Drug-induced disseminated intravascular coagulation: a pharmacovigilance study on World Health Organization's database.

BACKGROUND: Disseminated intravascular coagulation (DIC) occurs in several clinical conditions, including drug therapy. We aim to investigate the association between the administration of several drug classes and the onset of DIC by using the reports of Adverse Drug Reactions (ADR) collected in Vigibase, the World Health Organization (WHO) database of ADR. METHODS: We collected reports of drug-related DIC from 1968 to September 2015, classified in Vigibase according to the MedDRA (Medical Dictionary for Regulatory Activities) term "Disseminated intravascular coagulation". A disproportionality analysis using Reporting Odds Ratio (ROR) with 95% Confidence Interval (CI95%) was performed. RESULTS: Overall, 4653 reports of drug-associated DIC were retrieved and the 75.9% of them was serious according to WHO seriousness criteria. DIC was significantly (ROR > 1, lower limit of CI95% > 1) associated with 88 drugs, mainly antineoplastic agents, antithrombotic agents and antibacterials for systemic use. Among of the most frequently reported individual drugs we found dabigatran (94 reports) ROR = 1.34 (CI95% 1.08-1.67), oxaliplatin and bevacizumab both with 75 reports and ROR = 1.77 (1.38-2.27) and 2.02 (1.57-2.61), respectively. CONCLUSION: A substantial number of drugs, widely used in the clinical practice, may be associated with the potential occurrence of DIC. For many of these drugs, the ADR is not acknowledged in the corresponding Summary of Product Characteristics. The high number of drugs involved underlines the importance of evaluate this condition such as an ADR that might occur during drug therapy.

Evolving Treatments for Acute Ischemic Stroke.

The purpose of this article is to review advances in stroke treatment in the hyperacute period. With recent evolutions of technology in the fields of imaging, thrombectomy devices, and emergency room workflow management, as well as improvement in statistical methods and study design, there have been ground breaking changes in the treatment of acute ischemic stroke. We describe how stroke presents as a clinical syndrome and how imaging as the most important biomarker will help differentiate between stroke subtypes and treatment eligibility. The evolution of hyperacute treatment has led to the current standard of care: intravenous thrombolysis with tissue-type plasminogen activator and endovascular treatment for proximal vessel occlusion in the anterior cerebral circulation. All patients with acute ischemic stroke are in need of hyperacute secondary prevention because the risk of recurrence is highest closest to the index event. The dominant themes of modern stroke care are the use of neurovascular imaging and speed of diagnosis and treatment.

[Antithrombotic therapy in patients with peripheral artery diseases]. / Antitromboticheskaia terapiia u bol'nykh s zabolevaniiami perifericheskikh arterii.

Complications of cardiovascular diseases whose substrate is atherothrombosis continue to occupy leading positions in the structure of mortality worldwide. Peripheral artery diseases (PAD), in particular, are characterized by an especially unfavourable life prognosis for patients with cardiovascular diseases. In order to decrease the risks of ischaemic complications in patients with PAD, various approaches to antithrombotic therapy have over the last two decades been studied, with the resulting standard of therapy continuing to be acetylsalicylic acid. Even more difficult today is the task of selecting antithrombotic therapy in patients having endured revascularization.

[Antithrombotic therapy after bypass grafting below the inguinal ligament]. / Antitromboticheskaia terapiia posle shuntirovaniia nizhe pakhovoi sviazki.

The importance of antithrombotic therapy following reconstructive operations on arteries below the inguinal ligament is beyond question. The pharmaceutical market offers a wide variety of antiaggregant and anticoagulant agents, with many studies (including randomised and multicenter ones) performed worldwide on the problem of choosing optimal antithrombotic therapy in the postoperative period after arterial reconstructions. Nevertheless, the problem of selecting adequate antithrombotic therapy after shunting operations remains undetermined. Presented in the article is a review of foreign studies on the problem concerned. This is followed by discussing the results of many large international studies, including such trials as the BOA and CASPAR. Based on the findings obtained in these studies, Cochrane reviews, European and American guidelines, the authors express their opinion on the algorithms of choosing an appropriate variant of antithrombotic therapy during the postoperative period in patients after arterial reconstructions below the inguinal ligament.

