New Oral Anticoagulants Research Articles

Treatment of Cryptogenic Stroke with Active Cancer with a New Oral Anticoagulant

Low-molecular weight heparin (LMWH) was shown to be effective and safe in treating venous thromboembolism, and generally used for stroke in cancer patients, but its effects on stroke are unclear. We compared clinical outcomes between LMWH and new oral anticoagulant (NOAC) in patients with cancer-related stroke. We enrolled patients with cryptogenic ischemic stroke with active cancer who were treated with LMWH or NOAC between May 2012 and June 2015. The clinical outcomes, including early neurologic deterioration, early radiologic recurrence, 3-month modified Rankin scale score, 90-day mortality, cardio-cerebrovascular recurrence, and bleeding complications, were compared. Among 48 patients, 7 patients were treated with NOAC, and the remaining 41 patients with LMWH. Overall, the participants presented poor outcomes, including 20 (42%) early neurologic deteriorations, 28 (58%) early radiologic recurrences, 34 (71%) poor modified Rankin scale scores, 27 (56%) 90-day mortality events, 24 (50%) cardio-cerebrovascular recurrences, and 18 (38%) bleeding complications, that led to a change or temporary hold in medication in 12 cases. No statistical differences were found between the 2 groups in terms of demographic, clinical, or cardiovascular risk factors and clinical outcomes. NOAC showed the similar clinical outcomes and safety compared with LMWH in the treatment of cryptogenic ischemic stroke in active cancer patients.

Effect of New Oral Anticoagulants on Prescribing Practices for Atrial Fibrillation in Older Adults.

To determine the effect of new oral anticoagulants (NOACs) on prescribing practices in older adults with atrial fibrillation (AF). Retrospective observational cohort study. Academic medical center in St. Louis, Missouri. Individuals aged 75 and older with AF admitted to the hospital from October 2010 through September 2015 (N = 6,568, 50% female, 15% non-white). Information on NOACs and warfarin prescribed at discharge was obtained from hospital discharge summaries, and linear regression was used to examine quarterly trends in their use. Multivariable logistic regression was used to assess independent predictors of anticoagulant use. NOAC use increased over time (correlation coefficient (r) = 0.87, P < .001), warfarin use did not change (r = -0.16, P = .50), and overall anticoagulant use (NOACs and warfarin) increased (r = 0.68, P = .001). NOAC use increased over time in all age groups (75-79, 80-84, 85-89) except aged 90 and older, but increasing age attenuated the rate of NOAC uptake. There was no consistent relationship between age and warfarin or overall anticoagulant use, except that individuals aged 90 and older had consistently lower use. Overall, fewer than 45% of participants were prescribed an anticoagulant. In multivariable analysis, younger age, white race, female sex, higher hemoglobin, higher creatinine clearance, being on a medical service, hypertension, stroke or transient ischemic attack, no history of intracranial hemorrhage, and a modified HAS-BLED score of less than 3 increased the likelihood of receiving NOACs. Prescription of anticoagulants for AF increased in older adults primarily because of an increase in the use of NOACs. Nonetheless, fewer than 45% of participants were prescribed an anticoagulant. Additional research is needed to optimize prescribing practices for older adults with AF.

Comparison of the Effectiveness and Safety of Apixaban, Dabigatran, Rivaroxaban, and Warfarin in Newly Diagnosed Atrial Fibrillation

