Use Of Platelet Inhibitors Research Articles

Pathophysiology and targeted treatment of cholesterol crystal embolism and the related thrombotic angiopathy.

Cholesterol crystal (CC) embolism is a complication of advanced atherosclerotic plaques located in the major arteries. This pathological condition is primarily induced by interventional and surgical procedures or occurs spontaneously. CC can induce a wide range of tissue injuries including CC embolism syndrome, a spontaneous or intervention-induced complication of advanced atherosclerosis, while treatment of CC embolism has remained empiric. Vascular occlusions caused by CC embolism may exceed the ischemia tolerance of many tissues, particularly when small arteries are affected. The main approach to CC embolism is primary prophylaxis in patients at risk by stabilizing atherosclerotic plaques and avoiding unnecessary catheter interventions. During CC embolism, the use of platelet inhibitors to avoid abnormal activation and aggregation and anticoagulants may reduce the risk of vascular occlusions and tissue ischemia. This probably explains the relatively low prevalence of clinical manifestations of CC embolism, which are frequently found in autopsy studies. In this review, we summarized the current knowledge on the pathophysiology of CC embolism syndrome deriving from clinical observations and experimental mouse models. Furthermore, we described the risk factors of CC embolism in humans as well as the experimental studies based on empiric treatments. We also discuss potential therapeutic interventions based on recent experimental data and emerging drug options evolving from other research domains. Given the substantial unmet medical need to improve the outcomes of CC embolism, the identification of effective treatment strategies is urgently needed.

Proton pump inhibitors and gastroprotection in patients treated with antithrombotic drugs: A cardiologic point of view.

Aspirin, other antiplatelet agents, and anticoagulant drugs are used across a wide spectrum of cardiovascular and cerebrovascular diseases. A concomitant proton pump inhibitor (PPI) treatment is often prescribed in these patients, as gastrointestinal complications are relatively frequent. On the other hand, a potential increased risk of cardiovascular events has been suggested in patients treated with PPIs; in particular, it has been discussed whether these drugs may reduce the cardiovascular protection of clopidogrel, due to pharmacodynamic and pharmacokinetic interactions through hepatic metabolism. Previously, the concomitant use of clopidogrel and omeprazole or esomeprazole has been discouraged. In contrast, it remains less known whether PPI use may affect the clinical efficacy of ticagrelor and prasugrel, new P2Y12 receptor antagonists. Current guidelines recommend PPI use in combination with antiplatelet treatment in patients with risk factors for gastrointestinal bleeding, including advanced age, concurrent use of anticoagulants, steroids, or non-steroidal anti-inflammatory drugs, and Helicobacter pylori (H. pylori) infection. In patients taking oral anticoagulant with risk factors for gastrointestinal bleeding, PPIs could be recommended, even if their usefulness deserves further data. H. pylori infection should always be investigated and treated in patients with a history of peptic ulcer disease (with or without complication) treated with antithrombotic drugs. The present review summarizes the current knowledge regarding the widespread combined use of platelet inhibitors, anticoagulants, and PPIs, discussing consequent clinical implications.

Diagnosis and treatment of MPN in real life: exploratory and retrospective chart review including 960 MPN patients diagnosed with ET or MF in Germany

PurposeThe WHO 2016 re-classification of myeloproliferative neoplasms resulted in a separation of essential thrombocythemia (ET) from the pre-fibrotic and fibrotic (overt) phases of primary myelofibrosis (MF). This study reports on a chart review conducted to evaluate the real life approach regarding clinical characteristics, diagnostic assessment, risk stratification and treatment decisions for MPN patients classified as ET or MF after implementation of the WHO 2016 classification.MethodsIn this retrospective chart review, 31 office-based hematologists/oncologists and primary care centers in Germany participated between April 2021 and May 2022. Physicians reported available data obtained from patient charts via paper–pencil based survey (secondary use of data). Patient features were evaluated using descriptive analysis, also including diagnostic assessment, therapeutic strategies and risk stratification.ResultsData of 960 MPN patients diagnosed with essential thrombocythemia (ET) (n = 495) or myelofibrosis (MF) (n = 465) after implementation of the revised 2016 WHO classification of myeloid neoplasms was collected from the patient charts. While they met at least one minor WHO-criteria for primary myelofibrosis, 39.8% of those diagnosed with ET did not have histological BM testing at diagnosis. 63.4% of patients who were classified as having MF, however, did not obtain an early prognostic risk assessment. More than 50% of MF patients showed characteristics consistent with the pre-fibrotic phase, which was emphasized by the frequent use of cytoreductive therapy. Hydroxyurea was the most frequently used cytoreductive medication in 84.7% of ET and 53.1% of MF patients. While both ET and MF cohorts showed cardiovascular risk factors in more than 2/3 of the cases, the use of platelet inhibitors or anticoagulants varied between 56.8% in ET and 38.1% in MF patients.ConclusionsImproved histopathologic diagnostics, dynamic risk stratification including genetic risk factors for cases of suspected ET and MF are recommended for precise risk assessment and therapeutic stratification according to WHO criteria.

