Abstract

Atherosclerosis is a slowly progressive disease of the arteries that may undergo a sudden transition to life-threatening conditions following thrombus formation at sites of plaque disruption (atherothrombosis). Platelets play a key role in such late events. This review discusses the evidence supporting the use of oral antiplatelet agents in the long-term prevention of atherothrombotic events.

In ST-elevation acute myocardial infarction and in non-ST elevation acute coronary syndromes, dual antiplatelet therapy with aspirin and clopidogrel has been proved effective in reducing death and myocardial infarction, and prolonged treatment at least up to 1 year is associated with sustained benefit. In some high-risk patients, especially in the setting of urgent percutaneous coronary interventions, adjunctive glycoprotein IIb–IIIa inhibitors confer additional benefit. In chronic coronary artery, cerebrovascular and peripheral arterial disease aspirin reduces the risk of cardiovascular events in both men and women; the adjunctive benefit of clopidogrel is questionable here. In primary prevention, the administration of aspirin is recommended only among patients at high risk.

Introduction

The term ‘atherothrombosis’ was originally coined to define thrombosis occurring at a site of an atherosclerotic plaque. It may involve multiple arterial beds and is the major cause of myocardial infarction (MI), stroke, and vascular death. Atherothrombosis involves the interacting mechanisms of plaque inception, progression, and complications, as well as thrombus formation.

Atherosclerosis is a slowly progressive disease occasionally complicated, in a sudden transition from a stable disease to a life-threatening condition, by the denudation of the intima, due to intimal erosion or plaque disruption, followed by thrombosis.1

Endothelial dysfunction is a common denominator in all phases of atherosclerosis.2 Among the many relevant functions of the endothelium, covering the arterial intima in normal conditions—inhibiting vascular tone, maintaining a perm-selective barrier, inhibiting cell growth in outer layers of the vessel wall, providing a thrombo-resistant surface, and inhibiting the adhesion of circulating cells—the loss of the last two is particularly relevant in cases of plaque complications. In most cases, the thin fibrous cap separating the lipid-rich core of the plaque from the lumen tears or breaks, leading to the exposure of subendothelial highly thrombogenic components, such as tissue factor—the main activator of coagulation—and collagen. Platelet activation occurs at such sites. The majority of such acute vascular lesions resolve spontaneously through a repair phenomenon involving mural thrombosis (Figure 1). However, in a certain proportion of cases, platelet-initiated mural thrombosis progresses to a degree causing impairment of flow or the total occlusion of the vessel, phenomena at the basis of acute coronary syndromes (ACS).

Figure 1

The process of atherothrombosis. Atherothrombosis begins with the development of an atherosclerotic plaque within the arterial intima. Rupture or erosion of the plaque exposes thrombogenic components to the flowing blood, causing platelets to adhere to the damaged area. Thrombi may then become incorporated into the plaque, increasing its size and rapidly decreasing the arterial lumen. By this mechanism, or by the decrease of the arterial lumen caused by the slow progression of atherosclerosis, the process may cause secondary forms of myocardial ischaemia when the distal microcirculatory vasodilatory reserve is exhausted. Occasionally, however, through the sudden growth of the arterial thrombus or its dislodgement and embolization, atherothrombosis causes primary reductions of blood flow, causing an acute cardiovascular event.

Figure 1

The process of atherothrombosis. Atherothrombosis begins with the development of an atherosclerotic plaque within the arterial intima. Rupture or erosion of the plaque exposes thrombogenic components to the flowing blood, causing platelets to adhere to the damaged area. Thrombi may then become incorporated into the plaque, increasing its size and rapidly decreasing the arterial lumen. By this mechanism, or by the decrease of the arterial lumen caused by the slow progression of atherosclerosis, the process may cause secondary forms of myocardial ischaemia when the distal microcirculatory vasodilatory reserve is exhausted. Occasionally, however, through the sudden growth of the arterial thrombus or its dislodgement and embolization, atherothrombosis causes primary reductions of blood flow, causing an acute cardiovascular event.

Arterial thrombosis and antiplatelet agents

Platelets are essential for primary haemostasis, but also key players in atherothrombosis.3 By forming the first layer adhering to a damaged intima, all arterial thrombi are initially platelet-rich (white thrombi). When such thrombi progress to the total occlusion of the lumen, the thrombus becomes enriched of a large component of fibrin, trapping red blood cells (red thrombus). This typically occurs in ST-elevation myocardial infarction (STEMI) and is susceptible to lysis by fibrinolytic agents. In non-ST-elevation acute coronary syndromes (NSTE-ACS), the thrombus remains mostly platelet-rich, causing incomplete lumen occlusion and remaining resistant to fibrinolytic agents.4 Against such pathophysiological background, one can easily understand why antiplatelet therapy is so relevant in atherothrombosis. In a cohort study of 1358 consecutive patients admitted for a suspected ACS, subjects who had recently withdrawn oral antiplatelet therapy, despite a similar cardiovascular risk profile, had higher 30-day rates of death or MI (21.9 vs. 12.4%, P = 0.049) than prior users.5

