RESUMO
BACKGROUND: Debates persist regarding the optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in coronary artery disease (CAD). Recent trials have introduced a novel approach involving P2Y12 inhibitor monotherapy with ticagrelor or clopidogrel, after a short DAPT. However, the effectiveness and safety of this strategy remains to be established. We aimed to perform a meta-analysis comparing monotherapy with P2Y12 inhibitors versus standard DAPT in patients undergoing PCI at 12 months. METHODS: Multiple databases were searched. Six RCTs with a total of 24877 patients were included. The primary endpoint was all-cause mortality at 12 months of follow-up. The secondary endpoints were cardiovascular mortality, myocardial infarction, probable or definite stent thrombosis, stroke events, and major bleeding. The study is registered with PROSPERO (CRD42024499529). RESULTS: Monotherapy with P2Y12 inhibitor ticagrelor significantly reduced both allcause mortality (HR 0.71, 95 CI [0.55-0.91], P = 0.007) and cardiovascular mortality (HR 0.66, 95% CI [0.49-0.89], P = 0.006) compared to standard DAPT. In contrast, clopidogrel monotherapy did not demonstrate a similar reduction. The decrease in mortality associated with ticagrelor was primarily due to a lower risk of major bleeding (HR 0.56, 95% CI [0.43-0.72], P < 0.001), while the risk of myocardial infarction (MI) remained unchanged (HR 0.90, 95% CI [0.73-1.11], P = 0.32). The risk of stroke was found to be similar across treatments. CONCLUSIONS: In comparison to standard DAPT, P2Y12 inhibitor monotherapy with ticagrelor may lead to a reduced mortality. The clinical benefits are driven by a reduction of bleeding risk without ischemic risk trade-off.
Assuntos
Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária , Antagonistas do Receptor Purinérgico P2Y , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Intervenção Coronária Percutânea/métodos , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Inibidores da Agregação Plaquetária/uso terapêutico , Resultado do Tratamento , Terapia Antiplaquetária Dupla/métodos , Ticagrelor/uso terapêuticoRESUMO
Patients with isolated tricuspid valve (TV) disease have poor prognosis with no consensus on their management. Transcatheter TV intervention is emerging as a valid option in patients with prohibitive surgical risk. We analyzed studies of patients who underwent isolated TV surgery to identify the features associated with successful clinical outcomes. We performed a systematic review and meta-analysis of studies reporting clinical outcomes of isolated surgical TV intervention, namely TV repair, TV replacement with a bioprosthetic valve (TVR-B), or TV replacement with a mechanical valve (TVR-M). Twenty-seven studies involving 10,478 patients (4,931 TV repair, 3,821 TVR-B, and 1,713 TVR-M) were included. Early mortality occurred in 9% and did not differ between TV surgical approaches. Late mortality was 27% at a median follow-up of 4 (3 to 6) years and was significantly higher for all-TVR (30% vs 25%, rate ratio 1.18, 95% confidence interval 1.05 to 1.31, p = 0.004) and TVR-B (28% vs 24%, rate ratio 1.15, 95% confidence interval 1.02 to 1.30, p = 0.02) compared with TV repair. Late mortality did not differ between TVR-B and TVR-M. Across all studies, early complications included bleeding (7.4%), acute kidney injury (18.7%), permanent pacemaker (13.7%), cerebrovascular accidents (1.2%), and infection (8.9%). Late clinical outcomes included reintervention (3.7%), structural valve deterioration (2.4%), valve thrombosis (2.6%), and TV regurgitation recurrence after 1 year (15.0%). In conclusion, in isolated TV surgeries, TV repair has favorable long-term mortality compared with TV replacement. This supports the development and refinement of transcatheter TV repair approaches. Future research is recommended to provide comparative data for various transcatheter TV interventions.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Doenças das Valvas Cardíacas , Implante de Prótese de Valva Cardíaca , Insuficiência da Valva Tricúspide , Humanos , Valva Tricúspide/cirurgia , Implante de Prótese de Valva Cardíaca/efeitos adversos , Resultado do Tratamento , Insuficiência da Valva Tricúspide/complicações , Doenças das Valvas Cardíacas/complicações , Estudos RetrospectivosRESUMO
