Suboptimal Platelet Inhibition Research Articles

Parenteral Antiplatelet Drugs in ST-Elevation Myocardial Infarction: Current Status and Future Directions.

Oral inhibitors of the platelet P2Y12 receptor are indispensable in the treatment of ST-elevation myocardial infarction (STEMI), improving outcomes and even reducing mortality in some studies. However, these drugs are limited by delayed absorption and suboptimal platelet inhibition at the time of primary percutaneous coronary intervention. Despite efforts to achieve faster and more sustained platelet inhibition, strategies such as prehospital administration, higher loading doses, and crushed formulations have not led to improved coronary reperfusion. Parenteral glycoprotein IIb/IIIa inhibitors act sooner and are more potent than oral P2Y12 inhibitors, but their use has been limited by the increased risk of major bleeding and thrombocytopenia. Hence, there is a clinical need to refine drugs that deliver rapid, effective, yet safe platelet inhibition in the setting of STEMI. Novel parenteral antiplatelet drugs, such as cangrelor, selatogrel, and zalunfiban, have been recently developed to achieve rapid, potent antiplatelet effects while preserving hemostasis. We provide a description of currently available parenteral antiplatelet agents and of those in clinical development for prehospital administration in STEMI patients.

Primary Percutaneous Coronary Intervention with High-Bolus Dose Tirofiban: The FASTER (Favorite Approach to Safe and Effective Treatment for Early Reperfusion) Multicenter Registry.

Objectives To investigate the safety and clinical efficacy of tirofiban during primary percutaneous coronary interventions (pPCI). Background Gp IIb/IIIa inhibitors (GPI) use during pPCI has declined over years, mainly for the increased hemorrhagic risk associated to their use and for the availability of potent, fast-acting oral antiplatelet drugs. However, several pharmacodynamic studies showed suboptimal platelet inhibition with P2Y12-blockers, such as prasugrel or ticagrelor. Methods Patients with ST-segment elevation myocardial infarction (STEMI) undergoing pPCI were prospectively enrolled in a multicenter registry conducted in high-volume centers in Italy. All patients received intraprocedural tirofiban. The primary safety endpoint was the occurrence of in-hospital bleedings according to the Bleeding Academic Research Consortium definition. In-hospital major adverse coronary events (MACE, defined as death, reinfarction, stent thrombosis, and target vessel revascularization), final TIMI flow, myocardial blush grade, and ST-segment resolution were also evaluated. Results A total of 472 patients (mean age 61 ± 11 years, 83% males) were enrolled in 16 Italian centers from October 2015 to June 2018. Mean basal thrombus grade score was 3.47 ± 1.25. PCI was performed by transradial approach in 88% of patients. We observed a very low rate of 30 days BARC bleedings (2.1%) and MACE (0.8%). Complete (>70%) ST-segment resolution was observed in 67% of patients. Conclusions In the FASTER registry, the use of tirofiban during primary PCI, performed with a transradial approach in most cases, in patients with high thrombus burden was associated with high rates of complete ST-segment resolution and low rates of in-hospital bleeding and MACE.

Abstract 1122‐000231: A Review of Effect of Ticagrelor on Platelet Inhibition in Clopidogrel Non‐Responders Undergoing Neuroendovascular Procedure

Introduction : Neuroendovascular procedures are becoming more routine in the treatment of intracranial conditions such as aneurysms, arterial stenosis, and ischemic stroke. These patients are frequently treated with antiplatelet agents prior to the procedure to prevent thrombotic complications. The combination of aspirin and a P2Y12 inhibitor such as clopidogrel is often initiated days before elective procedures or as loading doses for emergent procedures. However, some patients may still experience post procedural thrombotic or hemorrhagic complications which may be related to platelet inhibition. Methods : A retrospective review of patients who underwent a neuroendovascular procedure from 1/2017 to 12/2019 in a single tertiary care academic hospital. Procedures included flow‐diverting stent placement for aneurysms, intracranial, and cervical carotid artery stenting. Patients undergoing elective procedure were started on Aspirin and Clopidogrel 75 mg daily. Patients undergoing emergent procedures were given loading doses of Aspirin (650 mg) and Clopidogrel (600 mg). P2Y12 assay was checked prior to receiving Platelet inhibitor and from 3–6 hours after Clopidogrel loading dose. Optimal platelet inhibition was classified as reduction in P2Y12 assay by at least 60%. Patients with suboptimal platelet inhibition <60% were given Ticagrelor loading dose (180 mg) and P2y12 assay was rechecked. Patients who did not have complete chart information, patients with AFib requiring DOAC and patients previously on ADP inhibitors, were excluded from analysis. Results : Total neuroendovascular procedures requiring stents were 687 over the period of 3 years. mean age of patients was 61 years. This neuroendovascular procedure consisted of aneurysm stenting (239), aneurysm stent‐assisted coiling 112, intracranial stent for failed mechanical thrombectomy 62, carotid artery stent 108. Suboptimal platelet inhibition was noted in 54% (282) of 523 patients after receiving Clopidogrel. After receiving Ticagrelor, optimal inhibition was noted in 80% (226) of 282 patients with median increase of 26%. 62 patients with suboptimal response to Ticagrelor, 47 were started on Prasugrel. Thrombotic complications were noted in 7 patients, 6 of them were noted to have <50% platelet inhibition. Hemorrhagic complications were noted in 17 patients, amongst them >70% platelet inhibition was noted in 14 patients with mean P2Y12 value of 59. Conclusions : Patients receiving P2Y12 ADP antiplatelet therapy may have suboptimal platelet inhibition which results in increased thrombotic risk. Patients who have significant platelet inhibition (>70%) after loading dose are at increased risk for hemorrhagic complications. Better platelet inhibition was achieved with Ticagrelor in Clopidogrel hypo‐response patients. In patients with Clopidogrel hyper‐response, dosing was changed to half the dose or alternate day to reduce hemorrhagic complications. As the use of endovascular therapies requiring dual anti‐platelet agents becomes more established, there is an increasing need to develop titration protocols that minimize the risk of thrombotic and hemorrhagic events based on platelet inhibition.

