Ischaemic stroke in women with atrial fibrillation: temporal trends and clinical implications.

BACKGROUND AND AIMS: Female sex has been linked with higher risk of ischaemic stroke (IS) in atrial fibrillation (AF), but no prior study has examined temporal trends in the IS risk associated with female sex. METHODS: The registry-linkage Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) study included all patients with AF in Finland from 2007 to 2018. Ischaemic stroke rates and rate ratios were computed. RESULTS: Overall, 229 565 patients with new-onset AF were identified (50.0% women; mean age 72.7 years). The crude IS incidence was higher in women than in men across the entire study period (21.1 vs. 14.9 events per 1000 patient-years, P < .001), and the incidence decreased both in men and women. In 2007-08, female sex was independently associated with a 20%-30% higher IS rate in the adjusted analyses, but this association attenuated and became statistically non-significant by the end of the observation period. Similar trends were observed when time with and without oral anticoagulant (OAC) treatment was analysed, as well as when only time without OAC use was considered. The decrease in IS rate was driven by patients with high IS risk, whereas in patients with low or moderate IS risk, female sex was not associated with a higher IS rate. CONCLUSIONS: The association between female sex and IS rate has decreased and become non-significant over the course of the study period from 2007 to 2018, suggesting that female sex could be omitted as a factor when estimating expected IS rates and the need for OAC therapy in patients with AF.

Temporal trends of gender disparities in oral anticoagulant use in patients with atrial fibrillation.

AIMS: To investigate sex-specific temporal trends in the initiation of oral anticoagulant (OAC) therapy among patients diagnosed with atrial fibrillation (AF) in Finland between 2007 and 2018. METHODS: The registry-linkage Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) Study included all patients with incident AF in Finland from 2007 to 2018. The primary outcome was the initiation of any OAC therapy. RESULTS: We identified 229,565 patients with new-onset AF (50.0% women; mean age 72.7 years). The initiation of OAC therapy increased continuously during the observation period. While women were more likely to receive OAC therapy overall, after adjusting for age, stroke risk factors and other confounding factors, female sex was associated with a marginally lower initiation of OACs (unadjusted and adjusted hazard ratios comparing women to men: 1.08 (1.07-1.10) and 0.97 (0.96-0.98), respectively). Importantly, the gender disparities in OAC use attenuated and reached parity by the end of the observation period. Furthermore, when only patients eligible for OAC therapy according to the contemporary guidelines were included in the analyses, the gender inequalities in OAC initiation appeared minimal. Implementation of direct OACs for stroke prevention was slightly slower among women. CONCLUSION: This nationwide retrospective cohort study covering all patients with incident AF in Finland from 2007 to 2018 observed that although female sex was initially associated with a lower initiation of OAC therapy, the sex-related disparities resolved over the course of the study period.

Trends and burden of diabetes in patients with atrial fibrillation during 2007-2018: A Finnish nationwide cohort study.

AIMS: We assessed the temporal trends in the prevalence of diabetes and in its associations with outcomes among patients with atrial fibrillation (AF). METHODS: The registry-based FinACAF study covered all patients with incident AF in Finland between 2007 and 2018. Ischemic stroke (IS) and mortality rates were computed using Poisson regression model. RESULTS: We identified 229565 patients (50.0% female; mean age 72.7 years; mean follow-up 4.0 years) patients with incident AF. The prevalence of diabetes increased steadily from 15.5% in 2007 to 26.3% in 2018. A decrease in IS and mortality rates was observed during the study period both in patients with and without diabetes. Diabetes was associated with IS and mortality (adjusted incidence rate ratios with 95% confidence intervals 1.22 (1.17-1.26) and 1.32 (1.29-1.34), respectively). The impact of diabetes on IS risk remained stable, while its effect on mortality increased slightly during the observation period. CONCLUSIONS: The prevalence of diabetes has increased considerably among patients with AF between 2007 and 2018. There have been substantial improvements in the prognosis of AF patients with diabetes. However, diabetes remains a significant risk factor for IS and mortality in this patient population.

