Adenosine Diphosphate Receptor Inhibitors Research Articles

Long-term combined antiplatelet therapy for secondary prevention of noncardioembolic stroke

Introduction. The high risk of recurrent ischemic events after non-cardioembolic ischemic stroke(IS), the prevalence of which is 25% of all strokes in the Russian Federation, determines the need to search for effective and safe secondary prevention strategies.Аim. The study was to evaluate the efficacy and safety of a combination of ADP receptor inhibitors (dipyridamole) with acetylsalicylic acid in patients with ischemic stroke (IS) in the secondary prevention of noncardioembolic stroke.Materials and methods. 229 patients in the early recovery period of noncardioembolic IS (139 women, 90 men), with an average age of 59.0 ± 5.7 years were included in the study. The duration of IS was 54.4 ± 6.1 days. All patients received a multimodal medical rehabilitation (MMR) program. Long-term double antiplatelet therapy with acetylsalicylic acid (ASA) 75 mg per day and dipyridamole at a daily dose of 225 mg divided into 3 doses were prescribed to all the patients. The neurological and neuropsychological status of the patient, quality of life and hemorheological parameters were assessed initially (T0), after MMR (T1, 6 weeks) and 12 months after IS(T2).Results. Motor and coordination indicators of patients as well as the cognitive and emotional parameters were significantly (p < 0,05) improved due to MMR technology. These were confirmed by the dynamics of the corresponding scales. The prescribed double antiplatelet therapy did not cause significant adverse events and worsening of the patients’ well-being both during the MMR process and during the observation period. The combination of ASA with dipyridamole was well tolerated. At the end of the study, recurrent IS, myocardial infarctions, and fatal bleeding were not recorded. In 5.2% patients with severe risks of cardiovascular complications there was occurred TIA. The effectiveness of the dual antiplatelet therapy was confirmed by a decrease in the level of platelet aggregation (p < 0,05).Conclusions. The high effectiveness of secondary prevention of IS with a combination of ASA and dipyridamole with good tolerability and safety in patients after IS has been shown.

Thrombin-induced platelet inhibition by 2′,4′-dihydroxychalcone and 2′,4′-dihydroxydihydrochalcone is mediated by inhibition of ROS production and Thromboxane synthase a activity: structure-activity relationship of polyphenol secondary metabolites from Empetrum nigrum

In this study, we expanded our previous work by testing compounds 1–12 for their ability to inhibit platelet activation at low (30 µM) concentration by inhibition of ROS production, thromboxane synthase (TxS) activity, and activation of cyclic nucleotide pathways. We also investigated whether some of these compounds could potentiate the effects of P2Y12 ADP receptor inhibitor action and discussed possible structure-activity relationships of the tested compounds. We showed that at this concentration only compounds 7 and 12 significantly inhibited thrombin-induced platelet activation which was accompanied by inhibition of ROS production and thromboxane synthase activity. Correspondingly, these compounds significantly potentiated the inhibitory effect of cangrelor on thrombin-induced platelet activation. In some other cases, inhibition of ROS production and thromboxane synthase activity did not correlate with platelet inhibition, indicating that these compounds could affect some, still unidentified, activatory pathways in platelets that counteract their inhibitory effects.

Development in long-term prognosis of first-time myocardial infarction in relation to use of guideline-recommended treatments: Danish total population cohort study