Three at least partly complementary strategies provide effective antiplatelet therapy: (i) platelet cyclooxygenase-1 inhibition with aspirin, (ii) inhibition of platelet adenosine diphosphate P2Y12 receptor (ticlopidine, clopidogrel, prasugrel, AZD16140, and cangrelor), and (iii) inhibition of platelet glycoprotein (GP) IIb/IIIa (abciximab, tirofiban, and eptifibatide).

Aspirin, with a 325 mg loading dose and a 75–100 mg maintenance dose, is now widely recommended in primary and secondary prevention of vascular disease and is a mainstay of therapy in all patients with ACS.6,7 Additional antiplatelet treatments are used with aspirin in ACS. Such strategies will be briefly reviewed here.

Antiplatelet therapy in different clinical scenarios

ST-elevation myocardial infarction

Patients with STEMI generally have a total coronary occlusion. The therapeutic objective is to achieve a rapid, complete, and sustained myocardial reperfusion, first provided by a recanalization of the culprit coronary artery. This can be achieved by either primary percutaneous coronary intervention (PCI) or fibrinolytic therapy. Platelet inhibition is a necessary complement of both recanalization strategies.

In the ClOpidogrel and Metoprolol in Myocardial Infarction (COMMIT) Trial, among 45 852 patients with STEMI—about a half of whom treated with fibrinolysis—clopidogrel added to aspirin produced a significant absolute reduction of 0.9% in the composite endpoint of death, re-infarction or stroke and of 0.6% of death after 4 weeks, without excessive bleeding. The effect was consistent across a wide range of patients and independent of other treatments being used, with a benefit being more evident among patients admitted 0–6 h from symptoms onset when compared with patients arriving late or receiving fibrinolytic agents alone.8

In the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)–Thrombolysis in Myocardial Infarction (TIMI) 28 trial,9 the addition of clopidogrel to aspirin reduced the combined endpoint of an occluded infarct-related artery [Thrombolysis in Myocardial Infarction (TIMI) flow grade 0 or 1], in-hospital death or recurrent MI in patients receiving fibrinolysis. The reduction in cardiovascular death, MI, or stroke obtained with clopidogrel pre-treatment was consistent also among those patients who underwent PCI within 8 days from the admission.10

Clopidogrel appeared to improve clinical outcomes more likely by maintaining late coronary patency and preventing re-occlusion of open arteries rather than by facilitating early reperfusion. This speculation stems from a subanalysis of a cohort of the study patients in whom ST-segment resolution—an early non-invasive marker of coronary reperfusion—was analysed at 90 and 180 min after randomization: when patients were stratified according to ST-segment resolution categories, clopidogrel administration was associated with a significant reduction in the odds of an in-hospital death or MI in subjects who achieved partial [odds ratio (OR) 0.30, P = 0.003] or complete ST-segment resolution at 90 min (OR 0.49, P = 0.056), whereas a clinical benefit was not apparent in patients who had no ST-segment resolution.11

The hypothetical benefit deriving from ‘facilitated’ primary PCI was based on the premise that the pre-treatment with a drug potentially affecting coronary thrombus would decrease the thrombus burden, improve coronary flow before PCI, reduce the occurrence of distal embolization, and ultimately improve myocardial salvage.12 In a recent meta-analysis, Keeley et al.13 showed that, despite a two-fold higher initial TIMI grade 3 flow, facilitation strategies did not result in better clinical outcomes than primary PCI.

In the setting of STEMI, the patient profile, the estimated (absolute or relative) delay to primary PCI, and drug characteristics should help to draw an algorithm based on current evidence (Figure 2). Fibrinolytic agents achieve a vessel patency in two thirds of cases, but are not immediate in action, becoming effective about 90 min after their administration; in case PCI is performed before this time interval, it is likely that the patient does not benefit from the previous administration of fibrinolytic agents, but is however exposed to the adverse effect of increased bleeding. GP IIb–IIIa inhibitors (with abciximab being by far the most largely tested drug) do not have any fibrinolytic property, but are extremely useful in reducing the ‘thrombus burden’ and exert most of their benefit if administered ‘upstream’ (at the time of the first medical contact) and in higher-risk patients with a low bleeding profile. Adjunctive clopidogrel also appears to improve clinical outcomes more likely by preventing re-occlusion of open arteries rather than by facilitating early reperfusion.