Bedside testing of CYP2C19 vs. conventional clopidogrel treatment to guide antiplatelet therapy in ST-segment elevation myocardial infarction patients

BackgroundST-segment elevation myocardial infarction (STEMI) patients are treated with dual antiplatelet therapy comprising aspirin and a P2Y12 inhibitor. Clopidogrel is widely used in these patients in several areas worldwide, such as Middle East, but is associated to sub-optimal platelet inhibition in up to 1/3 of treated patients. We investigated a CYP2C19 genotype-guided strategy to select the optimal P2Y12 inhibitor. MethodsThis prospective randomized clinical trial included STEMI patients. The standard-treatment group received clopidogrel, while the genotype-guided group were genotyped for CYP2C19 loss-of-function alleles and carriers were prescribed ticagrelor and noncarriers were prescribed clopidogrel. Primary outcome was a combined ischemic and bleeding outcome, comprising myocardial infarction, non-fatal stroke, cardiovascular death, or Platelet Inhibition and Patient Outcomes major bleeding one year after STEMI. ResultsSTEMI patients (755) were randomized into a genotype-guided- (383) and standard-treatment group (372). In the genotype-guided group, 31 patients carrying a loss-of-function allele were treated with ticagrelor, while all other patients in both groups were treated with clopidogrel. Patients in the genotype-guided group had a significantly lower risk of primary outcome (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.20–0.59,), recurrent myocardial infarction (OR 0.25, 95%CI 0.11–0.53), cardiovascular death (OR 0.16, 95%CI0.06–0.42) and major bleeding (OR 0.49, 95%CI 0.32–0.74). There was no significant difference in the rate of stent thrombosis (OR 0.85, 95%CI 0.43–1.71). ConclusionA genotype-guided escalation of P2Y12 inhibitor strategy is feasible in STEMI patients treated with clopidogrel and undergoing PCI and is associated with a reduction of primary outcomes compared to conventional antiplatelet therapy.

Feasibility and safety of cangrelor in patients with suboptimal P2Y12 inhibition undergoing percutaneous coronary intervention: rationale of the Dutch Cangrelor Registry

BackgroundDespite the advances of potent oral P2Y12 inhibitors, their onset of action is delayed, which might have a negative impact on clinical outcome in patients undergoing percutaneous coronary intervention (PCI). Trials conducted in the United States of America have identified cangrelor as a potent and rapid-acting intravenous P2Y12 inhibitor, which has the potential of reducing ischemic events in these patients without an increase in the bleeding. As cangrelor is rarely used in The Netherlands, we conducted a nationwide registry to provide an insight into the use of cangrelor in the management of patients with suboptimal platelet inhibition undergoing (primary) PCI (the Dutch Cangrelor Registry).Study designThe Cangrelor Registry is a prospective, observational, multicenter, single-arm registry with cangrelor administered pre-PCI in: (1) P2Y12 naive patients with ad-hoc PCI, (2) patients with STEMI/NSTEMI with suboptimal P2Y12 inhibition including (3) stable resuscitated/defibrillated patients with out-of-hospital cardiac arrest (OHCA) due to acute ischemia and (4) STEMI/NSTEMI patients with a high thrombotic burden. Primary endpoint is 48 h Net Adverse Clinical Events (NACE), which is a composite endpoint of all-cause death, recurrent myocardial infarction (MI), target vessel revascularization (TVR), stroke, stent thrombosis (ST) and BARC 2-3-5 bleeding.SummaryThe Dutch Cangrelor Registry will assess the feasibility and safety of cangrelor in patients with suboptimal P2Y12 inhibition undergoing (primary) PCI in the setting of acute coronary syndrome (ACS) and stable coronary artery disease (CAD) in the Netherlands.

Low hemoglobin predicts high-platelet reactivity and major cardiovascular ischemic events at long-term follow-up among ACS patients receiving dual antiplatelet therapy with ticagrelor.