Long-term antithrombotic therapy after coronary artery bypass grafting in patients with preoperative atrial fibrillation. A nationwide observational study from the SWEDEHEART registry

To provide data guiding long-term antithrombotic therapy after coronary artery by-pass grafting (CABG) in patients with preoperative atrial fibrillation (AF). From the SWEDEHEART registry, we included all patients, between January 2006 and September 2016, with preoperative AF and CHA2DS2-VASC score ≥2, undergoing CABG. Based on dispensed prescriptions 12 to 18 months after CABG, patients were divided in 3 groups: use of platelet inhibitors (PI) only, oral anticoagulant (OAC) only or a combination of OAC+PI. Outcomes were: Major adverse cardiac and cerebrovascular events (MACCE, [all-cause death, myocardial infarction, or stroke]), net adverse clinical events (NACE, [MACCE or bleeding]) and the individual components of NACE. Inverse probability of treatment weighting was used to adjust for the non-randomized study design. Among 2,564 patients, 1,040 (41%) were treated with PI alone, 1,064 (41%) with OAC alone, and 460 (18%) with PI+OAC. Treatment with PI alone was associated with higher risk for MACCE (adjusted HR 1.43, 95% CI 1.09-1.88), driven by higher risk for stroke and MI, compared with OAC alone. Treatment with PI+OAC, was associated with higher risk for NACE (adjusted HR 1.40, 95% CI 1.06-1.85), driven by higher risk for bleeds, compared with OAC alone. In this real-world observational study, a high proportion of patients with AF, undergoing CABG, did not receive a long-term OAC therapy. Treatment with OAC alone was associated with a net clinical benefit, compared with PI alone or PI+OAC.

Effects of Guideline-Based Correction of Platelet Inhibition on Outcomes in Moderate to Severe Isolated Blunt Traumatic Brain Injury.

Platelet dysfunction has been demonstrated after traumatic brain injury (TBI) regardless of the use of platelet inhibitors. The purpose of this study was to determine the efficacy of a platelet-mapping thromboelastography (PM-TEG) in predicting TBI patients who would benefit from platelet transfusion. We hypothesized that adenosine diphosphate (ADP) and arachadonic acid (AA) inhibition in patients with TBI is associated with increased mortality and can be corrected with platelet transfusion. This is a retrospective review of patients admitted to a level 1 trauma center from January 2016 through September 2017 with moderate to severe blunt TBI (msTBI), defined by an initial Glasgow Coma Scale (GCS) ≤12 with intracranial hemorrhage. Patients received PM-TEG. Those with platelet dysfunction (ADP or AA inhibition ≥60%) received one unit of platelets followed by repeat PM-TEG, until inhibition <60% or three units of platelets. Cohorts were defined as patients initially without (NPI) and with (PI) inhibition and subdivided into those whose inhibition corrected (PI-C) versus those whose did not correct (PI-NC). From 69 patients with isolated blunt TBI, 40 (58%) presented with NPI, 29 (42%) with PI. Of those with PI, 16 (55%) were with PI-C and 13 (45%) with PI-NC. Platelet inhibition in msTBI patients undergoing guideline-based transfusion is associated with age and GCS and an increase in mortality. Platelet inhibition seems to have a more adverse effect on patients >55 years of age or with GCS <8. Correction of platelet inhibition normalized mortality to that of NPI.

Use of platelet inhibitors for digital ulcers related to systemic sclerosis: EUSTAR study on derivation and validation of the DU-VASC model.

