| 1. |
- Erlinge, David, et al.
(författare)
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Clopidogrel metaboliser status based on point-of-care CYP2C19 genetic testing in patients with coronary artery disease
- 2014
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 111:5, s. 943-950
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Tidskriftsartikel (refereegranskat)abstract
- We compared results obtained with the Nanosphere Verigene (R) System, a novel point-of-care (POC) genetic test capable of analysing 11, CYP2C19 variants within 3 hours, to an established, validated genotyping method (Affymetrix (TM) DMET+; reference assay) for identifying extensive and reduced metabolisers of clopidogrel. Based on genotyping, patients (N=82) with stable coronary artery disease on clopidogrel 75 mg daily were defined as extensive metabolisers (*1/*1, *1/*17,*17/*17), reduced metabolisers (*1/*2,*1/*8,*2/*2,*2/*3), or of indeterminate metaboliser status (*2/*17). Pharmacokinetic exposure to clopidogrel's active metabolite and pharmacodynamic measures with P2Y12 reaction units (PRU) (VerifyNow (R) P2Y12 assay), and VASP PRI (PRI) were also assessed. There was a 99.9% overall; concordance of marker-level data between the Nanosphere Verigene and DMET+ systems in identifying the CYP2C19 variants and 100% agreement in classifying the patients as extensive (n=59) or reduced metabolisers (n=15). Extensive metabolisers had significantly higher active metabolite exposure than reduced metabolisers (LS means 12.6 ng*h/ml vs 7.7 ng*h/ml; p<0.001). Extensive metabolisers also had lower PRU (LS means 158 vs 212; p=0.003) and VASP PRI (LS means 48% vs 63%, p=0.01) compared to reduced metabolisers. Rates of high on-treatment platelet reactivity were higher in reduced metabolisers compared to extensive metabolisers (VASP PRI >= 50%: 79% vs 47%; PRU >235: 33% vs 16%). The Nanosphere Verigene CBS system identified 11 CYP2C19 alleles in less than 3 hours with a high degree of accuracy when compared to a conventional method, and was further validated against pharmacokinetic and pharmacodynamic phenotypes.
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| 2. |
- Erlinge, David, et al.
(författare)
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Prasugrel 5 mg in the Very Elderly Attenuates Platelet Inhibition But Maintains Noninferiority to Prasugrel 10 mg in Nonelderly Patients
- 2013
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 62:7, s. 577-583
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Tidskriftsartikel (refereegranskat)abstract
- Objectives This study assessed pharmacodynamic (PD) response to the reduced prasugrel maintenance dose of 5 mg in very elderly (VE) patients (andgt;= 75 years of age). less thanbrgreater than less thanbrgreater thanBackground In the TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction 38) study prasugrel 10 mg reduced ischemic events versus clopidogrel 75 mg, but increased bleeding in VE patients. less thanbrgreater than less thanbrgreater thanMethods We examined PD and active metabolite pharmacokinetics (PKs) with prasugrel 5 and 10 mg and clopidogrel 75 mg in a 3-period (12 days each) blinded, crossover study in VE (n = 73; mean: 79 +/- 3 years of age) or (n 82) nonelderly (NE) (andgt;= 45 to andlt;65 years of age; mean: 56 +/- 5 years of age) stable coronary artery disease (CAD) patients receiving background aspirin. Assays included light transmission aggregometry (LTA), VerifyNow P2Y12 (VN-P2Y12), and vasodilator-associated stimulated phosphoprotein (VASP). The primary comparison was noninferiority of maximum platelet aggregation (MPA) comparing the median for prasugrel 5 mg in VE versus the 75th percentile for prasugrel 10 mg in NE, using a pre-specified 1-sided 97.5% confidence interval for the difference andlt;15%. less thanbrgreater than less thanbrgreater thanResults Prasugrel 5 mg in VE met the primary PD noninferiority criterion versus prasugrel 10 mg in NE. For prasugrel 5 mg, MPA was significantly lower (57 +/- 14%) than clopidogrel (63 +/- 14%; p andlt; 0.001) in VE but higher than prasugrel 10 mg in NE (46 +/- 12%; p andlt; 0.001). PD response by LTA, VN-P2Y12, and VASP during all treatments appeared similar between age cohorts. Prasugrel 5 mg resulted in fewer VE poor responders than clopidogrel. Rates of mild bleeding were higher with prasugrel 10 mg but similar for prasugrel 5 mg versus clopidogrel 75 mg. less thanbrgreater than less thanbrgreater thanConclusions In aspirin-treated stable CAD patients, prasugrel 5 mg in VE attenuated platelet inhibition while meeting pre-specified noninferiority criterion versus prasugrel 10 mg in NE, with significantly better PD response and fewer poor responders compared to clopidogrel 75 mg in VE. (Comparison of Prasugrel and Clopidogrel in Very Elderly and Non-Elderly Patients With Stable Coronary Artery Disease [GENERATIONS]; NCT01107912)
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| 3. |
- Franchi, Francesco, et al.