Reduced levels of hemoglobin (Hb) represent an established marker of impaired outcomes and increased cardiovascular risk in patients with coronary artery disease, challenging the management of dual antiplatelet therapy (DAPT). However, while anemia has emerged as an independent predictor of suboptimal platelet inhibition in patients receiving clopidogrel, no study has so far evaluated the impact of Hb levels on high-on treatment platelet reactivity (HRPR) with ticagrelor and their prognostic consequences, that were the aim of the present study. Patients on DAPT with ASA + Ticagrelor (90 mg/twice a day) after percutaneous coronary revascularization for ACS were scheduled for platelet function assessment 30-90 days post-discharge. Aggregation tests were performed by multiple electrode aggregometry. Suboptimal platelet inhibition (HRPR-high residual platelet reactivity was defined if above the lower limit of normality (417 AU*min). The primary study endpoint was defined as the occurrence of major cardiovascular events (a composite of cardiovascular death, recurrent acute coronary syndrome [MI], target vessel revascularization) at longest available follow-up. We included 397 patients that were divided according to tertiles values of Hb (< 12.7, 12-7-14.09, ≥14.1g/dl). Patients with lower Hb were older and displayed a more severe cardiovascular risk profile. Mean levels of platelet reactivity were enhanced in patients with lower Hb after stimulation with TRAP peptide (TRAP test, p=.03) and ADP (p=.02). Elevated platelet reactivity (HRPR) on Ticagrelor was more frequent among patients with reduced Hb (16.4% vs. 12% vs. 5.4%, p=.005, adjusted OR [95%CI]=1.71[0.996;3.01], p=.056). At a mean follow-up of 820.9 ± 553.4 days, 21.4% of the patients experienced the primary composite endpoint, with a higher rate of events in patients with lower Hb (27.6% vs. 22.6% vs. 13.5%, p=.006, adjusted HR [95%CI]=1.51[1.12; 2.03], p=.006), mainly driven by a higher rate of recurrent ACS. After correction for baseline differences lower Hb tertiles but not HRPR emerged as independent predictor of MACE (adjusted HR [95%CI]=0.98[0.50; 1.92], p=.95). In the present study, we demonstrated that among patients on DAPT with ASA and ticagrelor after PCI for ACS, lower Hb levels are independently associated with a higher rate of HRPR and an increased rate of major ischemic events, and especially for recurrent ACS, although with no impact on survival. Neutral prognostic effect of HRPR was observed across Hb tertiles.

Bridging the gap: Current and future insights for improving suboptimal platelet inhibition in STEMI

Antiplatelet therapy is one of the cornerstones in the acute treatment of patients with ST-elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (PCI). However, hemodynamic changes and delayed intestinal absorption of P2Y12 inhibitors leads to a delay in the onset of antiplatelet effects resulting in a gap of platelet inhibition. Several strategies have been proposed to bridge this gap, such as pre-hospital administration of antiplatelet therapy, higher loading doses of P2Y12 inhibitors, crushing or chewing tablets, subcutaneous or intravenous administration of platelet inhibitors, or use of pain relievers alternative to opioids that do not delay intestinal absorption of oral platelet inhibitors. These strategies may improve platelet inhibition with the goal of optimizing clinical outcomes in the acute phase of STEMI. In this review we present current and future insights for bridging the gap in platelet inhibition in STEMI patients undergoing primary PCI.

Higher neutrophil-to-lymphocyte ratio (NLR) increases the risk of suboptimal platelet inhibition and major cardiovascular ischemic events among ACS patients receiving dual antiplatelet therapy with ticagrelor

BackgroundNeutrophil to lymphocyte ratio (NLR) has emerged as a useful and easy-to-assess prognostic tool and biomarker of cardiovascular risk. However, few studies have evaluated its role on platelet inhibition among patients on dual antiplatelet therapy (DAPT), and especially in the settings of acute coronary syndromes (ACS). We aimed at assessing the impact of NLR on platelet reactivity and the risk of major ischemic events at long-term follow-up among ACS patients on DAPT with ticagrelor. MethodsPatients on dual antiplatelet therapy with ASA + ticagrelor (90 mg/twice a day) after percutaneous coronary revascularization for ACS were scheduled for platelet function assessment 30–90 days post-discharge. Aggregation tests were performed by Multiple Electrode Aggregometry (MEA). Suboptimal platelet inhibition (HRPR-high residual platelet reactivity was defined if above the lower limit of normality (417 AU*min). The primary study endpoint was defined as the occurrence of major cardiovascular events (a composite of cardiovascular death, recurrent acute coronary syndrome, target vessel revascularization) at longest available follow-up. ResultsWe included 397 patients, that were divided according to NLR tertiles. Patients with higher NLR were older (p < .001), less frequently smokers (p = .03), with higher rates of renal failure (p = .001), previous bypass surgery (p = .05) and use of statins (p = .03) and diuretics (p = .01). Higher white blood cells count and C-reactive protein (p < .001) and lower haemoglobin (p = .001) were associated with NLR. Mean platelet reactivity and the prevalence of high platelet reactivity (HRPR) on ticagrelor were significantly associated to higher NLR tertiles values (7% vs 12% vs 14.3%, p = .04), with a significant relationship between NLR and platelet reactivity being confirmed for all the different activating stimuli.At a mean follow-up of 939 ± 581.4 days, 21.2% of the patients experienced the primary composite endpoint, with a trend for a higher risk of events across NLR tertiles (15.4% vs 24.2% vs 24.4%, p = .09), that became statistically significant after correction for baseline confounders (adjusted HR[95%CI] = 1.13[1.008–1.26], p = .036). Moreover, NLR was significantly associated to overall mortality and recurrent ACS (adjusted p = .008, p = .06 and p = .02 respectively). ConclusionsIn the present study we found that among ACS patients treated with ASA and ticagrelor after PCI, suboptimal platelet inhibition despite DAPT was significantly increased for higher values of Neutrophil-to-Lymphocyte Ratio. Moreover, mortality and the risk of recurrent major ischemic events at long-term were associated to NLR.