Abstract Background Evidence from randomized trials during the previous decades have led to several improvements in acute and secondary preventive treatments for myocardial infarction (MI). However, there is a lack of recent knowledge about the implementation of these treatments and how they affected developments in the long-term prognosis of MI. Purpose To investigate developments in long-term outcomes after first-time MI and their relation to use of guideline-recommended treatments in a contemporary total population cohort. Methods All patients with a first-time MI from 2001 to 2018 were identified through Danish nationwide registries with follow-up through October 6, 2021. The study period was divided into 3-year periods. In each period, the Aalen-Johansen method was used to estimate the absolute 1-year risk for mortality, recurrent MI, heart failure, bleeding hospitalization, and ischemic stroke. The relative frequencies of pharmaceutical treatments and use of coronary procedures were calculated. In each calendar period, the 1-year mortality and recurrent MI risk was standardized to the 2016–2018 distribution of patient characteristics, procedure use, and treatment initiation. Treatment, standardized risks, and recurrent MI risk were evaluated in patients who survived to day 28 post discharge. Results In total, 134,884 patients (median age 69 years, 36.5% female) were included and 120,473 survived to day 28 post discharge (median age 68 years, 35.2% female). From 2001–2003 to 2016–2018, the 1-year risks of mortality (23.5% to 12.1%), recurrent MI (6.8% to 3.2%), and ischemic stroke (1.8% to 1.3%) decreased. Risk of heart failure remained relatively stable, whereas the 1-year risk of bleeding hospitalization increased from 2.1% to 3.0%. This pattern remained consistent during very long durations of follow-up (Figure 1). Initiation of statins (58.0% to 86.4%) and adenosine diphosphate receptor inhibitors (42.5% to 85.6%) increased considerably. Use of coronary angiography (37.3% to 84.5%) and percutaneous coronary intervention (24.8% to 63.5%) also increased. There was an attenuated decrease in the standardized 1-year risks of mortality and recurrent MI compared to the observed reference risks: from 8.7% (reference: 11.1%) in 2001–2003 to 6.1% in 2016–2018 for mortality and from 5.6% (reference: 6.8%) in 2001–2003 to 3.1% in 2016–2018 for recurrent MI (Figure 2). Conclusions There was a substantial improvement in the long-term risk of mortality and recurrent MI for patients with first-time MI. This improved prognosis was related to an increased use of guideline recommended treatments. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Danish Heart Foundation

Formulation, Optimization and Evaluation of Ticagrelor Loaded Self Microemulsifying Chewable Tablets

Abstract: Ticagrelor is a new generation Adenosine diphosphate receptor inhibitor drug which is highly lipohilic having poor aqueous solubility used in the treatment of Acute Coronary Syndrome and prevention of Thrombotic events like Stroke and Heart Attack. An approach has been made to develop Chewable tablets of drug loaded on Self-microemulsifying drug delivery systems (SMEDDS), screen suitable adsorbent for solidification of formulated SMEDDS and to study the effect of superdisintegrants in chewable tablets. Methods: On basis of Pseudoternary diagrams constructed for selected oil, surfactant and cosurfactant, SMEDDS formulation was formulated using Capmul MCM EP oil with surfactant (Cremophor RH 40) and co-surfactant (PEG 400) which was solidified using selected adsorbent. Chewable tablets were compressed by direct compression method using superdisintegrants. Results: IR Studies and DSC studies revealed compatibility and stability of drug in formulation. Compression blend containing Solidified SMEDDS possessed good flow and compressibility. Chewable tablets compressed using Soy Polysaccharides as super disintegrant showed least wetting and disintegration time, drug release of 97.68% within 30 min. Short term stability studies revealed no significant change in physical and chemical properties. Conclusion: These results suggest that the Ticagrelor loaded self microemulsifying chewable tablets can be a promising oral drug delivery system to improve the solubility and dissolution profile of Ticagrelor. Key words: Ticagrelor, SMEDDS, Adsorbents, Chewable tablets, Acute coronary syndrome.

Aspirin Administered for Venous Thromboembolism Prophylaxis May Protect Against Stiffness Following Total Knee Arthroplasty.

Aspirin has become the main agent for venous thromboembolism (VTE) prophylaxis following total knee arthroplasty (TKA). This study assessed whether aspirin is associated with less knee stiffness compared to warfarin and other chemoprophylaxis agents. This is a retrospective review of all primary and revision TKAs performed between January 2009 and October 2020 at a high volume institution. Demographics, comorbidity data, and operative variables were extracted from medical records. VTE prophylaxis administered during this time period included aspirin, warfarin, and "others" (factor Xa, unfractionated heparin, low-molecular-weight heparin, fondaparinux, adenosine diphosphate receptor inhibitor, and direct thrombin inhibitor). The primary outcome assessed was manipulation under anesthesia (MUA) performed within 6 months of index surgery. Secondary outcome included major bleeding events. Univariate followed by multivariate regression analyses were performed. A total of 15,903 cases were included in the study, of which 531 (3.3%) patients developed stiffness that required MUA. The rates of MUA were 2.7% (251/9223) for patients receiving aspirin, 4.2% (238/5709) for patients receiving warfarin, and 4.3% (42/971) for all others (P's < .001). Multivariate regression analysis confirmed that aspirin is associated with lower rates of VTE compared to warfarin (adjusted odds ratio 1.423, 95% confidence interval 1.158-1.747, P < .001) and compared to other anticoagulation medications (adjusted odds ratio 1.742, 95% confidence interval 1.122-2.704, P= .013). Major bleeding events were also significantly lower in patients who received aspirin compared to the other 2 groups (P's= .001). Aspirin prophylaxis is associated with lower rates of MUA following TKA compared to warfarin and other VTE chemoprophylactic agents when grouped together.

