Coagulation on Cellular Surfaces

A cell-based model of coagulation underscores the importance of TF-bearing cells and activated platelets serving as a scaffold for procoagulant proteins to assemble and ultimately form a localized fibrin clot. In this integrated model system, coagulation occurs in three overlapping stages: 1) initiation, amplification, and propagation ( Fig. 8.3 ). Initiation occurs primarily after exposure of the TF/VIIa complex at a site of vascular injury. This complex activates localized human Factor (F)X, which then combines with FVa to form the prothrombinase complex and generate a small amount of thrombin; 2) Thrombin then primes the system for rapid amplification by activating platelets, FXI, FVIII, and additional FV; 3) In the propagation stage, activated FIX, generated through both FXIa and TF/VIIa, combines with FVIIIa to form the tenase complex and generate FX on the platelet surface. Subsequent formation of the prothrombinase complex provokes a burst of thrombin, converting fibrinogen to stable fibrin monomers, which then polymerize and are covalently stabilized by FXIIIa.

The cell-based model of coagulation describes an interaction between procoagulant surfaces and proteases essential for coagulation. Coagulation occurs on the surface of tissue factor (TF) -bearing cells and activated platelets in three overlapping steps: (1) initiation of the pathway follows FVIIa binding to exposed TF, provoking the generation of a small amount of thrombin; (2) thrombin then activates other coagulation proteases and platelets, facilitating coagulation protease assembly in the priming phase of coagulation and; (3) the surface of activated platelets serves as the biological template for a burst of thrombin generation, with resulting thrombus propagation. vWF , von Willebrand factor.

(Data from Hoffman M, Monroe III DM. A cell-based model of hemostasis. Thromb Haemostasis 2001;85:958–965.)

Contact and Intrinsic Pathway-Mediated Coagulation

The contact system includes FXII, FXI, kallikrein, and high-molecular-weight kininogen (HMWK) and participates actively in inflammation (FXII, kallikrein, HMWK) and coagulation (FXII, FXI). The contact system is activated following exposure of FXII to a number of anionic surfaces, generating activated FXII (FXIIa) that triggers the intrinsic pathway of coagulation, beginning with FXI and followed by factors IX and VIII. Although it was previously believed that all coagulation factors play a similar role in hemostasis and thrombosis, evidence points to differing functions for FXI and FXII. Specifically, the contact activation proteins contribute to pathologic thrombus formation without being actively involved in normal hemostasis ( Fig. 8.4 ).

The contact-based model of coagulation plays a fundamental role for the interface of coagulation, immunity and inflammation.

Plasma Proteins

In general, positively charged surfaces favor thrombus formation whereas negatively charged surfaces are comparatively resistant to thrombus formation. Although these properties may reflect the normally negative charge of vascular endothelial cells, surface elements, circulating blood components, and plasma proteins likely play an important role as well. Artificial surfaces with a net positive charge are highly adsorptive of plasma proteins (and blood cells), all of which have a negative charge of physiologic importance. The diffusive mobility and concentration of plasma proteins exceed those of platelets, which suggests that artificial surfaces are probably coated with proteins before platelets adhere and form a confluent monolayer. Electron microscopy has shown that a thin film of plasma components (primarily proteins) develops within several seconds on all artificial surfaces exposed to whole blood. As a result, it seems likely that the composition, concentration, and conformational characteristics of surface-bound protein molecules initially determine the thrombogenicity of the underlying artificial material.

Fibrinogen, a prominent plasma protein readily available in high concentrations, is the first protein adsorbed to an artificial surface exposed to blood. Depending on the orientation of the molecules (either standing “on end” or horizontal in tightly packed layers), the surface concentration of fibrinogen may exceed that found normally in plasma by 100-fold, and experimental evidence supports a direct role for surface-bound fibrinogen in determining relative thrombogenicity. The adsorption of other plasma proteins—including von Willebrand factor, fibronectin, and thrombospondin, as well as circulating coagulation factors—also contributes but predominantly in a secondary capacity.

The initial adsorption of plasma proteins to an artificial surface is often followed by a period of “prothrombosis,” which may be followed by a relative state of thromboresistance. This metamorphosis, often referred to as “passivation,” varies according to physical and chemical alterations of the surface proteins, their electrostatic potential, and perhaps most important an intrinsic capacity or inherent propensity to interact with platelets and coagulation factors.

Aspirin Dosing

An updated meta-analysis of the Antiplatelet Trialists’ Collaboration provides additional information on the differential effects of aspirin dosing. Among 3570 patients in three trials directly comparing aspirin (≥ 75 mg daily versus aspirin < 75 mg daily) there were significant differences in vascular events (two trials compared 75–325 mg aspirin daily versus < 75 mg daily and one trial compared 500–1500 mg aspirin daily versus < 75 mg daily). Considering both direct and indirect comparisons of aspirin dose, the proportional reduction in vascular events was 19% with 500–1500 mg daily, 26% with 160–325 mg daily and 32% with 75–150 mg daily. The effect of antiplatelet drugs other than aspirin (versus control) were assessed in 166 trials that included 81,731 patients. Indirect comparisons provided no clear evidence of differences in reducing serious vascular events (χ ² for heterogeneity between any aspirin regimen and other antiplatelet drugs = 10.8 ns). Most direct comparisons assessed the effects of replacing aspirin with another antiplatelet agent. While there remains interest in optimal dosing frequency for aspirin, particularly among individuals with diabetes mellitus, once-daily dosing is currently the standard of care.

Aspirin Before CABG

In the ATACAS study, 2100 patients scheduled to undergo CABG received either aspirin 100 mg or placebo preoperatively. The primary outcome was a composite of death and thrombotic complications (nonfatal MI, stroke, pulmonary embolism [PE], renal failure or bowel infarction) within 30 days of surgery. The primary outcome occurred in 19.3% and 20.4% of patients, respectively (RR 0.94; 95% CI 0.80 to 1.12; P = 0.55). Major hemorrhage rates did not differ between groups. There are several limitations to the study that require consideration. The investigators chose to use an enteric-coated aspirin preparation that is known to have delayed absorption and peak effect. Patients participating in the “Continuing versus Stopping Aspirin” study were given a 100-mg enteric-coated aspirin 1–2 hours prior to surgery. Based on the well-known pharmacokinetics of aspirin, there is a high likelihood that there was not sufficient time to reach maximum concentration (C _max ) and maximum platelet inhibition prior to the start of the surgery. Once surgery begins and the patient is placed on cardiopulmonary bypass, local concentrations and related pharmacodynamics effects, i.e., at coronary sites of plaque of newly placed bypass conduits, would be quite low. This study had a higher than expected rate of MI in both groups. The ATACAS investigators speculate that this was the end-result of closer monitoring and increased troponin surveillance, i.e., higher detection rate. Could this actually be because aspirin was stopped in many patients at least 4 days prior to surgery, leading to a higher risk of complications? By stopping aspirin early, there could have also been patients who were excluded from participating in the study if they experienced a coronary event in the interim before CABG. This would have biased the outcomes. Perhaps there is a separate take-home message that applies to some high-risk patients: aspirin should not be stopped prior to CABG.

A number of clinical trials have been conducted to determine the effectiveness of antiplatelet therapy in preventing early (≤ 10 days) and late (6–12 months) saphenous vein graft occlusion. Ten of the trials investigated aspirin doses ranging from 100 mg to 975 mg daily. Several also evaluated patients receiving internal mammary artery coronary bypass grafts. Considered collectively, and aided by the Antiplatelet Trialists’ Collaboration overview, the data show improved saphenous vein graft patency with aspirin administration. Although a direct benefit on internal mammary bypass graft patency has not been established, treatment is recommended given the common coexistence of vascular disease (and the risk for thrombotic events).