The Effect of Ticagrelor on Platelet Reactivity in Patients with Clopidogrel Resistance Undergoing Neuroendovascular Procedures.

Suboptimal platelet inhibition by clopidogrel (clopidogrel resistance) may be associated with high rates of stent thrombosis and ischemic events. Our objective was to determine if ticagrelor, a P2Y12 receptor inhibitor, can result in platelet inhibition in patients with clopidogrel resistance. A thromboelastography-platelet mapping assay was used in all patients undergoing neuroendovascular procedures requiring oral clopidogrel. In patients with suboptimal platelet inhibition (<60%) on clopidogrel, ticagrelor was imitated after an oral bolus of 180 mg followed by 90 mg twice daily and the platelet mapping assay was repeated. The primary endpoint was hemorrhagic complications classified as major (hemoglobin decrease >5 g/dL or intracranial hemorrhage with deficits), minor (hemoglobin decrease 3-5 g/dL or intracranial hemorrhage without residual deficits), or insignificant. Suboptimal platelet inhibition on clopidogrel was seen in 70 of 106 patients undergoing neuroendovascular procedures. There was a significantly higher magnitude of platelet inhibition with ticagrelor compared with clopidogrel in patients with clopidogrel resistance (mean ±SD: 85.90 ± 10.74% vs. 29.26 ± 17.71%; P<.001); 50 of 70 patients showed optimal inhibition. Two patients had major (fatal) hemorrhagic events (both received either intravenous thrombolytics and/or eptifibatide infusion). Three patients had minor hemorrhagic events, and two patients had insignificant hemorrhagic events. Four of seven hemorrhagic events occurred in patients with optimal response to clopidogrel, two occurred in patients with suboptimal response to ticagrelor, and one occurred in a patient with optimal response to ticagrelor. Oral ticagrelor can augment platelet inhibition in patients who have clopidogrel resistance.

CRT-100.28 The Impact of Ticagrelor Loading Dose Timing in Patients With STEMI

Patients with STEMI undergoing primary percutaneous coronary intervention (PPCI) frequently have suboptimal platelet inhibition in the early hours after the ticagrelor loading dose. It has been hypothesized that early loading dose administration optimizes platelet inhibition in PPCI and, therefore,

Homocysteine levels and platelet reactivity in coronary artery disease patients treated with ticagrelor

Background and aimRecurrent atherothrombotic events have been reported in certain higher risk subsets of patients even with ticagrelor, a potent first-line antiplatelet agent for the management of patients with acute coronary syndrome (ACS). Hyperhomocysteinemia is a known determinant of platelet function abnormalities. Therefore, the aim of our study was to evaluate the impact of homocysteine (Hcy) levels on platelet reactivity in patients receiving Ticagrelor. Methods and resultsPatients with ACS undergoing percutaneous coronary revascularization and on dual antiplatelet therapy with ASA + Ticagrelor (90mg/twice a day) were scheduled for platelet function assessment 30–90 days post-discharge. Aggregation tests were performed by Multiple Electrode Aggregometry (MEA). Suboptimal platelet inhibition HRPR-high residual platelet reactivity was defined if above the lower limit of normality (417 AU*min).We included 432 patients, divided according to Hcy tertiles. Higher Hcy levels were associated with age, renal failure, creatinine levels and use diuretics (p < 0.001).Patients with higher Hcy levels displayed a higher platelet reactivity at COL test (p = 0.002), and ADP test (p = 0.04), with a linear relationship between Hcy and platelet aggregation after stimulation with collagen (r = 0.202, p < 0.001), thrombin receptor peptide (r = 0.104, p = 0.05) and ADP (r = 0.145, p = 0.006).However, Hcy levels did not significantly affect the rate of HRPR with Ticagrelor (9.9% vs 13.7% vs 10.7%, p = 0.89; adjusted OR [95% CI] = [0.616–1.51], p = 0.99). ConclusionsAmong patients with ACS, despite the elevated platelet reactivity associated to hyperhomocysteinemia, DAPT with ticagrelor could overcome such phenomenon, achieving an adequate platelet inhibition in the majority of the patients.