No studies have performed direct pairwise comparisons of the effectiveness and safety of warfarin and the new oral anticoagulants (NOACs) apixaban, dabigatran, and rivaroxaban. Using 2013 to 2014 claims from a 5% random sample of Medicare beneficiaries, we identified patients newly diagnosed with atrial fibrillation who initiated apixaban, dabigatran, rivaroxaban, warfarin, or no oral anticoagulation therapy in 2013 to 2014. Outcomes included the composite of ischemic stroke, systemic embolism (SE) and death, any bleeding event, gastrointestinal bleeding, intracranial bleeding, and treatment persistence. We constructed Cox proportional hazard models to compare outcomes between each pair of treatment groups. The composite risk of ischemic stroke, SE, and death was lower for NOACs than for warfarin: hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76 to 0.98 for apixaban; 0.73, 95% CI 0.63 to 0.86 for dabigatran; and 0.82, 95% CI 0.75 to 0.89 for rivaroxaban, all compared with warfarin. There were no differences in effectiveness across NOACs. The risk of any bleeding was lower with apixaban than with warfarin, but higher with rivaroxaban than with warfarin. Apixaban (HR 0.69, 95% CI 0.60 to 0.79) and dabigatran (HR 0.79, 95% CI 0.69 to 0.92) were associated with lower bleeding risk than rivaroxaban. Treatment persistence was highest for apixaban (82%), and lowest for dabigatran and warfarin (64%) (p value <0.001). Compared with warfarin, NOACs are more effective in preventing stroke but their risk of bleeding varies, with rivaroxaban having higher risk than warfarin. Altogether, apixaban had the most favorable effectiveness, safety, and persistence profile.

Treatment of cancer-associated venous thromboembolism by new oral anticoagulants: a meta-analysis

Background: The efficacy and safety of newer oral anticoagulants (NOAs) compared to vitamin K antagonist (VKA) in preventing the recurrence of venous thromboembolism (VTE) is well documented. However, it still needs to be determined whether this pattern holds when compared to the combination of low-molecular-weight heparin (LMWH) and VKA in patients with VTE and malignancy. Methods: For this analysis, the authors searched available databases for randomized controlled trials (RCTs) comparing the NOAs with standard treatment (combination of LMWH and VKA) in patients with VTE and those comparing NOAs with LMWH only for prevention of VTE. All these RCTs included small proportion of patients with cancer. The authors then assessed the pooled treatment effects of VTE recurrence, as well as major and non-major clinically relevant bleeding in the two groups. Results: Twelve studies met our inclusion criteria, yielding 2,054 patients. Five studies with rivaroxaban, three each with dabigatran and apixaban, and one with edoxaban compared NOAs with standard treatment. There was a non-significant reduction in VTE recurrence by the NOAs (3.95%) compared to standard treatment (5.62%) [risk ratio (RR) =0.68; 95% confidence interval (CI) =0.42–1.10; P=0.12]. The major bleeding rate with NOAs was (2.62%) compared to the corresponding rate for standard treatment (3.75%) (RR =0.66; 95% CI =0.36–1.20; P=0.17). The non-major clinically relevant bleeding rate with NOAs was (12.82%) compared to the rate for standard treatment (15.52%) (RR =0.85; 95% CI =0.65–1.10; P= 0.22). However, compared to LMWH only, both higher major (RR =2.18; 95% CI =0.32–14.80; P=0.42) and non-major clinically relevant (RR =2.39; 95% CI =0.75–7.56; P=0.14) bleeding rates were noted with NOAs use in acutely-ill hospitalized patients. Conclusions: NOAs seem to be comparable to standard treatment in both their efficacy and safety in patients with VTE and malignancy. However, increased rates of bleeding were observed with their use compared to LMWH use in acutely-ill hospitalized patients.

Risk analysis of new oral anticoagulants for gastrointestinal bleeding and intracranial hemorrhage in atrial fibrillation patients: a systematic review and network meta-analysis.

Antithrombotic therapy using new oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) has been generally shown to have a favorable risk-benefit profile. Since there has been dispute about the risks of gastrointestinal bleeding (GIB) and intracranial hemorrhage (ICH), we sought to conduct a systematic review and network meta-analysis using Bayesian inference to analyze the risks of GIB and ICH in AF patients taking NOACs. We analyzed data from 20 randomized controlled trials of 91 671 AF patients receiving anticoagulants, antiplatelet drugs, or placebo. Bayesian network meta-analysis of two different evidence networks was performed using a binomial likelihood model, based on a network in which different agents (and doses) were treated as separate nodes. Odds ratios (ORs) and 95% confidence intervals (CIs) were modeled using Markov chain Monte Carlo methods. Indirect comparisons with the Bayesian model confirmed that aspirin+clopidogrel significantly increased the risk of GIB in AF patients compared to the placebo (OR 0.33, 95% CI 0.01-0.92). Warfarin was identified as greatly increasing the risk of ICH compared to edoxaban 30 mg (OR 3.42, 95% CI 1.22-7.24) and dabigatran 110 mg (OR 3.56, 95% CI 1.10-8.45). We further ranked the NOACs for the lowest risk of GIB (apixaban 5 mg) and ICH (apixaban 5 mg, dabigatran 110 mg, and edoxaban 30 mg). Bayesian network meta-analysis of treatment of non-valvular AF patients with anticoagulants suggested that NOACs do not increase risks of GIB and/or ICH, compared to each other.