Percutaneous Coronary Intervention

PCI, including plain old balloon angioplasty (POB), rotational atherectomy, and laser angioplasty, with or without stent placement, is associated with vascular injury, atheromatous plaque disruption, platelet activation, and coronary thromboembolism. Several studies have documented reduced periprocedural complications, including thrombus formation, abrupt closure, and MI, with antiplatelet therapy given prior to PCI (relative risk reduction [RRR], 60%). The current recommendations for PCI include aspirin 81–325 mg prior to PCI and 81–325 mg daily after PCI for secondary prevention of cardiovascular events. For patients unable to tolerate aspirin, pretreatment with clopidogrel (600 mg oral loading dose) followed by 75 mg daily is suggested.

Peripheral Artery Disease

Although proven to reduce cardiovascular mortality in CAD, there are modest data evaluating the efficacy of aspirin in patients with PAD. The 2002 Antiplatelet Trialists’ meta-analysis demonstrated a significant 23% odds reduction in ischemic events when antiplatelet agents were compared to placebo. Two-thirds of the trials included in the meta-analysis evaluated agents other than aspirin. Since that time, three randomized, controlled trials have evaluated aspirin versus placebo in patients with PAD. Two of these studies enrolled asymptomatic patients with ABI ≤ 0.99 and 0.95, respectively, and failed to show a benefit from aspirin use. The third trial, the Critical Leg Ischemia Prevention Study (CLIPS), enrolled patients with either symptomatic PAD or ABI < 0.85 and demonstrated a risk reduction in cardiovascular and vascular ischemic events of 64% in patients randomized to aspirin. By contrast, a 2009 meta-analysis of aspirin therapy in patients with PAD showed no significant change in cardiovascular events, all-cause mortality, or cardiovascular mortality. The current recommendations from the AHA/ACC are as follows: antiplatelet therapy with aspirin alone (75–325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce MI, stroke and vascular death in patients with symptomatic PAD (level IA).

Left Ventricular Assist Device

Low-dose aspirin is not routinely discontinued prior to left ventricular assist device (LVAD) implantation; however, if it is, restarting is suggested postoperatively on day 2 or 3 and continued indefinitely unless bleeding occurs. The recommended aspirin dose for the HeartMate II is 81–325 mg daily, while a dose of 325 mg daily is recommended for the HeartWare LVAD.

Aspirin Response Variability

Aspirin’s ability to inhibit platelet aggregation is variable and influenced by the population studied, conditions, and the methodology employed. Laboratory response can also be affected by concomitant administration of Ibuprofen and by acute illness. Given that there appears to be little or no variability in the level of COX-1-dependent platelet aggregation among patients compliant with recommended doses of aspirin, much of the variability in aspirin response is believed to be due to biological variability and heritability of COX-1-independent ADP, collagen, and epinephrine responses.

The COX-2 enzyme prevalent in inflammatory cells may play a role in aspirin response variability. Specifically, pharmacogenomic analyses have shown associations between polymorphisms in PTGS2, the gene encoding COX-2, and the efficacy of aspirin-mediated reduction in thromboxane B ₂ production.

The most convincing data supporting genetic determination of aspirin response variability exists for the Pl ^A polymorphism of the ITGB3 gene encoding GPIIIa. GPIIIa is pivotal for platelet binding of fibrinogen, von Willebrand factor, fibronectin, and vitronectin. Carriers of Pl ^A2 are more resistant to the antithrombotic effect of aspirin than carriers of Pl ^A1 , and multiple studies have suggested a heightened increased risk of MI, cerebral vascular events, and venous thrombosis. Despite several interesting observations, the findings of multiple studies on the effect of Pl ^A polymorphisms have been divergent and several meta-analyses have drawn different conclusions.

Clinical Impact of Aspirin Response Variability

Despite its proven benefit, aspirin does have inherent limitations, and the evidence compiled over several decades shows that patients receiving aspirin can still experience cardiovascular events. Although multiple studies and meta-analyses have documented increased risk of cardiovascular events in patients defined as in vitro nonresponders, other studies have demonstrated no difference in clinical outcomes based on in vitro aspirin responsiveness or based on genetic polymorphisms associated with in vitro resistance. As a result, routine platelet function testing is not recommended.

Drug Therapy After Peripheral Artery Revascularization

In contrast to the data for aspirin administration in asymptomatic PAD, there are data supporting its use as adjuvant therapy following lower extremity bypass. In a meta-analysis, the Antiplatelet Trialists’ Collaboration demonstrated an odds reduction of 43% for the prevention of vascular occlusion with aspirin therapy compared to placebo. The analysis consisted primarily of patients who had undergone lower extremity bypass; however, two studies did assess the usefulness of aspirin as adjuvant therapy in patients undergoing lower extremity angioplasty. A subsequent randomized trial and two Cochrane systematic reviews support a more robust effect for aspirin in prosthetic grafts than in autologous conduits.

Percutaneous transluminal angioplasty (PTA), often with stent insertion, is a common treatment approach for patients with aorto-iliac and superficial femoral artery obstructive disease. An early Cochrane review supported aspirin, 50–330 mg daily either with or without dipyridamole, initiated before femoro-politeal endovascular treatment, as an effective and safe strategy to reduce reocclusion at 6 and 12 months as compared to placebo or VKA. The ACCF/AHA guidelines give aspirin a class I indication for patients undergoing lower extremity revascularization, either bypass grafting or endovascular intervention.

Based on the beneficial effect of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel for preventing coronary stent thrombosis, there has been significant interest in the effect of DAPT after lower extremity PTA with stenting. Ticlopidine has been shown to reduce loss of vessel patency (odds ratio [OR] 0.53; 95% CI 0.33–0.85) and amputation (OR 0.29; 95% CI 0.08–1.01). A strategy of aspirin plus clopidogrel for 24 hours before and 4 weeks after endovascular procedures has become a common approach to the reduction of acute and subacute thrombotic complications after endovascular procedures.

The clopidogrel and acetylsalicylic acid in bypass surgery for peripheral artery disease (CASPAR) trial randomized patients to either clopidogrel plus aspirin or placebo plus aspirin with a primary composite outcome of graft occlusion, revascularization, above ankle amputation or death. There was a nonsignificant difference in the primary endpoint in the overall population and venous graft subgroups; however, in the prosthetic graft subgroup, aspirin plus clopidogrel significantly reduced the primary endpoint (HR 0.65; 95% CI 0.45–0.95; P = 0.025) without an increase in severe bleeding. As a result, the ACCF/AHA guidelines give DAPT a class IIb (may be considered) recommendation in patients previously revascularized who are at high risk for ischemic events.

Venous Thromboembolism

Becattini and colleagues reported a marked reduction in recurrent venous thromboembolism among 402 carefully selected patients with unprovoked events who were randomly assigned to either aspirin (100 mg daily) or placebo and were followed for 2 years (recurrence rate per year, 6.6% versus 11.2%; HR 0.58, 95% CI 0.36–0.93). The adverse-event profile accompanying aspirin treatment was acceptable to most patients and physicians. A majority of the recurrences of venous thromboembolism occurred in the absence of known risk factors; death attributed to PE was infrequent, and major or clinically relevant nonmajor bleeding was rare.

Contraindications to Aspirin

The major contraindications are aspirin intolerance, recent GI bleeding, active or recurring peptic ulcer, other potential sources of GI or genitourinary bleeding, and anaphylaxis. The risk of aspirin-induced GI bleeding is increased by alcohol, corticosteroid therapy, and nonsteroid antiinflammatory drugs (NSAIDs). Hemophilia (A, B, or C) is not an absolute contraindication to aspirin when there are strong cardiovascular indications; however, working closely with the patient and a hematology specialist is suggested.

Drug Interactions With Aspirin

Concurrent warfarin and aspirin therapy increases the risk of bleeding, especially with an aspirin dose above 75 mg daily. Among NSAIDs, those with dominant COX-1 activity (e.g., ibuprofen and naproxen), but not those with dominant COX-2 activity (e.g., diclofenac), may interfere with the cardioprotective effects of aspirin. Angiotensin-converting enzyme (ACE) inhibitors and aspirin have potentially opposing effects on renal hemodynamics, with aspirin inhibiting and ACE inhibitors promoting the formation of vasodilatory prostaglandins. Phenobarbital, phenytoin, and rifampin decrease the efficacy of aspirin through induction of the hepatic enzymes metabolizing aspirin. The effect of oral hypoglycemic agents and insulin may be enhanced by aspirin.