Figure 2

A management algorithm for ST-elevation myocardial infarction (STEMI). The patient's profile and the estimated delay to primary PCI (PPCI) are main determinants of the management algorithm for such patients (Modified from Zimarino M et al.12). Relative delay to PPCI is door-to-balloon less door-to-needle time. Absolute delay to PPCI is door-to-balloon time. High-risk patients: subjects with a TIMI risk score28 for STEMI ≥4. GP, glycoprotein; PCI, percutaneous coronary intervention; TIMI, Thrombolysis in Myocardial Infarction. *GP IIb-IIIa inhibitors should be administered as first-line treatment.

Figure 2

A management algorithm for ST-elevation myocardial infarction (STEMI). The patient's profile and the estimated delay to primary PCI (PPCI) are main determinants of the management algorithm for such patients (Modified from Zimarino M et al.12). Relative delay to PPCI is door-to-balloon less door-to-needle time. Absolute delay to PPCI is door-to-balloon time. High-risk patients: subjects with a TIMI risk score28 for STEMI ≥4. GP, glycoprotein; PCI, percutaneous coronary intervention; TIMI, Thrombolysis in Myocardial Infarction. *GP IIb-IIIa inhibitors should be administered as first-line treatment.

Non-ST-elevation acute coronary syndromes and percutaneous coronary intervention

Patients with NSTE-ACS have a lower hospital mortality than STEMI (5 vs. 7%, respectively), but mortality rates become similar (12 vs. 13%) at 6 months; by 4 years, death rates are twice as high in patients with NSTE-ACS as in patients with STEMI.14

In the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial,15 among patients with NSTE-ACS receiving clopidogrel for 9–12 months in addition to aspirin, a significant 2.1% risk reduction for death, non-fatal MI, or stroke was observed compared with patients treated with aspirin alone; a 1% increase in major non-life-threatening bleeds occurred, however, among patients in the clopidogrel arm. In the subgroup of patients undergoing PCI, an absolute 2% reduction in the rate of death and MI was observed with adjunctive clopidogrel for 9 months when compared with the standard 4 weeks treatment after the procedure.16

Similarly, in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial,17 patients who were randomized to clopidogrel pre-treatment who continued to receive the drug up to 1 year showed a 3% absolute risk reduction (P = 0.02) in the composite of death, MI, or stroke. Event-free survival curves from both PCI-CURE and CREDO trials clearly continue to diverge after the first month (Figure 3), suggesting that the enhanced long-term antiplatelet protection decreases the incidence of all thrombotic events beyond stent thrombosis, including MI and strokes. Unfortunately, no data are available from these trials on long-term outcome, documenting the effect of this aggressive antiplatelet therapy beyond 1 year.

Figure 3

The occurrence of death or myocardial infarction (MI) as a function of time in the PCI-Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE)16 study, and of death, MI, or stroke in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial.17 Notice that in the PCI-CURE study, the PCI was performed after a median of 10 days from randomization, and only events occurring after PCI were taken into account. PCI, percutaneous coronary intervention.

Figure 3

The occurrence of death or myocardial infarction (MI) as a function of time in the PCI-Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE)16 study, and of death, MI, or stroke in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial.17 Notice that in the PCI-CURE study, the PCI was performed after a median of 10 days from randomization, and only events occurring after PCI were taken into account. PCI, percutaneous coronary intervention.

With the concern for stent thrombosis, current guidelines recommend clopidogrel 75 mg daily for a minimum of 1 month after implantation of a bare-metal stent and for 12 months after implantation of a drug-eluting stent, and ideally in all patients after a PCI who are not at high risk of bleeding.18 However, the additive effects of clopidogrel and aspirin still do not abolish platelet function completely; the residual platelet function, and—possibly even more relevant—the inter-individual variability of such residual platelet function, may have clinical relevance in certain high-risk scenarios.

Two strategies have documented an earlier and more profound platelet inhibition paralleled by a significant clinical relevance: intravenous GP IIb–IIIa inhibitors in adjunction with clopidogrel and aspirin19 and oral prasugrel, as an alternative to clopidogrel, in addition to aspirin.20 The addition of abciximab to aspirin and clopidogrel reduces the composite endpoint of death, MI, and urgent vessel revascularization in patients with NSTE-ACS and positive troponin undergoing PCI.21 More recently, prasugrel, in comparison with clopidogrel, was associated with significantly reduced rates of ischaemic events, including stent thrombosis, but with a somewhat increased risk of major bleeding in patients with NSTE-ACS undergoing PCI.22

Long-term cardiovascular disease prevention outside of acute situations

In secondary prevention, the Antithrombotic Trialists' Collaboration showed that aspirin (optimal daily dose: 75–150 mg) reduces the risk of death, MI, and stroke in both men and women.23

