Intravenous antiplatelet therapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention : A report from the INVEST-STEMI group.

The use of intravenous antiplatelet therapy during primary percutaneous coronary intervention (PPCI) is not fully standardized. The aim is to evaluate the effectiveness and safety of periprocedural intravenous administration of cangrelor or tirofiban in a contemporary ST-segment elevation myocardial infarction (STEMI) population undergoing PPCI. This was a multicenter prospective cohort study including consecutive STEMI patients who received cangrelor or tirofiban during PPCI at seven Italian centers. The primary effectiveness measure was the angiographic evidence of thrombolysis in myocardial infarction (TIMI) flow < 3 after PPCI. The primary safety outcome was the in-hospital occurrence of BARC (Bleeding Academic Research Consortium) 2-5 bleedings. The study included 627 patients (median age 63 years, 79% males): 312 received cangrelor, 315 tirofiban. The percentage of history of bleeding, pulmonary edema and cardiogenic shock at admission was comparable between groups. Patients receiving cangrelor had lower ischemia time compared to tirofiban. TIMI flow before PPCI and TIMI thrombus grade were comparable between groups. At propensity score-weighted regression analysis, the risk of TIMI flow < 3 was significantly lower in patients treated with cangrelor compared to tirofiban (adjusted OR: 0.40; 95% CI: 0.30-0.53). The risk of BARC 2-5 bleeding was comparable between groups (adjusted OR:1.35; 95% CI: 0.92-1.98). These results were consistent across multiple prespecified subgroups, including subjects stratified for different total ischemia time, with no statistical interaction. In this real-world multicenter STEMI population, the use of cangrelor was associated with improved myocardial perfusion assessed by coronary angiography after PPCI without increasing clinically-relevant bleedings compared to tirofiban.

[GDF-15 and the risk of bleeding in patients with stable CAD receiving multicomponent antithrombotic therapy: the results of the prospective REGATA register].

AIM: To evaluate the prognostic value of GDF-15 in relation the development of bleeding and events in stable CAD patients, receiving combined antithrombotic therapy. MATERIALS AND METHODS: The data was obtained from the prospective registry REGATA, 343 CAD patients (249 males), median age 68 [IQR 62; 75] years) were enrolled. Patients with sinus rhythm and concomitant PAD received acetylsalicylic acid in combination with rivaroxaban 2.5 mg bid (31.8%) or clopidogrel (24.8%). Other 43.4% with concomitant atrial fibrillation (AF) received direct oral anticoagulants in combination with antiplatelet therapy after elective percutaneous coronary interventions. Median follow-up was 12 months [IQR 9.0; 18.0]. The safety end point was major and clinically relevant bleedings (type 2-5) according to the BARC classification. Plasma samples for GDF-15 identification were taken at the inclusion and analyzed using ELISA assay. RESULTS: Frequency of BARC 2-5 bleedings was 16% (BARC 2 - 46; BARC 3 - 9; BARC 4-5 - 0), median GDF-15 level was 1185.0 pg/ml [850.0; 1680.0]. In patients with AF and concomitant MFA, the level of GDF-15 was significantly higher than in the subgroups of patients with only AF or MFA (p=0.0022). According to the quintile analysis, GDF-15 values in the top three quintiles of distribution (cut-off value >943 pg/ml) were associated with higher frequency of bleeding events: 23.2% versus 5.1%; p=0.0001. The multivariable logistic regression model demonstrated that bleeding events were independently associated with GDF-15 level>943 pg/ml (OR 2.65, 95% CI 1.11-6.30; p=0.0275), AF (OR 2.61, 95% CI 1.41-4.83; p=0.0023) and chronic kidney disease (OR 1.92, 95% CI 1.03-3.60; p=0.0401). Clinical factors determining the risk of bleeding events also determined a GDF-15 elevation. CONCLUSION: Assessment of GDF-15 level may improve bleeding risk stratification in CAD patients with concomitant AF and/or PAD receiving combined antithrombotic therapy.

Identification of risk factors for adverse drug reactions in a pharmacovigilance database.

