevention and treatment of coronary atherothrombosis are the end results of several decades of investigation, highlighted by robust collaborative efforts between cardiology, pathology, and hematology communities in response disease pathologies ( Table 21.1 ). This chapter summarizes CV medicine's rapid evolution, with particular focus on antiplatelet therapy in coronary atherosclerotic disease (CAD) and outlining the major evidence in support of both primary and secondary prevention. Emphasis is placed on evidence-based use of antithrombotic therapy in routine clinical practice and the practical management of drug-induced hemostatic impairment in patients with CV disease.

TABLE 21.1
Partial List of Abbreviations Used by Cardiology in This Chapter and Their Meanings to Assist the Hematology Reader
ACCF American College of Cardiology Foundation FDA Food and Drug Administration
ACS Acute coronary syndrome ICH Intracranial hemorrhage
ADA American Diabetes Association IHD Ischemic heart disease
AHA American Heart Association MACE Major adverse cardiovascular event
ASA American Stroke Association NSTEMI Non-ST elevation myocardial infarction
BMS Bare metal stent PAD Peripheral arterial disease
CAD Coronary atherosclerotic disease PCI Percutaneous coronary intervention
CCTA Coronary computed tomographic angiography SIHD Stable ischemic heart disease
CHD Coronary heart disease STEMI ST elevation myocardial infarction
CVD Cardiovascular disease UA Unstable angina
DAPT Dual antiplatelet therapy USPSTF US Preventive Services Task Force
DES Drug-eluting stent VASP Vasodilator-stimulated phosphoprotein

Coronary Atherosclerotic Disease

Epidemiology

According to the most recent American Heart Association (AHA) statistics, an estimated 16.5 million Americans have coronary heart disease (CHD), with the cost from CV disease and stroke being approximately $316 billion in 2013. This includes direct health expenditures (physicians and other health professionals, hospitalizations, rehabilitation programs and nursing home services, cost of medications, and home health care) and indirect costs (loss of productivity in the workplace) .

Vascular Atherogenesis

Following monocyte attachment to the morphologically intact but dysfunctional vascular endothelium, there is a net directed migration of cells through the endothelium to the subendothelial space, where they undergo differentiation. This activation and differentiation play an important role in atherosclerosis, particularly in plaque remodeling and lesion progression. This complex process proceeds by at least two mechanisms: (1) the generation of reactive oxygen species and (2) the phenotypic modulation and expression of a scavenger receptor or family of receptors. The chemical modification of low-density lipoprotein (LDL) results in its avid uptake by monocytes (now considered macrophages) leading to foam cells. The specific receptor responsible for the uptake of modified LDL fails to effectively downregulate; as a result, a substantial amount of intracellular LDL cholesterol accumulates. When the influx of LDL particles exceeds the capacity of the macrophage scavenger receptors to remove them from the intracellular space, oxidized LDL particles accumulate within the arterial intima and irreversibly injure endothelial cells, smooth muscle cells, and macrophages. Disruption of relatively fragile macrophage-derived foam cells ensues, leading to the release of cytotoxic lipid material into the intima and extracellular compartment. This results in the formation of a cholesteryl ester–rich atheromatous core.

Arterial Thrombogenesis

The clinical expression of atherosclerotic vascular disease is determined by pathologic events leading to coronary thrombosis (or thromboembolism). There are two key factors: (1) the propensity of plaques to rupture and (2) the thrombogenicity of exposed plaque components.

The morphologic characteristics of plaques destined to rupture have been determined from careful analysis of lesions exhibiting disruption. Observational studies using necropsy and atherectomy tissue samples have shown convincingly that plaques associated with intraluminal thrombosis are rich in extracellular lipid and that the lipid core of these vulnerable or rupture-prone plaques occupies a large proportion of the overall plaque volume. The degree of cross-sectional narrowing of the vessel lumen is typically less than 50%. In addition to a large lipid core, vulnerable plaques are characterized by a thin fibrous cap and high macrophage density. Advances in imaging technology are now allowing identification of vulnerable plaques: low attenuation, positive remodeling, and the “napkin-ring sign” on coronary computed tomographic angiography (CCTA) indicate a 5- to 20-fold increase in ACS. The genetic and acquired determinants of plaque type (vulnerable vs. nonvulnerable) and predisposition to disruption are subjects of intense investigation.

Under normal physiologic conditions, cellular blood components interact with the vessel wall for the purpose of normal vascular repair. The exposure of circulating blood to disrupted or dysfunctional surfaces initiates a series of complex yet orderly steps that give rise to the rapid deposition of platelets, erythrocytes, leukocytes, and insoluble fibrin, which, if poorly regulated, establishes a mechanical barrier to blood flow.