Bezdzietna kobieta w wieku 21 lat z zatorowością płucną — leczenie w dobie nowych doustnych antykoagulantów

Zatorowość płucna (PE) jest stanem nagłym wymagającym szybkiej diagnostyki i niezwłocznego wdrożenia terapii. Podstawowym leczeniem PE są leki przeciwkrzepliwe — zarówno podawane parenteralnie, jak i doustnie. W leczeniu początkowym stosuje się heparyny (frakcjonowane lub drobnocząsteczkowe), a następnie leki doustne. Coraz częściej leczenie jest kontynuowane nowymi doustnymi antykoagulantami (NOAC), które skutecznością dorównują antagonistom witaminy K, a nie wymagają monitorowania międzynarodowego współczynnika znormalizowanego. Obecnie, ze względu na brak randomizowanych badań, nie zaleca się stosowania NOAC u kobiet w ciąży. W niniejszej pracy autorki zastanawiają się nad wyborem sposobu leczenia u młodej bezdzietnej kobiety w wieku rozrodczym z rozpoznaną PE.

Geographic Variation in the Use of Oral Anticoagulation Therapy in Stroke Prevention in Atrial Fibrillation.

Underuse of oral anticoagulation in stroke prevention in atrial fibrillation is common; however, it remains unknown how it varies geographically. The objective of this study was to evaluate geographic variation in oral anticoagulation use and in the initiation of new oral anticoagulants (NOACs). Using 2013 to 2014 claims data from a 5% random sample of Medicare beneficiaries, we identified patients newly diagnosed with atrial fibrillation who initiated NOACs (n=8659), warfarin (n=11 771) or no oral anticoagulation therapy (n=18 226) in 2013 to 2014. Each patient was assigned to 1 of the 306 Dartmouth hospital-referral regions based on his/her zip code. We constructed logistic regressions to calculate the mean adjusted probability of initiating oral anticoagulation and the mean adjusted probability of initiating an NOAC among patients on oral anticoagulation in each hospital-referral region, after adjustment for demographic, clinical, and provider characteristics and type of insurance. Finally, we computed the correlation between 2 probabilities. Higher in the Midwest (0.54) and Northeast (0.54) and lowest in the South (0.47), the mean adjusted probability of initiating oral anticoagulation was 0.51, ranging from 0.32 to 0.72. The mean adjusted probability of being prescribed an NOAC among those on oral anticoagulation was 0.42 and was highest in the South (0.50) and lowest in the Midwest (0.36) and Northeast (0.39). In areas with the lower use of oral anticoagulation, patients on any oral anticoagulation therapy had a higher likelihood of being prescribed an NOAC (correlation coefficient, -0.16; P=0.006). Large geographic variation exists in oral anticoagulation use in atrial fibrillation. The use of oral anticoagulation is lower in the South, where the rates of stroke are unusually high. In the future, it will be important to analyze whether the high rates of stroke in the South can be partially attributed to the underuse of oral anticoagulation in this region.