INTRODUCTION: In addition to identifying new safety signals, pharmacovigilance databases could be used to identify potential risk factors for adverse drug reactions (ADRs). OBJECTIVE: To evaluate whether data mining in a pharmacovigilance database can be used to identify known and possible novel risk factors for ADRs, for use in pharmacovigilance practice. METHOD: Exploratory data mining was performed within the Swedish national database of spontaneously reported ADRs. Bleeding associated with direct oral anticoagulants (DOACs)-rivaroxaban, apixaban, edoxaban, and dabigatran-was used as a test model. We compared demographics, drug treatment, and clinical features between cases with bleeding (N = 965) and controls who had experienced other serious ADRs to DOACs (N = 511). Statistical analysis was performed by unadjusted and age adjusted logistic regression models, and the random forest based machine-learning method Boruta. RESULTS: In the logistic regression, 13 factors were significantly more common among cases of bleeding compared with controls. Eleven were labelled or previously proposed risk factors. Cardiac arrhythmia (e.g., atrial fibrillation), hypertension, mental impairment disorders (e.g., dementia), renal and urinary tract procedures, gastrointestinal ulceration and perforation, and interacting drugs remained significant after adjustment for age. In the Boruta analysis, high age, arrhythmia, hypertension, cardiac failure, thromboembolism, and pharmacodynamically interacting drugs had a larger than random association with the outcome. High age, cardiac arrhythmia, hypertension, cardiac failure, and pharmacodynamically interacting drugs had odds ratios for bleeding above one, while thromboembolism had an odds ratio below one. CONCLUSIONS: We demonstrated that data mining within a pharmacovigilance database identifies known risk factors for DOAC bleeding, and potential risk factors such as dementia and atrial fibrillation. We propose that the method could be used in pharmacovigilance for identification of potential ADR risk factors that merit further evaluation.

Direct oral anticoagulants: patient reported adherence and minor bleedings.

Data regarding adherence and minor bleeding on direct oral anticoagulants in everyday life are still sparse. Inclusion criteria: treatment initiated with dabigatran, rivaroxaban or apixaban in non-valvular atrial fibrillation patients from a center in northern Sweden between 2011 and 2019 (n = 668). Exclusion criteria: cognitive impairment, dose dispensing, need of interpreter or hospital admission (n = 67). By a telephone interview adherence was measured in 569 patients (response rate 94.8%) using the 8-item Morisky medication adherence scale and minor bleeding was asked for. CHA2DS2-VASc and HAS-BLED scores were collected from medical records. The number (n), mean age, mean treatment duration, mean (points) CHA2DS2-VASc and HAS-BLED scores was with dabigatran (n = 175, 73.3 years, 17.8 months, 3.6 p and 2.2 p), rivaroxaban (n = 198, 73.7 years, 21months, 3.8 p and 2.1 p) and apixaban (n = 196, 72.7 years, 15.2 months, 3.4 p and 2.1 p). Adherence was high for dabigatran, rivaroxaban and apixaban in 54%, 76% and 53%; intermediate in 37%, 20% and 37% or low in 9%, 4% and 10% respectively. High adherence (Morisky score 8) distinguished rivaroxaban (p < 0.0001) and in patients with CHA2DS2-VASc ≥ 4 p, (p < 0.0001). Patients on rivaroxaban/apixaban reported more minor bleedings (37% / 28%) compared to dabigatran (13%), (p < 0.001). Only 61% of the patients followed prescription. Adherence to rivaroxaban was significantly better, maybe due to the once daily dosing regimen, and furthermore among patients with higher risk for stroke. Minor bleedings were less common in the dabigatran group. The impact of minor bleedings on adherence and a possible relationship to clinical outcomes need to be further studied.

A comparison of postoperative complications following cardiac implantable electronic device procedures in patients treated with antithrombotic drugs.