Cancer risk and mortality after solid organ transplantation: A population-based 30-year cohort study in Finland.

Cancer is a significant cause of morbidity and mortality after solid organ transplantation (SOT) and related to lifelong immunosuppression. This retrospective registry study assessed for the first time in Finland population-based cancer risk and cancer mortality after all SOTs (lung and childhood transplantations included) as standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs). Data from transplant registries were linked with the data of Finnish Cancer Registry and Statistics Finland. We followed 6548 consecutive first SOT recipients from 1 January 1987 to 31 December 2016 translating to 66 741 person-years (median follow-up time 8.9 years [interquartile range 4.0-15.1]). In total, 2096 cancers were found in 1483 patients (23% of all patients). Majority of cancers (53%) were nonmelanoma skin cancers (NMSCs). The overall SIR was 3.6 (95% confidence interval [CI]: 3.5-3.8) and the SIR excluding NMSCs was 2.2 (95% CI: 2.0-2.3). SIR for all cancers was highest for heart (5.0) and lowest for liver (2.7) recipients. Most common cancer types after NMSCs were non-Hodgkin lymphoma (NHL), SIR 9.9 (95% CI: 8.5-11.4) and kidney cancer, SIR 7.3 (95% CI: 6.0-8.8). Cancer-related deaths were 17% (n = 408) of all deaths after first month post transplantation. SMR for all cancers was 2.5 (95% CI: 2.2-2.7) and for NHL 13.6 (95% CI: 10.7-16.8). Notably, overall SIR for cancer was lower in later period (2000-2016), 3.0 (95% CI: 2.8-3.2), than in earlier period (1987-1999), 4.3 (95% CI: 4.0-4.5), P < .001. Decrease in cancer incidence was temporally associated with major changes in immunosuppression in the 2000s.

Cost-utility of venoarterial extracorporeal membrane oxygenation in cardiogenic shock and cardiac arrest.

BACKGROUND: The use of venoarterial extracorporeal membrane oxygenation in cardiogenic shock keeps increasing, but its cost-utility is unknown. METHODS: We studied retrospectively the cost-utility of venoarterial extracorporeal membrane oxygenation in a five-year cohort of consequent patients treated due to refractory cardiogenic shock or cardiac arrest in a transplant centre in 2013-2017. In our centre, venoarterial extracorporeal membrane oxygenation is considered for all cardiogenic shock patients potentially eligible for heart transplantation, and for selected postcardiotomy patients. We assessed the costs of the index hospitalization and of the one-year hospital costs, and the patients' health-related quality of life (response rate 71.7%). Based on the data and the population-based life expectancies, we calculated the amount and the costs of quality-adjusted life years gained both without discount and with an annual discount of 3.5%. RESULTS: The cohort included 102 patients (78 cardiogenic shock; 24 cardiac arrest) of whom 67 (65.7%) survived to discharge and 66 (64.7%) to one year. The effective costs per one hospital survivor were 242,303€. Median in-hospital costs of the index hospitalization per patient were 129,967€ (interquartile range 150,340€). Mean predicted number of quality-adjusted life years gained by the treatment was 20.9 (standard deviation 9.7) without discount, and the median cost per quality-adjusted life year was 7474€ (interquartile range 10,973€). With the annual discount of 3.5%, 13.0 (standard deviation 4.8) quality-adjusted life years were gained with the cost of 12,642€ per quality-adjusted life year (interquartile range 15,059€). CONCLUSIONS: We found the use of venoarterial extracorporeal membrane oxygenation in refractory cardiogenic shock and cardiac arrest justified from the cost-utility point of view in a transplant centre setting.

Cancer incidence and mortality after heart transplantation - A population-based national cohort study.