Conventional dual antiplatelet therapy (DAPT) for patients with acute coronary syndromes undergoing percutaneous coronary intervention comprises aspirin with a potent P2Y purinoceptor 12 (P2Y12) inhibitor (prasugrel or ticagrelor) for 12 months. Although this approach reduces ischaemic risk, patients are exposed to a substantial risk of bleeding. Strategies to reduce bleeding include de-escalation of DAPT intensity (downgrading from potent P2Y12 inhibitor at conventional doses to either clopidogrel or reduced-dose prasugrel) or abbreviation of DAPT duration. Either strategy requires assessment of the ischaemic and bleeding risks of each individual. De-escalation of DAPT intensity can reduce bleeding without increasing ischaemic events and can be guided by platelet function testing or genotyping. Abbreviation of DAPT duration after 1-6 months, followed by monotherapy with aspirin or a P2Y12 inhibitor, reduces bleeding without an increase in ischaemic events in patients at high bleeding risk, particularly those without high ischaemic risk. However, these two strategies have not yet been compared in a head-to-head clinical trial. In this Consensus Statement, we summarize the evidence base for these treatment approaches, provide guidance on the assessment of ischaemic and bleeding risks, and provide consensus statements from an international panel of experts to help clinicians to optimize these DAPT approaches for individual patients to improve outcomes.
Assuntos
Síndrome Coronariana Aguda , Trombose Coronária , Intervenção Coronária Percutânea , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Cloridrato de Prasugrel/efeitos adversos , Trombose Coronária/etiologia , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/etiologia , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Aspirina/efeitos adversos , Hemorragia/induzido quimicamente , Intervenção Coronária Percutânea/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: The intensity of inflammation during COVID-19 is related to adverse outcomes. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in low-density lipoprotein receptor homeostasis, with potential influence on vascular inflammation and on COVID-19 inflammatory response. OBJECTIVES: The goal of this study was to investigate the impact of PCSK9 inhibition vs placebo on clinical and laboratory outcomes in patients with severe COVID-19. METHODS: In this double-blind, placebo-controlled, multicenter pilot trial, 60 patients hospitalized for severe COVID-19, with ground-glass opacity pneumonia and arterial partial oxygen pressure to fraction of inspired oxygen ratio ≤300 mm Hg, were randomized 1:1 to receive a single 140-mg subcutaneous injection of evolocumab or placebo. The primary endpoint was death or need for intubation at 30 days. The main secondary endpoint was change in circulating interleukin (IL)-6 at 7 and 30 days from baseline. RESULTS: Patients randomized to receive the PCSK9 inhibitor had lower rates of death or need for intubation within 30 days vs placebo (23.3% vs 53.3%, risk difference: -30%; 95% CI: -53.40% to -6.59%). Serum IL-6 across time was lower with the PCSK9 inhibitor than with placebo (30-day decline: -56% vs -21%). Patients with baseline IL-6 above the median had lower mortality with PCSK9 inhibition vs placebo (risk difference: -37.50%; 95% CI: -68.20% to -6.70%). CONCLUSIONS: PCSK9 inhibition compared with placebo reduced the primary endpoint of death or need for intubation and IL-6 levels in severe COVID-19. Patients with more intense inflammation at randomization had better survival with PCSK9 inhibition vs placebo, indicating that inflammatory intensity may drive therapeutic benefits. (Impact of PCSK9 Inhibition on Clinical Outcome in Patients During the Inflammatory Stage of the COVID-19 [IMPACT-SIRIO 5]; NCT04941105).
