Residual platelet reactivity on aspirin therapy and recurrent cardiovascular events — A meta-analysis

doi:10.1016/j.ijcard.2007.12.010

International Journal of Cardiology

Volume 128, Issue 2, 18 August 2008, Pages 166-171

https://doi.org/10.1016/j.ijcard.2007.12.010 Get rights and content

Abstract

Background

Recently, a growing body of evidence on the possible role of residual platelet reactivity (RPR) in affecting clinical events has accumulated. The aim of this study was to systematically assess the relationship between RPR on acetylic salicylic acid (ASA) therapy and the occurrence of recurrent events in a meta-analysis of prospective studies.

Methods

A systematic literature search of MEDLINE, EMBASE, Science Citation Index, the Cochrane Systematic Review Database and bibliographies of retrieved articles through May 2007 was conducted. Studies were included if they analysed RPR in coronary heart disease patients in relation to the occurrence of adverse coronary events during follow-up.

Results

Eleven prospective studies, incorporating 1952 patients with coronary heart disease followed for a time ranging from 6 days to 4 years, met the inclusion criteria. The pooled analysis demonstrated a significantly increased relative risk of adverse clinical events during follow-up for patients with RPR on ASA therapy (RR: 3.11, 95%CI 1.88–5.15; p < 0.0001). Moreover, the association between RPR and cardiovascular recurrences remained to be statistically significant even when subgroup analyses performed according to the duration of follow-up, ASA dosage, characteristics of the study population, and laboratory method were conducted.

Conclusions

The present meta-analysis documents a significant association between RPR on ASA treatment and recurrent cardiovascular events. More prospective studies are needed to determine the independent prognostic importance of RPR during aspirin therapy and possible benefit of individually tailored anti-platelet treatment strategies in these patients.

Introduction

Antiplatelet drugs have an established place in the secondary prevention of a variety of vascular events, such as fatal and non-fatal coronary heart disease (CHD), stroke and peripheral arterial disease [1]. Indeed, results from the meta-analysis of the “Antiplatelet Trialists’ Collaboration” demonstrated that acetyl salicylic acid (ASA) therapy is able to reduce the risk of non-fatal myocardial infarction by 35% and the risk of total vascular events by 18% in patients with manifest coronary heart and cerebrovascular disease [1].

However, in a consistent proportion of vascular patients on ASA therapy residual platelet reactivity (RPR), the so-called aspirin resistance, is detectable [2]. A systematic review that recently assessed the prevalence of RPR in patients with CHD on ASA therapy reported an overall prevalence of 25% among all the published studies [3]. The question whether this phenomenon has a significant clinical implication on the occurrence of atherothrombotic events has not been, to date, definitely answered. Some studies evaluating the occurrence of clinical events during follow-up in patients with RPR have been conducted [4], [5], [6], and a recent meta-analysis by Snoep et al., evidenced an association between a laboratory-defined aspirin resistance and a higher risk of recurrent cardiovascular events [7]. The aim of this study is to systematically review all the available studies that prospectively investigated the possible association between RPR on ASA therapy and the occurrence of major adverse cardiovascular events in patients with CHD.

Section snippets

Search strategy

An extensive systematic literature search in order to identify studies evaluating the association between RPR and the occurrence of secondary cardiovascular events was conducted. The search was performed by using a combined text word and MeSH search strategy of the terms “acetyl salicylic acid”, “aspirin”, “antiplatelet”, “residual platelet reactivity”, and “persistent platelet reactivity” in combination with “resistance”, “failure”, “recurrence” and “major adverse cardiovascular events”,

Search results

The search strategy generated 26 potentially relevant studies. Eight studies were eliminated because they were not prospective studies, 4 because they reported only clopidogrel resistance, 2 because they did not evaluate clinical cardiovascular recurrences during the follow-up but only surrogate markers, and 1 because only a meeting abstract was available. As a result, a total of 11 prospective studies were included in the meta-analysis [8], [9], [10], [11], [12], [13], [14], [15], [16], [17],

Discussion

The present meta-analysis conducted in 11 prospective studies, with an overall population of 1952 CHD patients followed for a time ranging from 6 days to 4 years, showed a significant increased risk of clinical recurrences for patients who manifested RPR on ASA treatment. This association remained statistically significant even when subgroup analyses according to the duration of follow-up, ASA dosage, patients' characteristics, and laboratory method were performed.