To develop and validate the prognostic prediction model DU-VASC to assist the clinicians in decision-making regarding the use of platelet inhibitors (PIs) for the management of digital ulcers in patients with systemic sclerosis. Secondly, to assess the incremental value of PIs as predictor. We analysed patient data from the European Scleroderma Trials and Research group registry (one time point assessed). Three sets of derivation/validation cohorts were obtained from the original cohort. Using logistic regression, we developed a model for prediction of digital ulcers (DUs). C-Statistics and calibration plots were calculated to evaluate the prediction performance. Variable importance plots and the decrease in C-statistics were used to address the importance of the predictors. Of 3710 patients in the original cohort, 487 had DUs and 90 were exposed to PIs. For the DU-VASC model, which includes 27 predictors, we observed good calibration and discrimination in all cohorts (C-statistic = 81.1% [95% CI: 78.9%, 83.4%] for the derivation and 82.3% [95% CI: 779.3%, 85.3%] for the independent temporal validation cohort). Exposure to PIs was associated with absence of DUs and was the most important therapeutic predictor. Further important factors associated with absence of DUs were lower modified Rodnan skin score, anti-Scl-70 negativity and normal CRP. Conversely, the exposure to phosphodiesterase-5 inhibitor, prostacyclin analogues or endothelin receptor antagonists seemed to be associated with the occurrence of DUs. Nonetheless, previous DUs remains the most impactful predictor of DUs. The DU-VASC model, with good calibration and discrimination ability, revealed that PI treatment was the most important therapy-related predictor associated with reduced DU occurrence.

Post-discharge major bleeding, myocardial infarction and mortality risk after coronary artery bypass grafting: a nationwide cohort study from the SWEDEHEART registry

Abstract Background Platelet inhibition and occasionally oral anticoagulants are used after coronary artery bypass grafting (CABG) to reduce ischaemic events but may increase bleeding risk. The impact of post-discharge major bleeding and myocardial infarction on mortality risk in CABG patients is unknown. Methods All patients who underwent first-time isolated CABG in Sweden 2006–2017 and survived 14 days after discharge were included. Individual patient data from five mandatory national registries (SWEDEHEART, National Patient Register, Swedish Prescribed Drug Register, Cause of Death Register and The Swedish Population Register) were merged. Post-discharge major bleeding and myocardial infarction were defined as hospitalization with a bleeding or myocardial infarction diagnosis as main diagnosis respectively. A Cox proportional piecewise hazard model for the effect of time-updated bleeding and myocardial infarction as first post-discharge event on subsequent mortality risk was developed. The model was adjusted for age, sex, year of surgery, comorbidities at baseline and time-updated use of platelet inhibitors, oral anticoagulants and other secondary prevention medications. To estimate the time-dependent risk on mortality after an event, hazard ratios were calculated for &amp;lt;30 days, 30–365 days and &amp;gt;365 days after first incidence of major bleeding and myocardial infarction. Results In total 36 633 patients were included and median follow-up was 6.0 years (25th-75th percentile 3.0–9.0 years). During follow-up, 2265 (6.2%) patients suffered a major bleeding and 2108 (5.8%) patients a myocardial infarction as a first post-discharge event. In total 6683 (18.2%) died during follow-up. Both major bleeding and myocardial infarction were significantly associated with increased mortality risk compared to patients without any major bleeding or myocardial infarction. The adjusted hazard ratios for mortality &amp;lt;30 days after major bleeding were 21.45 (95% CI 18.27–25.20) and 22.00 (95% CI 18.29–26.45) after myocardial infarction, 4.04 (95% CI 3.57–4.56) and 4.54 (95% CI 3.88–5.31) 30–365 days after the event and 1.57 (95% CI 1.43–1.72) and 2.07 (95% CI 1.86–2.30) &amp;gt;365 days after the event, all compared to patients without major bleeding or myocardial infarction. Conclusion Major bleeding and myocardial infarction as first post-discharge event after CABG had similar incidence and were associated with a significant and comparable increase in mortality risk. The risk was highest during the first 30 days after the event. Strategies to prevent myocardial infarction and major bleeding events after CABG are of great importance to improve survival. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Swedish Heart-Lung FoundationSparbanken Sjuhärads stiftelse för forskning vid Södra Älvsborgs Sjukhus Forest plot

Trends in the incidence and mortality of intracerebral hemorrhage, and the associated risk factors, in Denmark from 2004 to 2017.