Assuntos
COVID-19 , Pró-Proteína Convertase 9 , Humanos , Interleucina-6 , LDL-Colesterol , SARS-CoV-2 , Inflamação , Resultado do Tratamento , Método Duplo-CegoRESUMO
The first international guidance on antithrombotic therapy in the elderly came from the European Society of Cardiology Working Group on Thrombosis in 2015. This same group has updated its previous report on antiplatelet and anticoagulant drugs for older patients with acute or chronic coronary syndromes, atrial fibrillation, or undergoing surgery or procedures typical of the elderly (transcatheter aortic valve implantation and left atrial appendage closure). The aim is to provide a succinct but comprehensive tool for readers to understand the bases of antithrombotic therapy in older patients, despite the complexities of comorbidities, comedications and uncertain ischaemic- vs. bleeding-risk balance. Fourteen updated consensus statements integrate recent trial data and other evidence, with a focus on high bleeding risk. Guideline recommendations, when present, are highlighted, as well as gaps in evidence. Key consensus points include efforts to improve medical adherence through deprescribing and polypill use; adoption of universal risk definitions for bleeding, myocardial infarction, stroke and cause-specific death; multiple bleeding-avoidance strategies, ranging from gastroprotection with aspirin use to selection of antithrombotic-drug composition, dosing and duration tailored to multiple variables (setting, history, overall risk, age, weight, renal function, comedications, procedures) that need special consideration when managing older adults.
Assuntos
Fibrilação Atrial , Acidente Vascular Cerebral , Substituição da Valva Aórtica Transcateter , Humanos , Idoso , Fibrinolíticos/efeitos adversos , Resultado do Tratamento , Aspirina/efeitos adversos , Substituição da Valva Aórtica Transcateter/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Anticoagulantes , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/tratamento farmacológico , Fibrilação Atrial/tratamento farmacológico , Inibidores da Agregação Plaquetária/efeitos adversosRESUMO
INTRODUCTION: Atrial fibrillation (AF) is frequent after any cardiac surgery, but evidence suggests it may have no significant impact on survival if sinus rhythm (SR) is effectively restored early after the onset of the arrhythmia. In contrast, management of preoperative AF is often overlooked during or after cardiac surgery despite several proposed protocols. This study sought to evaluate the impact of preoperative AF on mortality in patients undergoing isolated surgical aortic valve replacement (AVR). METHODS: We performed a retrospective, single-center study involving 2628 consecutive patients undergoing elective, primary isolated surgical AVR from 2008 to 2018. A total of 268/2628 patients (10.1%) exhibited AF before surgery. The effect of preoperative AF on mortality was evaluated with univariate and multivariate analyses. RESULTS: Short-term mortality was 0.8% and was not different between preoperative AF and SR cohorts. Preoperative AF was highly predictive of long-term mortality (median follow-up of 4 years [Q1-Q3 2-7]; hazard ratio [HR]: 2.24, 95% confidence interval [CI]: 1.79-2.79, p < .001), and remained strongly and independently predictive after adjustment for other risk factors (HR: 1.54, 95% CI: 1.21-1.96, p < .001) compared with preoperative SR. In propensity score-matched analysis, the adjusted mortality risk was higher in the AF cohort (OR: 1.47, 95% CI: 1.04-1.99, p = .03) compared with the SR cohort. CONCLUSIONS: Preoperative AF was independently predictive of long-term mortality in patients undergoing isolated surgical AVR. It remains to be seen whether concomitant surgery or other preoperative measures to correct AF may impact long-term survival.