Impact of aging on platelet reactivity in diabetic patients receiving dual antiplatelet therapy.

Advanced age and diabetes represent summative conditions in the determination of cardiovascular risk, and especially for the management of dual antiplatelet therapy (DAPT), often requiring balancing between bleeding and thrombotic complications. However, few studies have so far evaluated the impact of age on platelet reactivity and suboptimal platelet inhibition (high-on treatment platelet reactivity-HRPR) on DAPT among diabetic patients, that was, therefore the aim of the present study. In diabetic patients treated with DAPT (ASA + clopidogrel or ticagrelor) platelet reactivity was assessed at 30-90days post-discharge for an acute coronary syndrome or elective PCI. Aggregation was assessed by multiple-electrode aggregometry. HRPR was defined for values above the lower limit of normality (in non-treated patients). Elderly patients were considered ≥ 75years of age. We included 462 patients, among them 149 (32.2%) were ≥ 75years. Elderly patients were more often females (p = 0.006), with lower body size (p = 0.04), acute coronary syndrome at presentation and renal failure (p < 0.001), non-smokers (p = 0.002), in therapy with insulin (p = 0.02) and diuretics (p < 0.001) and lower rate of betablockers (p = 0.02). Age directly related with C reactive protein (p = 0.01), creatinine levels and inversely with hemoglobin (p < 0.001) and triglycerides (p = 0.003). No association was found at linear regression analysis for platelet reactivity and age with different activating stimuli, but for ASPI test (r = 0.12; p = 0.03). No significant difference in HAPR was found in elderly patients (2.4 vs. 3.2%, p = 0.76, OR[95% CI] = 0.45[0.1-2.11], p = 0.31). HRPR for ADP antagonists was similarly not affected by age (30.1% vs. 35.7%, p = 0.28, adjusted OR[95% CI] = 0.78[0.47-1.29], p = 0.33). Comparable results were obtained when considering separately the DAPT strategies with clopidogrel or ticagrelor, or when adjusting our results according to propensity score values. Among diabetic patients receiving dual antiplatelet therapy for an acute coronary syndrome or elective percutaneous coronary intervention, age does not affect platelet reactivity or the rate of high-on treatment platelet reactivity. Similar results were obtained for ASA and clopidogrel or ticagrelor.

Prevalence and predictors of high-on treatment platelet reactivity during prasugrel treatment in patients with acute coronary syndrome undergoing stent implantation

BackgroundADP-antagonists such as prasugrel have reduced but yet not overcome the phenomenon of high-on treatment platelet reactivity (HRPR), that has been shown to increase the rate of major cardiovascular events after an acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI). However, the exact prevalence and the principal determinants of suboptimal platelet inhibition in patients treated with dual antiplatelet therapy (DAPT) with prasugrel have not been completely clarified and were therefore the aim of the present study. MethodsWe included patients (<75 years and >60kg) treated with DAPT (aspirin+prasugrel) after PCI, mainly for an ACS. Platelet function test evaluation was performed at 1–3 months from discharge. HRPR was assessed by multiplate impedance aggregometry and defined for results above upper limit of normal after ADP stimulation. ResultsWe included 190 post-ACS patients. HRPR with prasugrel was observed in 19 patients (10%). The prevalence of HRPR was stable in different high-risk subgroups of patients (female gender, hypercholesterolemic, and chronic kidney disease) whereas it was increased in diabetic patients (p=0.045), with a significant interaction between diabetic status and HRPR (p=0.04). However, at multivariate analysis, an impaired metabolic status, with higher levels of glycosylated hemoglobin and low-density lipoprotein (LDL) cholesterol, but not diabetic status, emerged as independent predictors of HRPR with prasugrel [OR (95% CI)=2.1 (1.32–3.33), p=0.002 and OR (95% CI)=1.03 (1.01–1.05), p=0.003, respectively], with a stronger linear relationship between ADP-mediated platelet aggregation and glycosylated hemoglobin levels (r=0.24, p=0.002), than for LDL-cholesterol (r=0.13, p=0.09). ConclusionsIn post-ACS patients treated with PCI and receiving DAPT with prasugrel, HRPR is observed in about 10% of patients. Impaired metabolic status, and especially elevated glycosylated hemoglobin, emerged as independent predictors of the suboptimal effectiveness of prasugrel.