Pharmacodynamics

The dipyridamole component of aggrenox and cilostazol, both phosphodiesterase inhibitors, is used predominantly in patients with peripheral vascular and cerebrovascular disease. Aggrenox is a combination platelet antagonist that includes aspirin (25 mg) and dipridamole (200 mg extended-release preparation). It is typically taken twice daily. Aspirin’s mechanism of action has been discussed previously. Dipyridamole inhibits cyclic adenosine monophosphate (cAMP)-phosphodiesterase (PDE) and cyclic-3’, 5’-GMP-PDE. Dipyridamole inhibits platelet aggregation by two mechanisms. First, it attenuates adenosine uptake into platelets (as well as endothelial cells and erythrocytes). The resulting increase elicits a rise in cellular adenylate cyclase concentrations, resulting in elevated cAMP levels, which inhibit platelet activation to several stimuli, including ADP, collagen, and platelet-activating factor. Dipyridamole also inhibits PDE. The subsequent increase in cAMP elevates nitric oxide concentration, facilitating platelet inhibitory potential.

Pharmacokinetics

The pharmacokinetic profile of aspirin has been summarized previously. Peak dipyridamole levels in plasma are achieved within several hours of oral administration (400 mg dose of Aggrenox). Extensive metabolism via conjugation with glucuronic acid occurs in the liver. There are no significant pharmacokinetic interactions between aspirin and dipyridamole coadministered as Aggrenox.

Adverse Effects

The European Stroke Prevention Study-2 (ESPS) reported that 79.9% of patients experienced at least one on-treatment adverse event. The most common side effects were GI complaints and headache. Dipyridamole has vasodilatory effects and should be used with caution in patients with severe CAD in whom episodes of angina pectoris may increase. Patients receiving Aggrenox should not be given adenosine for myocardial perfusion studies.

Administration in Older Patients

Plasma concentrations of dipyridamole are approximately 40% higher in patients greater than 65 years of age compared with younger individuals.

Clinical Experience

Aggrenox has not been studied in patients with ACS. The European Stroke Study (ESPS)-2 included 6602 patients with ischemic stroke (76% of the total population) or transient ischemic attack who were randomized to receive aggrenox, dipyridamole alone, aspirin alone, or placebo. Aggrenox reduced the risk of stroke by 22.1% compared with aspirin and by 24.4% compared with dipyridamole. Both differences were statistically significant ( P = 0.008 and P = 0.002, respectively).

Aggrenox is not considered inter changeable with its individual components, particularly aspirin, which may be required in larger doses among patients with CAD. In addition, the vasodilatory effects of dipyridamole can cause coronary “steal” and angina pectoris. Accordingly, Aggrenox should be used cautiously, if at all, in the setting of advanced CAD.

Pharmacodynamics

Cilostazol, a guinolinone derivative, and several of its metabolites inhibit phosphodiesterase III activity and suppress cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively. Increasing cAMP concentrations within endothelial cells causes vasodilation, whereas elevated levels in platelets impair their ability to aggregate.

Pharmacokinetics

Cilostazol is well absorbed after oral administration, particularly when given with a high-fat meal. Metabolism occurs via the hepatic cytochrome P450 (CYP450) enzymes, and most of the metabolites are excreted in the urine (75% of overall clearance). One of the two active metabolites is responsible for more than 50% of PDE III inhibition. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11 to 13 hours. Cilostazol and its active metabolites accumulate about twofold with chronic administration and reach steady state blood levels within a few days.

Adverse Effects

The most common adverse effect associated with cilostazol administration is headache. Other relatively frequent causes of drug discontinuation include palpitations and diarrhea. Several PDE III inhibitors have been associated with decreased survival in patients with class III/IV congestive heart failure. Cilostazol is contraindicated in patients with heart failure of any severity. Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III–IV heart failure.

Use in Older Patients

The clearance of cilostazol (and its metabolites) has not been determined in patients older than age 65.

Use in Patients With Renal Insufficiency

Moderate-to-severe renal impairment increases cilostazol metabolite levels and alters protein binding of the parent compound. Patients with advanced renal insufficiency have not been studied.

Aspirin

Short-term (less than or equal to 4 days) coadministration of aspirin with Cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or Cilostazol alone. Short-term (less than or equal to 4 days) coadministration of aspirin with Cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to Cilostazol alone and by 48% compared to aspirin alone.

Clinical Experience

Cilostazol is approved for the treatment of intermittent claudication. Across seven clinical trials, the improvement in walking distance (compared with placebo) was approximately 30 meters. Although there is experience with cilostazol after coronary arterial stenting, its long-term administration to patients with CAD has not been studied. Short-term coadministration with aspirin reduced ADP-mediated platelet aggregation by 30% to 40% (compared with aspirin alone). The CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation trial (CILON-T) randomized 960 patients to DAPT with aspirin and clopidogrel versus aspirin and clopidogrel plus 6 months of cilostazol. While the addition of cilostazol resulted in a reduction in platelet reactivity at 6 months (201.7 ± 87.9 platelet reactivity units versus 255.7 ± 73.7 PRU, P < 0.001), there was no difference in the primary endpoint of cardiac death, nonfatal MI, ischemic stroke, or target lesion revascularization (8.5 versus 9.2%, P = 0.74). Cilostazol should not be considered a substitute for aspirin or clopidogrel in patients with ACS who have concomitant peripheral artery disease.

Vorapaxar

Vorapaxar is a tricyclic himbacine-derived selective inhibitor of protease activated receptor (PAR-1). By inhibiting PAR-1, a thrombin receptor expressed on platelets, vorapaxar prevents thrombin-mediated platelet activation and aggregation.

Pharmacodynamics

Vorapaxar inhibits platelet aggregation through the reversible antagonism of PAR-1, also known as thrombin receptor. PARs are a family of G-protein coupled receptors highly expressed on platelets and activated by serine protease activity of thrombin to mediate thrombotic response. By blocking PAR-1 activation, vorapaxar inhibits thrombin-induced platelet aggregation and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. Vorapaxar does not inhibit platelet aggregation induced by other agonists such as ADP, collagen, or a thromboxane mimetic.

Pharmacokinetics

After oral administration, vorapaxar is rapidly absorbed and peak concentrations occur at a median tmax of 1 hour under fasting conditions. The mean absolute bioavailability is 100%. Vorapaxar is primarily eliminated as its metabolite M19 through the feces (91.5%), and partially eliminated in the urine (8.5%). It has an effective half-life of 3–4 days with an apparent terminal half-life of 8 days.

Adverse Effects

Hemorrhagic complications were observed in the two large phase III clinical trials of vorapaxar. In TRA-2P, moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (HR 1.66; 95% CI 1.43–1.93; P < 0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0% versus 0.5% in the placebo group, P < 0.001). In TRACER, rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (HR 1.35; 95% CI 1.16–1.58; P < 0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (HR 3.39; 95% CI 1.78–6.45; P < 0.001). The trial was stopped by the data and safety monitoring committee. Rates of nonhemorrhagic adverse events were similar in the two groups.

Clinical Experience

In the TRA-2P study, 26,449 patients who had a history of MI, ischemic stroke, or PAD were randomized to receive vorapaxar (2.5 mg daily) or matching placebo and followed for a median of 30 months. The primary efficacy endpoint was the composite of death from cardiovascular causes, MI, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. At 3 years, the primary endpoint had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (HR 0.87; 95% CI 0.80–0.94; P < 0.001). Cardiovascular death, MI, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (HR 0.88; 95% CI 0.82–0.95; P = 0.001). Among the 3787 patients with PAD at study entry, there was no difference in the primary outcomes between treatment groups (11.3% and 11.9%, respectively; 0.94 [0.78, 1.14]; P = 0.22).