Assuntos
Fibrilação Atrial , Implante de Prótese de Valva Cardíaca , Valva Aórtica/cirurgia , Fibrilação Atrial/complicações , Fibrilação Atrial/cirurgia , Humanos , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
AIMS: Choosing an antiplatelet strategy in patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) at high bleeding risk (HBR), undergoing post-percutaneous coronary intervention (PCI), is complex. We used a unique open-source approach (crowdsourcing) to document if practices varied across a small, global cross-section of antiplatelet prescribers in the post-PCI setting. METHODS AND RESULTS: Five-hundred and fifty-nine professionals from 70 countries (the 'crowd') completed questionnaires containing single- or multi-option and free form questions regarding antiplatelet clinical practice in post-PCI NSTE-ACS patients at HBR. A threshold of 75% defined 'agreement'. There was strong agreement favouring monotherapy with either aspirin or a P2Y12 inhibitor following initial DAPT, within the first year (94%). No agreement was reached on the optimal duration of DAPT or choice of monotherapy: responses were in equipoise for shorter (≤3 months, 51%) or longer (≥6 months, 46%) duration, and monotherapy choice (45% aspirin; 53% P2Y12 inhibitor). Most respondents stated use of guideline-directed tools to assess risk, although clinical judgement was preferred by 32% for assessing bleeding risk and by 46% for thrombotic risk. CONCLUSION: The crowdsourcing methodology showed potential as a tool to assess current practice and variation on a global scale and to achieve a broad demographic representation. These preliminary results indicate a high degree of variation with respect to duration of DAPT, monotherapy drug of choice following DAPT and how thrombotic and bleeding risk are assessed. Further investigations should concentrate on interrogating practice variation between key demographic groups.
Assuntos
Síndrome Coronariana Aguda , Crowdsourcing , Intervenção Coronária Percutânea , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/epidemiologia , Quimioterapia Combinada , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Studies using whole blood platelet aggregometry as a laboratory research tool, provided important insights into the mechanism and modulators of platelet aggregation. Subsequently, a number of point-of-care (POC) platelet function tests (PFTs) were developed for clinical use, based on the concept that an individual's thrombotic profile could be assessed in vitro by assessing the response to stimulation of platelet aggregation by specific, usually solo agonists such as adenosine diphosphate (ADP), collagen and thrombin. However, adjusting antiplatelet medication in order to improve the results of such POC PFTs has not translated into a meaningful reduction in cardiovascular events, which may be attributable to important differences between the POC PFT techniques and in vivo conditions, including patient-to-patient variability. Important limitations of most tests include the use of citrate-anticoagulated blood. Citrate directly and irreversibly diminishes platelet function and even after recalcification, it may result in altered platelet aggregation in response to ADP, epinephrine or collagen, and interfere with thrombin generation from activated platelets. Furthermore, most tests do not employ flowing blood and therefore do not assess the effect of high shear forces on platelets that initiate, propagate and stabilize arterial thrombi. Finally, the effect of endogenous thrombolysis, due to fibrinolysis and dislodgement, which ultimately determines the outcome of a thrombotic stimulus, is mostly not assessed. In order to accurately reflect an individual's predisposition to arterial thrombosis, future tests of thrombotic status which overcome these limitations should be used, to improve cardiovascular risk prediction and to guide pharmacotherapy.
Assuntos
Plaquetas/patologia , Átrios do Coração/patologia , Testes de Função Plaquetária/métodos , Testes Imediatos , Trombose/diagnóstico , Animais , Coagulação Sanguínea , Plaquetas/citologia , Humanos , Agregação Plaquetária , Testes de Função Plaquetária/instrumentação , Trombose/sangue , Trombose/patologiaRESUMO
Arterial medial calcification (AMC), the deposition of hydroxyapatite in the medial layer of the arteries, is a known risk factor for cardiovascular events. Oxidative stress is a known inducer of AMC and endogenous antioxidants, such as glutathione (GSH), may prevent calcification. GSH synthesis, however, can be limited by cysteine levels. Therefore, we assessed the effects of the cysteine prodrug 2-oxothiazolidine-4-carboxylic acid (OTC), on vascular smooth muscle cell (VSMC) calcification to ascertain its therapeutic potential. Human aortic VSMCs were cultured in basal or mineralising medium (1 mM calcium chloride/sodium phosphate) and treated with OTC (1-5 mM) for 7 days. Cell-based assays and western blot analysis were performed to assess cell differentiation and function. OTC inhibited calcification ≤90%, which was associated with increased ectonucleotide pyrophosphatase/phosphodiesterase activity, and reduced apoptosis. In calcifying cells, OTC downregulated protein expression of osteoblast markers (Runt-related transcription factor 2 and osteopontin), while maintaining expression of VSMC markers (smooth muscle protein 22α and α-smooth muscle actin). GSH levels were significantly reduced by 90% in VSMCs cultured in calcifying conditions, which was associated with declines in expression of gamma-glutamylcysteine synthetase and GSH synthetase. Treatment of calcifying cells with OTC blocked the reduction in expression of both enzymes and prevented the decline in GSH. This study shows OTC to be a potent and effective inhibitor of in vitro VSMC calcification. It appears to maintain GSH synthesis which may, in turn, prevent apoptosis and VSMCs gaining osteoblast-like characteristics. These findings may be of clinical relevance and raise the possibility that treatment with OTC could benefit patients susceptible to AMC.