37 Thromboembolic events in left ventricular endocardial pacing: long-term outcomes from a multicentre uk registry

Background Endocardial left ventricular (LV) pacing is an effective alternative in patients with failed coronary sinus lead. However, the major concern is the unknown long-term thromboembolic risk and much of the data has come from a small number of centres. We examined the safety and efficacy of endocardial LV pacing across 4 UK centres, to determine the long-term thromboembolic risk. Methods and Results Independent prospective registries from four UK centres were combied to include 68 consecutive patients from 2010–2015. Medical records were reviewed and patients were contacted for follow-up. Thromboembolic events were confirmed on imaging. Baseline patient demographics are shown in Table 1. 65% patients were already anticoagulated (39 AF, 1 DVT, 2 prosthetic valve, 2 previous LV thrombus). Mean CHADS2VASC2 score for the cohort was 3.5. 44% patients had trans-ventricular LV lead. The mean procedure and fluoroscopy times were 200±120 and 32±28 min. 75% had a silicone-insulated pacing lead. Post-procedure, three patients had haematomas and one had tamponade requiring pericardial drain. Functional improvement was noted with decrease in mean NYHA from 3.5±1 to 2.1±1.2 (p=0.001) and increase in LVEF from 26.5±12 to 34±18.1 (p=0.005) over a 20 month follow-up. Re-do procedure due to lead displacement was required in two patients. One patient underwent system extraction and surgical epicardial lead after device infection. The ischaemic stroke rate, defined as transient or permanent loss of function associated with imaging confirmation of a cerebral infarct in the appropriate territory, occurred in 4 patients (6%) providing an annual event rate of 3.6%. In multivariate analyses, the only significant correlation with the risk of CVA was sub-therapeutic INRs (p Conclusion Endocardial LV lead in heart failure patients has a good success rate at 1.6 year follow-up. However, it is associated with a modest thromboembolic risk largely due to sub-therapeutic anticoagulation. These results have potential for improvement and newer oral anticoagulants might play a role in this setting.

New Oral Anaticoagulant Prescribing Decisions amongst General Practitioners: Handle with Care.

Background: Prescribing oral anticoagulants for atrial fibrillation patients is becoming more challenging as more alternatives enter the market. While warfarin has dominated the market it is a challenging medicine to use owing to its narrow therapeutic range, increased bleeding risk and requirement for continuous monitoring. The introduction of new oral anticoagulants (NOACs) offers a wider choice but they are more costly and their use also brings additional pharmacological considerations. Objective: This paper investigates if the identified risk factors (renal impairment, hepatic impairment, other co-morbidities & drug interactions) influence GPs' NOAC prescribing decisions, using a multivariate probit model, while controlling for other GP characteristics. Methods: Employing primary data, collected using a dedicated survey of Irish GPs in November 2015, a multivariate probit is employed. This measures the joint decision making process of prescribing a NOAC based on four risk factors - renal impairment, hepatic impairment, other comorbidities and drug interactions. Results: Younger GPs are more likely to consider 'other co-morbidities' and 'renal impairment' as important when making NOAC prescribing decisions. Male GPs are more likely to consider 'other co-morbidities' and 'drug interactions' as important when prescribing NOACs compared to female GPs. Prescribers who have initiated NOACs are more likely to consider 'renal impairment' as important compared with non-initiators. Conclusions: Our study highlights the importance for general practitioners prescribing NOACs and caring for patients on oral anticoagulants, of adequate education, of appropriate patient selection and of appropriate monitoring of such patients. While warfarin prescribing remains predominant, NOAC prescribing is increasing. Incorporating the risk factors into prescribing decisions signals responsible prescribing for atrial fibrillation patients. Existing prescribing guidelines/toolkits need to be used in an effective manner.

Cancer associated thrombosis in patients taking direct oral anticoagulants (DOACs): Retrospective review of a single institutional series.

e14080 Background: Venous thromboembolism (VTE) is a common and often serious complication for patients with malignancy. Even though low molecular weight heparin (LMWH) is recommended as first line therapy for initial and long term anticoagulation, patient choice may demand oral anticoagulants. This retrospective review illustrates the repeated observation of recurrent thromboembolic disease in patients taking the new class of oral anticoagulant, DOAC. Methods: The pharmacy database at our institution was searched to identify oncology patients who had received a prescription for a DOAC (rivaroxaban or apixiban). Sixtyfive patients were identified and case records were then examined for evidence of venous thromboembolism. Results: Five seperate episodes of recurrent venous thromboembolism were identified in four patients in our cohort., one patient having two seperate episodes of pulmonary embolus. All were on recommended therapeutic doses of DOAC at the time of thromboembolic event. Two patients experienced proven pulmonary embolus on CT pulmonary angiography (1 twice), one lower limb deep vein thrombosis and one upper limb deep vein thrombosis. Conclusions: This retrosepctive review reinforces the clinical guidelines stated by the Cochrane review and ASCO that LMWH should always be first line for the initial and continuation treatment of a VTE. The guidelines did not focus on the suboptimal anticoagulation aspect of the newer oral anticoagulants but more on the safety issues. Research has been mainly focused on comparing LMWH with unfractionated heparin (UFH) or oral warfarin. Comparisons between DOAC versus Warfarin as an oral form of therapy have also been made. In the available published literature, there is a paucity of research comparing DOACs to LMWH. We have identified four patients out of sixtyfive treated with therapeutic doses of DOAC who developed subsequent thromboembolism. This is additional supportive evidence that newer oral anticoagulant agents may not be efficacious in malignancy driven VTE and that LMWH should remain the standard of care. Patients specifically requesting DOAC for cancer associated VTE should be made aware of this data.