ASA is currently the most

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Cited by (77)

Commentary: Better late than never!
2019, Journal of Thoracic and Cardiovascular Surgery
On-Treatment Platelet Reactivity is a Predictor of Adverse Events in Peripheral Artery Disease Patients Undergoing Percutaneous Angioplasty
2018, European Journal of Vascular and Endovascular Surgery
Citation Excerpt :
In this setting a different entity of on-treatment platelet function inhibition is associated with different clinical outcomes. Several studies have demonstrated that high on-treatment platelet reactivity (HPR), so called antiplatelet resistance, is associated with an increased risk of ischaemic complications (especially stent thrombosis),3–5 and there is a growing body of evidence that, on the contrary, low on-treatment platelet reactivity (LPR) could be associated with bleeding risk.6 High on-aspirin platelet reactivity measured by light transmission aggregometry (LTA) induced by arachidonic acid (HPR by AA) and high on-clopidogrel platelet reactivity measured by LTA induced by adenosine diphosphate (ADP) (HPR by ADP) have been used to defined the variable responses to antiplatelet therapy in major clinical studies.
Few data are available on the association between a different entity of platelet inhibition on antiplatelet treatment and clinical outcomes in patients with peripheral artery disease (PAD). The aim of this study was to evaluate the degree of on-treatment platelet reactivity, and its association with ischaemic and haemorrhagic adverse events at follow up in PAD patients undergoing percutaneous transluminal angioplasty (PTA).
In this observational, prospective, single centre study, 177 consecutive patients with PAD undergoing PTA were enrolled, and treated with dual antiplatelet therapy with aspirin and a P2Y12 inhibitor. Platelet function was assessed on blood samples obtained within 24 h from PTA by light transmission aggregometry (LTA) using arachidonic acid (AA) and adenosine diphosphate (ADP) as agonists of platelet aggregation. High on-treatment platelet reactivity (HPR) was defined by LTA ≥ 20% if induced by AA, and LTA ≥ 70% if induced by ADP. Follow up was performed to record outcomes (death, major amputation, target vessel re-intervention, acute myocardial infarction and/or myocardial revascularisation, stroke/TIA, and bleeding).
HPR by AA and HPR by ADP were found in 45% and 32% of patients, respectively. During follow up (median duration 23 months) 23 deaths (13%) were recorded; 27 patients (17.5%) underwent target limb revascularisation (TLR), two (1.3%) amputation, and six (3.9%) myocardial revascularisation. Twenty-four patients (15.6%) experienced minor bleeding. On multivariable analysis, HPR by AA and HPR by ADP were independent predictors of death [HR 3.8 (1.2–11.7), p = .023 and HR 4.8 (1.6–14.5), p = .006, respectively]. The median value of LTA by ADP was significantly lower in patients with bleeding complications than in those without [26.5% (22–39.2) vs. 62% (44.5–74), p < .001). LTA by ADP ≤ 41% was independently associated with bleeding HR 14.6 (2.6–24.0), p = .001] on multivariable analysis.
In this study a high prevalence of on-clopidogrel and aspirin high platelet reactivity was found, which was significantly associated with the risk of death. Conversely, a low on-clopidogrel platelet reactivity was associated with a higher risk of bleeding. These results document that the entity of platelet inhibition is associated with both thrombotic and bleeding complications in PAD patients.
Prevalence of high on-treatment (aspirin and clopidogrel) platelet reactivity in patients with critical limb ischemia
2018, Cardiovascular Revascularization Medicine
Citation Excerpt :
The mortality in patients with CLI approaches 22% and 50% at one and five years, respectively [1–3]. High on-treatment platelet reactivity (HPR) in patients treated with aspirin and clopidogrel (previously referred to as “resistance”) is associated with an increased risk of recurrent cardiovascular events after percutaneous coronary interventions and acute coronary syndromes [4,5]. The prevalence of HPR in patients with CLI treated with ASA and/or clopidogrel is not known.