In chronic stable coronary artery disease, the addition of clopidogrel to aspirin was hypothesized to provide additional benefit with an acceptable increased bleeding risk. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study24 was designed to test the hypothesis that long-term treatment with a combination of clopidogrel plus aspirin may provide greater protection against cardiovascular events than aspirin alone in a broad population of patients at high risk. About 15 000 patients >45 years of age with either multiple atherothrombotic risk factors or documented cardiovascular (coronary, cerebral, or peripheral) disease were randomized to receive clopidogrel (75 mg/day) plus aspirin (75–162 mg/day) or aspirin alone for >2 years. Such ambitious primary hypothesis was not proven to be true, as the combined occurrence of MI, stroke, or death from cardiovascular causes was similar between patients receiving aspirin and clopidogrel (6.8%) and those receiving aspirin alone (7.3%, P = 0.22); the rate of bleeding was slightly higher among patients who received aggressive antiplatelet therapy (1.7 vs. 1.3%, P = 0.09).

The results of this large-scale study were clearly bimodal: adjunctive clopidogrel was associated with a higher rate of death from cardiovascular causes (3.9 vs. 2.2%, P = 0.01) among patients with multiple risk factors, but was associated with a lower mortality among subjects already with clinically evident vascular disease (6.9 vs. 7.9%, P = 0.046) (Figure 4).

Figure 4

Summary of the main results of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial.24 The rate of the primary efficacy endpoint [death, myocardial infarction (MI), and stroke] was similar in the two groups: 6.8% with clopidogrel plus aspirin and 7.3% with placebo plus aspirin; the rates of severe bleeding were 1.7 and 1.3% (P = 0.09), respectively. In the subgroup with clinically evident vascular disease (n = 12 153), the rate of death from cardiovascular (CV) causes was 6.9% with clopidogrel and 7.9% with placebo (P = 0.046). Conversely, the rate of death was higher with clopidogrel (3.9 vs. 2.2%, P = 0.01) among patients with multiple risk factors (n = 3284).

Figure 4

Summary of the main results of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial.24 The rate of the primary efficacy endpoint [death, myocardial infarction (MI), and stroke] was similar in the two groups: 6.8% with clopidogrel plus aspirin and 7.3% with placebo plus aspirin; the rates of severe bleeding were 1.7 and 1.3% (P = 0.09), respectively. In the subgroup with clinically evident vascular disease (n = 12 153), the rate of death from cardiovascular (CV) causes was 6.9% with clopidogrel and 7.9% with placebo (P = 0.046). Conversely, the rate of death was higher with clopidogrel (3.9 vs. 2.2%, P = 0.01) among patients with multiple risk factors (n = 3284).

In primary prevention, the use of aspirin to prevent cardiovascular events has been tested, but once again, the results varied. Among >40 000 healthy women aged >45 years, low-dose aspirin (100 mg every other day) compared with placebo reduced the risk of MI (P = 0.01) had no significant effect on the risk of stroke, but increased the risk of gastrointestinal bleeding requiring transfusion;25 the most consistent benefit of aspirin was observed among women aged ≥65 years. By contrast, the aggregate data on men show that aspirin therapy is associated with a significant 32% reduction (P = 0.001) in the risk of MI and a non-significant increase in the risk of stroke.

The European Society of Cardiology has recently renewed the recommendation to administer aspirin (75–150 mg daily) in all patients with documented cardiovascular disease—including diabetic subjects—unless contraindicated; in asymptomatic subjects, the recommendation is still vague, as ‘aspirin should only be considered when the 10-year risk of cardiovascular mortality is markedly increased and the blood pressure is controlled.’26

Conclusions

Atherothrombosis is a complex disease in which thrombus formation plays a major role. Plaque rupture is the most common trigger of arterial thrombosis. Autopsy studies have identified a thin-cap fibroatheroma as the single most accurate predictor of plaque rupture, but such information is not easily obtainable: only recently the in vivo measurement of the thickness of the fibrous cap has become possible with the development of intravascular optical coherence tomography, which provides high-resolution cross-sectional images of vascular tissues in the setting of interventional procedures.27 Although it is not possible to identify which specific subject will undergo a vascular event, antiplatelet therapy seems the single most effective strategy to confer long-term survival benefit to patients with atherosclerotic vascular disease. The aggressiveness (intensity) of this approach should however be individualized, with a careful evaluation of the benefit/risk balance.

Funding

Financial support provided by Daiichi Sankyo, Inc. and Eli Lilly and Company.

Conflict of interest: M. Z. has acted as a consultant to The Medicines Company. R. D. C. has acted as a consultant to AstraZeneca Pharmaceuticals LP, Bayer AG, Boehringer Ingelheim GmbH, and sanofi-aventis LLC, and has received research support from AstraZeneca Pharmaceuticals LP, GlaxoSmithKline plc, and Servier Laboratories.

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