BACKGROUND: The incidence of postoperative complications following cardiac implantable electronic device (CIED) procedures in patients treated with antithrombotic drugs has not been studied sufficiently. Here we present a comparison of complications after CIED implantations. METHODS: Using an observational study design, the study included 1807 patients with a taking antiplatelet drugs (n: 1601), nonvitamin K anticoagulants (NOAC) (n: 136), and warfarin (n: 70) undergoing CIED surgery. Primary endpoint was accepted as cumulative events including composite of clinically significant hematoma (CSH), pericardial effusion or tamponade, pneumothorax, and infection related to device system. Secondary outcomes included each compenent of cumulative events. Multivariable analysis was performed to identify predictors of cumulative events. RESULTS: The overall cumulative event rate was 3.7% (67 of 1807). Cumulative events occured 3.1% (50 of 1601) in the antiplatelet, 5.1% (7 of 136) NOAC, and 14.3% (10 of 70) warfarin groups (p < 0.001). CSH occurred in 2 of 70 patients (2.9%) in the warfarin group, as compared with 5 of 1601 (0.3%) in the antiplatelet group (p: 0.032). However, no significant differences were found between NOAC and warfarin groups in terms of CSH (0.7% vs. 2.9% respectively, p: 0.267). Warfarin treatment was an independent predictor of cumulative events and increased 2.9-fold the risk of cumulative events. Major surgical complications were rare and did not differ significantly between the study groups. CONCLUSIONS: The incidence and severity of complications may be lower in patients treated with periprocedurally antiplatelet or NOAC therapy when compared with warfarin therapy. Further randomized control studies are required to confirm our findings.

Feasibility and safety of a new endoscopic synthetic sealant nebulizing device over gastric endoscopic submucosal dissections.

BACKGROUND: Endoscopic Submucosal Dissection (ESD) is the treatment of choice of superficial neoplastic gastrointestinal lesions. Delayed bleedings and perforations are still current clinical concerns. Glubran 2 is a synthetic cyanoacrylate-derived glue nowadays already widely used as an effective tissue adhesive. ENDONEB is a novel device thought for enabling the sealant nebulization over a specific targeted surface during laparotomy, laparoscopy, and thoracotomy. The aim of this single-center preclinical animal trial is to evaluate the feasibility and safety of the same nebulization technique during ESD in the perspective that further clinical studies would demonstrate the efficacy of Glubran 2 in preventing post-ESD adverse events. METHODS: Four live Landrace pigs were enrolled. Two approximately 30-mm-wide gastric ESDs were performed in each pig (experimental ESD and control ESD). About 0.5 mL of Glubran 2 was nebulized on the experimental ESDs. Subjective perception of the feasibility of the Glubran 2 nebulization was reported. Pigs were clinically monitored at follow-up and upper GI endoscopy was performed at 24 and 48 hours, when animals were euthanized to perform a macroscopic and histological analysis of the specimens. RESULTS: No peri-procedural adverse events were reported. Glubran 2 nebulization over experimental ESDs showed to be technically easy and time-effective. Clinical and endoscopic animal monitoring was negative at follow-up. At 24 hours, the Glubran 2 film was clearly visible on the eschar of the ESDs and signs of initial hydrolysis were discernable at 48 hours. No signs of peritoneal reaction were observed at the macroscopic examination. Equal transmural inflammation was described at the histological examination of both types of ESDs. CONCLUSIONS: Safety and feasibility profiles of Glubran 2 nebulizing ENDONEB device over ESD surfaces were excellent. Further evidences and human trials are needed to investigate its effectiveness in ESDs' eschars sealing and, thus, in delayed micro-perforations and bleedings prevention and treatment.

Increasing use of anticoagulants in Germany and its impact on hospitalization rates for genitourinary bleeding.