The goal of this study is to establish the prevalence of high on-treatment platelet reactivity to aspirin (HPRA) and clopidogrel (HPRC) in patients with critical limb ischemia (CLI).
CLI is associated with an increased risk of death and cardiovascular events. Unlike other patient populations with atherosclerotic cardiovascular disease, previous studies failed to demonstrate a benefit of antiplatelet therapy in patients with CLI.
From June 2014 to November 2016, we performed platelet reactivity studies for P2Y12 and thromboxane A2 (TXA2) inhibition in 100 CLI patients receiving daily treatment with aspirin and clopidogrel. P2Y12 inhibition was measured by two assays: vasodilator-stimulated phosphoprotein (VASP) and VerifyNow P2Y12 assays. HPRC was defined as VerifyNow P2Y12 reactive units (PRU) > 208 and VASP-platelet reactivity index (VASP-PRI) > 50%. TXA2 inhibition was measured with the VerifyNow aspirin test and HPRA was defined as aspirin reaction units (ARU) > 550.
Mean age was 67 ± 11 years, 50% were male, 80% had diabetes mellitus, and 26% had chronic renal insufficiency. Thirty-three percent of patients had a PRU > 208 and 46% a VASP-PRI > 50%. HPRC was present in 26% of patients based on the criteria of both a PRU > 208 and VASP-PRI > 50%. HPRA was present in 25% of patients. The overall prevalence of HPR to ASA or clopidogrel was 35% and HPR to both drugs was present in 8% of patients. Clinical characteristics were similar between groups.
HPR to aspirin or clopidogrel is highly prevalent in patients with CLI. Nearly one in ten patients with CLI is a hyporesponder to both aspirin and clopidogrel.
Platelet Function Testing in Patients with Acute Ischemic Stroke: An Observational Study
2017, Journal of Stroke and Cerebrovascular Diseases
The measurement of platelet reactivity in patients with stroke undergoing antiplatelet therapies is not commonly performed in clinical practice. We assessed the prevalence of therapy responsiveness in patients with stroke and further investigated differences between patients on prevention therapy at stroke onset and patients naive to antiplatelet medications. We also sought differences in responsiveness between etiological subtypes and correlations between Clopidogrel responsiveness and genetic polymorphisms.
A total of 624 stroke patients on antiplatelet therapy were included. Two different groups were identified: “non-naive patients”, and “naive patients”. Platelet function was measured with multiple electrode aggregometry, and genotyping assays were used to determine CYP2C19 polymorphisms.
Aspirin (ASA) responsiveness was significantly more frequent in naive patients compared with non-naive patients (94.9% versus 82.6%, P < .0010). A better responsiveness to ASA compared with Clopidogrel or combination therapy was found in the entire population (P < .0010), in non-naive patients (P < .0253), and in naive patients (P < .0010). Multivariate analysis revealed a strong effect of Clopidogrel as a possible “risk factor” for unresponsiveness (odds ratio 3.652, P < .0001). No difference between etiological subgroups and no correlations between responsiveness and CYP2C19 polymorphisms were found.
In our opinion, platelet function testing could be potentially useful in monitoring the biological effect of antiplatelet agents. A substantial proportion of patients with stroke on ASA were “resistant”, and the treatment with Clopidogrel was accompanied by even higher rates of unresponsiveness. Longitudinal studies are needed to assess whether aggregometry might supply individualized prognostic information and whether it can be considered a valid tool for future prevention strategies.
High on treatment platelet reactivity to aspirin and clopidogrel in ischemic stroke: A systematic review and meta-analysis
2017, Journal of the Neurological Sciences
