Elsevier

Progress in Cardiovascular Diseases

Volume 52, Issue 2, September–October 2009, Pages 141-152
Progress in Cardiovascular Diseases

Aspirin Resistance

https://doi.org/10.1016/j.pcad.2009.05.001Get rights and content

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The Role of Platelets in Thrombotic Events

Under physiologic conditions, platelets circulate in blood as disc-shaped anucleate fragments without attaching to normal vessel wall. They play an important role during hemostasis by forming a clot at the site of vascular injury to prevent excessive blood loss. In the setting of pre-existing dysfunctional endothelium and atheroinflammatory conditions during acute coronary syndromes and following coronary interventions, platelet activation and aggregation are central to the development of

Rationale for Antiplatelet Therapy

Platelet activation and high platelet reactivity to agonists in acute coronary syndromes and following percutaneous coronary intervention (PCI) have been associated with stent thrombosis, restenosis, inflammation, and myocardial infarction.2, 3 Platelet activation is also associated with diabetes, hypertension, and hyperlipidemia.2 Through crosstalk with the coagulation system, platelets play a fundamental role in generating a hypercoagulable state, which has been demonstrated as an independent

Aspirin

Aspirin (acetylsalicylic acid) is one of the oldest and most widely prescribed pharmacologic agents. It was first synthesized by Felix Hoffman in 1897 at the Bayer Pharmacological Research Laboratories as a palatable alternative to the widely used bitter tasting painkiller salicylic acid. In 1971, Sir John Vane discovered aspirin's antithrombotic potential.6 Since then, it has been widely prescribed as an antiplatelet agent for the treatment of cardiovascular (CV) and cerebrovascular diseases.

Pharmacokinetics and Pharmacodynamics

Aspirin is readily absorbed in the upper gastrointestinal tract while enteric coated aspirin requires a longer time to be absorbed. Peak plasma levels of aspirin were observed within 40 minutes and platelet inhibition and also prolongation of bleeding time can be observed within an hour. The systemic bioavailability of aspirin is approximately 50%.9 Aspirin is mainly metabolized by the liver and intestinal human carboxyeasterase-2 to acetyl and salicylate moieties.10 Aspirin has a half-life of

Relation of Aspirin to Inflammation

In the Physician's Health Study sub-analysis, the association of aspirin (325 mg on alternative days) with the reduction of a first myocardial infarction was directly related to plasma C-reactive protein (CRP) levels suggesting an important effect of aspirin in the presence of vascular inflammation. Aspirin treatment was particularly beneficial in the presence of high plasma CRP levels.28 However, the same relation was not seen in other prospective studies.29, 30 Aspirin-mediated inhibition of

Primary and Secondary Prevention Trials of Aspirin

The extensive analysis of primary and secondary prevention trials has indicated that aspirin treatment is associated with a 20% to 40% reduction in adverse CV events.33 The meta-analysis of 287 trials by the Antiplatelet Trialists' Collaboration indicated that long-term aspirin treatment reduced the risk in “high-risk” patients up to 20% to 25%, and these benefits were similar irrespective of sex, age, or the presence of diabetes or hypertension. Although a wide range of aspirin doses (30 to

Variability in Aspirin Efficacy Dependent on Disease

The benefit of aspirin treatment may be dependent on the type of clinical setting. Although a repeated dose of 30 mg per day is reportedly sufficient to fully inhibit COX-1 activity in platelets, a 75- to 150-mg daily dose for long-term prevention and a 150- to 300-mg/d dose to provide rapid and complete inhibition in high-risk CV patients is recommended. However, even higher doses have been recommended for patients with cerebrovascular disease to prevent ischemic complications.9, 33 The

Aspirin Resistance

Wide variability in the pharmacodynamic response to aspirin has been reported. Aspirin resistance has been regarded as the failure of aspirin to inhibit COX-1 and platelet function after stimulation by various agonists (“laboratory aspirin resistance”) or the failure to protect from CV events (“clinical aspirin resistance” or more specifically, “treatment failure”). Because multiple signaling pathways mediate platelet activation, a treatment strategy that inhibits a single pathway cannot be

COX-1–Specific Methods

Complete blockade of PG synthesis was demonstrated by nanomolar concentrations of aspirin within 20 minutes in in vitro experiments with purified COX enzyme and isolated platelets. There were no additional effects of higher aspirin concentrations and longer exposures.9 TxB2 levels have also been measured in platelet-rich plasma obtained from subjects treated with aspirin following agonist stimulation. Other studies have used in vitro incubation of blood with aspirin. In these experiments, a

Cyclooxygenase-1 Nonspecific Assays

It has been suggested that TxA2 synthesis is essential for the amplification of the platelet response only when platelets are activated by low concentrations of other agonists, that is, 1 to 5 μg/mL collagen, 1 to 3 μmol/L ADP, and 5 to 10 μmol/L epinephrine.73 It has also been suggested that arachidonic acid release in response to low level collagen exposure is independent of granule release (ADP release).74, 75 In a recent study, both in vitro and ex vivo examination of the antiplatelet

Variability in Antiplatelet Effect of Aspirin Over Time

A progressive decrease in antiplatelet effect of aspirin as measured by ADP- and collagen-induced platelet aggregation has been observed indicating that aspirin inhibition of COX-1 nonspecific pathways may be blunted following long-term treatment.81 Santilii et al82 observed poor inhibition and wide variation in ADP- and collagen-induced platelet aggregation in response to 100 mg aspirin in healthy volunteers, whereas a significant level of inhibition of serum TxB2 (99%), AA-LTA (80%), and

Clinical Relevance of Aspirin Resistance (Table 2)

Grotemeyer et al48 found that patients exhibiting aspirin resistance as measured by an elevated platelet aggregates ratio had a 10-fold increase in the risk of recurrent vascular events as compared to aspirin sensitive patients (44% vs 4.4%, P < .001). Using whole blood aggregometry to evaluate aspirin resistance, Mueller et al85 found an 87% increase in the incidence of reocclusion in aspirin resistant patients who underwent balloon angioplasty and were treated with 100 mg aspirin daily for 18

Conclusions

In conclusion, aspirin is highly effective in blocking COX-1 as indicated by arachidonic acid-induced platelet function and other COX-1 specific assays. The prevalence of aspirin resistance is highly assay dependent, with significantly higher measurements of resistance using methods employing agonists other than arachidonic acid (COX-1 nonspecific assays). The observation of dose-related effects despite near complete inhibition of arachidonic-acid induced aggregation suggests that aspirin

Statement of Conflict of Interest

All authors declare that there are no conflicts of interest.

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