ANMCO Position Paper: the use of non-vitamin K dependent new oral anticoagulant(s) in pulmonary embolism therapy and prevention.

The new oral anticoagulants (NOACs) have radically changed the approach to the treatment and prevention of thromboembolic pulmonary embolism. The authors of this position paper face, in succession, issues concerning NOACs, including (i) their mechanism of action, pharmacodynamics, and pharmacokinetics; (ii) the use in the acute phase with the ‘double drug single dose’ approach or with ‘single drug double dose’; (iii) the use in the extended phase with demonstrated efficacy and with low incidence of bleeding events; (iv) the encouraging use of NOACs in particular subgroups of patients such as those with cancer, the ones under- or overweight, with renal insufficiency (creatinine clearance > 30 mL/min), the elderly (>75 years); (v) they propose a possible laboratory clinical pathway for follow-up; and (vi) carry out an examination on the main drug interactions, their potential bleeding risk, and the way to deal with some bleeding complications. The authors conclude that the use of NOACs both in the acute phase and in the extended phase is equally effective to conventional therapy and associated with fewer major bleeding events, which make their use in patients at higher risk of recurrences safer.

Time in the Therapeutic Range for Patients Taking Warfarin in Clinical Trials: Useful, but Also Misleading, Misused, and Overinterpreted.

The time in the therapeutic range (an international normalized ratio [INR] between 2.0 and 3.0) (TTR) has been used as a measure of warfarin (W) therapy quality. Although generally useful in clinical care and better than other alternatives, in recent new oral anticoagulant (NOAC) versus W trials in atrial fibrillation (AF), its utility has been overvalued. TTRs have typically been assessed by the Rosendaal method1 (± variable alterations, such as including versus excluding the first 7 days on W and after stopping W), where the INR is assumed to change linearly from the last INR until the INR at next check. TTR indicates the days with INRs of 2.0 to 3.0 over total day counts using these integrated numbers. But, if an INR is 3.0, and time between checks is long (weeks), the calculated TTR will be falsely low. In real life, if a measured INR is out of range, the W dose is changed and within days the INR has increased. On average, it takes 3 days for W’s effect to reach a stable value when W concentrations are constant.2 For example, if W dosing were changed the day a physician learned an INR was 1.5, but an INR was not rechecked for a month, the INR would rise within days but, per Rosendaal, it would only slowly increase to the value at next check a month later (see Figure). Thus, if INR-recheck frequency differs, Rosendaal …