The distribution of the major modifiable risk factors for intracerebral hemorrhage (ICH) changes rapidly. These changes call for contemporary data from large-scale population-based studies. The aim of the present study was to examine trends in incidence, risk factors, and mortality in ICH patients from 2004 to 2017. In a population-based cohort study, we calculated age- and sex-standardized incidence rates (SIRs), incidence rates (IRs) stratified by age and sex per 100,000 person-years, and trends in risk profiles. We estimated absolute mortality risk, and the Cox proportional hazards regression multivariable-adjusted hazard ratios for 30-day and 1-year mortality. We included 16,902 patients (53% men; median age 75years) from 2004 to 2017. The SIR of ICH decreased from 33 (95% confidence interval [CI] 32-34) in 2004/2005 to 28 (95% CI 27-29) in 2016/2017. Among patients aged ≥70years, the IR decreased from 137 (95% CI 130-144) in 2004/2005 to 112 (95% CI 106-117) in 2016/2017. The IR in patients aged <70years was unchanged. From 2004 to 2017, the proportion of patients with hypertension increased from 49% to 66%, the use of oral anticoagulants increased from 7% to 18%, and the use of platelet inhibitors decreased from 40% to 28%. The adjusted hazard ratio for 30-day mortality in 2016/2017 was 0.94 (95% CI 0.89-1.01) and 1-year mortality was 0.98 (95% CI 0.93-1.04) compared with 2004/2005. The incidence of spontaneous ICH decreased from 2004 to 2017, with no clear trend in mortality. The risk profile of ICH patients changed substantially, with increasing proportions of hypertension and anticoagulant treatment. Given the high mortality rate of ICH, further advances in prevention and treatment are urgently needed.

ANMCO/AIGO Intersocietary consensus document: Gastroprotection in patients receiving antiplatelet and/or anticoagulant drugs

Aspirin and P2Y12 receptor antagonists are widely used across the spectrum of cardiovascular and cerebrovascular diseases. Gastrointestinal complications, including ulcer and bleeding, are relatively common during antiplatelet treatment and, therefore, concomitant proton pump inhibitor (PPI) treatment is often prescribed. However, potential increased risk of cardiovascular events has been suggested for PPIs, and, in recent years, it has been discussed whether these drugs may reduce the cardiovascular protection by aspirin and, even more so, clopidogrel. Indeed, pharmacodynamic and pharmacokinetic studies suggested an interaction through CYP2C19 between PPIs and clopidogrel, which could translate into clinical inefficacy, leading to higher rates of cardiovascular events. The Food and Drug Administration and the European Medicines Agency sent a warning in 2010 discouraging the concomitant use of clopidogrel with omeprazole or esomeprazole. In addition, whether the use of PPIs may affect the clinical efficacy of the new P2Y12 receptor antagonists, ticagrelor and prasugrel, remains less known. According to current guidelines, PPIs in combination with antiplatelet treatment are recommended in patients with risk factors for gastrointestinal bleeding, including advanced age, concurrent use of anticoagulants, steroids or non-steroidal anti-inflammatory drugs, and Helicobacter pylori infection. Like traditional anticoagulants, novel oral anticoagulants may cause gastrointestinal bleeding. Results from both randomized clinical trials and observational studies suggest that high-dose dabigatran (150 mg bid), rivaroxaban and high-dose edoxaban (60 mg daily) are associated with a higher risk of gastrointestinal bleeding as compared with warfarin. However, the usefulness of PPIs in patients receiving these anticoagulants deserves to be further demonstrated. Given the large number of patients treated with antithrombotic drugs and PPIs, even a minor reduction of platelet inhibition or anticoagulant effect potentially carries a considerable clinical impact. The present joint statement by ANMCO and AIGO summarizes the current knowledge regarding the widespread use of platelet inhibitors, anticoagulants, and PPIs in combination. Moreover, it outlines evidence supporting or opposing drug interactions between these drugs and discusses consequent clinical implications.

Pre-admission use of platelet inhibitors and short-term stroke mortality: a population-based cohort study.

