Carlos Martinez

Therapy persistence in newly diagnosed non-valvular atrial fibrillation treated with warfarin or NOAC. A cohort study.

Efforts to reduce stroke in atrial fibrillation (AF) have focused on increasing physician adherence to oral anticoagulant (OAC) guidelines, but high early vitamin K antagonist (VKA) discontinuation is a limitation. We compared persistence of non-VKA OAC (NOAC) with VKA treatment in the first year after OAC inception for incident AF in real-world practice. We studied 27,514 anticoagulant-naïve patients with incident non-valvular AF between January 2011 and May 2014 in the UK primary care Clinical Practice Research Datalink, with full medication use linkage: mean age 74.2 ± 12.4, 45.7% female, mean follow-up 1.9 ± 1.1 years. After treatment initiation and follow-up until 1/2015, the proportion remaining on OAC at one year (persistence) was estimated using competing risk survival analyses. OAC was commenced ≤ 90 days after incident AF in 13,221 patients (48.1%): 12,307 VKA and 914 NOAC (apixaban, dabigatran, rivaroxaban). Amongst those treated with OAC, the proportion commencing NOAC increased from zero in 1/2011 to 27.0% in 5/2014, and OAC prescriptions for CHA2DS2VASc score ≥ 2 (guideline adherence) increased from 41.2% to 65.5%. Persistence with OAC declined over 12 months to 63.6% for VKA and 79.2% for NOAC (p< 0.0001). Persistence for those with CHA2DS2VASc ≥ 2 was significantly greater for NOAC (83.0%) than VKA (65.3%, p< 0.0001) at one year and all earlier time points. Comparison of VKA and NOAC cohorts matched on individual CHA2DS2VASc components showed consistent results. In conclusion, persistence was significantly higher with NOAC than VKA, and could alone lead to fewer cardioembolic strokes. Increased guideline adherence following NOAC introduction could further decrease AF stroke burden.

Epidemiology of first and recurrent venous thromboembolism: A population-based cohort study in patients without active cancer

Contemporary data from population studies on the incidence and complications of venous thromboembolism (VTE) are limited. An observational cohort study was undertaken to estimate the incidence of first and recurrent VTE. The cohort was identified from all patients in the UK Clinical Practice Research Datalink (CPRD) with additional linked information on hospitalisation and cause of death. Between 2001 and 2011, patients with first VTE were identified and the subset without active cancer-related VTE observed for up to 10 years for recurrent VTE. The 10-year cumulative incidence rates (CIR) were derived with adjustment for mortality as a competing risk event. A total of 35,373 first VTE events (12,073 provoked, 16,708 unprovoked and 6592 active cancer-associated VTE) among 26.9 million person-years of observation were identified. The overall incidence rate (IR) of VTE was 131.5 (95% CI, 130.2-132.9) per 100,000 person-years and 107.0 (95% CI, 105.8-108.2) after excluding cancer-associated VTE. DVT was more common in the young and PE was more common in the elderly. VTE recurrence occurred in 3671 (CIR 25.2%). The IR for recurrence peaked in the first six months at around 11 per 100 person years. It levelled out after three years and then remained at around 2 per 100 person years from year 4-10 of follow-up. The IRs for recurrences were particularly high in young men. In conclusion, VTE is common and associated with high recurrence rates. Effort is required to prevent VTE and to reduce recurrences.

Adverse prognosis of incidentally detected ambulatory atrial fibrillation

It was the aim of this study to determine prognosis of incidentally detected ambulatory atrial fibrillation (IA-AF) and its response to antithrombotic therapy. We performed a cohort study of 5,555 patients with IA-AF (mean age 70.9 ± 10.1, 38.4% female) and 24,705 age- and gender-matched controls without AF followed three years using UK Clinical Practice Research Datalink. We measured incidence rates of stroke, all-cause mortality, myocardial infarction, major bleeding, and effect of antithrombotic therapy. Patients with IA-AF had mean CHA2DS2VASc score 2.5 ± 1.5, 73% with score ≥2. The stroke incidence rate (IR) was 19.4 (95% confidence interval 17.1 - 21.9)/1,000 person-years vs 8.4 (7.7 - 9.1) in controls (p<0.001), mortality 40.1 (36.8 - 43.6)/1,000 person-years vs 20.9 (19.8 - 22.0) in controls (p<0.001), and myocardial infarction 9.0 (7.5 - 10.8)/1,000 person-years vs 6.5 (5.9 - 7.2) in controls (p<0.001). IRs of all endpoints increased with age. Oral anticoagulant ± antiplatelet therapy received by 51.0% in year following IA-AF was associated with adjusted hazard ratio (HR) of 0.35 (0.17 - 0.71) for stroke, and 0.56 (0.36 - 0.85) for death compared to no therapy, while antiplatelet treatment was associated with a non-significant reduction of HR: 0.81 (0.51 - 1.29) for stroke, and 0.80 (0.55 - 1.15) for death, though both carried a similar small non-significant adjusted excess IR of major bleeding. In conclusion, asymptomatic AF detected incidentally is associated with a significant adverse effect on stroke and death, with reduction in both associated with oral anticoagulant but not antiplatelet treatment. This provides justification to assess cost-effectiveness of community screening to detect unknown AF.