EVALUATION OF NEW ORAL ANTICOAGULENTS IN MANAGEMENT OF DEEP VEIN THROMBOSIS

Background: Low molecular weight heparin (LMWH) and vitamin K antagonists (VKAs) have been considered the first line option for the prevention and treatment of venous thromboembolism (VTE) for several yearsafter decades during which warfarin was the only oral anticoagulation option; newer anticoagulants have the potential to change the management of coagulation disorders. The new oral anticoagulants (NOACs) differ from VKAs in their action mechanism because of direct inhibition of proteins of the coagulation cascade. They have more predictable pharmacokinetics leading to fixed and convenient dosing regimens and no need for routine monitoring, as well as in a rapid onset of action, and importantly, high efficacy and low risk of bleeding. Some of their limitations are the higher cost, limited monitoring (if needed, as only qualitative measures available) and the lack of a specific antidote. Objectives: To evaluate the efficacy and side effects of the new groups of oral anticoagulants in comparison to traditional oral anticoagulants in management of deep vein thrombosis. Patient and methods: This work was done over 50 patients, divided into 2 equal groups: Group I received oral rivaroxaban for 3 months, and group II received warfarin guided with INR measurement for 3 months. The following was done for all patients: Complete blood count, coagulation profile, liverfunction tests, kidney function tests and duplex scan. Results: Rivaroxaban (group I) included 9 males and 16 females with a mean age of 37.6 (27-60), and a mean body weight of 83.7± 16.3. Warfarin group II included 7 males and 18 females with a mean age of 37.9 (27-52), and a mean body weight of 84.2± 13. The main symptoms of our patients were leg pain in 86%, leg swelling in 78%, tenderness in 74%, redness/warmth in the leg in 34%, the main risk factors for DVT were hormonal contraceptive in 44%, immobilizations in 34%, hypercoagulability in 30%, operative history in 24%, history of orthopedic surgery in 22%, old age in 8%, with no statistical significant differences between the 2 arms of the study. Conclusion: Rivaroxaban have the advantage of more predictable anticoagulation, fewer drug interactions, and vascular outcomes compared with warfarin. New oral anticoagulants have shown to have a favorable balance between efficacy and safety compared with warfarin because recanalization occurred, with high percentage in new oral anticoagulants more than warfarin. Rivaroxaban has a rapid onset of anticoagulant that can be given in fixed doses without routine monitoring.

The role of new oral anticoagulants in orthopaedics: an update of recent evidence.

Rivaroxaban, dabigatran, apixaban and edoxaban are the four available new oral anticoagulants (NOAC) which are currently approved for venous thromboembolism prophylaxis after total hip and knee replacement. Large phase 3 and phase 4 studies comparing NOAC with low molecular weight heparins have shown similar results regarding the efficacy and safety of these two categories of anticoagulants. Management of bleeding complications is a matter of great significance. Three reversal agents have been developed: idarucizumab, andexanet alfa and ciraparantag. Idarucizumab is now commercially available. Regarding the perioperative management of NOAC, two main scientific groups have published their own recommendations. The European Heart Rhythm Association recommends 48-h period of stoppage preoperatively for factor Xa inhibitors and at least 3 or 4days for dabigatran, while the French Study Group on Thrombosis and Haemostasis recommends 5-day discontinuation for all NOAC. Conventional clot tests can only be used as rough indicators for laboratory assessment of the activity of NOAC. Specific laboratory tests have been developed for more accurate measurements of NOAC blood levels, including a dilute thrombin time test (Hemoclot test) and the ecarin clot test for dabigatran and chromogenic anti-factor Xa assays for direct factor Xa inhibitors. Due to the beneficial properties of NOAC, these drugs are gaining ground in daily orthopaedic practice, and many studies are being conducted in order to extend the indications of these anticoagulants agents.

The cost savings of newer oral anticoagulants in atrial fibrillation-related stroke prevention

Newer oral anticoagulants (NOACs) are considered as better alternatives compared to warfarin for stroke prevention in atrial fibrillation (AF) in terms of clinical effectiveness although the drug acquisition cost is more substantial. This study determined the direct stroke costs based on inpatient hospitalization in a subgroup of the National Health Service (NHS) Grampian, Scotland, stroke patients, to evaluate the differences in costs related to AF stroke, and to ascertain whether the use of NOACs within this study population would produce greater cost savings. Hospitalization records over 5 years involving 3,601 stroke patients were analyzed. Direct costs were based on the costs of inpatient length of stay per day. The potential cost savings if AF patients had been on NOACs were estimated using efficacy data from a landmark clinical trial involving rivaroxaban. Out of the total stroke cases, 29.5% of total stroke cases were secondary to AF, and these cases were more severe with longer hospitalizations. Only 254 patients (39.4%) with confirmed AF were anticoagulated with warfarin prior to admission. AF patients incurred higher median costs (£4,719 (interquartile range (IQR) £1,815-£12,452) compared to non-AF patients (£3,267 (IQR £1,175-£11,368)), although the association was statistically insignificant. The use of NOACs in AF-related patients with ischemic strokes would potentially prevent more strokes (leading to 58 fewer cases in comparison to warfarin), resulting in 17.1% in total cost reduction. AF stroke patients incurred higher total direct costs compared to non-AF cases. However, more cost savings were evident with NOACs, due to more strokes being prevented through the use of NOACs compared to warfarin. .