(författare)
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Impact of Diabetes Mellitus and Chronic Kidney Disease on Cardiovascular Outcomes and Platelet P2Y12 Receptor Antagonist Effects in Patients With Acute Coronary Syndromes : Insights From the PLATO Trial
- 2019
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Ingår i: Journal of the American Heart Association. - 2047-9980 .- 2047-9980. ; 8:6
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Tidskriftsartikel (refereegranskat)abstract
- Background-There are limited data on how the combination of diabetes mellitus (DM) and chronic kidney disease (CKD) affects cardiovascular outcomes as well as response to different P2Y(12) receptor antagonists, which represented the aim of the present investigation. Methods and Results-In this post hoc analysis of the PLATO (Platelet Inhibition and Patient Outcomes) trial, which randomized acute coronary syndrome patients to ticagrelor versus clopidogrel, patients (n=15 108) with available DM and CKD status were classified into 4 groups: DM+/CKD+ (n=1058), DM+/CKD- (n=2748), DM-/CKD+ (n=2160), and DM-/CKD- (n=9142). The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke at 12 months. The primary safety end point was PLATO major bleeding. DM+/CKD+ patients had a higher incidence of the primary end point compared with DM-/CKD- patients (23.3% versus 7.1%; adjusted hazard ratio 2.22; 95% CI 1.88-2.63; P<0.001). Patients with DM+/CKD- and DM-/CKD+ had an intermediate risk profile. The same trend was shown for the individual components of the primary end point and for major bleeding. Compared with clopidogrel, ticagrelor reduced the incidence of the primary end point consistently across subgroups (P-interaction=0.264), but with an increased absolute risk reduction in DM+/CKD+. The effects on major bleeding were also consistent across subgroups (P-interaction=0.288). Conclusions-In acute coronary syndrome patients, a gradient of risk was observed according to the presence or absence of DM and CKD, with patients having both risk factors at the highest risk. Although the ischemic benefit of ticagrelor over clopidogrel was consistent in all subgroups, the absolute risk reduction was greatest in patients with both DM and CKD.
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| 4. |
- Gurbel, Paul A., et al.