Background: Cancer is currently one of the most important factors affecting the long-term health and survival of heart transplant patients. Material and methods: We calculated the standardized incidence ratios (SIR) for different cancer sites and the cancer-specific standardized mortality ratio (SMR) by linking a cohort of 479 adult heart transplant recipients transplanted in 1985-2014 (4491.6 person-years of follow-up) with data from the national Finnish Cancer Registry until the end of 2015, and with the data from the Statistics Finland's national registry of causes of death. Results: A total of 267 cancers occurred in 143 patients (SIR 6.0; 95% confidence interval (CI) 5.3-6.7). The SIR for overall cancer was considerably higher for men (SIR 6.7; 95% CI 5.9-7.5) than for women (1.4; 95% CI 0.6-2.6). Most frequent cancers were non-melanoma skin cancers (basal cell carcinoma 83 cases, squamous cell skin cancer (SCC) 56 cases), followed by Non-Hodgkin lymphoma (NHL) (36 cases), lung cancer (17), cancer of prostate (16) and cancer of kidney (12). SIRs were highest for SCC (51.9; 95% CI 39.2-67.4), lip cancer (47.4; 95% CI 19.1-97.7), cancer of tongue (26.3; 95% CI 7.2-67.4), and NHL (25.7; 95% CI 18.0-35.6). For most cancers, SIRs increased steadily by time since transplantation. Cancer mortality was three times higher for heart transplant recipients than for the population (SMR 3.1; 95% CI 2.1-4.1). Conclusions: Both cancer incidence and mortality are remarkably increased after heart transplantation, with the relative incidence most elevated for SCC, lip and other oral cancers, and for NHL.

Extracorporeal membrane oxygenation for refractory cardiogenic shock: patient survival and health-related quality of life.

OBJECTIVES: Our goal was to study the outcome of patients with cardiogenic shock who were treated with venoarterial extracorporeal membrane oxygenation (VA ECMO), including the subsequent long-term health-related quality of life (HRQoL). METHODS: We conducted a retrospective study of 133 consecutive patients treated in a single centre from 2007 to 2016. The HRQoL was studied using the EuroQuol-5 dimensions-3 level questionnaire and the RAND 36-Item Short Form Health Survey at a minimum of 1 year after VA ECMO. RESULTS: Of all patients, 66 (49.6%) were weaned from VA ECMO and 16 (12.0%) patients were bridged directly to a transplant, 15 (11.3%) to a ventricular assist device and 1 (0.8%) to a total artificial heart. Survival to discharge was 63.9% and to 1 year, 60.9%. A higher in-hospital mortality rate was independently associated with lower HCO3 at VA ECMO implantation [odds ratio (OR) 1.2/decrease of 1 mmol/l in HCO3 (95% confidence interval 1.1-1.3, P < 0.001)] and with increased need of red blood cells transfused during intensive care [OR 1.9/unit of red blood cells needed/day (95% confidence interval 1.4-2.6, P < 0.001)]. HRQoL measured with the EuroQuol-5 dimensions-3 level questionnaire was equal to the HRQoL of the general population. In the 36-Item Short Form questionnaire, patients reported better emotional well-being and equal energy, pain and general health perception compared to the general population. Limitations were experienced only in physical health. In total, 56% of the patients ≤ 60 years had returned to work. CONCLUSIONS: VA ECMO can provide acceptable long-term survival with good HRQoL for selected patients with refractory cardiogenic shock. Timing of patient assessment and of VA ECMO implantation is essential because deeper acidosis is associated with a higher in-hospital mortality rate.

Laboratory-monitored fondaparinux and coagulation activity in association with total hip replacement.