Clopidogrel-induced neutropenia in an 80-year-old patient with chronic kidney disease who underwent percutaneous coronary intervention: a case report and literature review

BackgroundClopidogrel is a widely-used antiplatelet and acts as an adenosine diphosphate receptor inhibitor. Neutropenia is a rare but serious adverse effect of clopidogrel. It is unknown whether this adverse effect has any association with impaired kidney function.Case presentationAn 80-year-old male with chronic kidney disease was diagnosed with non-ST elevation myocardial infarction and underwent percutaneous coronary intervention. During hospitalization, the patient was diagnosed with contrast-induced nephropathy, treated symptomatically, and discharged with a back-to-baseline creatinine level. Two weeks later, the patient presented to the emergency department with fever and chills. Complete blood count showed leukopenia (0.84 × 103/mm3) and severe neutropenia (0.13 × 103/mm3). Blood cultures were positive for Pseudomonas aeruginosa. Clopidogrel was stopped immediately and switched into ticagrelor. Imipenem and granulocyte colony-stimulating factor were administered to the patient. The patient’s white blood cell and absolute neutrophil count were within the normal range after four days of treatment. The patient was discharged after a 10-day hospitalization, and his complete blood counts were normal during further follow-ups.ConclusionsClopidogrel was the most likely primary cause of neutropenia in our case. The incidence of clopidogrel-induced neutropenia is low and the exact mechanism is not fully explained. We provide suggestions on the management of clopidogrel-associated neutropenia, and summarize all five cases of clopidogrel-induced neutropenia in patients with impaired kidney function.

Mitochondrial Dysfunction in Trauma-Related Coagulopathy: Is There Causality? Study Protocol for a Prospective Observational Study

Hemorrhage control often poses a great challenge for clinicians due to trauma-induced coagulopathy (TIC). The pathogenesis of TIC is not completely revealed; however, growing evidence attributes a central role to altered platelet biology. The activation of thrombocytes and subsequent clot formation are highly energetic processes being tied to mitochondrial activity, and the inhibition of the electron transport chain (ETC) impedes on thrombogenesis, suggesting the potential role of mitochondria in TIC. Our present study protocol provides a guide to quantitatively characterize the derangements of mitochondrial functions in TIC. One hundred eleven severely injured (injury severity score ≥16), bleeding trauma patients with an age of 18 or greater will be included in this prospective observational study. Patients receiving oral antiplatelet agents including cyclooxygenase-1 or adenosine diphosphate receptor inhibitors (aspirin, clopidogrel, prasugrel, and ticagrelor) will be excluded from the final analysis. Hemorrhage will be confirmed and assessed with computer tomography. Conventional laboratory markers of hemostasis such as prothrombin time and international normalized ratio will be measured and rotational thromboelastometry (ROTEM) will be performed directly upon patient arrival. Platelets will be isolated from venous blood samples and subjected to high-resolution fluororespirometry (Oxygraph-2k, Oroboros Instruments, Innsbruck, Austria) to evaluate the efficacy of mitochondrial respiration. Oxidative phosphorylation (OxPhos), coupling of the ETC, mitochondrial superoxide formation, mitochondrial membrane potential changes, and extramitochondrial Ca²⁺-movement will be recorded. The association between OxPhos capacity of platelet mitochondria and numerical parameters of ROTEM aggregometry will constitute our primary outcome. The relation between OxPhos capacity and results of viscoelastic assays and conventional markers of hemostasis will serve as secondary outcomes. The association of the OxPhos capacity of platelet mitochondria upon patient arrival to the need for massive blood transfusion and 24-h mortality will constitute our tertiary outcomes. Mitochondrial dysfunction and its importance in TIC are yet to be assessed for the deeper understanding of this common, life-threatening condition. Disclosure of mitochondria-mediated processes in thrombocytes may reveal new therapeutic targets in the management of hemorrhaging trauma patients, thereby leading to a reduction of potentially preventable mortality. The present protocol was registered to ClinicalTrials.gov on 12 August 2021, under the reference number NCT05004844.

Comparison of Safety and Efficacy Between Clopidogrel and Ticagrelor in Elderly Patients With Acute Coronary Syndrome: A Systematic Review and Meta-Analysis.