The aim of the study was to compare nationwide time trends of prescribed oral anticoagulants (OAC) with the time trend of genitourinary bleedings (GUB) in Germany from 2005 through 2016. The annual numbers of hospitalized patients with GUB coded as "hematuria", "excessive, frequent and irregular menstruation", "postmenopausal bleeding" or "abnormal uterine and vaginal bleeding" were extracted from the nationwide hospitalization file by the Federal Bureau of Statistics. Hospitalization rates were age-standardized using the German standard population 2011. Defined daily doses (DDD) of prescribed anticoagulants among outpatients for the same calendar period were extracted from reports of the statutory health insurance drug information system. Based on DDD, drug treatment rates per 100,000 person years (py) were calculated. From 2005 to 2016, annual OAC treatment rates per 100,000 py increased by 135.8% (from 901.4 to 2125.9). Until 2011 direct oral anticoagulants (DOAC) represented less than 0.1% of all OAC, but 49.9% in 2016. In the same period age-standardized rates of hospitalizations for hematuria increased continuously (annual change of 1.03 (95% CI 0.94-1.11) per 100,000 py), that of "postmenopausal" (- 1.93; 95% CI - 2.38 to - 1.49) or "excessive, frequent and irregular menstruation" decreased (- 1.25; 95% CI -1.62 to - 0.87) and that of "abnormal uterine and vaginal haemorrhage" remained almost unchanged. From all cases with hematuria 5.3% received at least 1 red blood cell concentrate (RBC) in 2005 and 8.2% in 2016 whereas all cases with the other three types of bleeding counted for 1.9% in 2005 and 3.8% in 2016. The time trends for GUB in all subgroups changed steadily and showed no effect of the disproportional increase of DAOCs until 2011. Our ecologic nationwide comparison of OAC treatment rates in outpatients and hospitalization rates for GUBs revealed that despite increasing OAC treatment rates from 2011 to 2016 the hospitalization rates for GUB showed steady annual changes unaffected by the increasing prescription rates of DOACs since 2011.

Neonatal and maternal outcome after frozen embryo transfer: Increased risks in programmed cycles.

BACKGROUND: Frozen embryo transfer is associated with better perinatal outcome regarding preterm birth and low birthweight, yet higher risk of large for gestational age and macrosomia compared to fresh transfer. Further, higher rates of hypertensive disorders in pregnancy are noted after frozen embryo transfer. Whether these differences are due to the protocol used in frozen cycles remains unknown. OBJECTIVE: To analyze the obstetric outcome after frozen embryo transfer depending on protocol used. Comparison was also made for frozen vs fresh transfer and for frozen transfer vs spontaneous conception. STUDY DESIGN: A population-based retrospective registry study including all singletons born after frozen embryo transfer in Sweden from 2005 to 2015. The in vitro fertilization register was cross-linked with the Medical Birth Register, the Register of Birth Defects, the National Patient Register, the Swedish Neonatal Quality Register, and the Prescribed Drug Register. Singletons after frozen embryo transfer were compared depending on the presence of a corpus luteum in the actual cycle. All frozen transfer singletons were also compared with fresh transfer and spontaneous conception singletons. Primary outcomes were preterm birth (<37 w), low birthweight (<2500 g), hypertensive disorders in pregnancy, and postpartum hemorrhage (>1000 mL). Crude and adjusted odds ratio with 95% confidence interval were calculated and adjustment made for relevant confounders. RESULTS: A total of 9726 singletons were born after frozen embryo transfer (natural cycles, n = 6297; stimulated cycles, n = 1983; programmed cycles, n = 1446), 24,365 after fresh transfer, and 1,127,566 after spontaneous conception. No significant differences were noticed for preterm birth and low birthweight between the different protocols used in frozen embryo transfer. Compared to natural and stimulated frozen cycles, programmed frozen cycles were associated with a higher risk of hypertensive disorders in pregnancy (adjusted odds ratio, 1.78; 95% confidence interval, 1.43-2.21 and adjusted odds ratio, 1.61; 95% confidence interval, 1.22-2,10, respectively) and postpartum hemorrhage (adjusted odds ratio, 2.63; 95% confidence interval, 2.20-3.13 and adjusted odds ratio, 2.87; 95% confidence interval, 2.29-2.60, respectively). Moreover, higher risks for postterm birth (adjusted odds ratio, 1.59; 95% confidence interval, 1.27-2.01 and adjusted odds ratio, 1.98; 95% confidence interval, 1.47-2.68) and macrosomia (adjusted odds ratio, 1.62; 95% confidence interval, 1.26-2.09 and adjusted odds ratio, 1.40; 95% confidence interval, 1.03-1.90) were detected. There were no significant differences in any outcomes between stimulated and natural cycles. Frozen cycles in general compared to fresh cycles and compared to spontaneous conceptions showed neonatal and maternal outcomes in agreement with earlier studies. CONCLUSION: No significant difference could be seen regarding preterm birth and low birthweight between the different protocols. However, higher rates of hypertensive disorders in pregnancy, postpartum hemorrhage, postterm birth, and macrosomia were detected in programmed cycles. Stimulated cycles had outcomes similar to natural cycles. These findings are important in view of the increasing use of frozen cycles and the new policy of freeze-all cycles in in vitro fertilization. The results suggest a link between the absence of corpus luteum and adverse obstetric outcomes.