The impact of pre-admission antiplatelet treatment on prognosis after stroke is poorly understood. We, therefore, investigated whether pre-admission use of aspirin and clopidogrel was associated with mortality in patients hospitalized with ischaemic stroke, intracerebral haemorrhage (ICH), or subarachnoid haemorrhage (SAH). We used nationwide population-based registries to identify all first-time hospitalizations for stroke and subsequent mortality in patients treated with aspirin and clopidogrel in Denmark during 2004-2012. Based on redeemed prescriptions, we computed absolute 30-day mortality rates and mortality rate ratios (MRRs) for current platelet inhibitor users and non-users. We used Cox regression to control for potentially confounding factors. Among platelet inhibitor non-users, 30-day stroke mortality was 12.0% (8.8% for ischaemic stroke, 29.6% for ICH, and 21.2% for SAH). Compared with non-users, the adjusted 30-day MRR (aMRR) was increased among ICH patients using aspirin [1.19, 95% confidence interval (CI) 1.09-1.31]. Although wider CIs, similar increased point estimates were observed in users of both aspirin and clopidogrel (aMRR = 1.26, 95% CI 0.84-1.91). In contrast, current use of both aspirin and clopidogrel was associated with reduced mortality from ischaemic stroke (aMRR = 0.67, 95% CI 0.48-0.94), while use of aspirin alone was not. Among patients hospitalized for first-time ICH, pre-admission platelet inhibitor use was associated with increased 30-day mortality compared with non-use. In patients hospitalized for ischaemic stroke, 30-day mortality was reduced in users of both aspirin and clopidogrel, but not in users of aspirin alone.

The Role of Angiotensin-Converting Enzyme Inhibitors in Patients with Chronic Subdural Hematoma: A Scandinavian Population-Based Multicenter Study.

To investigate the role of angiotensin converting enzyme (ACE) inhibitors in the recurrence of chronic subdural hematoma (cSDH) after burr hole surgery. A retrospective review was conducted of a Scandinavian multicenter, population-based cohort of 1252 adults with cSDH who underwent with burr hole surgery between January 1, 2005, and December 31, 2010. The risk of cSDH recurrence was assessed in users of ACE inhibitors, users of angiotensin II receptor blockers (ARBs), and those without ACE inhibitor treatment (no ACE inhibitor group) using univariable and multivariable regression analyses. The cohort included 98 (7.8%) ACE inhibitor users and 63 (5%) ARB-only users. The recurrence rate was 16.3% (n= 16) in the ACE inhibitor group, compared with 13.3% (n= 153) in the no ACE inhibitor group (P= 0.39) and 14.3% (n= 9) in the ARB group (P= 0.73). When comparing groups, age (P= 0.01), Charlson Comorbidity Index (P= 0.01), use of platelet inhibitors (P= 0.001) and use of anticoagulants (P= 0.01) differed between the ACE inhibitor and no ACE inhibitor groups. Only age differed significantly between the ACE inhibitor and ARB groups (P= 0.03). In the analyses adjusted for differences in baseline characteristics, ACE inhibitor treatment did not influence the risk of recurrence (odds ratio, 1.2; 95% confidence interval, 0.7-2.2; P= 0.46). In this population-based study, the use of ACE inhibitors was not associated with the risk of recurrence following burr hole surgery for cSDH.

Editor's Choice – The National Norwegian Carotid Study: Time from Symptom Onset to Surgery is too Long, Resulting in Additional Neurological Events

The objective was to observe for 1 year all patients in Norway operated on for symptomatic carotid stenosis with respect to (i) the time from the index event to surgery and neurological events during this time; (ii) the level in the healthcare system causing delay of surgical treatment; and (iii) the possible relationship between peri-operative use of platelet inhibitors and neurological events while awaiting surgery. This was a prospective national multicentre study of a consecutive series of symptomatic patients. Patients were eligible for inclusion when referred for surgery. An index event was defined as the neurological event prompting contact with the healthcare system. All 15 departments in Norway performing carotid endarterectomy (CEA) participated. Three hundred and seventy one patients were eligible for inclusion between 1 April 2014 and 31 March 2015, and 368 patients (99.2%) were included. Fifty-four percent of the patients contacted their general practitioner on the day of the index event. Primary healthcare referred 84.2% of the patients to hospital on the same day as examined. In hospital median time from admission to referral for vascular surgery was 3 days. Median time between referral to the operating unit and actual CEA was 5 days. Overall, 61.7% of the patients were operated on within 2 weeks of the index event. Twelve patients (3.3%) suffered a new neurological event while awaiting surgery. The percentage of patients on dual antiplatelet therapy was lower (25.0%) in this group than among the other patients (62.6%) (p=.008). The combined 30day mortality and stroke rate was 3.8%. This national study with almost complete inclusion and follow-up shows that the delays occur mainly at patient level and in hospital. The delay is associated with new neurological events. Dual antiplatelet therapy is associated with reduced risk of having a new neurological event before surgery.