Background: Dual antiplatelet therapy combining aspirin with a P2Y12 adenosine diphosphate receptor inhibitor is a therapeutic mainstay for acute coronary syndrome (ACS). However, the optimal choice of P2Y12 adenosine diphosphate receptor inhibitor in elderly (aged ≥65 years) patients remains controversial. We conducted a meta-analysis to compare the efficacy and safety of ticagrelor and clopidogrel in elderly patients with ACS. Methods: We comprehensively searched in Web of Science, EMBASE, PubMed, and Cochrane databases through 29th March, 2021 for eligible randomized controlled trials (RCTs) comparing the efficacy and safety of ticagrelor or clopidogrel plus aspirin in elderly patients with ACS. Four studies were included in the final analysis. A fixed effects model or random effects model was applied to analyze risk ratios (RRs) and hazard ratios (HRs) across studies, and I2 to assess heterogeneity. Results: A total number of 4429 elderly patients with ACS were included in this analysis, of whom 2170 (49.0%) patients received aspirin plus ticagrelor and 2259 (51.0%) received aspirin plus clopidogrel. The ticagrelor group showed a significant advantage over the clopidogrel group concerning all-cause mortality (HR 0.78, 95% CI 0.63–0.96, I2 = 0%; RR 0.79, 95% CI 0.66–0.95, I2 = 0%) and cardiovascular death (HR 0.71, 95% CI 0.56–0.91, I2 = 0%; RR 0.76, 95% CI 0.62–0.94, I2 = 5%) but owned a higher risk of PLATO major or minor bleeding (HR 1.46, 95% CI 1.13–1.89, I2 = 0%; RR 1.40, 95% CI 1.11–1.76, I2 = 0%). Both the groups showed no significant difference regarding major adverse cardiovascular events (MACEs) (HR 1.06, 95% CI 0.68–1.65, I2 = 77%; RR 1.04, 95% CI 0.69–1.58, I2 = 77%). Conclusion: For elderly ACS patients, aspirin plus ticagrelor reduces cardiovascular death and all-cause mortality but increases the risk of bleeding. Herein, aspirin plus ticagrelor may extend lifetime for elderly ACS patients compared with aspirin plus clopidogrel. The optimal DAPT for elderly ACS patients may be a valuable direction for future research studies.

High Platelet Reactivity Despite Taking Adenosine Diphosphate Receptor Inhibitors: Do We Need to Care?

Platelet activation and aggregation play a key role in the development of adverse cardiovascular events after endovascular treatment of peripheral arterial disease (PAD). Adenosine diphosphate (ADP) receptor (P2Y12) inhibitors such as clopidogrel, prasugrel, and ticagrelor are used increasingly as single treatment or in conjunction with aspirin (dual antiplatelet therapy [DAPT]). However, the antiplatelet activity varies significantly among individuals, and firm evidence for use after peripheral endovascular procedures is lacking.

Blood transfusion in major emergency abdominal surgery.

Major emergency abdominal surgery is associated with excess mortality. Transfusion is known to be associated with increased morbidity and emergency surgery is an independent risk factor for perioperative transfusion. The primary objectives of this study were to identify risk factors for transfusion, and secondarily to investigate the influence of transfusion on clinical outcomes after major emergency abdominal surgery. This study combined retrospective observational data including intraoperative, postoperative, and transfusion data in patients undergoing major emergency abdominal surgery from January 2010 to October 2016 at a Danish university hospital. The primary outcome was a transfusion of any kind from initiation of surgery to postoperative day 7. Secondary outcomes included 7-, 30-, 90-day and long-term mortality (median follow-up = 34.6months, IQR = 13.0-58.3), lengths of stay, and surgical complication rate (Clavien-Dindo score ≥ 3a). A total of 1288 patients were included and 391 (30%) received a transfusion of any kind. Multivariate logistic regression identified age, hepatic comorbidity, cardiac comorbidity, post-surgical anemia, ADP-receptor inhibitors, acetylsalicylic acid, anticoagulants, and operation type as risk factors for postoperative transfusion. 60.1% of the transfused patients experienced a serious surgical complication within 30days of surgery compared with 28.1% of the non-transfused patients (p < 0.001). Among patients receiving a postoperative transfusion, unadjusted long-term mortality was increased with a hazard ratio of 3.8 (95% CI 2.9-5.0), p < 0.01. Transfused patients had significantly higher mortality at 7-, 30-, 90- and long-term, as well as a longer hospital stay but in the multivariate analyses, transfusion was not associated with mortality. Peri- and postoperative transfusion in relation to major emergency abdominal surgery was associated with an increased risk of postoperative complications. The potential benefits and harms of blood transfusion and clinical significance of pre- and postoperative anemia after major emergency abdominal surgery should be further studied in clinical prospective studies.