Aspirin intake in the morning is associated with suboptimal platelet inhibition, as measured by serum Thromboxane B2, during infarct-prone early-morning hours

Aspirin is traditionally taken once daily in the morning and considered to be effective throughout the 24h interval. Cardiovascular events occur most frequently in the early morning, suggesting that these hours are critical in terms of adequate platelet inhibition. This study therefore assed platelet function in the early morning—8.00 AM—in healthy volunteers, during a once-daily (OD) 80 mg morning in comparison with an OD evening regimen and a twice-daily (BID) 40 mg regimen. It was an open-label randomized cross-over study, comprising 12 healthy subjects. Subjects were allocated to three sequential dosage regimens: 80 mg OD at 8.00 AM, 80mg OD at 8.00 PM, and 40 mg BID at 8.00 AM and PM. Platelet function 12 and 24 hours after aspirin intake was measured by means of serum thromboxane B2 (sTxB2) levels, the collagen/epinephrine closure time (Platelet Function Analyzer(PFA)-200®) and the Aspirin Reaction Units (ARU, VerifyNow®). The results demonstrated that early morning sTxB2 concentrations were 5843pg in the morning regimen, 2877pg in the evening OD regimen, and 3343pg in the BID regimen (morning- vs evening regimen p = < 0.01; morning- vs BID regimen p = < 0.01). Early morning PFA-closure time (p = 0.12)) as well as VerifyNow ARU (p = 0.17) mean values were similar for all three regimens. In conclusion, the OD-morning regimen seems to acquire the lowest level of platelet inhibition during the critical early morning window. Switching to an OD-evening or BID intake seems prudent, although further research on clinical cardiovascular outcome in patients with stable cardiovascular disease is needed.

Risks of Opioids in ST-Elevation Myocardial Infarction: A Review.

Although opioids are recommended and frequently used in the acute phase of ST-elevation myocardial infarction (STEMI), their use is accompanied by serious side effects. In particular, gastrointestinal adverse effects may disturb absorption of essential oral medication like platelet inhibitors. This may cause suboptimal platelet inhibition and increased risk of acute stent thrombosis. Some clinical studies have already demonstrated these negative results. Alternative strategies to optimize platelet inhibition and pain relief in STEMI are being investigated. Clinicians should become more aware of the potential side effects of opioids in STEMI.

Impact of pre-procedural dual antiplatelet therapy on periprocedural myocardial infarction in patients undergoing percutaneous coronary interventions with adjunctive tirofiban

BackgroundRecent trials have failed to demonstrate any clinical benefit from pre-treatment with dual antiplatelet therapy (DAPT) in patients undergoing percutaneous coronary interventions, (PCI), even in the setting of acute coronary syndrome. However, suboptimal platelet inhibition during (PCI) has been shown to enhance the risk of acute ischemic complications, such as stent thrombosis and periprocedural myocardial infarction (PMI), thus raising the attention on the potential advantages of adjunctive glycoprotein IIbIIIa inhibitors to obviate to the delayed onset of action of oral antiplatelet drugs. The aim of the present study was then to evaluate the impact of platelet reactivity and pre-procedural DAPT on PMI in patients undergoing PCI with adjunctive tirofiban. MethodsIn a consecutive cohort of patients undergoing PCI with tirofiban (intracoronary/intravenous ± prolonged infusion), periprocedural myonecrosis was defined as troponin I increase by 3 times the ULN or by 50% of an elevated baseline value, whereas PMI as CKMB increase by 3 times the ULN or 50% of baseline. Platelet function was assessed by impedance aggregometry. ResultsA total of 168 patients were included, 77 (45.8%) of whom were on DAPT at the time of PCI. Patients on DAPT had more often a history of previous PCI (p = 0.03), higher ACS at admission (p < 0.001) and creatinine levels (p = 0.03). Coronary calcifications and type C lesions were more frequent in patients without DAPT (p = 0.02 and p = 0.03, respectively), as much as TIMI flow < 3 (p = 0.03), while procedural characteristics were comparable. Baseline platelet reactivity was significantly reduced in DAPT treated patients (p < 0.001 for ASPI, COL and ADP tests). However the rate of periprocedural myonecrosis did not differ according to pre-procedural DAPT (68.4%vs 67%, p = 0.87; adjusted OR[95%CI] = 1.34[0.71–2.53], p = 0.36) and neither the occurrence of PMI (13.3% vs 12.6%, p = 0.99; adjusted OR[95%CI] = 1.24[0.51–3.1], p = 0.64). Furthermore, baseline platelet reactivity was similar in patients with and without PMI/myonecrosis with no relationship between platelet function and Troponin I peak. ConclusionIn patients undergoing PCI with adjunctive GP IIb-IIIa inhibitors, preprocedural DAPT and baseline platelet reactivity are not associated to the risk of periprocedural myocardial infarction or myonecrosis. These data further support the role of periprocedural Gp IIb-IIIa inhibitors in order to overcome any suboptimal inhibition of platelet aggregation at the time of the procedure due to drug-resistance or delayed (downstream) administration of ADP antagonists, especially in complex high-risk procedures.