187 Novel thienopyridines are potent anti-platelet drugs, inhibiting platelet activation, aggregation and showing synergy with aspirin

Background Management of Acute Coronary Syndromes (ACS) often involves the use of platelet inhibitors. The most commonly used drug, clopidogrel, belongs to a class of thienopyridine molecules which targets the P2Y12 receptor on platelets and it is commonly used in combination with the COX-1 inhibitor acetylsalicylic acid (ASA). However, the effect of these treatments is variable amongst patients, highlighting a need for a refinement of this class of P2Y12 inhibitor. The aim of this study was to assess the efficacy of six novel thienopyridine derivatives synthesised by our group by examining their potential as in-vitro inhibitors of platelet function. Methods Healthy human platelets were isolated and incubated with novel thienopyridine compounds (DJ0081, DJ0199, DJ0021, DJ0206, DJ0171, DJ0097) (10 µM, 30 min) prior to stimulation with ADP (10µM) and analysis of alpha granule secretion (CD62P expression), GPIIbIIIa activation (PAC1 expression) and platelet leukocyte aggregate (PLA) formation using flow cytometry. Furthermore, light transmission aggregometry (LTA) was used to assess ADP-stimulated aggregation after these treatments. Synergy with ASA (30 µM) was also analysed by LTA following incubation with ASA and thienopyridine. All results were compared to ADP-stimulated samples and samples treated with clopidogrel (10 µM, 30 min) prior to ADP stimulation. Results All six novel compounds demonstrated a significant reduction in ADP-mediated platelet aggregation (p Conclusion The study demonstrates the potential for new thienopyridine compounds as modulators of platelet function and points to the possibility of future use in patients at risk of platelet hyperactivity and thrombosis.

Abstract B62: Role of the blood microenvironment in the upregulation of oncoproteins in circulating pancreatic cancer cells

Abstract Background: Platelets are promoters of cancer cell proliferation at the metastatic niche, however the exact mechanism(s) by which platelets drive cancer cell proliferation remain ill-defined. The oncoprotein c-MYC, which governs neoplastic proliferation, is overexpressed in pancreatic tumors at the metastatic site as compared to primary tumors, with the overexpression of c-MYC indicative of a poor clinical outcome for patients with cancer. At present, the oncogenic pathways mediating c-MYC upregulation in metastatic cancer cells are largely unknown. Our exciting preliminary data demonstrate for the first time that platelets upregulate c-MYC protein levels in PANC-1 pancreatic cancer cells, suggesting a novel prometastatic role for platelets in pancreatic cancer. Aims: To define the mechanisms by which platelets upregulate c-MYC protein levels in PANC-1 pancreatic cancer cells. Methods: We utilized a co-culture platform to examine the effect of resting and thrombin-stimulated human platelets as well as platelet fractions (platelet-derived membrane bound molecules and soluble molecules) on c-MYC expression in PANC-1 cancer cells. Platelet inhibitors, including the GPIIbIIIa blocker Integrilin, were used to study the molecular mechanisms by which platelets upregulate c-MYC expression in cancer cells. Changes in c-MYC oncoprotein were detected by Western Blotting. The physical association between platelets and PANC-1 cancer cells was quantified by immunoblotting with an anti-GPIIb antibody against the platelet-specific integrin GPIIbIIIa. Results: Resting and activated platelets as well as platelet fractions induced an upregulation of c-MYC expression in PANC-1 cancer cells. The effect of platelets on c-MYC expression was largely dependent on direct contact with the cancer cells, as the preincubation of platelets with Integrilin reduced platelet-induced c-MYC expression. Conclusion: We show that the expression of c-MYC in PANC-1 cancer cells can be upregulated by platelets, revealing a novel mechanism of platelet action in the progression of cancer and suggesting that the overexpression of c-MYC at the metastatic niche may be inhibited through the use of platelet inhibitors. We are currently characterizing the molecular underpinnings of platelet-mediated c-MYC regulation with respect to the contribution of platelets to cancer cell proliferation and growth. Citation Format: Annachiara Mitrugno, Katherine Pelz, Rosalie Sears, Owen McCarty. Role of the blood microenvironment in the upregulation of oncoproteins in circulating pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B62.