Adenosine diphosphate receptor inhibitor monotherapy with ticagrelor or clopidogrel following percutaneous coronary intervention: a systematic review and meta-analysis of randomized controlled trials

Abstract Background and purpose In patients undergoing percutaneous coronary intervention (PCI) with implantation of coronary stents, the risk of stent thrombosis is mitigated with antiplatelet therapy. While current clinical practice is to treat patients with dual antiplatelet therapy (DAPT) combining aspirin with an adenosine diphosphate receptor inhibitor (ADPri), prolonged therapy is associated with heightened bleeding risk. Limiting DAPT to a shorter period after PCI, followed by ADPri monotherapy, may be an attractive strategy for optimizing the balance between thrombotic and bleeding risks. While several randomized controlled trials (RCTs) have been published examining this strategy, the optimal duration of abbreviated DAPT run-in and the ideal choice of ADPri remain uncertain. Methods We undertook a systematic review and meta-analysis of RCTs assessing abbreviated DAPT followed by ADPri monotherapy post coronary stenting. Our primary outcomes were defined as clinically important bleeding, major adverse cardiovascular events (MACE), and all-cause mortality. We searched Ovid MEDLINE and EMBASE from their inceptions to November 2019 with study selection and data extraction performed in duplicate. We pooled data at one year using random effects models; relative risks (RRs) with 95% confidence intervals (95% CIs) were generated using the inverse variance method. Pre-specified sub-group analyses were undertaken according to duration of DAPT and the primary ADPri employed. Results Four trials (n=29084) were eligible for inclusion. Mean age was 65 years and 51.5% of patients were recruited in the context of acute coronary syndrome. Following meta-analysis, the occurrence of clinically significant bleeding events was significantly lower in patients receiving ADPri monotherapy (4 studies; n=29084; RR=0.60; 95% CI, 0.43–0.83; I2=73%; Figure-A), with no significant difference in the rates of all-cause mortality (4 studies; n=29084; RR=0.87; 95% CI, 0.71–1.06; I2=0%; Figure-B) or MACE (4 studies; n=29084; RR=0.90; 95% CI, 0.79–1.03; I2=1%; Figure-C). In subgroup analysis, trends toward lower rates of both all-cause mortality (2 studies; n=23082 participants; RR=0.81; 95% CI, 0.65–1.01; I2=0%; Figure-B) and MACE (2 studies; n=23082 participants; RR=0.90; 95% CI, 0.79–1.03; I2=25%; Figure-C) were seen in the studies employing ticagrelor as opposed to clopidogrel; however, neither analysis reached statistical significance (p-values=0.06 and 0.19, respectively). There was no differential treatment effect based on the duration of abbreviated DAPT prior to ADPri monotherapy in sub-group analysis. Conclusions Following PCI in patients with coronary disease, an abbreviated course of DAPT followed by ADPri monotherapy significantly reduces rates of bleeding with no difference in rates of MACE or all-cause mortality. Future studies are required to conclusively determine whether the use of ticagrelor in this setting may also reduce rates of all-cause mortality. Meta-analysis of included studies Funding Acknowledgement Type of funding source: None

ADENOSINE DIPHOSPHATE RECEPTOR INHIBITOR MONOTHERAPY WITH TICAGRELOR OR CLOPIDOGREL FOLLOWING PERCUTANEOUS CORONARY INTERVENTION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

In patients undergoing percutaneous coronary intervention (PCI) with implantation of coronary stents, the risk of stent thrombosis is mitigated with antiplatelet therapy. While current clinical practice is to treat patients with dual antiplatelet therapy (DAPT), combining aspirin with an adenosine diphosphate receptor inhibitor (ADPri), prolonged therapy is associated with heightened bleeding risk. Limiting DAPT to a shorter period after PCI, followed by ADPri monotherapy, may be an attractive strategy for optimizing the balance between thrombotic and bleeding risks. While several randomized controlled trials (RCTs) have been published examining this strategy, the optimal duration of abbreviated DAPT run-in and the ideal choice of ADPri remain uncertain.

Adenosine Diphosphate Receptor Inhibitors: Balancing Perioperative Bleeding and Protection From Adverse Coronary Events

In this issue of The Annals of Thoracic Surgery, Voetsch and colleagues1 describe an observational study of the relationship between preoperative withdrawal time of 3 adenosine diphosphate-platelet receptor (P2Y12 receptor) antagonists (prasugrel, ticagrelor, and clopidogrel) and bleeding outcomes after cardiac operations. They studied 299 coronary artery bypass grafting ± valve patients whose dual-antiplatelet therapy was discontinued within 7 days of operation and measured red blood cell loss and Bleeding Academic Research Consortium type 4 (CABG-related bleeding within 48 hours) bleeding outcomes in these patients.