In the TRACER study, vorapaxar was compared with placebo in 12,944 patients who had ACS without ST-segment elevation. The primary endpoint was a composite of death from cardiovascular causes, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349–667), the primary endpoint occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% versus 19.9%; HR 0.92; 95% CI 0.85–1.01; P = 0.07). A composite of death from cardiovascular causes, MI, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; HR 0.89; 95% CI 0.81–0.98; P = 0.02). Among 936 patients with PAD at study entry, there were no differences in the primary outcome between groups (HR 0.85; 95% CI 0.67–1.08).

Vorapaxar is indicated for reducing the incidence of thrombotic cardiovascular events in patients with a history of MI or with peripheral artery disease.

Pharmacodynamics

Ticlopidine hydrochloride, after oral ingestion, interferes with platelet membrane function by inhibiting ADP-induced platelet-fibrinogen binding and subsequent platelet-to-platelet interactions. The effect on platelet function is irreversible for the life of the platelet. Ticlopidine causes a time and dose-dependent inhibition of both platelet aggregation and release of platelet granule constituents.

Pharmacokinetics

After oral administration of a single 250 mg dose, ticlopidine is rapidly absorbed with peak plasma levels occurring at approximately 2 hours after dosing and is extensively metabolized. Absorption is greater than 80%. Administration after meals results in a 20% increase in the mean area under the concentration curve (AUC) of ticlopidine. The apparent half-life of ticlopidine after a single 250 mg dose is about 12.6 hours; with repeat dosing at 250 mg BID, the terminal elimination half-life rises to 4 to 5 days. Steady-state trough values in elderly patients (mean age 70 years) are about twice those in younger volunteer populations.

Ticlopidine is metabolized extensively by the liver; only trace amounts of intact drug are detected in the urine. Following an oral dose of radioactive ticlopidine hydrochloride administered in solution, 60% of the radioactivity is recovered in the urine and 23% in the feces.

Adverse Effects

Ticlopidine is associated with a risk of life-threatening blood dyscrasias, including thrombotic thrombocytopenic purpura (TTP), neutropenia/agranulocytosis, and aplastic anemia. Hemorrhagic events most often effecting the GI tract can also occur.

Ticlopidine

Despite limited clinical use because of side effects such as neutropenia, agranulocytosis, and thrombotic thrombocytopenic purpura, ticlopidine has been proven effective in preventing MI, stroke, and transient ischemic attack (TIA) in patients with PAD. Specifically, in the randomized, double-blind Swedish Ticlopidine Multicentre Study (STIMS), ticlopidine reduced mortality by 29.1% as compared to placebo. Ticlopidine may also be effective in reducing the progression of femoral atherosclerosis and be beneficial in maintaining patency of peripheral bypasses. Among patients with a prior TIA or stroke, ticlopidine should be reserved for patients who are intolerant or allergic to aspirin therapy or who have failed aspirin therapy. Safer options are available.

Pharmacodynamics

Clopidogrel, a thienopyridine derivative, is a platelet antagonist that is several times more potent than ticlopidine but associated with fewer adverse effects (described below). The important role of ADP-mediated platelet activation and aggregation in atherothrombotic vascular disease has made the surface P2Y ₁₂ receptor a favored target for drug development. Clopidogrel irreversibly inhibits the binding of ADP to its platelet receptor (P2Y ₁₂ ) and the subsequent G-protein linked mobilization of intracellular calcium and activation of the glycoprotein (GP) IIb/IIIa complex. At steady state, the average inhibition to ADP is between 40% and 60%.

Pharmacokinetics

Clopidogrel is rapidly absorbed following oral administration with peak plasma levels of the predominant circulating metabolite occurring approximately 60 minutes later. As a prodrug, it is extensively metabolized in the liver to an active compound with a plasma elimination half-life of 7.7 ± 2.3 hours. Dose-dependent inhibition of ADP-mediated platelet aggregation is observed several hours after a single oral dose of clopidogrel, with a more significant inhibition achieved with loading doses (≥ 300 mg). A 600-mg oral loading dose achieves effective platelet inhibition in 2–3 hours. Repeated doses of 75 mg clopidogrel per day (without a loading dose) inhibit aggregation with steady state being reached between day 3 and day 7.

Adverse Effects and Safety

The available information suggests that clopidogrel offers safety advantages over ticlopidine, particularly with regard to bone marrow suppression and other hematologic abnormalities. Although Idiopathic thrombocytopenic purpura (ITP) and TTP have been reported with clopidogrel, their occurrence is rare.

Peripheral Artery Disease

The well-documented benefit derived from platelet inhibition in patients with vascular disease, coupled with a concerning adverse-effect profile observed ticlopidine, fostered the rapid development of clopidogrel. The Clopidogrel versus Aspirin in Patients at Risk for Ischemic Events (CAPRIE) Study randomized patients with atherosclerotic vascular disease, defined as recent stroke, MI, or PAD, to either clopidogrel 75 mg per day or aspirin 325 mg daily. Patients treated with clopidogrel (by intention-to-treat analysis) had a 5.32% annual risk of ischemic stroke, MI, or vascular death compared with 5.83% among aspirin-treated patients (RRR 8.7%; 95% CI 0.3–16.5; P = 0.043). There was no major difference in safety between treatment groups; however, a greater proportion of patients receiving aspirin had the study drug permanently discontinued because of GI hemorrhage, indigestion, nausea, or vomiting. Approximately 1 out of every 1000 patients treated with clopidogrel experienced neutropenia (< 1.2 × 10 ⁹ cells/L) (similar to aspirin treatment).

The trial design employed in CAPRIE was not configured to answer the important question of benefit and risk for dual platelet inhibition (aspirin plus clopidogrel). Accordingly, an additional study was undertaken. The CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) study randomly assigned 15,603 patients with clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel plus aspirin or low-dose aspirin plus placebo. Patients were subsequently followed for a median of 28 months. Respective rates for the principal secondary endpoint, which included hospitalization for ischemic events, were 16.7% and 17.9%, respectively (relative risk 0.92; 95% CI,0.86–0.995; P = 0.04). Rates of severe bleeding were 1.7% and 1.3%, respectively. Among patients with clinically evident atherothrombosis, the secondary endpoint occurred in 6.9% of patients receiving combination therapy versus 7.9% of those given aspirin alone (RR 0.88; 95% CI 0.77–0.998; P = 0.046). By contrast, patients with multiple risk factors (but no documented atherothrombotic disease) experienced a primary endpoint rate of 6.6% with combination therapy versus 5.5% with aspirin alone (RR 1.2; 95% CI 0.91–1.59; P = 0.2). The rate of death from cardiovascular causes was higher with combination therapy (3.9% versus 2.2%, P = 0.01).

On the basis of data from CHARISMA, one should conclude that the combination of clopidogrel plus aspirin is not more effective than aspirin alone in reducing the rate of MI, stroke, or death from cardiovascular causes among patients with stable cardiovascular disease or multiple cardiovascular risk factors. By contrast, benefit may be expected among individuals with symptomatic atherothrombotic disease.

Coronary Arterial Stenting

A multicenter, randomized, controlled trial, Clopidogrel Plus aspirin vs Ticlopidine Plus aspirin in Stent Patients Study (CLASSICS) included 1020 patients undergoing PCI who received either aspirin (325 mg qd) plus ticlopidine (250 mg BID), aspirin plus clopidogrel (75 mg daily), or aspirin plus front-loaded clopidogrel (300 mg as an initial dose followed by 75 mg qd). Treatment was continued for 28 days after stent placement. Intravenous (IV) GPIIb/IIIa antagonists were not administered to patients enrolled in the trial. The primary safety endpoint was a composite of neutropenia, thrombocytopenia, bleeding, and drug discontinuation for adverse events (noncardiac). The secondary efficacy endpoint was a composite of MI, target vessel revascularization, and cardiovascular death. The primary endpoint was reached in 9.1% of ticlopidine-treated patients, 6.3% of clopidogrel-treated patients, and 2.9% of front-loaded clopidogrel-treated patients. Early drug discontinuation occurred in 8.2%, 5.1%, and 2.0% of patients, respectively. The most common adverse events prompting drug discontinuation were allergic reactions, GI distress, and skin rashes. The secondary cardiovascular endpoint was reached by 0.9%, 1.5%, and 1.3% of patients, respectively.