Thrombi occurring in the arterial circulatory system are composed of platelets and fibrin in a tightly packed network. Overall, the site, size, and composition of thrombi forming within the heart and arterial circulatory system are determined by alterations in blood flow and by the following:

  • Thrombogenicity of vascular and endocardial surfaces

  • Concentration and reactivity of plasma cellular components

  • Preservation and functional capability of physiologic protective mechanisms

Platelet Deposition

Platelets attaching to disrupted vascular surfaces adhere, activate, and aggregate to form a rapidly enlarging platelet mass. This represents the first and primary step in hemostasis. In contrast, pathologic thrombosis is characterized by a poorly regulated response to vessel wall injury that escalates to the point of circulatory compromise.

The biology of platelet deposition involves several processes:

  • Platelet attachment to collagen or exposed surface adhesive proteins

  • Platelet activation and intracellular signaling

  • The expression of platelet receptors for adhesive proteins

  • Platelet aggregation

  • Platelet recruitment mediated by thrombin, thromboxane A 2 , adenosine diphosphate (ADP), and other mediators

Activation of Coagulation Factors

Thrombin is generated rapidly in response to vascular injury. It also plays a central role in platelet recruitment and formation of an insoluble fibrin network. The thrombotic process is localized, amplified, and modulated by a series of biochemical reactions driven by the reversible binding of circulating proteins (coagulation factors) to damaged vascular cells, elements of exposed subendothelial connective tissue (especially collagen), platelets (which also express receptor sites for coagulation factors), and macrophages. These events lead to an assembly of enzyme complexes that increases local concentrations of procoagulant material; in this way a relatively minor initiating stimulus can be greatly amplified to yield a thrombus.

From this biologic cascade, it is abundantly clear that platelets play the primary role in initiating thrombus formation. Thus decades of research have unearthed how to inactivate platelets via multiple mechanisms to prevent formation of arterial thrombi.

Platelet-Directed Therapies

Summarized in Table 21.2 .

TABLE 21.2
Antiplatelet Drugs Used in Cardiovascular Medicine
Drug Brand Name Mechanism Half-Life Black Box? Reversal Possibilities
Acetylsalicylic acid (ASA) multiple Irreversible COX-1 inhibitor Platelet life span ~7–10 days None New platelet production or platelet transfusion
Clopidogrel Plavix Platelet P2Y 12 inhibitor 6 h Genetic variance of drug metabolism New platelet production or platelet transfusion
Prasugrel Effient Platelet P2Y 12 inhibitor 2–15 h Bleeding warning; not to be used in patients with TIA/CVA New platelet production or platelet transfusion
Ticagrelor Brilinta ADP analogue 6–13 h Do not use with active bleeding or history of ICH New platelet production or platelet transfusion
Vorapaxar Zontivity PAR-1 antagonist 3–4 days Do not use if prior CVA, TIA, or ICH New platelet production or platelet transfusion
Abciximab ReoPro GP2b/IIIa inhibitor 10–30 min None Infusion cessation and platelet transfusion
Tirofiban Aggrastat GP2b/IIIa inhibitor 2 h None Infusion cessation and platelet transfusion
eptifibatide Integrilin GP2b/IIIa inhibitor 15 min None Infusion cessation and platelet transfusion
ADP , Adenosine diphosphate; COX , cyclooxygenase; CVA , cerebrovascular accident; GP , glycoprotein; ICH , intracranial hemorrhage; PAR-1 , protease-activated receptor 1; TIA , transient ischemic attack.

Aspirin

Aspirin is one of the oldest antiplatelet agents and has been in use for more than a century. It remains the mainstay of prevention and treatment of vascular events, including stroke, myocardial infarction (MI), peripheral artery disease (PAD), and sudden death. The majority of older adults will receive aspirin for both primary and secondary prevention indications.

Pharmacodynamics.

Aspirin irreversibly inhibits cyclooxygenase (COX), leading to impaired prostaglandin and thromboxane A 2 synthesis. As a result, platelet aggregation in response to collagen, ADP, and thrombin is attenuated. At low doses, aspirin will primarily inhibit COX-1 (found primarily in platelets), whereas at higher doses it will also inhibit COX-2 (expressed in tissues in response to an inflammatory stimulus), thus requiring only low doses for individuals with vascular pathology.

Pharmacokinetics.

Aspirin is rapidly absorbed in the duodenum and has peak serum levels within 15 to 20 minutes and platelet inhibition within 40 to 60 minutes. Enteric coated aspirin is less well absorbed and inhibits platelets only after 90 minutes. Aspirin decays rapidly, with a half-life of 20 minutes, but the platelet inhibition persists throughout the platelet's life span (7 ± 2 days). Because 10% of circulating platelets are replaced every 24 hours, platelet activity increases to ≥50% of normal within 5 to 6 days after the last aspirin dose.

Adverse effects.