Effects of colchicine on platelet aggregation in patients on dual antiplatelet therapy with aspirin and clopidogrel.

Platelets aggregation leading to thrombosis plays a pivotal role in the pathophysiology of acute coronary syndrome (ACS) and of stent thrombosis. Antiplatelet therapy with aspirin plus an ADP-receptor inhibitor (ticagrerol, prasugrel or clopidogrel) is recommended to reduce the risk of other platelet-mediated events. Clopidogrel is recommended in patients with Chronic Coronary Syndromes (CCS) or in ACS patients at high bleeding risk. Unfortunately, up to 30% of patients are non-responders to clopidogrel and show residual high platelet reactivity (HPR). Colchicine (COLC) is a drug with cardiovascular effects. We have demonstrated that COLC might exert protective cardiovascular effects by interfering with cytoskeleton rearrangement, a phenomenon involved in platelet aggregation. Here, we investigate in vitro the effects of colchicine on platelet aggregation of patients on DAPT with clopidogrel. Platelets obtained from 35 CCS patients on therapy with clopidogrel were pre-incubated with COLC 10 µM before being stimulated with ADP (20 µM), or TRAP (25 µM) at 0, 30, 60 and 90 min to measure max aggregation by LTA. Platelets not COLC-preincubated served as controls. Seven patients were pre-selected as clopidogrel non-responders. COLC significantly reduced TRAP-induced platelet aggregation in clopidogrel responders and non-responders. Interestingly, COLC inhibited ADP-induced platelet aggregation in clopidogrel non-responders in which ADP still caused activation despite DAPT. We demonstrate that COLC inhibits platelet aggregation in clopidogrel non-responders with HPR despite DAPT with this ADP receptor-inhibitor. Further in vivo studies should be designed to evaluate the opportunity to prescribe colchicine after ACS/CCS to overcome the clopidogrel limitations in the DAPT therapy.

The Role of Desmopressin on Hematoma Expansion in Patients with Mild Traumatic Brain Injury Prescribed Pre-injury Antiplatelet Medications.

Desmopressin (DDAVP) has been suggested for antiplatelet medication reversal in patients with traumatic brain injury (TBI) but there are limited data describing its effect on clinical outcomes. The purpose of this study was to evaluate the effect of DDAVP on hematoma expansion and thrombosis in patients with TBI who were prescribed pre-injury antiplatelet medications. Consecutive adult patients who were admitted to our level I trauma center and prescribed pre-injury antiplatelet medications between July, 2012, and May, 2018, were retrospectively identified. Patients were excluded if their hospital length of stay was < 24h, if DDAVP was administered by any route other than intravenous, if they received a DDAVP dose < 0.3 mcg/kg or there was no evidence of brain hemorrhage on computed tomography (CT) scan. Patients were stratified based on the use of DDAVP, and the incidence of hematoma expansion was compared between groups. Thrombotic events were reviewed as a secondary outcome. Multivariate analysis was utilized to control for confounding variables. Of 202 patients included in analysis, 158 (78%) received DDAVP. The mean age was 76 ± 12years; the most common injury mechanism was falls (76%); 69% had acute subdural hematoma, and 49% had multi-compartmental hemorrhage. Initial Glasgow coma score was between 13 and 15 for 91% of patients. Aspirin was the most common antiplatelet regimen prescribed (N = 151, 75%), followed by dual antiplatelet regimens (N = 26, 13%) and adenosine diphosphate (ADP)-receptor inhibitors (N = 25, 12%). The incidence of hematoma expansion was 14% and 30% for patients who did and did not receive DDAVP, respectively (p = 0.015). After controlling for age, injury severity score, multi-compartmental hemorrhage, and receipt of pre-injury high-dose aspirin (> 81mg), ADP-receptor inhibitors, oral anticoagulants, prothrombin complex concentrates or platelets in a multivariate analysis, the association between DDAVP and hematoma expansion remained significant (adjusted OR 0.259 [95% CI 0.103-0.646], p = 0.004). Thrombotic events were similar between the two groups (DDAVP, 2.5%, no DDAVP, 4.5%; p = 0.613). DDAVP was associated with a lower incidence of hematoma expansion in patients with mild TBI who were prescribed pre-injury antiplatelet medications. These results justify a randomized controlled trial to further evaluate the role of DDAVP for this indication.