(författare)
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The effect of CYP2C19 gene polymorphisms on the pharmacokinetics and pharmacodynamics of prasugrel 5-mg, prasugrel 10-mg and clopidogrel 75-mg in patients with coronary artery disease
- 2014
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Ingår i: Thrombosis and Haemostasis. - : Schattauer. - 0340-6245 .- 2567-689X. ; 112:3, s. 589-597
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Tidskriftsartikel (refereegranskat)abstract
- CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. Here, we assessed effects of CYP2C19 metaboliser status on pharmacokinetics (PK) and pharmacodynamic (PD) responses to prasugrel 5-mg and 10-mg and clopidogrel 75-mg using data from two PK/PD studies in stable coronary artery disease (CAD) patients (GENERATIONS and FEATHER). Active metabolite concentrations (area under the curve, AUC([0-tlast])), maximum platelet aggregation (MPA) measured by light transmission aggregometry, vasodilator-stimulated phosphoprotein platelet reactivity index, and VerifyNow P2Y12-platelet reaction units (VN-PRU) were analysed by CYP2C19-predicted phenotype (extensive metaboliser [EM; N=154], *2-*8 non-carriers, vs reduced metaboliser [RM; N=41],*2-*8 carriers/*17 non-carriers). AUC((0-tlast)) was unaffected by metaboliser status for prasugrel 5-mg and 10-mg (geometric mean EM/RM ratios 1.00, 95% confidence interval [Cl]: 0.86,1.17, p>0.99; and 0.97, 95% CI:0.85,1.12, p=0.71, respectively), but was lower among RMs receiving clopidogrel 75-mg (1.37, 95% CI:1.14,1.65, p<0.001). Platelet reactivity was not significantly affected by CYP2C19 metaboliser status for prasugrel 5-mg, or for prasugrel 10-mg by MPA and VN-PRU, but for clopidogrel 75-mg was significantly higher in reduced metabolisers (all measures p<0.01). Prasugrel 10-mg showed greater antiplatelet effects vs clopidogrel 75-mg (all comparisons p<0.001). Prasugrel 5-mg showed greater antiplatelet effects vs clopidogrel 75-mg in RMs (all p<0.001), and comparable effects in EMs (all p >= 0.37). In contrast to clopidogrel, prasugrel active metabolite PK was not influenced by CYP2C19 genotype. Antiplatelet effect for prasugrel 10-mg was greater irrespective of metaboliser status and for prasugrel 5-mg was greater for RMs and comparable for EMs as compared to clopidogrel 75-mg.
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| 5. |
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| 6. |
- Kubica, Jacek, et al.
(författare)
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Prolonged antithrombotic therapy in patients after acute coronary syndrome : A critical appraisal of current European Society of Cardiology guidelines
- 2020
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Ingår i: CARDIOLOGY JOURNAL. - : VM Media SP. zo.o VM Group SK. - 1897-5593 .- 1898-018X. ; 27:6, s. 661-676
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Tidskriftsartikel (refereegranskat)abstract
- The increased risk of non-cardiovascular death in patients receiving clopidogrel or prasugrel in comparison with the placebo group in the Dual Antiplatelet Therapy (DAPT) trial in contrast to the decreased risk of cardiovascular death and all-cause death seen in patients treated with low-dose ticagrelor in the EU label population of the PEGASUS-TIMI 54 trial, resulted in inclusion in the 2020 ESC NSTE-ACS guidelines the recommendation for use of clopidogrel or prasugrel only if the patient is not eligible for treatment with ticagrelor. The prevalence of the primary outcome composed of cardiovascular death, stroke, or myocardial infarction was lower in the low-dose rivaroxaban and acetylsalicylic acid (ASA) group than in the ASA-alone group in the COMPASS trial. Moreover, all-cause mortality and cardiovascular mortality rates were lower in the rivaroxaban-plus-ASA group. Comparison of the PEGASUS-TIMI 54 and COMPASS trial patient characteristics clearly shows that each of these treatment strategies should be addressed at different groups of patients. A greater benefit in post-acute coronary syndrome (ACS) patients with a high risk of ischemic events and without high bleeding risk may be expected with ASA and ticagrelor 60 mg b.i.d. when the therapy is continued without interruption or with short interruption only after ACS. On the other hand, ASA and rivaroxaban 2.5 mg b.i.d. seems to be a better option when indications for dual antithrombotic therapy (DATT) appear after a longer time from ACS (more than 2 years) and/or from cessation of DAPT (more than 1 year) and in patients with multiple vascular bed atherosclerosis. Thus, both options of DATTs complement each other rather than compete, as can be presumed from the recommendations. However, a direct comparison between these strategies should be tested in future clinical trials.