Transradial versus transfemoral ancillary approach in complex structural, coronary, and peripheral interventions. Results from the multicenter ancillary registry: A study of the Italian Radial Club.

OBJECTIVES: to understand the role of a transradial (TR) secondary approach during complex percutaneous interventions. BACKGROUND: The value of the TR route for ancillary vascular approach has not been adequately validated in this setting, and there is scant data on its role in reducing bleeding complications. METHODS: In the present study we retrospectively included patients undergoing the following interventions requiring two vascular approaches at nine high-volume centers in Italy: structural cardiac interventions, complex PCI, endovascular aortic repair (EVAR) and complex lower limb angioplasty. We compared procedural outcomes according to the type of ancillary vascular approach selected, namely TR or transfemoral/transbrachial (TF/TB). Primary endpoints of the study were procedural success and in-hospital BARC grade 3-5 bleedings. RESULTS: We included 906 patients, 433 receiving TR and 473 TF/TB ancillary approaches. Baseline characteristics did not differ significantly. Patients underwent the following types of intervention: structural 50%, complex coronary PCI 37%, EVAR 11%, peripheral angioplasty 2%. Procedural success was similar (90% in TR and 92% TF/TB, P = NS). In-hospital BARC 3/5 bleedings were more common in TF/TB group as compared to TR group (19.7% vs. 6.7%,P < 0.001). In TF/TB group we also observed a higher postprocedural hemoglobin drop (1.92 vs 1.13 g/dl, P = 0.008) and longer hospital stay as compared to TR group. Similar results were observed in a propensity score-matched population of 450 patients. CONCLUSIONS: In our study TR ancillary approach was associated with a significant reduction in the risk of major bleedings, without jeopardizing the success of complex structural, coronary, and peripheral percutaneous interventions. The value of the transradial route for ancillary vascular approach during percutaneous interventions has not been adequately validated yet. We retrospectively included 906 patients, 433 receiving TR and 473 TF/TB ancillary approach at nine high-volume centers for the following interventions: structural cardiac interventions, complex PCI, EVAR and complex peripheral angioplasty. Procedural success was similar, whereas in-hospital BARC bleedings were more common in the transfemoral/brachial group. Similar results were observed in a propensity score-matched population. In our study TR ancillary approach was associated with a significant reduction in the risk of major bleedings, without jeopardizing the success of complex interventions. © 2017 Wiley Periodicals, Inc.

Death by hanging: a retrospective case-control investigation of the intervertebral disc vacuum phenomenon on PMCT.

During hanging gravitational forces affect the spine. Intervertebral vacuum phenomenon (VP) implies that gas accumulations in the discs are caused by degeneration of the spine and trauma. It was hypothesized that VP detected on postmortem computed tomography (PMCT) has a higher incidence in hanging deaths, which can be correlated to age, degenerative spinal changes and type of hanging (complete-incomplete). Secondly, it was investigated whether the presence of Simon's bleedings is related to hanging type and VP on PMCT. A retrospective hanging case-control study of 72 cases was conducted. PMCT data were evaluated by two observers for the presence of VP and its localization within the thoracic and lumbar discs, and for any degenerative changes of the spine. Autopsy protocols were assessed for the presence of Simon's bleedings during autopsy. VP did not statistically differ among hanging and control cases but it was statistically correlated to complete hanging, increasing age and degenerative spinal changes. Centrally located VP within the discs was correlated to hanging, especially complete hanging, and younger ages, contrary to control cases that showed gas at the disc periphery. Simon's bleedings were correlated with complete hanging and centrally located VP. Centrally located VP within the discs increases the probability for complete hanging, while increasing age and degenerative changes reduce this probability. Intervertebral VP is multifactorial radiological entity. The presence of centrally located VP can indicate that hanging could be considered as an alternative mechanism of death and that great forces and loads may have affected the spine perimortem, especially with decreasing age and when Simon's bleedings are present.