The importance of adequate platelet inhibition in patients undergoing PCI was confirmed in the PCI-CURE study. A total of 2658 patients undergoing PCI were randomized to double-blind treatment with clopidogrel or placebo (aspirin alone) for, on average, 6 days before the procedure followed by 4 weeks of open-label thienopyridine (after which study drug was resumed for 8 months). The primary endpoint (cardiovascular death, MI, or urgent target vessel revascularization within 30 days) was reached in 4.5% of clopidogrel-treated patients and 6.4% of placebo-treated patients (30% relative risk reduction). Long-term administration of clopidogrel was associated with a lower rate of death, MI, or any revascularization with no increased bleeding complications.

Non-ST-Segment Elevation Myocardial Infarction (NSTEMI) and Unstable Angina

The benefit of therapy with aspirin and clopidogrel was investigated in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial. A total of 12,562 patients experiencing an ACS without ST-segment elevation received clopidogrel (300 mg immediately, 75 mg daily) plus aspirin (75–325 mg daily) or aspirin alone for 3–12 months. The composite of death, MI, or stroke occurred in 9.3% and 11.4 % of patients, respectively (RR reduction 20%). In hospital refractory ischemia, congestive heart failure, and revascularization procedures were also less frequent in clopidogrel-treated patients. There was a greater risk of major hemorrhage with combination therapy (3.7% versus 2.7%, RR 1.38); however, life-threatening bleeding and hemorrhagic stroke occurred at similar rates between groups.

Pre-PCI Treatment, Duration of Therapy, and Clinical Benefit

The CREDO (Clopidogrel for the Reduction of Events During Observation) trial evaluated the long-term benefit (12 months) of treatment with clopidogrel after PCI as well as the potential benefit of initiating clopidogrel with a preprocedure loading dose (both in addition to aspirin therapy). A total of 2116 patients scheduled for elective PCI were randomly assigned to receive clopidogrel (300 mg) or placebo 3 to 24 hours before PCI. All patients received aspirin (325 mg). A majority of patients had either a recent MI or unstable angina as an indication for PCI. Thereafter, all patients received clopidogrel (75 mg daily) through day 28. From day 29 through 12 months, patients in the loading dose group received clopidogrel (75 mg daily) or placebo. Both groups continued to receive standard therapy including aspirin (81–325 mg daily). Pretreatment with clopidogrel was associated with a statistically nonsignificant 18.5% RRR for the combined endpoint of death, MI or target vessel revascularization at 28 days.

To better determine the optimal dosage for clopidogrel loading, the Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty (ARMYDA-2) trial randomized patients scheduled to undergo PCI to either a 300 mg or 600 mg loading dose of clopidogrel. The 600 mg loading dose was associated with a decrease in the primary endpoint of death, MI, or target vessel revascularization (4% versus 12%, P = 0.041) without a significant increase in bleeding.

Duration of Dual Antiplatelet Therapy After PCI

In the DAPT study patients were enrolled after they had undergone a coronary stent procedure in which a drug-eluting stent (DES) was placed. After 12 months of treatment with a thienopyridine drug (clopidogrel or prasugrel) and aspirin, patients were randomly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months; all patients continued receiving aspirin. The coprimary efficacy endpoints were stent thrombosis and major adverse cardiovascular and cerebrovascular events (CVEs) (a composite of death, MI, or stroke) during the period from 12 to 30 months. The primary safety endpoint was moderate or severe bleeding. A total of 9961 patients were randomly assigned to continue thienopyridine treatment (most were receiving clopidogrel) or to receive placebo. Continued treatment with thienopyridine, as compared with placebo, reduced the rates of stent thrombosis (0.4% versus 1.4%, HR 0.29; 95% CI 0.17–0.48; P < 0.001) and major adverse cardiovascular and CVEs (4.3% versus 5.9%, HR 0.71; 95% CI 0.59–0.85; P < 0.001). The rate of MI was lower with thienopyridine treatment than with placebo (2.1% versus 4.1%, HR 0.47; P < 0.001). The rate of death from any cause was 2.0% in the group that continued thienopyridine therapy and 1.5% in the placebo group (HR 1.36; 95% CI 1.00–1.85; P = 0.05). The rate of moderate or severe bleeding was increased with continued thienopyridine treatment (2.5% versus 1.6%, P = 0.001). An elevated risk of stent thrombosis and MI was observed in both groups during the 3 months after discontinuation of thienopyridine treatment. DAPT beyond 1 year after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and major adverse cardiovascular and CVEs but was associated with an increased risk of bleeding.

Clinical Decision-Making and Dual Antiplatelet Therapy

Complex PCI is associated with higher ischemic risk, which can be mitigated by long-term DAPT. However, concomitant high bleeding risk (HBR) may also be present, making it unclear whether short or long-term DAPT should be prioritized. A study by Costa and colleagues investigated the effects of ischemic (by PCI complexity) and bleeding (by PRECISE-DAPT [PREdicting bleeding Complications in patients undergoing stent Implantation and SubsequEnt Dual AntiPlatelet Therapy] score) risks on clinical outcomes and on the impact of DAPT duration after coronary stenting. Complex PCI was defined as ≥ three stents implanted and/or ≥ three lesions treated, bifurcation stenting, and/or stent length > 60 mm, and/or chronic total occlusion revascularization. Ischemic and bleeding outcomes in high (≥ 25) or nonhigh (< 25) PRECISE-DAPT strata were evaluated based on randomly allocated duration of DAPT. Among a total of 14,963 patients from eight randomized trials, 3118 underwent complex PCI and experienced a higher rate of ischemic, but not bleeding, events. Long-term DAPT in non-HBR patients reduced ischemic events in both complex (absolute risk difference: − 3.86%; 95% CI − 7.71 to + 0.06) and noncomplex PCI strata (absolute risk difference: − 1.14%; 95% CI − 2.26 to − 0.02), but not among HBR patients, regardless of complex PCI features. The bleeding risk according to the TIMI scale was increased by long-term DAPT only in HBR patients, regardless of PCI complexity.

ST-Segment Elevation Myocardial Infarction (STEMI)

The CLARITY-TIMI 28 trial and the Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study (COMMIT/CCS-2-Clopidogrel) trial suggested a role for clopidogrel in the treatment of ST-segment elevation MI (STEMI). In the CLARITY-TIMI 28 study, addition of clopidogrel (300 mg loading dose, then 75 mg/day) to a regimen of aspirin plus thrombolysis before angiography improved infarct-related artery patency and reduced ischemic complications in patients who presented within 12 hours of onset of STEMI. The primary efficacy endpoint (a composite of infarct-related arterial occlusion [TIMI grade 0/1], death or recurrent MI before angiography) was reduced by 36% with clopidogrel, with the effect being driven predominantly by a reduction in arterial reocclusion. There was no increase in major bleeding or intracranial hemorrhage.

In the COMMIT trial, 45,852 patients with STEMI or bundle branch block (93%) and ST-segment depression (7%) were randomized to clopidogrel 75 mg daily or placebo in addition to aspirin 162 mg daily and usual care. Treatment with clopidogrel was associated with a 9% (95% CI 3%–14%) reduction in death, re-infarction, or stroke (2121 [9.2%] clopidogrel versus 2310 [10.1%] placebo, P = 0.002). This was accompanied by a 7% reduction in all-cause mortality (1726 [7.5%] versus 1845 [8.1%], P = 0.03). Similar to CLARITY-TIMI 28, there was no increase in overall bleeding, or bleeding among patients receiving fibrinolytic therapy.