Mortality among head trauma patients taking preinjury antithrombotic agents: a retrospective cohort analysis from a Level 1 trauma centre

BackgroundBleeding represents the most well-known and the most feared complications caused by the use of antithrombotic agents. There is, however, limited documentation whether pre-injury use of antithrombotic agents affects outcome after head trauma. The aim of this study was to define the relationship between the use of preinjury antithrombotic agents and mortality among elderly people sustaining blunt head trauma.MethodsA retrospective cohort analysis was performed on the hospital based trauma registry at Oslo University Hospital. Patients aged 55 years or older sustaining blunt head trauma between 2004 and 2006 were included. Multivariable logistic regression analyses were used to identify independent predictors of 30-day mortality. Separate analyses were performed for warfarin use and platelet inhibitor use.ResultsOf the 418 patients admitted with a diagnosis of head trauma, 137 (32.8 %) used pre-injury antithrombotic agents (53 warfarin, 80 platelet inhibitors, and 4 both). Seventy patients died (16.7 %); 15 (28.3 %) of the warfarin users, 12 (15.0 %) of the platelet inhibitor users, and two (50 %) with combined use of warfarin and platelet inhibitors, compared to 41 (14.6 %) of the non-users. There was a significant interaction effect between warfarin use and the Triage Revised Trauma Score collected upon the patients’ arrival at the hospital. After adjusting for potential confounders, warfarin use was associated with increased 30-day mortality among patients with normal physiology (adjusted OR 8,3; 95 % CI, 2.0 to 34.8) on admission, but not among patients with physiological derangement on admission. Use of platelet inhibitors was not associated with increased mortality.ConclusionsThe use of warfarin before trauma was associated with increased 30-day mortality among a subset of patients. Use of platelet inhibitors before trauma was not associated with increased mortality. These results indicate that patients on preinjury warfarin may need closer monitoring and follow up after trauma despite normal physiology on admission to the emergency department.

Use of Antithrombotic Therapy and Long-Term Clinical Outcome Among Patients Surviving Intracerebral Hemorrhage

The effectiveness and safety of antithrombotic therapy (AT) among patients with a history of intracerebral hemorrhage remain uncertain. We therefore determined the prevalence of indication for AT among patients hospitalized with first-time intracerebral hemorrhage and examined the impact of subsequent AT use on the long-term clinical outcome. We performed a population-based cohort study using nationwide Danish medical registries. Patients with risk of thromboembolism surviving the first 30 days after hospitalization because of intracerebral hemorrhage were identified and followed up. We estimated the hazard ratio of all-cause death, thromboembolic events, or major bleeding according to use of AT. We identified 6369 patients between 2005 and 2013. Among these patients, 2978 (47%) had indication for AT, and during the follow-up, (median: 2.3 year) 1281 (43%) died, 497 (17%) had a thromboembolic event, and 536 (18%) had major bleeding. Postdischarge use of oral anticoagulation therapy among patients with indication for oral anticoagulation therapy was associated with a significant lower risk of death (adjusted hazard ratio, 0.59; 95% confidence interval, 0.43-0.82) and thromboembolic events (adjusted hazard ratio 0.58; 95% confidence interval, 0.35-0.97) and no increased risk of major bleeding (adjusted hazard ratio 0.65; 95% confidence interval, 0.41-1.02). In contrast, use of platelet inhibitors among patients with indication for platelet inhibitors was not related to statistically significantly improved clinical outcome. Approximately 1 of 2 patients surviving intracerebral hemorrhage had a high risk of thromboembolism. Postdischarge use of oral anticoagulation therapy was associated with a lower risk of all-cause mortality and thromboembolic events and no increased risk of major bleeding.

Medication Safety

Medication Safety

Effectiveness and outcome of management strategies for dabigatran- or warfarin-related major bleeding events