Bivalirudin versus heparin and provisional GP IIb/IIIa inhibitors in patients treated for ST-segment elevation myocardial infarctions: Comparison of outcomes in a "real-world" setting.

INTRODUCTION: The beneficial effects of bivalirudin during primary PCIs are controversially discussed, data on unselected patients are rare. It was the aim of the study to compare bivalirudin versus heparin and provisional glycoprotein IIb/IIIa inhibitors (GPIs) in a "real-world" study. METHODS: From 05/2013 until 11/2014, the STEMI-patients in the Bremen STEMI registry were treated with periinterventional bivalirudin; before and after this period the standard anticoagulative treatment was heparin and provisional GPIs. RESULTS: In 714 patients bivalirudin was used for PCI, this cohort was compared to 683 patients with heparin and provisional GPIs. In patients with bivalirudin a significantly lower rate of hospital bleedings was observed compared to patients with heparin (4.6% vs 8.1%, P < 0.01, multivariate HR 0.57, 95%CI 0.35-0.93), in an exclusive analysis of severe bleedings a trend toward less bleedings was found in patients with bivalirudin (2.0% vs 3.5%, P = 0.07, multivariate HR 0.66, 95%CI 0.30-1.42). The rate of stent thromboses reinfarctions and mortality was not different between the bivalirudin and the heparin group. During 1-year follow-up bivalirudin was associated with a lower rate of bleedings and no significant differences in stent thromboses, reinfarctions, and mortality. Bivalirudin was not associated with an excess of bleedings or stent thromboses in subgroups that are regularly underrepresented in randomized trials (older patients, women, cardiogenic shock). CONCLUSIONS: In this "real-world" cohort of patients with STEMI bivalirudin compared to heparin and GPIs was associated with less bleedings and no significant differences in stent thromboses, reinfarctions, and mortality during hospital and long-term course.

Successful treatment with placenta-derived decidual stromal cells in a pediatric patient with life-threatening acute gastrointestinal graft-versus-host disease.

Severe aGvHD is a life-threatening complication after allogeneic HSCT. The GI tract is considered to play a key role in aGvHD, where the disease process can start and is one of the major target organs. Here, we present a case of a one-year-old child with a life-threatening GI-aGvHD stage IV, post-HSCT, resistant to steroids and MMF for 4 weeks. He was successfully treated with placenta-derived DSC.

[Use of a Delphi survey to assess the hospital economic impact of innovative products: The example of idarucizumab a dabigatran-specific reversal agent]. / Utilisation du questionnaire Delphi pour anticiper l'impact économique des innovations thérapeutiques à l'hôpital : application à l'idarucizumab, le nouvel agent de réversion spécifique au dabigatran.

OBJECTIVES: The economic impact of therapeutic innovations on the hospital patient management cannot be easily estimated. The objective of this study is to illustrate the use of a Delphi survey as a support tool to identify the changes following the use of idarucizumab in dabigatran-treated patients with uncontrolled/life-threatening bleeding or who required emergency surgery/urgent procedures. METHODS: The Delphi questionnaires have been administrated to 8 emergency physicians or anesthetists from 6 different hospital centers. Following the answers, an economic valorization has been carried out on every parameter on which a consensus was reached (at least 4 answers showing an identical trend). A mean management cost for each etiology with and without the use of idarucizumab has thus been identified. RESULTS: For gastro-intestinal and other life-threatening bleedings (excepted intracranial bleedings), the total management cost of the hospital stay was respectively 6058 € (-35%) and 6219 € (-34%) following the use of the reversal agent. The hospital management cost for intracranial bleeding is slightly increasing to 9790 € (+3%). The cost of a stay for emergency surgery decreases to 6962€ (-2%). CONCLUSIONS: This study shows a positive economic impact following the use of the dabigatran-specific reversal agent for patients with uncontrolled/life-threatening bleeding excepted in the case of intracranial bleeding. Moreover, it points out that a Delphi survey is an easy way to predict the hospital economic impact of a therapeutic innovation when no other evaluation is possible.

[Renal function in patients receiving long-term warfarin therapy: A five-year prospective follow-up]. / Funktsiia pochek u bol'nykh, dlitel'no prinimaiushchikh varfarin (5-letnee prospektivnoe nabliudenie).