The major adverse effect is hemorrhage, particularly gastrointestinal (GI) bleeding, and it is largely determined by dose and duration. Enteric coating of the aspirin has not been shown to reduce the likelihood of adverse effects involving the GI tract. Concomitant proton pump inhibitors are recommended for individuals with a history of upper GI bleeding.

Primary prevention.

Aspirin has been tested in multiple primary prevention trials enrolling tens of thousands of healthy individuals and collectively demonstrates a significant reduction in the risk of vascular events. However, for aspirin to be an effective primary prevention drug, the benefit must outweigh the risk of GI hemorrhage. Although the early studies included primarily white males, further analysis in various populations have furthered our understanding of its benefit.

For example, the Women's Health Study randomly assigned 39,876 healthy women aged 45 years or older to receive 100 mg of aspirin on alternate days or placebo and followed them for 10 years. There was a nonsignificant absolute risk reduction of 9% in major CV events.

However, when looking at ischemic stroke, there was a significant 24% reduction in ischemic stroke, with a nonsignificant increase in hemorrhagic stroke. Subgroup analysis showed that women aged 65 years or older had significantly decreased risk of major CV events, MI, and ischemic stroke. The risk of GI bleeding requiring transfusions was significantly increased by 40% in individuals taking aspirin.

There have been several meta-analyses of aspirin for primary prevention that have yielded discordant findings. Notably, a sex-specific meta-analysis of six primary prevention trials investigating the benefits of aspirin in 51,342 women and 41,114 men showed that aspirin use in women was associated with significant reductions in CV events (stroke, MI, or death from either cause) and ischemic strokes but no significant reduction of MI or CV disease mortality. In men, there was a significant reduction in CV events and MIs but no reduction in ischemic strokes or CV disease mortality.

As a result, the US Preventative Services Task Force (USPSTF) recommends aspirin for primary prevention in men and women aged 50 to 59 with a 10-year CVD risk greater than 10%. In individuals 60 to 69 years old who have a 10-year CVD risk greater than 10%, they suggest it for persons who are not at increased risk of bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years. Interestingly, in individuals aged 70 years and older, they report that there is insufficient evidence to assess the balance of benefits and harms of initiating aspirin use in primary prevention of CVD. This differs from the AHA and American Stroke Association (ASA) who recommend aspirin for primary prevention of CV disease in all individuals with a 10-year CVD risk greater than 6%. In addition, the American College of Chest Physicians suggests that patients older than 50 years without symptomatic CVD use aspirin as primary CVD prevention.

The AHA, American Diabetes Association (ADA), and American College of Cardiology Foundation (ACCF) released a meta-analysis and scientific statement in 2010 stating that although previous meta-analyses of data on aspirin therapy for primary prevention of CV events in diabetic patients had not shown statistically significant reductions in CV events, use of low-dose aspirin (75 to 162 mg daily) for prevention is reasonable for adults with diabetes who have no history of vascular disease and are at increased CV risk, and who are not at increased risk of bleeding (ACCF/AHA class IIa [reasonable to administer], level of evidence B [single randomized trial or nonrandomized studies]). Aspirin is not recommended for primary prevention in diabetic adults with low CV risk, because the adverse effects of bleeding offset potential benefits (ACCF/AHA class III [not recommended], level of evidence C [consensus opinion of experts]). Finally, low-dose aspirin (75 to 162 mg daily) may be considered for primary prevention in diabetic patients at intermediate CV risk until further research is available (ACCF/AHA class IIb [may be considered], level of evidence C).

In addition, aspirin has been compared with warfarin for prevention of ischemic heart disease (IHD). In the Thrombosis Prevention Trial, 5499 men at high risk of IHD were randomized in a two by two fashion to either aspirin or placebo and warfarin or placebo. Aspirin treatment provided a 32% reduction in nonfatal events, as well as a nonsignificant 12% increase in fatal events. Warfarin treatment reduced fatal events by 39% and nonfatal events by a nonsignificant 12%. The combined regimen of warfarin and aspirin reduced all events, fatal and nonfatal combined, by 34%. However, warfarin therapy increased the risk of hemorrhagic and fatal strokes, as well as ruptured or aortic dissections, and as such is not part of the standard of primary prevention for CVD.

Dual antiplatelet therapy (DAPT) with both aspirin and clopidogrel has been investigated as well. Clopidogrel for Higher Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) was a randomized controlled trial that evaluated aspirin therapy plus either clopidogrel or placebo in 15,603 patients at high risk of atherothrombotic events. There was no reduction in the composite of MI, stroke, or death from CV causes, and the rate of death from CV causes was actually higher in the clopidogrel group. Thus DAPT remains limited to secondary prevention, to be discussed later in this chapter.

Secondary prevention of vascular events.