Impact of adenosine A2a receptor polymorphism rs5751876 on platelet reactivity in ticagrelor treated patients

Dual antiplatelet therapy constitutes a key point in the management of patients with acute coronary syndromes. In particular, ticagrelor, an ADP-antagonist, can provide a more potent and predictable platelet inhibition as compared to clopidogrel, and adenosine-mediated pathways have been involved in its beneficial effects on mortality and myocardial perfusion. However, a quote of patients still displays a suboptimal platelet inhibition on ticagrelor, and, while the role of genetics in conditioning clopidogrel resistance is well established, few data have been reported for ticagrelor. We investigated the impact of rs5751876 C > T polymorphism of adenosine A2a receptor (ADORA2a) on platelet reactivity in patients during chronic treatment with ticagrelor.We included patients treated with ASA and ticagrelor for a recent ACS or elective coronary revascularization. Platelet reactivity was assessed at 30–90 days post-discharge by multiple-electrode aggregometry. HRPR for ticagrelor was defined as ADP-test results >417 AU*min. Genetic analysis was performed to assess the presence of rs5751876 C > T polymorphism of ADORA2a receptor.We included 244 patients in our study, 174 (71.3%) patients carried the polymorphism (T allele), 51 (20.9%) of them in homozygosis (T/T). C-allele carriers (homozygotes C/C and heterozygotes C/T) showed no difference in baseline characteristics but for lower HDL-cholesterol (p = 0.01). An absolute lower rate of HRPR on ticagrelor was observed in homozygotes T/T (p = 0.03). At multivariate analysis, C allele carriage was independently associated with the rate of HRPR on ticagrelor (adjusted OR[95%CI] = 4.63[1.02–21.01], p = 0.048).Our study results showed a significant independent association between rs5751876 allele C carriage and a higher rate of high residual platelet reactivity in patients on ticagrelor after a recent ACS or PCI.

Observational Study of Platelet Reactivity in Patients Presenting With ST-Segment Elevation Myocardial Infarction Due to Coronary Stent Thrombosis Undergoing Primary Percutaneous Coronary Intervention: Results From the European PREvention of Stent Thrombosis by an Interdisciplinary Global European Effort Registry

ObjectivesHigh platelet reactivity (HPR) was studied in patients presenting with ST-segment elevation myocardial infarction (STEMI) due to stent thrombosis (ST) undergoing immediate percutaneous coronary intervention (PCI). BackgroundHPR on P2Y12 inhibitors (HPR-ADP) is frequently observed in stable patients who have experienced ST. The HPR rates in patients presenting with ST for immediate PCI are unknown. MethodsConsecutive patients presenting with definite ST were included in a multicenter ST registry. Platelet reactivity was measured before immediate PCI with the VerifyNow P2Y12 or Aspirin assay. ResultsPlatelet reactivity was measured in 129 ST patients presenting with STEMI undergoing immediate PCI. HPR-ADP was observed in 76% of the patients, and HPR on aspirin (HPR-AA) was observed in 13% of the patients. HPR rates were similar in patients who were on maintenance P2Y12 inhibitor or aspirin since stent placement versus those without these medications. In addition, HPR-ADP was similar in patients loaded with a P2Y12 inhibitor shortly before immediate PCI versus those who were not. In contrast, HPR-AA trended to be lower in patients loaded with aspirin as compared with those not loaded. ConclusionsApproximately 3 out of 4 ST patients with STEMI undergoing immediate PCI had HPR-ADP, and 13% had HPR-AA. Whether patients were on maintenance antiplatelet therapy while developing ST or loaded with P2Y12 inhibitors shortly before undergoing immediate PCI had no influence on the HPR rates. This raises concerns that the majority of patients with ST have suboptimal platelet inhibition undergoing immediate PCI.

Vitamin D levels and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor

Background: Suboptimal platelet inhibition still represents an important challenge, especially for patients undergoing percutaneous coronary interventions (PCIs). However, very few are known so far on the predictors of high-residual platelet reactivity (HRPR) despite antiplatelet strategies. Increasing attention has been paid in the last years to the role of vitamin D in atherothrombosis. Therefore, the aim of our study was to evaluate the impact of vitamin D levels on platelet function in patients treated with dual antiplatelet therapy (DAPT). Patients treated with DAPT (ASA and clopidogrel or ticagrelor) after a recent acute coronary syndrome (ACS) or elective PCI were scheduled for platelet function assessment at 30–90 days post-discharge. Platelet function was assessed by whole blood impedance aggregometry (Multiplate®-Roche Diagnostics AG), HRPR was considered for ASPI test values > 862 AU*min (for ASA) and adenosine diphosphate (ADP) test values ≥417 AU*min (for ADP-antagonists). Fasting samples were obtained for main chemistry parameters and vitamin D level assessment.Our population is represented by 503 patients, who were divided according to vitamin D quartiles (≤9.1; 9.2–14.4; 14.5–21.7; >21.7 ng/ml). Lower vitamin D levels related with age (p = 0.04), diabetic status (p = 0.05), and previous coronary surgery (p = 0.007), therapy with beta-blockers and statins (p = 0.01 and p = 0.02). Vitamin D inversely related to the levels of total cholesterol (p = 0.01), triglycerides (p < 0.001), hemoglobin (p = 0.05), and HbA1c (p < 0.001). Significantly higher platelet reactivity was observed after platelet stimulation with ADP (p = 0.01), but not with other platelet activators. The prevalence of HRPR for ASA was low (1.2%) and not conditioned by Vitamin D levels (adjusted OR[95%CI] = 1.56[0.71–3.5], p = 0.27). HRPR with ADP-antagonists was observed in 26% of patients, and the rate increased with lower vitamin D quartiles (37.3% vs 22.2% vs 24.4% vs 20.2%, p = 0.005, adjusted OR[95%CI] = 1.23[1.02–1.49], p = 0.04).An absolute increase in HRPR with lower vitamin D levels was similarly observed among patients receiving ticagrelor (adjusted OR[95% CI] = 1.40[0.95–2.06], p = 0.08), and those on clopidogrel (adjusted OR[95%CI] = 1.31[0.99–1.75], p = 0.06).Thus, lower vitamin D levels are associated with higher platelet reactivity and impaired effectiveness of ADP-antagonists, while not influencing the effectiveness of ASA. Future studies will tell whether vitamin D supplementation can reduce platelet reactivity, overcoming the phenomenon of resistance to antiplatelet agents.