AIM: To investigate the prognostic value of renal function and to estimate glomerular filtration rate (GFR) changes during a 5-year follow-up of patients receiving warfarin therapy. SUBJECTS AND METHODS: 200 patients (124 men, 76 women) mainly from a group at high risk for thromboembolic events (mean CHA2DS2-VASc scores, 3.25±1.89) were examined. The patients' mean age was 62.3±9.4 years; the follow-up period was 5 years. 74% of the patients received warfarin monotherapy (international normalized ratio (INR) 2.0 to 3.0); 36% took vitamin K antagonists in combination with one or two antiplatelet agents. The CKD-EPI formula was used to estimate GFR in all the patients at baseline and throughout the investigation once a year. RESULTS: GFR less than 70.9 ml/min/1.73 m2 was found to be a predictor of fatal and nonfatal thrombotic events. The decreased GFR was unassociated with the development of major and clinically relevant hemorrhagic complications within 5 years of warfarin therapy. The initial decline in renal function (GFR <70.9 ml/min/1.73 m2) was associated only with an increased rate of recurrent minor hemorrhagic complications. During 5-year warfarin therapy, there was a significant decrease in GFR from 97.1±24.85 to 91.9±28.9 ml/min/1.73 m2; at the same time, a rapidly progressive loss of renal function (GFR ≥3 ml/min/1.73 m2/year) was recorded in 25.9% of the patients. Discriminant analysis showed that a baseline left ventricular ejection fraction of <40% was a predictor for the rapidly progressive loss of kidney function. CONCLUSION: Long-term warfarin therapy achieved the therapeutic range for INR is safe in the environment of the created patronage system. The initial decrease in GFR is a predictor of thrombotic events and is unassociated with an increased risk of bleeding.

Risk and Benefits of Triple Therapy in Patients Undergoing Coronary Stent Implantation Requiring Oral Anticoagulation: A Meta-Analysis of 16 Studies.

BACKGROUND: Patients with coronary artery disease who undergo stent implantation and have concomitant indication for long-term oral anticoagulation represent a considerable proportion of the overall population. To date there is still no consensus about the optimal antithrombotic strategy to choose in this kind of patients, due to the difficult balance between an increased risk of bleeding and thromboembolic complications. Therefore, the aim of this study was to perform a meta-analysis to evaluate the risk and benefits of triple antithrombotic therapy versus dual antithrombotic therapy in patients undergoing coronary stent implantation, requiring long-term oral anticoagulation. METHODS: We performed formal searches of PubMed, EMBASE, Cochrane central register of controlled trials and major international scientific session abstracts from January 1990 to September 2015 regarding the use of triple antithrombotic therapy (TT) versus dual therapy (DT) in patients undergoing percutaneous coronary stent implantation that required chronic oral anticoagulation. Data regarding study design, inclusion/exclusion criteria, number of patients, and selected endpoints was extracted by 2 investigators. Disagreements were resolved by consensus. RESULTS: Sixteen trials with a total of 21716 patients undergoing coronary stent implantation with indication to long term oral anticoagulation, were finally included. A total of 6950 received TT, whereas 14766 received DT alone. The follow-up period ranged from 180 to 730 days. Data regarding mortality were available in 21658 patients (99.7 %). All cause mortality was observed in 10.4 % patients in TT versus 16.3 % in DT (OR [95 % CI] =0.73 [0.66-0.80], p <0.001; p het <0.001). In addition, TT was associated with a reduced incidence of MI (6.4 versus 9.8 %, OR [95 % CI] = 0.74 [0.65-0.84], p < 0.001; phet < 0.001) and ischemic stroke (1.8 versus 3.9 %, OR [95 % CI] = 0.55 [0.45-0.68], p < 0.001; p het = 0.07). As expected, TT was associated with a significant increase in major bleeding events (10.8 versus 8.5 %, OR [95 % CI] = 1.38 [1.25-1.53], p < 0.001; p het = 0.02). By meta regression analysis we found that benefits in mortality with TT were inversely related with the risk of bleedings (beta [95 % CI] = 2.25 (1.55; 2.95), p < 0.00001). The benefits with TT regarding overall mortality, recurrent MI and ischemic stroke were also confirmed in a pre-specified analysis versus DAPT or oral anticoagulation in association with a single antiplatelet agent. CONCLUSION: This meta-analysis showed that among patients undergoing coronary stent implantation, requiring chronic OAC, the use of a TT is associated with a significant reduction in overall mortality, recurrent MI and ischemic stroke. As expected, we found a higher incidence of bleedings in patients treated with triple therapy. The benefits in mortality were lost in patients at high-risk for bleedings.