The Antiplatelet Trialists Collaboration, based on comprehensive evaluation of existing data, provided convincing evidence of aspirin's ability to prevent vascular events in high-risk patients. Overall, aspirin therapy has been shown to reduce nonfatal MI by one-third, nonfatal stroke by one-third, and vascular death by one-quarter.

Aspirin dosing.

An updated meta-analysis conducted by the Antiplatelet Trialists Collaboration provided additional information on the effects of different dosages of aspirin. Overall, among 3570 patients in three trials that directly compared aspirin dosages (≥75 mg daily vs. aspirin <75 mg daily), significant differences were seen in the incidence of vascular events (two trials compared 75 to 325 mg of aspirin daily with <75 mg daily, and one trial compared 500 to 1500 mg aspirin daily with <75 mg daily). Based on both direct and indirect comparisons of aspirin dosage, the proportional reduction in vascular events was 19% with 500 to 1500 mg daily, 26% with 160 to 325 mg daily, and 32% with 75 to 150 mg daily. The effect of antiplatelet drugs other than aspirin (compared with a control condition) was assessed in 166 trials that encompassed 81,731 patients. Indirect comparisons provided no clear evidence of differences in reducing serious vascular events (χ for heterogeneity between any aspirin regimen and other antiplatelet drugs, 10.8; not statistically significant). Most direct comparisons assessed the effects of replacing aspirin with another antiplatelet agent.

Coronary artery bypass.

Multiple clinical trials have been conducted to determine the effectiveness of antiplatelet therapy in preventing early (≤10 days) and late (6 to 12 months) saphenous vein graft occlusion. Ten of the trials investigated aspirin in dosages ranging from 100 mg to 975 mg daily. Several also evaluated antiplatelet therapy in patients receiving internal mammary coronary bypass grafts.

Considered collectively, and aided by the Antiplatelet Trialists’ Collaboration overview, the data reveal improved saphenous vein graft patency with aspirin administration. Although a direct benefit on internal mammary bypass grafts has not been established, treatment is recommended given the common coexistence of vascular disease (and the risk of thrombotic events) in these patients.

One question that remained is whether in the setting of undergoing coronary artery bypass grafting (CABG), aspirin should be held given the significant bleeding risk it poses. In a 2016 study, this question was addressed in a two-by-two factorial designed study in which 5784 eligible patients who were scheduled to undergo coronary artery surgery and were at risk of perioperative complications received aspirin or placebo and tranexamic acid or placebo. The primary outcome was a composite of death and thrombotic complications (nonfatal MI, stroke, pulmonary embolism, renal failure, or bowel infarction) within 30 days of surgery. Of eligible patients, 2100 were enrolled and randomized to either aspirin or placebo. The primary outcome occurred in 202 patients in the aspirin group and 215 in the placebo group (19.3% vs. 20.4%, RR 0.94, P = .55). There was no difference in major hemorrhage requiring reoperation or cardiac tamponade.

Percutaneous coronary intervention.

Percutaneous coronary intervention (PCI), including standard balloon angioplasty, rotational atherectomy, and laser angioplasty, with or without stent placement, is associated with vascular injury, atheromatous plaque disruption, platelet activation, and, at times, coronary thromboembolism. Several studies performed over the past decade have documented a reduction in periprocedural complications, including thrombus formation, abrupt closure, and MI, when antiplatelet therapy is given before PCI (relative risk reduction [RRR], 60%). The current recommendation for PCI is aspirin 325 mg before PCI and 81 mg daily after PCI for secondary prevention of CV events. For patients unable to tolerate aspirin, pretreatment with clopidogrel with a single oral dose of 600 mg followed by 75 mg daily orally is suggested.

Platelet P2Y 12 Receptor Antagonists

Clopidogrel

Pharmacodynamics.

Clopidogrel, a prodrug and a thienopyridine derivative, is a potent antiplatelet agent targeting the surface P2Y 12 receptor. It irreversibly inhibits the binding of ADP to the platelet receptor (P2Y 12 ) and the subsequent G protein cascade, preventing activation of GPIIb/IIIa complex.

Pharmacokinetics.

Clopidogrel is rapidly absorbed, with peak plasma levels within approximately 60 minutes, and is extensively metabolized in the liver to an active compound with a plasma half-life of 7.7 ± 2.3 hours. Dose-dependent ADP inhibition is observed within several hours of single-dose administration, and a more significant inhibition is achieved with loading dose. A 600 mg oral loading dose achieves effective platelet inhibition within 2 to 3 hours. Daily doses of 75 mg clopidogrel inhibit platelet aggregation and reach steady state between days 3 and 7.

Safety.

The main risks associated with clopidogrel remain related to bleeding, as with other antiplatelet agents. There are reports of TTP associated with clopidogrel, although they are extremely rare (11 cases per 3 million patients treated).

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