Assuntos
Glutationa/biossíntese , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Pró-Fármacos/farmacologia , Ácido Pirrolidonocarboxílico/farmacologia , Tiazolidinas/farmacologia , Calcificação Vascular/prevenção & controle , Fosfatase Alcalina/metabolismo , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Glutamato-Cisteína Ligase/metabolismo , Glutationa Sintase/metabolismo , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Osteoblastos/metabolismo , Osteoblastos/patologia , Diester Fosfórico Hidrolases/metabolismo , Pirofosfatases/metabolismo , Calcificação Vascular/metabolismo , Calcificação Vascular/patologiaRESUMO
Opiates are the traditional analgesics used in patients with ST-elevation myocardial infarction (STEMI). Pharmacodynamic studies indicate that opiates delay the absorption of orally administered P2Y12 inhibitors and the onset of platelet inhibition. Whether these negative effects on platelet inhibition have an impact on clinical outcomes is unclear. A systematic review and meta-analysis was performed searching PubMed, MEDLINE, and Cochrane Central Register of Controlled Trials to identify studies comparing morphine and no-morphine treatment in STEMI patients undergoing primary percutaneous coronary intervention. The primary end point was the occurrence of in-hospital myocardial infarction, and secondary end points were in-hospital stroke and death. Four observational studies were identified, including 3,220 patients with STEMI. Morphine-treated patients had a higher unadjusted rate of reinfarction compared with patients not receiving morphine (1.5% vs. 0.67%, odds ratio (OR) 2.41; 95% confidence interval (CI), 1.11-5.21; P = 0.03). Unadjusted mortality rate was lower in morphine-treated patients (1.7% vs. 4.2%, OR 0.43, 95% CI, 0.23-0.81; P = 0.009). Exclusion of the study with baseline differences between groups showed more frequent reinfarction in the morphine group, but this was no longer statistically significant (1.3% vs. 0.5%, OR 2.02; 95% CI, 0.39-10.43; P = 0.40). There was no difference in stroke according to morphine treatment. Patients pretreated with morphine appear to have a higher rate of reinfarction than patients not receiving morphine. This may be attributable to opiate-related delay in P2Y12 inhibitor absorption and resultant delay in onset of platelet inhibition. These concerning findings indicate the need for prospective, randomized trials to assess the impact of opiates on clinical outcomes in STEMI.
Assuntos
Morfina/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST/epidemiologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Interações Medicamentosas , Humanos , Morfina/administração & dosagem , Intervenção Coronária Percutânea/métodos , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Recidiva , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Infarto do Miocárdio com Supradesnível do Segmento ST/terapiaRESUMO
AIMS: To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 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 P2Y12 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 â¼30 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 P2Y12 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.