Anticoagulation for prosthetic heart valves: unresolved questions requiring answers.

PURPOSE OF REVIEW: The efficacy of anticoagulation for valvular prostheses is the result of a delicate balance between the risk of thromboembolic (TE) events and bleeding. Here, we review data on anticoagulation for valve prostheses with a focus on clinical trials that address key unanswered questions. RECENT FINDINGS: There are several unanswered questions in the field of prosthetic valve anticoagulation, including: optimal TE prophylaxis in the short term for bioprostheses, optimal TE prophylaxis following transcatheter aortic valve implantation, the safety and efficacy of lower levels of anticoagulation with the bileaflet mechanical prosthesis, the role of aspirin for patients with mechanical prostheses, and the management of anticoagulation for mechanical valves in pregnancy. Other areas of study include the role, if any, of nonwarfarin oral anticoagulants for prosthetic TE prophylaxis as well as self-INR monitoring. Finally, we briefly mention studies of newer anticoagulants, such as novel vitamin K antagonists and antisense oligonucleotides, that are on the horizon. SUMMARY: Optimal antithrombotic management is a key issue for patients with valvular prostheses, and the publication of recent trials has provided much-needed guidance. We highlight areas of progress, in addition to the major unanswered questions for which well-designed, prospective clinical trials are forthcoming.

Percutaneous Coronary Intervention: 2015 in Review.

In order to keep the interventional community up-to-date with the overwhelming amount of new data, we have selected where we believe to be the most important publications in percutaneous coronary intervention from January 1, 2015 to mid-November 2015. We hope that this will serve as an important overview of 2015, and ongoing reference for future years.

[Thrombolytic therapy for submassive/ intermediate risk Pulmonary Embolism Evidence and suggestions after PEITHO trial]. / Terapia trombolítica en TEP submasivo/riesgo intermedio: Evidencias y sugerencias post estudio Pulmonary Embolism Thrombolysis (PEITHO).

Therapy for submassive pulmonary embolism (intermediate risk), remains controversial. New evidence has appeared that may help us in the process of decision making. We review the relevant literature, outline prognostic factors, and discuss current recommendations and controversies regarding the available alternatives such as systemic and catheter-directed thrombolytic use.

[What physicians think and know about antithrombotic therapy in atrial fibrillation].

We conducted an anonymous survey among 382 physicians (58% internists, 42% cardiologists) in order to obtain information on their opinion on various aspects of antithrombotic therapy in atrial fibrillation. The survey revealed low level of awareness about algorithms of stratification of risks of stroke, systemic embolism, and bleeding. Reported rates of clinical use of recommended antithrombotic agents were: warfarin--30, aspirin monotherapy--19, dabigatran--10, rivaroxaban--8, and combination of aspirin and clopidogrel--8%. Rate of use of drugs without sufficient evidence base in AF was 25%. When asked to designate antithrombotic drug of choice 85% of physicians indicated warfarin and 12%--novel anticoagulants (NOAC). The following factors were considered as limiting wide application of NOAC: high cost (59%), lack of data on these drugs (14%), and impossibility to control safety of their administration (9%).

[Comparison of data from registries of acute coronary syndromes RECORD and RECORD-2: management of patients and its results in noninvasive hospitals].