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| 7. |
- Storey, Robert F., et al.
(författare)
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Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes
- 2020
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 41:33, s. 3132-3140
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Tidskriftsartikel (refereegranskat)abstract
- Aims To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y(12) receptor antagonist for subcutaneous administration, in patients with chronic coronary syndromes (CCS). Methods and results In this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcutaneous selatogrel (8 mg, n = 114; or 16 mg, n = 115) was compared with placebo (n = 116) (ClinicalTrials.gov: NCT03384966). Platelet aggregation was assessed over 24 h (VerifyNow assay) and 8 h (light transmittance aggregometry; LTA). Pharmacodynamic responders were defined as patients having P2Y(12) reaction units (PRU) <100 at 30 min post-dose and lasting >= 3 h. At 30 min post-dose, 89% of patients were responders to selatogrel 8 mg, 90% to selatogrel 16 mg, and 16% to placebo (P < 0.0001). PRU values (mean standard deviation) were 10 +/- 25 (8 mg), 4 +/- 10 (16 mg), and 163 +/- 73 (placebo) at 15 min and remained <100 up to 8 h for both doses, returning to pre-dose or near pre-dose levels by 24 h post-dose. LTA data showed similarly rapid and potent inhibition of platelet aggregation. Selatogrel plasma concentrations peaked similar to 30 min post-dose. Selatogrel was safe and well-tolerated with transient dyspnoea occurring overall in 7% (16/229) of patients (95% confidence interval: 4-11%). Conclusions Selatogrel was rapidly absorbed following subcutaneous administration in CCS patients, providing prompt, potent, and consistent platelet P2Y(12) inhibition sustained for >= 8 h and reversible within 24 h. Further studies of subcutaneous selatogrel are warranted in clinical scenarios where rapid platelet inhibition is desirable.
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| 8. |
- Angiolillo, Dominick J., et al.
(författare)
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International Expert Consensus on Switching Platelet P2Y(12) Receptor-Inhibiting Therapies
- 2017
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Ingår i: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7322 .- 1524-4539. ; 136:20, s. 1955-
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Tidskriftsartikel (refereegranskat)abstract
- Dual antiplatelet therapy with aspirin and a P2Y(12) inhibitor is the treatment of choice for the prevention of atherothrombotic events in patients with acute coronary syndromes and for those undergoing percutaneous coronary interventions. The availability of different oral P2Y(12) inhibitors (clopidogrel, prasugrel, ticagrelor) has enabled physicians to contemplate switching among therapies because of specific clinical scenarios. The recent introduction of an intravenous P2Y(12) inhibitor (cangrelor) further adds to the multitude of modalities and settings in which switching therapies may occur. In clinical practice, it is not uncommon to switch P2Y(12) inhibitor, and switching may be attributed to a variety of factors. However, concerns about the safety of switching between these agents have emerged. Practice guidelines have not fully elaborated on how to switch therapies, leaving clinicians with limited guidance on when and how to switch therapies when needed. This prompted the development of this expert consensus document by key leaders from North America and Europe with expertise in basic, translational, and clinical sciences in the field of antiplatelet therapy. This expert consensus provides an overview of the pharmacology of P2Y(12) inhibitors, different modalities and definitions of switching, and available literature and recommendations for switching between P2Y(12) inhibitors.
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| 9. |
- Navarese, Eliano P., et al.