Uric acid and high-residual platelet reactivity in patients treated with clopidogrel or ticagrelor.

BACKGROUND AND AIM: High residual platelet reactivity (HRPR) is still an important challenge, despite the advent of new potent ADP-antagonists. Therefore it is of extreme importance to identify factors that can influence platelet activation. Serum uric acid (SUA) has been largely addressed in the past as a possible risk factor for coronary artery disease, with a possible association with platelets hyperreactivity. So far no studies have assessed the role of serum uric acid on the response to dual antiplatelet therapy. Therefore, the aim of our study was to evaluate the impact of uric acid levels on platelet function in patients treated with dual antiplatelet therapy (DAPT) with clopidogrel or ticagrelor. METHODS AND RESULTS: We scheduled for platelet function assessment at 30-90 days post-discharge patients treated with DAPT (ASA + clopidogrel or ticagrelor) for an ACS or elective percutaneous coronary intervention (PCI). Platelet function was assessed by whole blood impedance aggregometry (Multiplate(®)-Roche Diagnostics AG), HRPR was considered for ASPI test >862 AU(∗)min (for ASA) and ADP test values ≥417 AU* min (for ADP-antagonists). RESULTS: We included a total of 493 patients (262 were on ASA and clopidogrel and 231 on ASA and ticagrelor). Patients were divided according to quartiles of serum uric acid levels measured at the time of platelet aggregation assessment (Group 1 <4.6 mg/dL, n = 114; Group 2, 4.7-5.8 mg/dL, n = 133; Group 3, 5.9-6.8 mg/dL, n = 124; Group 4, >6.9, n = 122). Patients with higher uric acid levels were older, more often smokers, with history of hypertension and previous coronary artery bypass surgery and renal failure and were more often on therapy with diuretics at admission. Patients with higher SUA had higher triglycerides and fibrinogen. Uric acid levels did not influence ASPI, COL, TRAP and ADP tests. High residual platelet reactivity (HRPR) was observed in 1.5% of patients treated with ASA, with no difference according to SUA quartiles (p = 0.60), confirmed at multivariate analysis after correction for baseline confounders (adjusted OR[95%CI] = 1.05 [0.44-2.52], p = 0.90). HRPR for ADP-antagonists was observed in 23.6% of patients, with no difference according to SUA quartiles (p = 0.47); this result was confirmed also after correction for baseline confounders (adjusted OR[95%CI] = 1.04 [0.84-1.28], p = 0.73). Moreover, no association was found between HRPR and uric acid levels both among patients treated with clopidogrel (p = 0.35) or ticagrelor (p = 0.74), that was confirmed after correction for baseline confounding factors (adjusted OR[95%CI] = 1.18 [0.90-1.55], p = 0.23) and (adjusted OR[95%CI] = 0.96 [0.63-1.47], p = 0.85). The absence of association between SUA and platelet reactivity was confirmed at linear regression analysis both with clopidogrel (r = 0.03, p = 0.55) or ticagrelor (r = -0.01, p = 0.85). CONCLUSION: This is the first large study showing that in patients receiving DAPT, uric acid levels do not influence response to ticagrelor and clopidogrel or the effectiveness of ASA.

[Modern Approaches to Prevention of Thromboembolic Complications in Patients With Nonvalvular Atrial Fibrillation With a Direct Thrombin Inhibitor Dabigatran].

RESULTS: of recently completed clinical studies and preliminary results of still ongoing studies that support safety and efficacy of dabigatran in patients with nonvalvular atrial fibrillation are under discussion in this article. Currently available data on clinical use of a specific dabigatran antidote idarucizumab are also presented.