Clopidogrel Pharmacodynamic Response Variability

High on-treatment platelet reactivity, defined as 1) platelet reactivity index > 50% by vasodilator stimulated phosphoprotein phosphorylation (VASP –P) analysis; 2) > 235 to 240 P2Y ₁₂ reaction units by VerifyNow P2Y ₁₂ assay; 3) > 46% maximal 5 μmol/l ADP-induced aggregation; and 4) > 468 arbitrary aggregation units/min in response to ADP by Multiplate analyzer has been proposed to be a predictor of outcome following PCI. The Gauging Responsiveness with a VerifyNow assay-Impact on Thrombosis and Safety (GRAVITAS) trial randomized 2214 patients with high on-treatment platelet reactivity (HPR) 12–24 hours after PCI with drug-eluting stents to high dose clopidogrel (600 mg initial dose, 150 mg daily thereafter) versus standard dose clopidogrel (no additional loading dose, 75 mg daily thereafter). Although high-dose clopidogrel provided a 22% absolute reduction in on-treatment platelet reactivity at 30 days (62% absolute reduction, 95% CI 59%–65% versus 40%, 95% CI 37%–43%; P < 0.001), at 6 months there was no significant difference in death from cardiovascular causes, nonfatal MI, or stent thrombosis. A secondary analysis of GRAVITAS determined the relationship between on-treatment platelet reactivity and cardiovascular outcomes. On-treatment reactivity of < 208 P2Y12 reaction units was associated with a significantly lower risk of the primary endpoint at 60 days (HR 0.23; 95% CI 0.05–0.98; P = 0.047) even after adjustment for other predictors of outcome. Taken together, these data suggest that on-treatment platelet reactivity does correlate with the risk of adverse cardiac events; however, multiple randomized trials have failed to translate the initial observations to routine clinical practice that includes dose adjustment based on either platelet activity or genetic polymorphisms for the CYP 2C19 gene (see section on pharmacogenomics).

MitraClip Implantation and Transcutaneous Mitral Valve Replacement (TMVR)

The administration of periprocedural antiplatelet and anticoagulant agents for patients receiving MitraClip implantation is important for reducing the risk of stroke, systemic embolism, and device thrombosis. However, no evidence-based guidelines have yet addressed the choice or duration of antiplatelet and anticoagulant regimens; thus current choices remain contingent on the operators’ experience and discretion. Many patients undergoing MitraClip or TMVR have coexisting morbidities such as atrial fibrillation requiring anticoagution. In the EVEREST trials, a regimen of aspirin 325 mg daily for 6–12 months was used. Clopidogrel at a dose of 75 mg daily was given for 1 month.

Atrial Septal Defect / Patent Foramen Ovale (ASD/PFO) Percutaneous Closure

In patients undergoing ASD/PFO closure, a postprocedural antithrombotic therapy regimen typically includes a combination of aspirin 75–325 mg daily plus clopidogrel 75 mg daily for 1–3 months followed by aspirin monotherapy for an additional 3–5 months.

Left Atrial Appendage (LAA) Closure

The patient population for whom left atrial appendage (LAA) closure (or exclusion) is recommended has a contraindication for long-term anticoagulation due to high risk of bleeding. A brief course of DAPT post procedure is generally administered followed by long-term aspirin monotherapy. The European Heart Rhythm Society consensus recommends using DAPT for up to 6 months after device implantation in patients with contraindications to OAC. In patients with a prohibitive risk of bleeding, a single antiplatelet agent may be reasonable.

Pharmacodynamics

Prasugrel, a third-generation thienopyridine P2Y ₁₂ inhibitor, was approved by the US Food and Drug Administration (FDA) in July 2009 for patients with ACS undergoing PCI.

Pharmacokinetics

Prasugrel, a prodrug, undergoes rapid deesterification to an intermediate thiolactone, which is then converted to the active metabolite via a single CYP-dependent step. Maximal plasma concentrations of prasugrel’s active metabolite are reached within 0.5 hours after oral administration. Inhibition of ADP binding to the platelet P2Y ₁₂ receptor begins 15–30 minutes after administration of a 60 mg loading dose, and a maximal 60%–70% platelet inhibition is achieved at 2–4 hours. During maintenance therapy with 10 mg daily dosing, there is a steady state of 50% platelet inhibition. After discontinuation of prasugrel, platelet aggregation returns to pretreatment levels within 7–10 days.

When compared to clopidogrel, administration of prasugrel results in earlier production and greater concentration of the equipotent active metabolites. Subsequently, prasugrel produces a more rapid onset and more consistent and greater level of platelet inhibition than clopidogrel in healthy subjects and patients with CAD.

Safety

In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38 (n = 13608), major bleeding was observed in 2.4% of patients treated with prasugrel and 1.8% of patients receiving clopidogrel (HR 1.32; 95% CI 1.03–1.68; P = 0.03). Prasugrel-treated patients experienced a higher incidence of life-threatening bleeding (1.4% versus 0.9%, P = 0.01) and fatal bleeding, including ICH (0.4% versus 0.1%, P = 0.002). Bleeding risks were greatest in patient’s ≥ 75 years old, those with a history of TIA or stroke, and those weighing < 60 kg. As a result, prasugrel is contraindicated in patients with a history of TIA or stroke, and a dosage of 5 mg daily should be considered for patients < 60 kg. In patient’s ≥ 75 years of age, prasugrel is generally not recommended and should be used only after careful consideration of the potential risks and benefits.

Acute Coronary Syndrome

The benefit of prasugrel in patients with ACS was demonstrated in the TRITON-TIMI 38 trial. Moderate-to high-risk ACS patients scheduled to undergo PCI were randomized to either prasugrel (60 mg loading dose and 10 mg maintenance dose) or clopidogrel (300 mg loading dose and 75 mg maintenance dose) for 6–15 months. The primary endpoint of death from cardiovascular causes, nonfatal MI, or nonfatal stroke was observed in 9.9% of patients receiving prasugrel and 12.1% of patients receiving clopidogrel (HR 0.81; 95% CI 0.73–0.90; P < 0.001). There was also a decrease in the secondary endpoints of MI (7.4% versus 9.7%, P < 0.001), urgent target-vessel revascularization (2.5% versus 3.7%, P < 0.001), and stent thrombosis (1.1% versus 2.4%, P < 0.001) with prasugrel versus clopidogrel.

Pharmacodynamics

Ticagrelor is a high-affinity ADP analogue that causes reversible inhibition of the P2Y ₁₂ receptor. Unlike the thienopyridines, ticagrelor does not require metabolic activation or conversion for platelet inhibition; however, an active metabolite exerts an equally potent effect.

Pharmacokinetics

Ticagrelor is rapidly absorbed and undergoes enzymatic degredation to an active metabolite, which has similar pharmokinetics to the parent compound. Due to its rapid absorption, plasma concentrations of ticagrelor peak 1–3 hours after oral administration in a dose-dependent manor. This results in an average of 60%–80% inhibition of ADP-induced platelet aggregation 2–4 hours after a 180-mg loading dose. Plasma half-life is 6–13 hours, necessitating twice-daily administration.

As compared to clopidogrel, ticagrelor administration results in earlier, more robust, and more consistent and pronounced platelet inhibition. In patients with NSTEMI previously treated with clopidogrel, ticagrelor administration provided further platelet inhibition, regardless of the patient’s level of responsiveness to clopidogrel.

Adverse Effects

In the Study of Platelet Inhibition and Patient Outcomes (PLATO) (n = 18,624), ticagrelor plus aspirin versus clopidogrel plus aspirin was associated with a higher rate of major bleeding not related to CABG (4.5% versus 3.8%, P = 0.03). Fatal bleeding did not differ between groups. There was no significant difference in the rates of overall major bleeding between ticagrelor and clopidogrel (11.6% versus 11.2%, P = 0.43). There was a numerically higher incidence of ICH among patients randomized to ticagrelor plus aspirin. Based on a comprehensive post hoc analysis of the US cohort of PLATO, a boxed warning was included in FDA approval stating that the use of ticagrelor with maintenance doses of aspirin above 100 mg daily decreased its effectiveness. Thus, an aspirin dose of ≤ 100 mg daily is recommended.