(författare)
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Comparative Efficacy and Safety of Oral P2Y12 Inhibitors in Acute Coronary Syndrome Network Meta-Analysis of 52 816 Patients From 12 Randomized Trials
- 2020
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 142:2, s. 150-160
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Tidskriftsartikel (refereegranskat)abstract
- Background: New randomized, controlled trials have become available on oral P2Y(12)inhibitors in acute coronary syndrome. We aimed to evaluate current evidence comparing the efficacy and safety profile of prasugrel, ticagrelor, and clopidogrel in acute coronary syndrome by a meta-analysis of randomized controlled trials.Methods: We performed a network meta-analysis and direct pairwise comparison analysis of efficacy and safety outcomes from 12 randomized controlled trials including a total of 52 816 patients with acute coronary syndrome.Results: In comparison with clopidogrel, ticagrelor significantly reduced cardiovascular mortality (hazard ratio [HR], 0.82 [95% CI, 0.72-0.92]) and all-cause mortality (HR, 0.83 [95% CI, 0.75-0.92]), whereas there was no statistically significant mortality reduction with prasugrel (HR, 0.90 [95% CI, 0.80-1.01] and HR, 0.92 [95% CI, 0.84-1.02], respectively). In comparison with each other, there were no significant differences in mortality (HR prasugrel versus ticagrelor, 1.10 [95% CI, 0.94-1.29] and 1.12 [95% CI, 0.98-1.28]). In comparison with clopidogrel, prasugrel reduced myocardial infarction (HR, 0.81 [95% CI, 0.67-0.98]), whereas ticagrelor showed no risk reduction (HR, 0.97 [95% CI, 0.78-1.22]). Differences between prasugrel and ticagrelor were not statistically significant. Stent thrombosis risk was significantly reduced by both ticagrelor and prasugrel versus clopidogrel (28%-50% range of reduction). In comparison with clopidogrel, both prasugrel (HR, 1.26 [95% CI, 1.01-1.56]) and ticagrelor (HR, 1.27 [95% CI, 1.04-1.55]) significantly increased major bleeding. There were no significant differences between prasugrel and ticagrelor for all outcomes explored.Conclusions: Prasugrel and ticagrelor reduced ischemic events and increased bleeding in comparison with clopidogrel. A significant mortality reduction was observed with ticagrelor only. There was no efficacy and safety difference between prasugrel and ticagrelor.
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| 10. |
- Navarese, Eliano Pio, et al.
(författare)
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Drug-coated balloons in treatment of in-stent restenosis : a meta-analysis of randomised controlled trials
- 2013
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Ingår i: Clinical Research in Cardiology. - : Springer Science and Business Media LLC. - 1861-0684 .- 1861-0692. ; 102:4, s. 279-287
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Drug-coated balloons (DCBs) have been developed for the percutaneous treatment of coronary artery disease. An initial focus has been the management of in-stent restenosis (ISR) but randomised controlled trials (RCTs) have been small and powered only for angiographic endpoints.OBJECTIVE:The aim of the work was to assess the clinical and angiographic outcomes of patients treated for ISR with DCB versus control (balloon angioplasty or drug-eluting stents) by a meta-analysis of RCTs.METHODS: A comprehensive search was performed of RCTs where patients with ISR were randomly assigned to either DCB or alternative coronary intervention. Outcome measurements were death, myocardial infarction (MI), target lesion revascularisation (TLR), binary definition of restenosis and in-lesion late luminal loss (LLL).RESULTS: Four studies were identified that fulfilled the inclusion criteria. Pooled odds ratios (ORs) were calculated for patients treated for ISR (n = 399). Mean follow-up duration was 14.5 months. DCBs were associated with lower rates of TLR [8.8 vs. 29.7 % OR (95 % confidence interval, CI) 0.20 (0.11-0.36), p < 0.0001], binary restenosis [10.3 vs. 41.3 % OR (95 % CI) 0.13 (0.07-0.24), p < 0.00001] and MI [0.5 vs. 3.8 %, OR (95 % CI) 0.21 (0.04-1.00), p = 0.05]. No significant heterogeneity was identified.CONCLUSION: Drug-coated balloons appear to be effective versus control in reducing TLR and possibly MI versus balloon angioplasty or drug-eluting stents in the management of ISR.
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