What Are Optimal P2Y12 Inhibitor and Schedule of Administration in Patients With Acute Coronary Syndrome?

Guidelines recommend treatment with a P2Y12 platelet adenosine diphosphate receptor inhibitor in patients undergoing elective or urgent percutaneous coronary intervention (PCI), but the optimal agent or timing of administration is still not clearly specified. The P2Y12 inhibitor was initially used for its platelet anti-aggregatory action to block thrombosis of the recanalized coronary artery or deployed stent. It is now recognized that these agents also offer potent cardioprotection against a reperfusion injury that occurs in the first minutes of reperfusion if platelet aggregation is blocked at the time of reperfusion. But this is difficult to achieve with oral agents which are slowly absorbed and often require time-consuming metabolic activation. Patients with ST-segment elevation myocardial infarction who usually have a large mass of myocardium at risk of infarction seldom have sufficient time for upstream-administered oral agents to achieve a therapeutic P2Y12 level of inhibition by the time of balloon inflation. However, optimal treatment could be assured by initiating an IV cangrelor infusion shortly prior to stenting followed by subsequent post-PCI transition to an oral agent, that is, ticagrelor, once success of the recanalization and absence of need for surgical intervention are confirmed. Not only should this sequence provide optimal protection against infarction, it should also negate bleeding if coronary artery bypass grafting should be required since stopping the cangrelor infusion at any time will quickly restore platelet reactivity. It is anticipated that cangrelor-induced myocardial salvage will help preserve myocardial function and significantly diminish postinfarction heart failure.

Prior Antiplatelet Therapy, Excluding Phosphodiesterase Inhibitor Is Associated with Poor Outcome in Patients with Spontaneous Intracerebral Haemorrhage.

There is conflicting results on whether prior antiplatelet therapy (APT) is associated with poor outcome in spontaneous intracerebral haemorrhage (ICH) patients. To determine whether prior APT is associated with spontaneous ICH, and whether there is a difference between the different types of APT, including cyclooxygenase inhibitor (COX-I), adenosine diphosphate receptor inhibitor (ADP-I) and phosphodiesterase inhibitor (PDE-I). A retrospective study of patients with ICH diagnosed between 2001 and 2013 in the National Health Insurance Research Database. Baseline unbalance between APT and non-APT groups was solved by multivariable adjustment (primary analysis) and propensity score matching (sensitivity analysis). Patients with prior APT had a higher rate of in-hospital death (odds ratio [OR], 1.16; 95% confidence interval [CI], 1.09-1.23) compared to non-APT group. Compared to non-APT group, there was a greater rate of in-hospital death with spontaneous ICH with ADP-I (OR, 1.49; 95% CI, 1.24-1.79) and COX-I (OR, 1.17; 95% CI, 1.09-1.25). PDE-I exhibited no difference in in-hospital death with spontaneous ICH (OR, 1.03; 95% CI, 0.91-1.16) compared to non-APT group. Remarkably, the in-hospital mortality rate was significantly higher in the ADP-I group than in the PDE-I group (hazard ratio, 1.45; 95% CI, 1.17-1.80). In this study, ADP-I and COX-1, but not PDE-I, are the most likely contributors to the association of APT with poor outcome with spontaneous ICH patients. These findings suggest that the complexity of the different mechanism of actions of prior APT can alter the outcome in spontaneous ICH.

Efficacy and safety with ticagrelor in patients with prior myocardial infarction in the approved European label: insights from PEGASUS-TIMI 54.

AimsIn PEGASUS-TIMI 54, ticagrelor significantly reduced the risk of the composite of major adverse cardiovascular (CV) events by 15–16% in stable patients with a prior myocardial infarction (MI) 1–3 years earlier. We report the efficacy and safety in the subpopulation recommended for treatment in the European (EU) label, i.e. treatment with 60 mg b.i.d. initiated up to 2 years from the MI, or within 1 year after stopping previous adenosine diphosphate receptor inhibitor treatment.Methods and resultsOf the 21 162 patients enrolled in PEGASUS-TIMI 54, 10 779 patients were included in the primary analysis for this study, randomized to ticagrelor 60 mg (n = 5388) or matching placebo (n = 5391). The cumulative proportions of patients with events at 36 months were calculated by the Kaplan–Meier (KM) method. The composite of CV death, MI, or stroke occurred less frequently in the ticagrelor group (7.9% KM rate vs. 9.6%), hazard ratio (HR) 0.80 [95% confidence interval (CI) 0.70–0.91; P = 0.001]. Ticagrelor also reduced the risk of all-cause mortality, HR 0.80 (0.67–0.96; P = 0.018). Thrombolysis in myocardial infarction major bleeding was more frequent in the ticagrelor group 2.5% vs. 1.1%; HR 2.36 (1.65–3.39; P < 0.001). The corresponding HR for fatal or intracranial bleeding was 1.17 (0.68–2.01; P = 0.58).ConclusionIn PEGASUS-TIMI 54, treatment with ticagrelor 60 mg as recommended in the EU label, was associated with a relative risk reduction of 20% in CV death, MI, or stroke. Thrombolysis in myocardial infarction major bleeding was increased, but fatal or intracranial bleeding was similar to placebo. There appears to be a favourable benefit-risk ratio for long-term ticagrelor 60 mg in this population.Clinical trial registration http://www.clinicaltrials.gov NCT01225562