Cardiovascular Risk Factors in Vegetarians: Normalization of Hyperhomocysteinemia with Vitamin B12 and Reduction of Platelet Aggregation with n-3 Fatty Acids

Hyperhomocysteinemia in association with vitamin B12 deficiency, and increased platelet aggregation, probably due to dietary lack of n-3 fatty acids, constitute cardiovascular risk factors frequently observed in vegetarians. We tested if administration of vitamin B12 normalizes the concentration of total plasma homocysteine, and if intake of eicosapentaenoic (20:5n-3) and docosahexaenoic (22:6n-3) fatty acids modulates platelet function in a population of lactoovovegetarians. One week after a single intramuscular injection of cyanocobalamin (10000 μg) in 18 individuals, serum vitamin B12 increased from 149±63 pg/mL to 532±204 pg/mL (p<0.0001) and total tHcy dropped from 12.4±4.7 to 7.9±3.1 μmol/L (p<0.0001). Ten of fourteen of these vegetarians completed an 8-week supplementation with 700 mg/day of each eicosapentaenoic and docosahexaenoic acids. Increased incorporation of these fatty acids into plasma lipids was observed in all of them, together with a significant reduction in maximum percentage or slope of platelet aggregation with all the agonists tested (ADP, epinephrin, collagen, arachidonic acid). No significant change in bleeding time was observed after n-3 fatty acid trial. Supplementation with vitamin B12 and n-3 fatty acids corrects hyperhomocysteinemia and reduces platelet reactivity to agonists in vegetarians. Whether this supplementation improves the already reduced cardiovascular morbidity and mortality associated with vegetarian diet has yet to be demonstrated.

Increasing incidence of non-valvular atrial fibrillation in the UK from 2001 to 2013

Objective To determine whether the incidence of atrial fibrillation (AF) is static or rising in the UK. Design Among the cohort of all individuals aged ≥45 years in the UK Clinical Practice Research Datalink (CPRD) (linked to hospital discharges) we identified incident non-valvular AF cases between 2001 and 2013. Overall and annual AF incidence rates were calculated and standardised to the UK population. Results The cohort of 2.23 million individuals included 91 707 patients with incident AF. The overall standardised AF incidence rate was 6.7 (95% CI 6.7 to 6.8) per 1000 person-years, increasing exponentially with age and higher in men of all ages. There was a small increase in the standardised incidence of AF in the last decade from 5.9 (5.8 to 6.1)/1000 person-years in 2001 to 6.9 (6.8 to 7.1)/1000 person-years in 2013, mostly attributable to subjects aged >80 years with a non-primary hospital discharge diagnosis of AF. Standardised incidence rates of AF among white patients was 8.1 (8.1 to 8.2)/1000 person-years, compared with 5.4 (4.6 to 6.3) for Asians and 4.6 (4.0 to 5.3) for black patients. AF diagnosis was first made in general practice in 39% of incident AF. Conclusions The incidence of AF in the UK has increased gradually in the last decade, with more than 200 000 first-ever non-valvular AF cases expected in 2015. This increase is only partly due to population ageing, though the principal increase has been in the elderly hospitalised for a reason other than AF.

Residual Risk of Stroke and Death in Anticoagulant-Treated Patients With Atrial Fibrillation

Residual Risk of Stroke and Death in AnticoagulantTreated Patients With Atrial Fibrillation Despite the impressive reduction of risk of stroke and death in patients with atrial fibrillation (AF) conferred by anticoagulation with warfarin or non–vitamin K antagonist oral anticoagulants,1,2 there is still an appreciable stroke risk during anticoagulant treatment, approximating 1.7% per year for warfarin and 1.4% per year for non–vitamin K antagonist oral anticoagulants at 2.2 years’ follow-up.2 This residual stroke rate is often regarded as treatment failure, but, to our knowledge, it has not been compared with a matched control population and could instead reflect the stroke rate in people of a comparable baseline risk without AF.

Risk of recurrent venous thromboembolism after discontinuation of vitamin K antagonist treatment: a nested case-control study.

Essentials Vitamin K antagonists (VKA) in venous thromboembolism (VTE) lower the risk of recurrences. 41 841 VKA‐treated VTE patients had 1242 recurrent VTEs on therapy or early after cessation. An increased risk of recurrence was found in the first 120 days after VKA cessation. Patient education for the early detection of recurrent VTE after VKA cessation is recommended.