Post-operative Bleeding Risk in Dental Surgery for Patients on Oral Anticoagulant Therapy: A Meta-analysis of Observational Studies.

Background and Objective: Minor dental surgery is invasive and hemorrhagic. Thus, in patients treated with anticoagulants, the bleeding risk related to these invasive procedures is concerning. The aim of this meta-analysis is to evaluate this risk by comparing the post-operative bleeding rates of oral anticoagulation treatment (OAT) patients (without interrupted or altered anticoagulant intake) with non-OAT patients.Methods: PubMed, Embase and the Cochrane Library were searched for eligible studies that compared the post-operative (following minor dental surgery) bleeding rates of OAT patients without interrupted or altered therapy with those of non-OAT patients. Relative risk (RR) and 95% confidence interval (CI) were calculated. Subgroup analyses were used to identify the association between the bleeding rate and different dental surgeries or anticoagulants.Results: Thirty two full text articles were assessed for eligibility and 20 studies were excluded according to the selection criteria. Finally, 12 studies and a total of 2102 OAT patients and 2271 non-OAT patients were included. A pooled analysis indicated that the post-operative bleeding risk in OAT patients is higher than that of non-OAT patients (RR: 2.794, 95% CI: 1.722–4.532, P = 0.000). The pooled RRs in the dental implant surgery and dental extraction subgroups were 2.136 (95% CI: 0.825–5.531, P = 0.118) and 2.003 (95% CI: 0.987–4.063, P = 0.054), respectively. As for the different oral anticoagulants, the pooled RR in the subgroup of new oral anticoagulants (NOACs) was 1.603 (95% CI: 0.430–5.980, P = 0.482), while the pooled RR in the vitamin K antagonists subgroup was 3.067 (95% CI: 1.838–5.118, P = 0.000).Conclusion: Under current evidence, OAT patients were under a higher post-operative bleeding risk than the non-OAT patients following minor dental surgery. For the dental implant surgeries and dental extractions, our study failed to demonstrate a higher risk of bleeding in the OAT patients compared with the non-OAT patients. Besides, The NOACs might be safer than the vitamin K antagonists in dental implant surgery. However, more well-designed studies are required for future research.

The importance of defining methodology for post-marketing observational studies on cardiovascular therapies

In recent years, a growing number of observational studies in cardiology have been carried out following the criticism that rigid design of randomized clinical trials produces information that is not applicable to the general patient. This approach is very common in several branches of medicine, first of all oncology, but has often been considered marginal in cardiology. The recent introduction of new oral anticoagulants (NOACs) on the market, however, has seen a proliferation of "real-life" studies, drawing the attention of cardiologists to the advantages and limitations of post-marketing studies. NOACs have been approved for use on the basis of large randomized clinical trials that have clearly documented their efficacy and safety. Since they have become available, the analysis of phase IV data has been considered crucial and therefore a great amount of information on the use of NOACs in daily practice has become available. It should be considered, however, that the possibility exists that results obtained from "real-world" studies, which do not apply rigid scientific criteria, may lead to incorrect conclusions. Accordingly, it is mandatory to fully define the operational standards of observational studies. All the protagonists of post-marketing analysis (physicians, epidemiologists, pharmacologists, statisticians) should handle the data strictly in order to ensure their reliability and comparability with other studies. To this end, it is crucial that researchers follow rigorous operational protocols for phase IV studies. Briefly, any "real-life" study should be prospective and adhere to what is prespecified by the research protocol - which must illustrate the background and rationale of the study, define its primary endpoint, and detail the methods, i.e. study design, population and variables.

Developments of Anticoagulants and New Agents with Anti-Coagulant Effects in Deep Vein Thrombosis.