Cohort analysis of desmopressin effect on hematoma expansion in patients with spontaneous intracerebral hemorrhage and documented pre-ictus antiplatelet use

Antiplatelet therapy at the time of spontaneous intracerebral hemorrhage (sICH) may increase risk for hemorrhage expansion and mortality. Current guidelines recommend considering a single dose of desmopressin in sICH associated with cyclooxygenase-1 inhibitors or adenosine diphosphate receptor inhibitors. Adult subjects with sICH and concomitant antiplatelet therapy admitted to a large, tertiary care center were included. We sought to compare the risk of hematoma expansion in patients that received desmopressin for antiplatelet reversal in the setting of sICH to similar patients that did not receive desmopressin. The primary outcomes were the incidence of relative and absolute hematoma expansion. In total, 71 patients (29 received desmopressin, 42 did not receive desmopressin) were analyzed. All patients in the desmopressin group received a 0.3 mcg/kg intravenous dose prior to hematoma expansion assessment. Relative hematoma expansion occurred in 5/29 (17%) with desmopressin compared to 11/42 (26%) without desmopressin (OR 0.59 [95% CI 0.18–1.92]). Absolute hematoma expansion occurred in 9/29 (30%) with desmopressin compared to 12/42 (28%) without desmopressin (OR 1.13 [95% CI 0.40–3.16]). Multiple logistic regression controlling for significant covariates did not reveal a significant effect of desmopressin on relative or absolute hematoma expansion (OR 0.65 [95% CI 0.18–2.43] and OR 1.55 [0.48–4.99], respectively). We failed to find evidence that desmopressin administration for antiplatelet reversal in sICH reduces the incidence of hematoma expansion. Larger studies, focusing on the early phase of sICH, are needed to characterize the clinical efficacy and safety of desmopressin for antiplatelet reversal before widespread implementation.

Acute and 1-Year Hospitalization Costs for Acute Myocardial Infarction Treated With Percutaneous Coronary Intervention: ResultsFrom the TRANSLATE-ACS Registry.

BackgroundHospitalization for acute myocardial infarction (MI) in the United States is both common and expensive, but those features alone provide little insight into cost‐saving opportunities.Methods and ResultsTo understand the cost drivers during hospitalization for acute MI and in the following year, we prospectively studied 11 969 patients with acute MI undergoing percutaneous coronary intervention at 233 US hospitals (2010–2013) from the TRANSLATE‐ACS (Treatment With ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) registry. Baseline costs were collected in a random subset (n=4619 patients, 54% ST‐segment–elevation MI [STEMI]), while follow‐up costs out to 1 year were collected for all patients. The mean index length of stay was 3.1 days (for both STEMI and non‐STEMI) and mean intensive care unit length of stay was 1.2 days (1.4 days for STEMI and 1.0 days for non‐STEMI). Index hospital costs averaged $18 931 ($19 327 for STEMI, $18 465 for non‐STEMI), with 45% catheterization laboratory–related and 20% attributable to postprocedure hospital stay. Patient factors, including severity of illness and extent of coronary disease, and hospital characteristics, including for profit status and geographic region, identified significant variations in cost. Intensive care was used for 53% of non‐STEMI and increased costs by $3282. Postdischarge 1‐year costs averaged $8037, and 48% of patients were rehospitalized (half within 2 months and 57% with a cardiovascular diagnosis).ConclusionsWhile much of the cost of patients with acute MI treated with percutaneous coronary intervention is probably not modifiable by the care team, cost reductions are still possible through quality‐preserving practice efficiencies, such as need‐based use rather than routine use of intensive care unit for patients with stable non‐STEMI.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00097591.