Suboptimal Antiplatelet Therapy Suggested By Platelet Aggregation Studies Does Not Correlate with a Change in Clinical Management

Introduction: With the expanding repertoire of antiplatelet drug targets and therapies, quantifiable parameters to assess their efficacy can prove to be useful in clinical decision-making. In this retrospective analysis we examined patients who had platelet aggregation testing done at our center between August 2008 and August 2013, focusing on those who were on some form of antiplatelet therapy during testing. Our goal was to define the impact of platelet aggregation testing on decision-making regarding continuation or change in antiplatelet therapy.Methods: Light transmission aggregometry (LTA) was used to assess efficacy of treatment with antiplatelet agents. Inhibition of platelet aggregation in response to ADP and arachidonic acid are reflective of the therapeutic effect of aspirin, while inhibition of platelet aggregation in response to ADP reflects the effect of P2Y12 receptor antagonists. As per parameters developed at our center, the combination of arachidonic acid aggregation <20 percent and ADP aggregation (at concentration of 5 uM) <70 percent is indicative of optimal therapeutic response to aspirin. Though not fully standardized, ADP aggregation < 40% is considered to be indicative of therapeutic response to clopidogrel. Descriptive statistics for frequency were used. Pearson coefficient was used to assess correlation.Results: We studied results of platelet aggregometry in 117 patients who were on some form of antiplatelet therapy - 81 on a single agent (72 on aspirin alone, 9 receiving P2Y12 antagonist alone), 34 on dual therapy (33 on aspirin + P2Y12 antagonist, 1 on aspirin + cilostazol), and 2 patients on triple therapy (1 on aspirin + P2Y12 antagonist + cilostazol, 1 on aspirin + dipyridamole + cilostazol). None of our patients were on Gp IIb/IIIa inhibitors. In total, 108 patients were on aspirin therapy and 43 patients were on P2Y12 inhibitors. In 65 out of these 117 patients, the primary indication for platelet aggregation testing was to monitor the efficacy of antiplatelet therapy, while in the remaining 52, testing was done for other indications. Fifty-nine of these 65 patients were tested in the setting of a recent thrombotic event in the cerebral, coronary, peripheral, or other vascular bed. While 68 (58%) patients had optimal therapeutic response, 49 (42%) patients - 38 of the 108 (35%) patients on aspirin, and 14 of the 43 (32%) patients on a P2Y12 inhibitor - had evidence of suboptimal response to the respective agent. However, antiplatelet therapy was changed or adjusted in only 8 of these 49 patients following these sub-optimal test results, and only 3 had repeat testing following the change (all three of whom were shown to have complete response). Among the 108 patients on aspirin therapy, the total daily dose did not correlate either with the PFA-100 closure times (Collagen/ADP or Collagen/epinephrine) or with the degree of platelet aggregation in response to any of the agonists (ADP, arachidonic acid, collagen, epinephrine or ristocetin).Conclusions: Most of the patients who underwent platelet aggregation testing to monitor the efficacy of antiplatelet therapy had a recent thrombotic event that prompted the test. Though 42% of patients on antiplatelet agent(s) had in vitro evidence of sub-optimal platelet inhibition, antiplatelet therapy was changed or adjusted in only 16% of these individuals, and only 6% had repeat testing following the change. This suggests that, though platelet aggregation testing was potentially useful in monitoring efficacy of platelet inhibition, clinical changes in antiplatelet therapy were guided more by other factors, casting uncertainty upon the cost effectiveness of platelet function testing in this population. No significant increment was found in the in vitro antiplatelet effect of aspirin with increasing daily doses, suggesting lack of a dose-response beyond 81 mg per day. DisclosuresMcCrae:Syntimmune: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Halozyme: Membership on an entity's Board of Directors or advisory committees; Momenta: Consultancy.