Acute Coronary Syndrome

The benefits of ticagrelor in ACS were established in the PLATO trial. Patients were randomized to either ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300–600 mg loading dose, 75 mg daily thereafter). At 12 months, the primary composite endpoint of death from vascular causes, MI, or stroke occurred in 9.8% of the ticagrelor group and 11.7% of the clopidogrel group (HR 0.84; 95% CI 0.77–0.92; P < 0.001). Secondary endpoints, including MI (5.8% in the ticagrelor group versus 6.9% in the clopidogrel group, P = 0.005) and death from vascular causes (4.0% versus 5.1%, P = 0.001), were also reduced by ticagrelor. As a result of these data, ticagrelor has a class I, level of evidence B, recommendation in patients undergoing PCI after ACS.

Long-Term Use of Ticagrelor

In the PEGASUS study, 21,162 patients who had experienced a MI 1 to 3 years earlier were randomized to ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. All patients received low-dose aspirin and were followed for a median of 33 months. The primary efficacy endpoint was the composite of cardiovascular death, MI, or stroke. The primary safety endpoint was TIMI major bleeding. The two ticagrelor doses each reduced, as compared with placebo, the rate of the primary efficacy endpoint, with Kaplan–Meier rates at 3 years of 7.85% in the group that received 90 mg of ticagrelor twice daily, 7.77% in the group that received 60 mg of ticagrelor twice daily, and 9.04% in the placebo group (HR for 90 mg of ticagrelor versus placebo 0.85; 95% CI 0.75–0.96; P = 0.008; HR for 60 mg of ticagrelor versus placebo 0.84; 95% CI 0.74–0.95; P = 0.004). Rates of TIMI major bleeding were higher with ticagrelor (2.60% with 90 mg and 2.30% with 60 mg) than with placebo (1.06%) ( P < 0.001 for each dose versus placebo); the rates of intracranial hemorrhage or fatal bleeding in the three groups were 0.63%, 0.71%, and 0.60%, respectively.

Peripheral Artery Disease

In the EUCLID trial, 13,885 patients with symptomatic peripheral artery disease were randomized to receive monotherapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Patients were eligible if they had an ABI of 0.80 or less or had undergone previous revascularization of the lower limbs. The primary efficacy endpoint was a composite of adjudicated cardiovascular death, MI, or ischemic stroke. The primary safety endpoint was major bleeding. The median follow-up was 30 months. The mean baseline ABI in all patients was 0.71, 76.6% of the patients had claudication, and 4.6% had critical limb ischemia. The primary efficacy endpoint occurred in 751 of 6930 patients (10.8%) receiving ticagrelor and in 740 of 6955 (10.6%) receiving clopidogrel (HR 1.02; 95% CI 0.92–1.13; P = 0.65). In each group, acute limb ischemia occurred in 1.7% of the patients (HR 1.03; 95% CI 0.79–1.33; P = 0.85) and major bleeding in 1.6% (HR 1.10; 95% CI 0.84–1.43; P = 0.49). The routine use of ticagrelor is not supported in the management of patients with PAD.

ST-Segment Elevation Myocardial Infarction

The efficacy of ticagrelor in the long-term post STEMI treated with fibrinolytic therapy remains uncertain. To evaluate the efficacy of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy, an international, multicenter, randomized, open-label with blinded endpoint adjudication trial enrolled 3799 patients (age < 75 years) with STEMI receiving fibrinolytic therapy. Patients were randomized to ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300–600 mg loading dose, 75 mg daily thereafter). The key outcomes were cardiovascular mortality, MI, or stroke, and the same composite outcome with the addition of severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events at 12 months. The combined outcome of cardiovascular mortality, MI, or stroke occurred in 129 of 1913 patients (6.7%) receiving ticagrelor and in 137 of 1886 patients (7.3%) receiving clopidogrel (HR 0.93; 95% CI 0.73–1.18; P = 0.53). The composite of cardiovascular mortality, MI, stroke, severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events occurred in 153 of 1,913 patients (8.0%) treated with ticagrelor and in 171 of 1886 patients (9.1%) receiving clopidogrel (HR 0.88; 95% CI 0.71–1.09; P = 0.25). The rates of major, fatal, and intracranial bleeding were similar between the ticagrelor and clopidogrel groups.

Platelet-Directed Therapies and Coronary Stent Thrombosis

Coronary stents improve outcomes in patients undergoing PCI, particularly those with ACS. However, stent thrombosis is a largely preventable and devastating complication associated with high rates of morbidity and mortality. A majority of events occur between 0 and 30 days after PCI and the expected rate of thrombosis during this time is < 1%. Late stent thrombosis, defined as thrombosis occurring greater than 30 days after PCI, occurs at a 0.2%–0.6% rate. The overall incidence of stent thrombosis is lessening with time, operator experience, and stent materials and design.

While the most common cause of stent thrombosis is nonadherence to DAPT, contributing factors include increased platelet activation, thrombin generation, and inflammation associated with ACS. Drug eluting stents (DES) impair endothelial healing, helping to attenuate in-stent restenosis while also increasing the risk of thrombus formation. Examination of necropsy samples from patients who underwent DES insertion revealed that the ratio of nonendothelial cell covered stent struts to total struts was the best predictor of subsequent thrombosis. Despite the fact that bare-metal stents (BMS) are thought to develop an endothelial cell monolayer more completely than DES, there remains no discernable difference in the rates of stent thrombosis between DES and BMS within the first 12 months after PCI.

Stent thrombosis typically presents as STEMI and is associated with significant morbidity and mortality. Accordingly, the American College of Cardiology (ACC) and the American Heart Association (AHA) have established guidelines regarding the use and length of antiplatelet therapy in patients with ACS following PCI (see Table 8.4 ). Aspirin should be continued indefinitely and a P2Y ₁₂ inhibitor should be continued for at least 1 year unless the morbidity from bleeding risk outweighs the expected benefit.

On-Treatment Platelet Reactivity Testing

Although the mechanisms of clopidogrel dose-response variability are not yet completely elucidated, multiple lines of evidence strongly suggest that variable active metabolite generation is the primary explanation. Variable levels of active metabolite generation following clopidogrel administration may be explained by (1) variable intestinal absorption affected by an ABCB1 gene polymorphism, (2) functional variability in P450 activity due to drug-to-drug interactions, and (3) single nucleotide polymorphisms (SNPs) of specific CYP450 genes. Coadministration of clopidogrel with proton pump inhibitors, lipophilic statins, and calcium channel blockers metabolized via CYP2C19 and CYP3A4 causes a diminished pharmacodynamics response to clopidogrel. Controversy remains, however, as to the clinical consequences of these interactions with respect to ischemic events.

High On-Treatment Platelet Reactivity and Post-PCI Events

The first prospective study demonstrating the link between HPR and ischemic events in patients treated with stents was the PREPARE POST-STENTING study. In this study by Gurbel et al., of 192 patients undergoing elective PCI and 300 mg loading dose of clopidogrel plus 75 mg daily maintenance dose, those patients with the highest quartile of on-treatment platelet reactivity had an OR of 2.7 for 6 month post-PCI ischemic events. Although this study employed light transmittance aggregometry, subsequent studies have used the VerifyNow P2Y ₁₂ assay, the VASP-phosphorylation assay, and the Multiplate analyzer to demonstrate that on-treatment platelet reactivity is an independent risk factor for ischemic events after PCI.