Positive changes are declared to occur during recent years in management of hospitalized patients with acute coronary syndromes (ACS) in Russia. Most of these changes are related to availability of invasive treatment. But considerable portion of patients (pts) are still treated in hospitals without facilities for invasive myocardial revascularization (noninvasive hospitals - NIHs). Aim of this study was to compare some characteristics of management of ACS in NIHs which participated in ACS registries RECORD (2007-2008, 8 NIHs from 6 cities; n=381) and RECORD-2 (2009-2011, 3 NIHs from 3 cities, n=680). Results. Groups of pts recruited in these NIHs had similar mean age and portion of women (67.6 and 66.5 years, 51.1 and 53.1 % in RECORD-2 and RECORD, respectively, p=0.64). Time from symptoms onset to hospitalization was shorter in RECORD-2 (3.2 vs 4.1 hours for ST-elevation [STE], =0.03; 4.0 vs 6.5 hours for non ST elevation [NSTE] ACS, <0.0001). Among RECORD-2 NSTEACS pts more had ST depressions (50.6 vs 28.7%, <0.0001), high risk of death according to GRACE score (39.1 vs 20.9 %, <0.0001), but less Killip class >II (15.0 vs 21.6%, p=0.025). No such differences existed among STEACS pts. Thrombolysis was more often used in RECORD-2 (62.6 vs 34.1%, <0.0001). Both STEACS and NSTEACS RECORD-2 pts more often received clopidogrel (63.5 vs 18.8%, p<0.0001, and 41.6 vs 11.1%, <0.0001, respectively). More NSTEACS RECORD-2 pts were given parenteral anticoagulants (93.4 vs 80.4%, <0.0001), low molecular weight heparins (23.4 vs. 3.4%, <0.0001) and fondaparinux (10.4 vs 0.7%, <0.0001), but still in 20% of NSTEACS RECORD-2 pts unfractionated heparin was given subcutaneously. Twenty RECORD-2 pts (2.9%) were transferred to invasive hospital but none during first 24 hours. There were no significant differences between registers in hospital mortality (20.0 vs 21.2%, =0.84; 4.2 vs 2.7%, =0.24 in STE and NSTE ACS pts of RECORD-2 and RECORD, respectively). Conclusions. Despite some improvement in management of pts occurring in 2-3 years NIHs mortality in STEACS remained very high. Numerically higher mortality in NSTEACS could be partially attributed to higher risk of RECORD-2 pts.

Impact of type of thrombolytic agent on in-hospital outcomes in ST-segment elevation myocardial infarction patients in the Middle East.

Little is known about the impact of thrombolytic agents on in-hospital outcomes in the Middle East. The objective of this study was to evaluate the impact of thrombolytic agents on in-hospital outcomes in ST-segment elevation myocardial infarction (STEMI) patients in six Middle Eastern countries. Gulf Registry of Acute Coronary Events was a prospective, multinational, multicentre, observational survey of consecutive acute coronary syndrome patients admitted to 65 hospitals in 2006 and 2007. Out of 1,765 STEMI patients admitted to hospitals within 12 h of symptoms onset, 25, 43, and 30% were treated with streptokinase, reteplase, and tenecteplase, respectively. Median age of the study cohort was 50 (45-59) years and majority were males (89%). The overall median symptom onset-to-presentation and median door-to-needle times were 130 min (65-240) and 45 min (30-75), respectively. Streptokinase patients had worse GRACE risk scores compared to patients who received fibrin specific thrombolytics. Academic hospitals and cardiologists as admitting physicians were associated with the use of fibrin specific thrombolytics. After significant covariate adjustment, both reteplase [odds ratio (OR), 0.38; 95% CI: 0.18-0.79; P = 0.009] and tenecteplase (OR, 0.30; 95% CI: 0.12-0.77; P = 0.012) were associated with lower all-cause in-hospital mortality compared with streptokinase. No significant differences in other in-hospital outcomes were noted between the thrombolytic agents. In conclusion, in light of the study's limitations, fibrin specific agents, reteplase and tenecteplase, were associated with lower all-cause in-hospital mortality compared to the non-specific fibrin agent, streptokinase. However, the type of thrombolytic agent used did not influence other in-hospital outcomes.

Eastern Association for the Surgery of Trauma Multicenter Trial: Comparison of pre-injury antithrombotic use and reversal strategies among severe traumatic brain injury patients.