Assuntos
Inibidores da Agregação Plaquetária , Antagonistas do Receptor Purinérgico P2Y , Plaquetas , Humanos , Organofosfonatos , Agregação Plaquetária , Testes de Função Plaquetária , Pirimidinas , SíndromeRESUMO
Although used routinely to reduce thrombotic events in patients with coronary disease, the effects of P2Y12 inhibitors on thrombus stability and endogenous fibrinolysis are largely unknown. Blood taken from patients pre- and post-aspirin (nâ¯=â¯20) and on aspirin alone and on dual antiplatelet therapy comprising aspirin plus clopidogrel (nâ¯=â¯20), ticagrelor (nâ¯=â¯20) or cangrelor (nâ¯=â¯20), was tested using the Global Thrombosis Test. The number of "rebleeds" or drops (D) after early platelet-rich thrombus formation (occlusion time, OT), and before final lasting occlusion, was used as an inverse measure of thrombus stability. Whilst clopidogrel had no effect, ticagrelor and cangrelor both increased D significantly, reflecting increased thrombus instability [D pre- and post-clopidogrel 4.3⯱â¯1.6 vs. 4.5⯱â¯1.4, pâ¯=â¯0.833; pre- and post-ticagrelor 4.1⯱â¯2.4 vs. 6.8⯱â¯5.1, pâ¯=â¯0.048; pre- and post-cangrelor 3.6⯱â¯2.0 vs. 7.9⯱â¯8.9, pâ¯=â¯0.046]. Platelet reactivity was reduced by all P2Y12 inhibitors, demonstrated by OT prolongation (clopidogrel 378⯱â¯87â¯s vs. 491⯱â¯93â¯s, pâ¯<â¯0.001; ticagrelor 416⯱â¯122â¯s vs. 549⯱â¯121â¯s, pâ¯<â¯0.001; cangrelor 381⯱â¯146â¯s vs. 613⯱â¯210â¯s, pâ¯<â¯0.001). The magnitude of OT prolongation compared to baseline (ΔOT) was significantly greater for cangrelor compared to clopidogrel and ticagrelor. Cangrelor was the only agent to enhance fibrinolysis (lysis time pre- and post-cangrelor 1622[1240-2048]s vs. 1388[960-1634]s, pâ¯=â¯0.005). We demonstrate the ability to assess the effect of pharmacotherapy on thrombus stability in vitro and show that P2Y12 inhibitors potentiate thrombus instability at high shear. Cangrelor, and to a lesser extent ticagrelor, de-stabilised thrombus formation and cangrelor also enhanced fibrinolysis. Potentiation of thrombus instability could become a new pharmacological target, that may be particularly important in acute coronary syndromes.
Assuntos
Fibrinólise/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Trombose/tratamento farmacológico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Idoso , Aspirina/uso terapêutico , Plaquetas/efeitos dos fármacos , Clopidogrel/uso terapêutico , Doença da Artéria Coronariana/complicações , Feminino , Tempo de Lise do Coágulo de Fibrina , Humanos , Masculino , Pessoa de Meia-Idade , Trombose/sangue , Trombose/etiologia , Ticagrelor/uso terapêuticoRESUMO
Ticagrelor is a state-of-the-art antiplatelet agent used for the treatment of patients with acute coronary syndromes (ACS). Unlike remaining oral P2Y12 receptor inhibitors ticagrelor does not require metabolic activation to exert its antiplatelet action. Still, ticagrelor is extensively metabolized by hepatic CYP3A enzymes, and AR-C124910XX is its only active metabolite. A post hoc analysis of patient-level (n = 117) pharmacokinetic data pooled from two prospective studies was performed to identify clinical characteristics affecting the degree of AR-C124910XX formation during the first six hours after 180 mg ticagrelor loading dose in the setting of ACS. Both linear and multiple regression analyses indicated that ACS patients presenting with ST-elevation myocardial infarction or suffering from diabetes mellitus are more likely to have decreased rate of ticagrelor metabolism during the acute phase of ACS. Administration of morphine during ACS was found to negatively influence transformation of ticagrelor into AR-C124910XX when assessed with linear regression analysis, but not with multiple regression analysis. On the other hand, smoking appears to increase the degree of ticagrelor transformation in ACS patients. Mechanisms underlying our findings and their clinical significance warrant further research.