Deep Vein Thrombosis (DVT) has been known as a common medical problem all over the world. Thrombus traveling in blood vessels may lead to pulmonary embolism (PE), associated with high rates of mortality. Anticoagulant therapy is the mainstay treatment of DVT. Common anticoagulants, Vitamin K antagonists (VKAs), unfractionated heparin (UFH) and Low-molecular-weight heparin (LMWH) have been used in clinical application over decades, but can increase the risk of hemorrhage. Thereby, several new oral anticoagulants (NOACs) have been developed, which includes direct thrombin inhibitors (DTI) and direct factor Xa inhibitors. To be contrast with VKAs and UFH, NOACs have many advantages such as rapid offset action, few drug/food interactions and no need for routine coagulation monitoring, etc. Many NOACs are still being evaluated in Phase III clinical trials such as Betrixaban and Darexaban (YM150). However, NOACs still have problems to be solved such as lack of antidotes and laboratory monitoring, high drug costs, etc. Besides, several agents have already shown the potential to be new anticoagulants. Factor Xa play an important role in thrombin generation and coagulation pathway. Thus, the new compounds directly targeting on factor Xa for prevention DVT are highly anticipated. DPC423, a new series of 6-substituted coumarin derivatives and Phenyltriazolinones as potent factor Xa inhibitors have been recently reported. Recent studies revealed that agents extracted from botanicals not only have anti-coagulant effects but also possess other pharmacological activities such as anti-inflammation to alleviate the post-thrombotic syndromes. All the evidence above suggests that many new compounds might have great potential to be more effective and safe oral anticoagulants.

New oral anticoagulants-TURKey (NOAC-TURK): Multicenter cross-sectional study.

Objective:New oral anticoagulants (NOACs) are increasingly used both for prevention of stroke in non-valvular atrial fibrillation (NVAF) and the treatment of venous thromboembolism (VTE). In this study, we aimed to evaluate the current patterns of NOACs treatment in Turkey. Moreover, demographic and clinical parameters and bleeding and/or embolic events under NOACs treatment were analyzed.Methods:The New Oral Anticoagulants-TURKey (NOAC-TURK) study was designed as a multicenter cross-sectional study. A total of 2,862 patients from 21 different centers of Turkey under the treatment of NOACs for at least three months were included in this study. Demographic, clinical, and laboratory characteristics of study participants with their medications used were obtained through the NOAC-TURK survey database. Additional necessary medical records were obtained from electronic health records of participating centers.Results:Of the 2. 862 patients, 1.131 (39.5%) were male and the mean age was 70.3±10.2 years. Hypertension was found as the most frequent comorbidity (81%). The most common indication for NOACs was permanent atrial fibrillation (83.3%). NOACs were mainly preferred because of inadequate therapeutic range or overdose during warfarin usage. The most frequent complication was bleeding (n=217, 7.6%), and major bleeding was observed in 1.1% of the patients. Embolic events were observed in 37 patients (1.3%). Rivaroxaban and dabigatran were both more preferred than apixaban. Almost half of the patients (47.6%) were using lower doses of NOACs, which is definitely much more than expected.Conclusion:The NOAC-TURK study showed an important overview of the current NOACs treatment regimens in Turkey. Although embolic and bleeding complications were lower than or similar to previous studies, increased utilization of low-dose NOACs in this study should be considered carefully. According to the results of this study, NOACs treatment should be guided through CHA2DS2-VASc and HASBLED scores to ensure more benefit and less adverse effects in NVAF patients.

DRUG INTERACTIONS OF NEW ORAL ANTICOAGULANTS: INSIDE AND OUTSIDE TABLE CELLS

The opinion is expressed in some domestic publications that rivaroxaban has the most favorable profile of drug interaction in comparison with other new oral anticoagulants (NOAC). The basis for such judgments is the summary table of drug interaction from the Guidelines of the European Heart Rhythm Association 2015 on the use of NOAC in patients with non-valvular atrial fibrillation. The paper discusses the issue that the abovementioned table contains some incorrect qualitative statements and quantitative data inconsistent with primary source of information of NOAC drug interactions, and provides the updated and extended information on changes in NOAC plasma concentrations when co-administered with drugs from the other groups. On the basis of the presented data, the authors come to the conclusion that the profile of drug interaction of rivaroxaban does not differ significantly from these of the other NOAC.