BackgroundStrategies used for the management of dabigatran-related major bleeding events (MBEs), and their effectiveness have not been systematically evaluated. MethodsReports on 1034 individuals experiencing 1121 MBEs (696 on dabigatran, and 425 on warfarin) in 5 phase III randomized controlled trials were assessed independently by two investigators. ResultsMBEs were managed either by drug discontinuation only (37%), or drug discontinuation with either transfusion of only red cell concentrates (38%), or plasma (23%). Few MBEs (2%) were treated with coagulation factor concentrates. The effectiveness of the management was assessed as good in significantly larger proportion of MBEs on dabigatran (91%) than on warfarin (84%, odds ratio [OR] 1.68; 95% confidence interval [CI], 1.14–2.49), which was consistent with the lower 30-day mortality (OR (OR 0.66; 95% CI, 0.44-1.00)). The effectiveness of bleeding management in non-traumatic bleeding was better in patients with dabigatran than with warfarin (OR 1.82; 95% CI, 1.18–2.79) but was similar in traumatic bleeding (OR 0.75; 95% CI, 0.25–2.30). The relative effectiveness of management of bleeding and 30-day mortality rates across other key subgroups of patients or sites of bleeding, the use of platelet inhibitors, age-, sex- and renal function subgroups, were comparable in MBEs on dabigatran or warfarin. ConclusionDespite the unavailability of a specific antidote at the time of these studies, bleeding in patients receiving dabigatran was managed in the overwhelming majority of patients without coagulation factor concentrates, with comparable or superior effectiveness and lower 30-day mortality rates versus those who bleed while receiving warfarin.

Proton Pump Inhibitors in Cardiovascular Disease: Drug Interactions with Antiplatelet Drugs.

Aspirin and P2Y12 receptor antagonists are widely used across the spectrum of cardiovascular diseases. Upper gastrointestinal complications, including ulcer and bleeding, are relatively common during antiplatelet treatment and, therefore, concomitant proton pump inhibitor (PPI) treatment is often prescribed.PPIs provide gastroprotection by changing the intragastric milieu, essentially by raising intragastric pH. In recent years, it has been heavily discussed whether PPIs may reduce the cardiovascular protection by aspirin and, even more so, clopidogrel. Pharmacodynamic and pharmacokinetic studies suggested an interaction between PPIs and clopidogrel, and subsequent clinical studies were conducted to evaluate the clinical impact of this interaction. More recently, it was reported that PPIs may also attenuate the antiplatelet effect of aspirin. This may be clinically important, because a fixed combination of aspirin and a PPI (esomeprazole) has recently been approved and because aspirin is the most widely used drug in patients with cardiovascular disease. The antiplatelet effect of the new P2Y12 receptor antagonists, ticagrelor and prasugrel, seems less influenced by PPI co-treatment.Given the large number of patients treated with antithrombotic drugs and PPIs, even a minor reduction of platelet inhibition potentially carries considerable clinical impact. The present book chapter summarizes the evidence regarding the widespread use of platelet inhibitors and PPIs in combination. Moreover, it outlines current evidence supporting or opposing drug interactions between these drugs and discusses clinical implications.

Distal Embolization During Lower Extremity Endovascular Interventions

Distal embolization (DE) during peripheral arterial endovascular interventions is a well-known complication that is poorly studied. The goal of this project was to determine the incidence, risk factors, and effect of DE on the outcomes of lower extremity endovascular interventions (LEI). All LEI between 2010 and 2014 in the Vascular Study Group of New England database were reviewed. Patient characteristics were analyzed to determine predictors of DE. LEI involving the superficial femoral artery (SFA) were reviewed to assess the effect of type of treatment on DE. The outcomes examined were loss of patency, limb loss, and mortality after LEI involving the SFA. A multivariable regression was used to determine predictors of DE. SAS and STAT 9.4 software were used for all analyses. There were a total of 10,856 procedures. The incidence of DE was 17.3/1000 procedures, and 68% required treatment (57% endovascular, 11% open surgery). DE was more common in patients with diabetes (relative risk [RR], 1.51; 95% confidence interval [CI], 1.11-2.04), and in urgent (RR, 1.91; 95% CI, 1.37-2.66) and emergency (RR, 3.43; 95% CI, 1.77-6.67) procedures compared with elective procedures. The use of aspirin/P2Y12 antagonists and statins were associated with lower incidence of DE (RR, 0.65; 95% CI, 0.46-0.92; RR, 0.66; 95% CI, 0.49-0.90, respectively). DE increased with the number of arteries treated (P < .0001), and with the length of occlusion (P < .0001). The SFA was the most commonly treated artery (4751 [43.7%]). The combined treatment modalities of balloon angioplasty and atherectomy as well as stenting and atherectomy had higher risk of DE compared with balloon angioplasty and stenting of the SFA (RR, 3.20; 95% CI, 1.91-5.37; RR, 3.15; 95% CI, 1.62-6.12, respectively). DE was not significantly associated with loss of patency, major amputation, or mortality. The incidence of DE during LEI is 1% to 2% and increases with atherectomy. The use of platelet inhibitors and statins seems to be protective.