BACKGROUND: Trauma teams are often faced with patients on antithrombotic (AT) drugs, which is challenging when bleeding occurs. We sought to compare the effects of different AT medications on head injury severity and hypothesized that AT reversal would not improve mortality in severe traumatic brain injury (TBI) patients. METHODS: An Eastern Association for the Surgery of Trauma-sponsored prospective, multicentered, observational study of 15 trauma centers was performed. Patient demographics, injury burden, comorbidities, AT agents, and reversal attempts were collected. Outcomes of interest were head injury severity and in-hospital mortality. RESULTS: Analysis was performed on 2,793 patients. The majority of patients were on aspirin (acetylsalicylic acid [ASA], 46.1%). Patients on a platelet chemoreceptor blocker (P2Y12) had the highest mean Injury Severity Score (9.1 ± 8.1). Patients taking P2Y12 inhibitors ± ASA, and ASA-warfarin had the highest head Abbreviated Injury Scale (AIS) mean (1.2 ± 1.6). On risk-adjusted analysis, warfarin-ASA was associated with a higher head AIS (odds ratio [OR], 2.43; 95% confidence interval [CI], 1.34-4.42) after controlling for Injury Severity Score, Charlson Comorbidity Index, initial Glasgow Coma Scale score, and initial systolic blood pressure. Among patients with severe TBI (head AIS score, ≥3) on antiplatelet therapy, reversal with desmopressin (DDAVP) and/or platelet transfusion did not improve survival (82.9% reversal vs. 90.4% none, p = 0.30). In severe TBI patients taking Xa inhibitors who received prothrombin complex concentrate, survival was not improved (84.6% reversal vs. 84.6% none, p = 0.68). With risk adjustment as described previously, mortality was not improved with reversal attempts (antiplatelet agents: OR 0.83; 85% CI, 0.12-5.9 [p = 0.85]; Xa inhibitors: OR, 0.76; 95% CI, 0.12-4.64; p = 0.77). CONCLUSION: Reversal attempts appear to confer no mortality benefit in severe TBI patients on antiplatelet agents or Xa inhibitors. Combination therapy was associated with severity of head injury among patients taking preinjury AT therapy, with ASA-warfarin possessing the greatest risk. LEVEL OF EVIDENCE: Prognostic, level II.

Antithrombotic therapy in patients with atrial fibrillation and acute coronary syndrome undergoing percutaneous coronary intervention; insights from a meta-analysis.

BACKGROUND: The optimal antithrombotic regimen for patients undergoing percutaneous coronary intervention in acute coronary syndrome with concomitant atrial fibrillation is largely under investigation. METHOD: PUBMED and EMBASE were searched through October 2019 for randomized trials or subgroup analyses of randomized trials investigating different antithrombotic strategies in patients with atrial fibrillation and acute coronary syndrome undergoing percutaneous coronary intervention. We compared dual antithrombotic therapy versus triple antithrombotic therapy. Dual antithrombotic therapy was defined as vitamin K antagonist or direct oral anticoagulant plus P2Y12 inhibitor. Triple antithrombotic therapy was defined as vitamin K antagonist or direct oral anticoagulant plus dual antiplatelet therapy (aspirin plus P2Y12 inhibitor). The primary safety outcome was trial outcome was trial defined major adverse cardiovascular events. RESULTS: Our search identified 5 eligible subgroup analyses of randomized controlled trials that enrolled a total of 4733 patients. Dual antithrombotic therapy significantly decreased the bleeding risk when compared with triple antithrombotic therapy (hazard ratio: 0.61; 95% confidential interval [0.51-0.71], P < 0.001, I = 31%). However, there were no significant differences in major adverse cardiovascular event between dual antithrombotic therapy versus triple antithrombotic therapy (hazard ratio: 1.08; 95% confidential interval: 0.89-1.31, P = 0.44, I = 0%). CONCLUSION: In patients with atrial fibrillation and acute coronary syndrome undergoing percutaneous coronary intervention, dual antithrombotic therapy was associated with lower bleeding risk compared with triple antithrombotic therapy while conferring similar major adverse cardiovascular event risk. Our results should be interpreted cautiously because we did not analyze the risk of stent thrombosis.

Bleeding and thrombotic risk in pregnant women with Fontan physiology.