Assuntos
Síndrome Coronariana Aguda/metabolismo , Ticagrelor/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Idoso , Ensaios Clínicos como Assunto , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Morfina/metabolismo , Inibidores da Agregação Plaquetária/metabolismo , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/uso terapêutico , Estudos Prospectivos , Análise de Regressão , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismo , Fumar/efeitos adversos , Ticagrelor/farmacocinética , Ticagrelor/uso terapêuticoRESUMO
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and it leads to significant morbidity and mortality, predominantly from ischemic stroke. Vitamin K antagonists, mainly warfarin, have been used for decades to prevent ischemic stroke in AF, but their use is limited due to interactions with food and other drugs, as well as the requirement for regular monitoring of the international normalized ratio. Rivaroxaban, a direct factor Xa inhibitor and the most commonly used non-vitamin K oral anticoagulant, avoids many of these challenges and is being prescribed with increasing frequency for stroke prevention in non-valvular AF. Randomized controlled trial (RCT) data from the ROCKET-AF(Rivaroxaban once daily oral direct Factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation) trial have shown rivaroxaban to be non-inferior to warfarin in preventing ischemic stroke and systemic embolism and to have comparable overall bleeding rates. Applicability of the RCT data to real-world practice can sometimes be limited by complex clinical scenarios or multiple comorbidities not adequately represented in the trials. Available real-world evidence in non-valvular AF patients with comorbidities - including renal impairment, acute coronary syndrome, diabetes mellitus, malignancy, or old age - supports the use of rivaroxaban as safe and effective in preventing ischemic stroke in these subgroups, though with some important considerations required to reduce bleeding risk. Patient perspectives on rivaroxaban use are also considered. Real-world evidence indicates superior rates of drug adherence with rivaroxaban when compared with vitamin K antagonists and with alternative non-vitamin K oral anticoagulants - perhaps, in part, due to its once-daily dosing regimen. Furthermore, self-reported quality of life scores are highest among patients compliant with rivaroxaban therapy. The generally high levels of patient satisfaction with rivaroxaban therapy contribute to overall favorable clinical outcomes.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Coagulação Sanguínea/efeitos dos fármacos , Isquemia Encefálica/prevenção & controle , Inibidores do Fator Xa/administração & dosagem , Rivaroxabana/administração & dosagem , Acidente Vascular Cerebral/prevenção & controle , Tromboembolia/prevenção & controle , Fibrilação Atrial/sangue , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/mortalidade , Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/mortalidade , Comorbidade , Esquema de Medicação , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/farmacocinética , Hemorragia/induzido quimicamente , Humanos , Segurança do Paciente , Satisfação do Paciente , Qualidade de Vida , Fatores de Risco , Rivaroxabana/efeitos adversos , Rivaroxabana/farmacocinética , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/mortalidade , Tromboembolia/sangue , Tromboembolia/diagnóstico por imagem , Tromboembolia/mortalidade , Resultado do TratamentoRESUMO
BACKGROUND: The very significant benefit of P2Y12 receptor inhibitor administration in patients with ST-elevation myocardial infarction (STEMI), in reducing future ischaemic events and stent thrombosis, is undisputed. Morphine analgesia is very frequently co-administered to these patients for pain relief, along with antiplatelet therapy, at the time of presentation, and prior to reperfusion with primary percutaneous coronary intervention. METHODS: Research and online content related to opiates use in STEMI was reviewed. Bibliographies of retrieved studies were searched manually for additional studies and reviews. RESULTS: There is sufficient data from pharmacokinetic and pharmacodynamic studies showing that the co-administration of morphine with oral P2Y12 receptor inhibitor results in delayed antiplatelet effects. However, whether this results in adverse outcomes remains unclear. Data from studies reporting the effect of morphine on clinical outcomes in STEMI are inconsistent, although they tend to be underpowered to show an effect on hard clinical outcomes, but some clearly show a relationship between morphine use and infarct size. Strategies to overcome the potentially significant negative impact of morphine on platelet reactivity in STEMI are discussed. CONCLUSION: Whilst clearly definitive, adequately powered, randomised controlled trials are lacking, we would recommend avoiding the combination of morphine with oral P2Y12 receptor inhibitors and recommend alternative strategies including intravenous platelet inhibitor strategies, in high risk patients.