Emerging studies highlight high on-treatment of platelet reactivity (HTPR) as a major hindrance to the secondary prevention of cardiovascular ischemic events. The aim of this systematic review and meta-analysis is to assess the prevalence of HTPR in patients with ischemic stroke (IS) or transient ischemic attack (TIA) and reveal a possible relation with a higher risk of cerebrovascular event recurrence. Studies were selected if they reported absolute numbers or percentages of HTPR with ASA or clopidogrel in IS/TIA patients at any time point after the cerebrovascular event onset and assessed with any type of platelet function tests. We included 52 full-text studies with a total of 8364 patients. Overall, the pooled prevalence of HTPR was 24% (95%CI: 20–27%). In subgroup analyses, the prevalence of HTPR on ASA was 23% (95%CI: 20–28%), on clopidogrel 27% (95%CI: 22–32%) and on dual antiplatelet treatment (DAPT) 7% (95%CI: 5–10%). The overall analysis of all studies providing data on the risk of IS/TIA recurrence, indicates that the patients with HTPR had a significantly higher risk for IS/TIA recurrence (RR = 1.81, 95%CI: 1.30–2.52; p < 0.001). In conclusion the present study shows a significant lower prevalence of HTPR in DAPT and an increased rate of recurrent cerebrovascular ischemic events in patients presenting HTPR.
Residual thrombin potential predicts cardiovascular death in acute coronary syndrome patients undergoing percutaneous coronary intervention
2016, Thrombosis Research
Citation Excerpt :
In the past, biochemical signs of coagulation activation in the acute phase of unstable angina or acute myocardial infarction (AMI) were demonstrated [1,2] and blood clotting activation markers were found to be independent risk factors for recurrence and long-term mortality [3–6]. In the last years the diffuse use of PCI and stenting stimulated several studies investigating primarily the role of platelet hyper-reactivity in determining clinical outcome [7,8]. On the other hand, scarce data are available on the possible role of blood clotting activation on the prognosis of ACS patients, in the era of PCI and stenting on the top of dual antiplatelet therapy.
Thrombin generation (TG) is a central step of the coagulation system involved in hemostatic and thrombotic roles. Scarce data evaluating in the acute phase the association between TG and the risk of cardiovascular death of acute coronary syndrome (ACS) patients are available, in the era of percutaneous coronary intervention (PCI) and stenting with the use of dual antiplatelet treatment.
We investigated TG in 292 ACS patients undergoing PCI with stent implantation on dual antiplatelet treatment. Venous samples were obtained 12–24 h after PCI. TG was assessed using the Calibrated Automated Thrombogram (CAT).
At two years of follow-up, 57 out of 292 patients (19.5%) died from cardiovascular causes. Higher values of endogenous thrombin potential (ETP) [1115.9 (705–1441.3) vs 940.2 (666.0–1253.1), p = 0.049], peak [176.1 (80.5–259.4) vs 107.3 (59.9–181.1), p = 0.002] and velocity index [61.75 (21.03–97.88) vs 25.64 (11.95–50.90), p < 0.001] were observed in relation to survival patients. At the multivariate model adjusted for the Global Registry of Acute Coronary Events risk score, the association between TG and cardiovascular death remained significant for ETP [OR (95% CI): 2.58 (1.10–6.03), p = 0.029], peak [OR (95%CI): 3.27 (1.35–7.92), p = 0.009] and velocity index [OR (95% CI): 3.06 (1.27–7.39), p = 0.013]. This result was confirmed after adjustment for high on-treatment platelet reactivity [ETP: OR (95% CI) 2.35 (1.11–5.00), p = 0.027; peak: OR (95% CI) 2.42 (1.13–5.15), p = 0.022; velocity index: OR (95% CI) 2.43 (1.14–5.20), p = 0.022].
ACS patients with a residual TG after PCI and stent implantation have a significantly higher risk of long-term cardiovascular death. These results might be useful in improving risk stratification for ACS patients and support the need of a tailored antithrombotic therapy.

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ReviewResidual platelet reactivity on aspirin therapy and recurrent cardiovascular events — A meta-analysis

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Search strategy

Search results

Discussion

Am J Cardiol

Am Heart J

Thromb Res

J Am Coll Cardiol

Am J Cardiol

Thromb Res

J Thromb Haemost

Eur J Intern Med

J Thromb Haemost

Thromb Res

Am Heart J

J Am Coll Cardiol

J Thromb Haemost

Review
Residual platelet reactivity on aspirin therapy and recurrent cardiovascular events — A meta-analysis