BACKGROUND/OBJECTIVES: Pregnancy may potentiate the inherent hypercoagulability of the Fontan circulation, thereby amplifying adverse events. This study sought to evaluate thrombosis and bleeding risk in pregnant women with a Fontan. METHODS: We performed a retrospective observational cohort study across 13 international centres and recorded data on thrombotic and bleeding events, antithrombotic therapies and pre-pregnancy thrombotic risk factors. RESULTS: We analysed 84 women with Fontan physiology undergoing 108 pregnancies, average gestation 33±5 weeks. The most common antithrombotic therapy in pregnancy was aspirin (ASA, 47 pregnancies (43.5%)). Heparin (unfractionated (UFH) or low molecular weight (LMWH)) was prescribed in 32 pregnancies (30%) and vitamin K antagonist (VKA) in 10 pregnancies (9%). Three pregnancies were complicated by thrombotic events (2.8%). Thirty-eight pregnancies (35%) were complicated by bleeding, of which 5 (13%) were severe. Most bleeds were obstetric, occurring antepartum (45%) and postpartum (42%). The use of therapeutic heparin (OR 15.6, 95% CI 1.88 to 129, p=0.006), VKA (OR 11.7, 95% CI 1.06 to 130, p=0.032) or any combination of anticoagulation medication (OR 13.0, 95% CI 1.13 to 150, p=0.032) were significantly associated with bleeding events, while ASA (OR 5.41, 95% CI 0.73 to 40.4, p=0.067) and prophylactic heparin were not (OR 4.68, 95% CI 0.488 to 44.9, p=0.096). CONCLUSIONS: Current antithrombotic strategies appear effective at attenuating thrombotic risk in pregnant women with a Fontan. However, this comes with high (>30%) bleeding risk, of which 13% are life threatening. Achieving haemostatic balance is challenging in pregnant women with a Fontan, necessitating individualised risk-adjusted counselling and therapeutic approaches that are monitored during the course of pregnancy.

Adverse Effect of Antithrombotic Medications on Bleeding Events and Comparison of Antithrombotic Agents in Hemodialysis Patients.

Antithrombotic medications (AM) are mandatory for many hemodialysis patients, but the bleeding risk associated with this therapy is elevated. The frequency of bleeding events requiring discontinuation of AM, cessation of heparin use, and/or hospitalization was compared between hemodialysis patients with and without AM. All the hemodialysis patients in our clinic were investigated. AM were prescribed in 130 of 222 patients. Except for patients with cilostazol, those with AM had significantly more frequent bleeding events than those without AM (P < 0.01). Bleeding event frequency per 10 000 days of aspirin, clopidogrel, cilostazol, and warfarin prescription was 7.37, 5.95, 2.41, and 9.81, respectively, when restricted to administration of a single AM, which was 4.96, 2.87, 0.7, and 16.06, respectively. In patients without AM, it was 0.91. The bleeding risk associated with AM is elevated in hemodialysis patients and differs markedly depending on the agent used, with the lowest risk associated with cilostazol.

A class of novel nitronyl nitroxide labeling basic and acidic amino acids: synthesis, application for preparing ESR optionally labeling peptides, and bioactivity investigations.

Aimed at optional ESR label 2-(4'-hydroxyl)phenyl-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl was introduced into the guanido of L-Arg-OH, the omega-amino group of L-Lys-OH with methylcarboxyl as a linker, and into the beta-carboxyl of L-Asp-OH and the gamma-carboxyl of L-Glu-OH with ethylamino as a linker. It was explored that the synthetic 30 novel ESR labeling amino acid derivatives were stable enough to the reaction conditions of peptide synthesis. Their incorporation led to 12 novel ESR optionally labeling PAK, RGDS, RGDV, and ECG. A series of NO related chemical tests, the in vitro and in vivo assays of these peptides confirmed that this strategy was practical.

Optimal long-term antithrombotic treatment of patients with stable coronary artery disease and atrial fibrillation: "OLTAT registry".