Assuntos
Analgésicos Opioides/administração & dosagem , Morfina/administração & dosagem , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Analgésicos Opioides/efeitos adversos , Esquema de Medicação , Interações Medicamentosas , Humanos , Morfina/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/instrumentação , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Stents , Resultado do TratamentoRESUMO
INTRODUCTION: ST-segment elevation myocardial infarction (STEMI) is attributable to an occluded coronary artery in almost 90% of patients. Accordingly, restoration of coronary perfusion as early as possible, preferably with primary percutaneous coronary intervention, is the recommended treatment by the European Society of Cardiology, to maximise myocardial salvage. However, not all cases of STEMI are because of coronary artery occlusion. ST-segment elevation myocardial infarction that occurs in the absence of obstructive coronary artery disease on angiography has been termed myocardial infarction with non-obstructive coronary arteries (MINOCA). CASE PRESENTATION: A 44-year-old man was admitted with retrosternal chest pain radiating to the left arm and jaw, and electrocardiography showed extensive anterior ST-segment elevation. Emergency coronary angiography showed all three coronary arteries were patent with Thrombolysis in Myocardial Infarction-3 flow and no evidence of dissection or thrombus. The ST-elevation and pain resolved spontaneously. Troponin-T level rose from <3 ng/L on arrival to 549 ng/L at 12 h. Subsequent cardiac magnetic resonance imaging (MRI) showed a structurally normal heart (without late gadolinium enhancement) but detected an incidental large, lobulated (90 × 31 × 71 mm) mediastinal mass containing multiple cysts in the anterior mediastinum with inflammation and oedema of the parietal pericardium. Tissue biopsy confirmed Hodgkin's lymphoma and the patient was initiated on chemotherapy. DISCUSSION: Some 3% of ST-segment myocardial infarctions occur in the absence of obstructive coronary disease (MINOCA), is more frequent in younger patients. Cardiac MRI is a useful tool to both identify some of the potential causes of MINOCA and also to confirm the diagnosis of infarction. Some 26% of MINOCA patients have significant biochemical evidence of myocardial injury but have a normal cardiac MRI. This case illustrates a very rare cause of myocardial infarction in a young patient with unobstructed coronary arteries, and highlights the need in such cases for further detailed imaging of the myocardium and thorax to establish the diagnosis and initiate appropriate treatment.
RESUMO
BACKGROUND: Data from available studies suggest that the presence of ST-elevation myocardial infarction (STEMI) may be associated with delayed and attenuated ticagrelor bioavailability and effect compared with non-ST-elevation myocardial infarction (NSTEMI). METHODS: In a single-center, prospective, observational trial 73 patients with myocardial infarction (STEMI n = 49, NSTEMI n = 24) underwent a pharmacokinetic and pharmacodynamic assessment after a 180 mg ticagrelor loading dose (LD). Ticagrelor and its active metabolite (AR-C124910XX) plasma concentrations were determined with liquid chromatography tandem mass spectrometry, and their antiplatelet effect was measured with the VASP assay and multiple electrode aggregometry. RESULTS: During the first six hours after ticagrelor LD, STEMI patients had 38% and 34% lower plasma concentration of ticagrelor and AR-C124910XX, respectively, than NSTEMI (ticagrelor AUC(0-6): 2491 [344-5587] vs. 3991 [1406-9284] ng*h/mL; p = 0.038; AR-C124910XX AUC(0-6): 473 [0-924] vs. 712 [346-1616] ng*h/mL; p = 0.027). STEMI patients also required more time to achieve maximal concentration of ticagrelor (tmax: 4.0 [3.0-12.0] vs. 2.5 [2.0-6.0] h; p = 0.012). Impaired bioavailability of ticagrelor and AR-C124910XX seen in STEMI subjects was associated with diminished platelet inhibition in this group, which was most pronounced during the initial hours of treatment. CONCLUSIONS: Plasma concentrations of ticagrelor and AR-C124910XX during the first hours after ticagrelor LD were one third lower in STEMI than in NSTEMI patients. This reduced and delayed ticagrelor bioavailability was associated with weaker antiplatelet effect in STEMI. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02602444 (November 09, 2015).