In order for platelet reactivity testing to be clinically useful, optimal cutpoints or “thresholds” must be established. In a majority of prior studies, cutpoints have been determined with receiver-operating characteristic (ROC) curve analysis in patients undergoing elective PCI. Despite the use of different ischemic endpoints (CV death, MI, stent thrombosis, and urgent revascularization), studies have suggested that the optimal cutpoint for VASP-PRI testing is between 48% and 53%. Similar studies using the VerifyNow P2Y ₁₂ assay have demonstrated that a cutoff value below 240 P2Y ₁₂ reaction units (PRU) is prognostic for thrombotic events (CV death, stent thrombosis, and nonfatal MI). While the negative predictive value for these cutoffs is high, the positive predictive value is low for all assays, likely because on-treatment platelet reactivity is not the only determinant of post-PCI ischemic events. The consistency of the platelet reactivity cutoffs determined by multiple studies suggests that there may be a threshold level of platelet reactivity below which ischemic events may be prevented. Given the bleeding risk associated with dual antiplatelet therapy after PCI, there may be a therapeutic window for P2Y ₁₂ receptor antagonist therapy associated with both a reduction in thrombotic events and a low rate of bleeding. Although there have been no large studies that have established a “cutpoint” for gauging bleeding risk, several observational studies have reported an association between low platelet reactivity on clopidogrel and increased in-hospital bleeding after PCI.

Pharmacogenomics and P2Y ₁₂ Inhibitor Therapy

Studies examining in vitro metabolism of clopidogrel and clinical outcomes have noted significant unfavorable variability in the production of its active metabolite related to genetic variation in patients. As a result, the FDA added a “boxed warning” to clopidogrel suggesting methods for testing for genetic differences and suggesting potential alternative drug therapies. No recommendations were made suggesting specific clinical scenarios in which genetic testing should be undertaken.

Although genetic variation in the generation of clopidogrel’s active metabolite is a function of heterogeneity in intestinal absorption, hepatic CYP metabolism, and P2Y ₁₂ receptor structure, it appears that variation in the CYP2C19 appears to be the most consistent determinant of differences in response to clopidogrel. Twenty-five SNPs lie within the CYP2C19 gene, of which the most clinically relevant variants are CYP2C19*2, CYP2C19*3, and CYP2C19*17. Of these variants, the first two account for greater than 90% of cases of poor metabolism and the third is responsible for a gain of function that results in increased metabolism. Because of the differential prevalence of certain SNPs within the nonwhite population, the prevalence of the poor metabolizer genotypes ranges from 20%–30% in white individuals, from 30%–45% in African Americans, and up to 50%–65% in East Asians.

The genetic variability in response seen with clopidogrel does not seem to extend to the newer P2Y ₁₂ agents, prasugrel and ticagrelor. Prasugrel undergoes metabolism to its active metabolite via rapid deesterification to an intermediate, thiolactone, which is then converted to active metabolite via a single CYP-dependent step that is more uniform, rapid, and complete than clopidogrel metabolism. As a result, prasugrel metabolism is not subject to variation in CYP2C19. Similarly, ticagrelor does not require CYP-dependent metabolism, and is thought to provide more consistent inhibition of P2Y ₁₂ receptors regardless of variation in CYP2C19. Multiple meta-analysis have correlated CYP2C19 genotype and clinical outcomes in post-PCI patients treated with clopidogrel. In pooling several studies of between 8000 and 12,000 high-risk patients, these meta-analyses reported that adverse cardiac outcomes increased by 30% and there was a twofold-higher risk of stent thrombosis per reduced function variant. The risk of adverse outcomes and stent thrombosis increased in a step-wise fashion with an increasing number of reduced-function alleles. The risk may be particularly high in Asian populations where CYP2C19 polymorphisms are prevalent.

TAILOR-PCI is the largest genotype-based cardiovascular clinical trial randomizing participants to conventional DAPT or prospective genotyping-guided DAPT. Enrolled patients completed surveys before and 6 months after randomization. A total of 1327 patients completed baseline surveys of whom 28%, 29%, and 43% were from Korea, Canada, and the US, respectively. Most patients (77%) valued identifying pharmacogenetic variants; however, fewer Korean (44%) as compared with Canadian (91%) and American (89%) patients identified pharmacogenetics as being important ( P < 0.001). After adjusting for age, sex, and country, those who were confident in their ability to understand genetic information were significantly more likely to value identifying pharmacogenetic variants (OR 30.0; 95% CI 20.5–43.8). Only 21% of Koreans, as opposed to 86% and 77% of patients in Canada and the United States, respectively, were confident in their ability to understand genetic information ( P < 0.001).

After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as MI, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights. Among 1815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 versus 8.7 per 100 patient-years; adjusted HR 2.26; 95% CI 1.18–4.32; P = 0.013). Similar results were observed among 1210 patients with acute coronary syndromes at the time of PCI (adjusted HR 2.87; 95% CI 1.35–6.09; P = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted HR 1.14; 95% CI 0.69–1.88; P = 0.60).

What Is the Role of Platelet Function Testing in Routine Clinical Practice?

To establish the clinical utility of platelet function testing several criteria must be met. First, there must be a reproducible and standardized assay to measure genotype or platelet function. Second, studies must consistently link specific genotypes or platelet function measures with clinical outcomes. Third, recommendations for modification of pharmacotherapy must be established, and these management strategies must be validated in appropriately powered randomized trials to demonstrate their efficacy and safety.

In the TRIGGER-PCI trial, patients with stable CAD and high on-treatment platelet reactivity (HTPR) (> 208 PRUs by the VerifyNow test) after elective PCI with at least one DES were randomly assigned to either prasugrel 10 mg daily or clopidogrel 75 mg daily. Platelet reactivity of the patients on the study drug was reassessed at 3 and 6 months. The study was stopped prematurely for futility because of a lower than expected incidence of the primary endpoint. In 212 patients assigned to prasugrel, PRU decreased from 245 (225–273 median [interquartile range]) at baseline to 80 (42–124) at 3 months, whereas in 211 patients assigned to clopidogrel, PRU decreased from 249 (225–277) to 241 (194–275) ( P < 0.001 versus prasugrel). The primary efficacy endpoint of cardiac death or MI at 6 months occurred in no patient on prasugrel versus one patient who was on clopidogrel. The primary safety endpoint of noncoronary artery bypass graft TIMI major bleeding at 6 months occurred in three patients (1.4%) on prasugrel versus one patient (0.5%) on clopidogrel.

The ARCTIC investigators randomly assigned 2440 patients scheduled for PCI to a strategy of platelet-function monitoring, with drug adjustment in patients who had a poor response to antiplatelet therapy, or to a conventional strategy without monitoring and drug adjustment. The primary endpoint was the composite of death, MI, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation. For patients in the monitoring group, the VerifyNow P2Y ₁₂ and aspirin point-of-care assays were used in the catheterization laboratory before stent implantation and in the outpatient clinic 2 to 4 weeks later. In the monitoring group, high platelet reactivity in patients taking clopidogrel (34.5% of patients) or aspirin (7.6%) led to the administration of an additional bolus of clopidogrel, prasugrel, or aspirin along with glycoprotein IIb/IIIa inhibitors during the procedure. The primary endpoint occurred in 34.6% of the patients in the monitoring group, as compared with 31.1% of those in the conventional-treatment group (HR 1.13; 95% CI 0.98 to 1.29; P = 0.10). The main secondary endpoint, stent thrombosis or any urgent revascularization, occurred in 4.9% of the patients in the monitoring group and 4.6% of patients in the conventional-treatment group (HR 1.06; 95% CI 0.74 to 1.52; P = 0.77). The rate of major bleeding events did not differ significantly between groups.

The ANTARCTIC investigators conducted a multicenter, open-label, blinded-endpoint, randomized controlled superiority study in patients aged 75 years or older who had undergone PCI for ACS to prasugrel 5 mg daily with dose or drug adjustment in case of inadequate response (monitoring group; n = 442) or oral prasugrel 5 mg daily with no monitoring or treatment adjustment (conventional group; n = 435). Platelet function testing was performed 14 days after randomization and repeated 14 days after treatment adjustment in patients in the monitoring group. The primary endpoint was a composite of cardiovascular death, MI, stroke, stent thrombosis, urgent revascularization, and Bleeding Academic Research Consortium-defined bleeding complications (types 2, 3, or 5) at 12 months’ follow-up. The primary endpoint occurred in 120 (28%) patients in the monitoring group compared with 123 (28%) patients in the conventional group (HR 1.003; 95% CI 0.78–1.29; P = 0.98). Rates of bleeding events did not differ significantly between groups.