Thrombin Generation in Platelet-Poor Plasma Is Normal in Patients with Hereditary Mucocutaneous Haemorrhages

Mild hereditary bleeding disorders presenting with mucocutaneous haemorrhages are usually difficult to diagnose. We measured thrombin generation in platelet-poor plasma (TG-PPP) in 206 patients with a clinically unequivocal bleeding tendency: 45 with von Willebrand disease (vWD), 49 with platelet aggregation/secretion defects (PASD), 10 with a combination of both and 102 who did not fit the diagnostic criteria for any known haemostatic disorder. TG-PPP was not significantly different from controls in all patient groups, indicating that an abnormality in the plasmatic clotting system is unlikely to contribute to the bleeding in patients with type 1 vWD and PASD. In patients with undiagnosed mild hereditary bleeding disorders, there must be other mechanisms which explain the abnormal haemorrhagic tendency, most likely as yet unrecognized defects in platelet-vessel wall interaction. As a next step we plan to investigate thrombin generation in PRP.

Impact of screening and exclusion of high anti-A titer donors on the risk of hemolytic anemia with intravenous immunoglobulin treatment: A hospital-based cohort study in the US

(3%) and MPL (3%). Interestingly, it has been hypothesized that MDS with ring sideroblasts (MDS-RS) can transform into MDS/MPN-RS-T with acquisition of the JAK-2 mutation. Poor prognostic factors in MDS/MPN-RS-T include older age (>80), low Hb (<8 g/dl), abnormal cytogenetics, the presence of SETBP-1 or ASXL-1 mutations and the absence of SF3B1 or JAK-2 mutations. It is interesting to compare outcomes and variables between MDS/MPN-RS-T and its sister conditions MDS-RS and essential thrombocythemia (ET). A recent study has shown that survival in MDS/MPN-RS-T significantly exceeds that of MDS-RS (76 months versus 63 months) and compares poorly with survival in ET (115 months). Thrombotic events in MDS/MPN-RS-T and ET were shown to exceed those of MDS-RS, which may be expected considering the disease characteristics. Rates of transformation to AML were similar in the two MDS subtypes but lower in ET, the myeloproliferative counterpart. This case is noteworthy as MDS/MPN-RS-T has a relatively low transformation rate to AML, with a leukemic transformation rate per 100 years of 1.8. A recent paper described two cases; both were patients who were aged greater than 70 years and had been diagnosed with MDS/MPN-RS-T at least two years prior to transformation. One patient had cytogenetics exhibiting clonal evolution, with 7q deletion detected in the marrow following transformation, and died from neutropenic sepsis with chemotherapy; the second did not have clonal evolution and was undergoing chemotherapy at the time of publication. Another case report involved a 70-year-old patient who died from AML transformed from MDS/MPN-RS-T; this case involved the development of a monosomy 7 clone in the leukemic marrow. The refractoriness of the transformed AML in our case to multiple lines of chemotherapy also serves to highlight the aggressive nature of the disease. In summary, we describe a case of MDS/MPN-RS-T with transformation to treatment-refractory AML highlighted by the presence of trisomy 13 and resistant thrombocytosis. Although transient, our patient’s relative “response” to oral busulfan was unexpected but does suggest that this therapy may be clinically useful in similar cases.

Thirteen-year trend in the persistence with vitamin K antagonists for venous thromboembolism in the UK: a cohort study

Abstract Background: Venous thromboembolism (VTE) comprises deep vein thrombosis (DVT) and pulmonary embolism (PE) and is associated with significant recurrence and mortality risk. Standard VTE treatment includes at least 3 months anticoagulation. The objective was to describe time trends in the duration of oral anticoagulation in patients initially treated with vitamin K antagonists (VKAs). Methods: A retrospective cohort study was conducted on patients with first VTE and VKA treatment initiation within 30 days, identified from the UK Clinical Practice Research Datalink from 2001 to 2014. VKA users were followed for the duration of oral anticoagulation which included switching to non-VKA oral anticoagulants. The probability of remaining on anticoagulation treatment (persistence) was estimated using Kaplan–Meier survival functions. Results: A total of 16,018 patients with VTE initiated VKA; 48.2% males, mean age 62.1 years, median VKA treatment duration 6.5 months. The 90-day persistence increased from 75.6% in 2001 to 91.2% in 2013 (p < .0001) and the 180-day persistence from 39.3% in 2001 to 61.1% in 2013 (p < .0001). This time trend was also shown for patients with DVT, PE, provoked VTE, unprovoked VTE, provoked DVT, unprovoked DVT, provoked PE and unprovoked PE. There were no major differences in persistence between patients with provoked and unprovoked VTE, but persistence was lower following DVT than PE (p < .0001). Conclusions: The increase in persistence was independent of the presentation of the first VTE (provoked or unprovoked), but higher for first PE. Whether the increasing persistence resulted in decreasing risk of recurrent VTE needs to be confirmed.