BACKGROUND: The optimal long-term antithrombotic treatment of patients with stable coronary artery disease (CAD) and atrial fibrillation (AF) is a challenge in daily practice. We sought to determine the prevalence of hemorrhagic complications and ischaemic events depending on antithrombotic strategy in patients with stable CAD and AF. METHODS: The primary outcome was major adverse cardiac and cerebrovascular events (MACCE) defined as a composite of cardiovascular mortality, myocardial infarction and ischaemic stroke. The subsequent risks of MACCE and clinically significant bleedings requiring hospitalisation (major safety outcome) were analyzed in a propensity score-matched analysis by adjusted Cox regression models. RESULTS: Six hundred and six patients with high thrombotic and bleeding risks (mean age 73.4 ±â€¯9.8 years, 25.2% female, CHA2DS2-VASc score:4.7 ±â€¯1.5, and HAS-BLED score:3.1 ±â€¯1.0) were included, and 127 propensity-matched pairs were analyzed. At inclusion, 172 patients (28.4%) were on oral anticoagulation (OAC) alone (75.6% on VKA and 24.4% on DOAC) and 434 patients (71.6%) on OAC + single antiplatelet therapy (SAPT) (71.9% on VKA and 28.1% on DOAC). At 5-year follow-up, MACCE rate did not significantly differ in both groups (30.9% in OAC + SAPT vs. 26.8% in OAC alone; adjusted HR 1.1 [0.8-1.5], p = 0.58), but clinically significant bleedings (28.3% vs. 18.5%; adjusted HR 1.8 [1.2-2.8], p = 0.005) and total deaths (29.5% vs. 20.8%; adjusted HR 1.4 [95% CI 1.0-2.2], p = 0.049) were higher in patients with OAC + SAPT than in patients with OAC alone. CONCLUSIONS: In patients with stable CAD and AF, the addition of antiplatelet therapy to VKA or DOAC therapy was independently associated with a higher risk of bleeding and overall mortality, without significant reduction in cardiac and cerebral ischaemic events.

Antithrombotic therapy for patients with STEMI undergoing primary PCI.

Antithrombotic therapy, including antiplatelet and anticoagulant agents, is the cornerstone of pharmacological treatment to optimize clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Intravenous anticoagulant drugs available for PPCI include the indirect thrombin inhibitors unfractionated heparin and low-molecular-weight heparin, and the direct thrombin inhibitor bivalirudin. Intravenous antiplatelet drugs mainly include glycoprotein IIb/IIIa inhibitors and the P2Y12-receptor inhibitor cangrelor. Dual antiplatelet therapy with aspirin and an oral P2Y12-receptor inhibitor is pivotal for the acute and long-term treatment of patients with STEMI undergoing PPCI. Prasugrel and ticagrelor provide a more prompt, potent, and predictable antiplatelet effect compared with clopidogrel, which translates into better clinical outcomes. Therefore, these agents are the first-line treatment in PPCI. However, patients can still experience adverse ischaemic events, which might be in part attributed to alternative pathways triggering thrombosis. Thrombin has an important role, suggesting the need for strategies directly targeting circulating thrombin or other factors of the coagulation cascade, such as oral anticoagulants (rivaroxaban), and the thrombin receptor on the platelet membrane (vorapaxar). In this Review, we provide an overview of currently available antithrombotic therapies used in patients with STEMI undergoing PPCI, results from pivotal clinical trials and their implications for guidelines, as well as recommendations for clinical practice.

Pharmacogenetics of antithrombotic drugs.

Antithrombotic therapy has improved the prognosis of patients with venous or arterial thrombosis. However, there is substantial interindividual variability in the response to antithrombotic drugs. This variability is due, in part, to genetics, which may affect the efficacy and safety of drugs used in the treatment and prevention of thrombosis. Pharmacogenetics studies the genetic factors related to interindividual variability in the response to drugs. Various polymorphisms in genes of the hemostatic system that have been reported to be markers of susceptibility to thromboembolic disease also seem to be implicated in the response to antithrombotic therapy. These include polymorphisms in platelet receptors (platelet glycoproteins) and coagulation factors (factors II, V, XII, XIII). There is also growing evidence on genetic polymorphisms affecting the metabolism (cytochrome P450), disposition, transporter proteins or cellular receptors of antithrombotic drugs. This review summarizes current knowledge on the pharmacogenetics of antithrombotic therapy, paying special attention to four therapeutic groups: antiplatelet agents, anticoagulants (vitamin K antagonists and heparin), fibrinolytics and other drugs used for the prevention of cardiovascular risk, such as statins and hormone replacement therapy in the menopause. The potential relevance of pharmacogenetics in the future of antithrombotic therapy and the design of clinical trials is also explored.