Fondaparinux, indirect factor Xa (FXa) inhibitor, is recommended for thromboprophylaxis for high-risk patients undergoing major orthopedic surgery. We evaluated the prothrombotic state and anticoagulant intensity of fondaparinux (2.5 mg daily) after total hip replacement (THR). Twenty patients underwent THR - seven bilateral and 13 unilateral. Blood samples were collected preoperatively and at 6 h, 8 h (2 h after fondaparinux), 1 day (12-14 h after fondaparinux), and 4 weeks (12-14 h after fondaparinux) postoperatively. Antithrombin (AT), fibrinogen, factor VIII activity, coagulation times, thrombin-AT (TAT) complex, D-dimer, C-reactive protein, prothrombinase-induced clotting time (PiCT) and anti-Xa activity were measured. The latter two were also tested after plasma spiking with fondaparinux 0-1.25 µg/ml. In spiked prophylactic fondaparinux samples (0-0.25 µg/ml), PiCT and anti-Xa activity correlated (r = 0.84) better than in the patient samples (r = 0.35). On the first day, anti-Xa activity and PiCT dissociated, and PiCT lost sensitivity for fondaparinux. AT decreased but stayed within the normal range, whereas TAT complex and D-dimer peaked at 6 h as signs of thrombin generation. On the first postoperative day, TAT and D-dimer halved. Bilateral THR associated with higher TAT and D-dimer levels up to 4 weeks. Perioperative FVIII levels were not affected, but were elevated in both groups (range 191-211%) after 4 weeks. Anti-Xa activity detected prophylactic fondaparinux with higher sensitivity than PiCT in vitro, but even more so in vivo. Thus, PiCT is not the method of choice to assess fondaparinux at least in association with THR. THR, bilateral more than unilateral, increased thrombin generation and D-dimer 7-11-fold early after surgery. Factor VIII activity and D-dimer remained elevated even after 4 weeks despite the compliant thromboprophylaxis with fondaparinux.

Thrombophilia and arteriovenous fistula survival in ESRD.

BACKGROUND AND OBJECTIVES: The role of thrombophilia in failing arteriovenous fistula (AVF) among patients with ESRD undergoing hemodialysis is not established. This study aimed to assess whether AVF primary patency is associated with thrombophilia and coagulation abnormalities. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This observational study screened 219 patients between 2002 and 2004 for thrombophilia before AVF surgery. Thrombophilia included factor V Leiden and prothrombin G20210A mutations, protein C and antithrombin activities, and protein S. Coagulation abnormalities included high factor VIII:C, homocysteine, fibrinogen, and d-dimer levels; presence of antiphospholipid antibodies; and short thrombin time. We reviewed patient charts for comorbid conditions, AVF maturation and interventions, kidney transplantation, and patient survival (mean follow-up duration, 3.6 [range, 2.3-5.8] years). Primary patency from the AVF placement and functional primary patency from the first AVF cannulation were analyzed with Kaplan-Meier and Cox proportional hazards models. RESULTS: Thrombophilia was present in 9% of the patients, and coagulation abnormalities occurred in 77%. One-year primary patency was 68%; 46% of the AVF failures occurred before the initiation of hemodialysis. Female sex (hazard ratio [HR], 2.6; 95% confidence interval [CI], 1.7-4.1) and thrombophilia (HR, 2.2; 95% CI, 1.2-4.2) were independent risk factors for loss of primary patency. Thrombophilia mutations or low antithrombin level (HR, 3.8), female sex (HR, 2.5), and diabetes (HR, 1.9) were associated with shortened functional primary patency of AVF. CONCLUSIONS: Against the background of frequent coagulation abnormalities, thrombophilia and female sex predispose patients with ESRD to access failure, mostly due to thrombosis or stenosis.

Active online assessment of patients using new oral anticoagulants: bleeding risk, compliance, and coagulation analysis.

Clinicians prescribing new oral anticoagulants (OACs; dabigatran, rivaroxaban, and apixaban) should be aware of the exclusion criteria related to bleeding risks defined in published clinical studies. At least a quarter of patients currently using warfarin have an exclusion criterion that may prevent easy transition to the new OACs. In the summary of product characteristics for dabigatran, as an example, the target populations appear generalized. Due to fixed dosing and predictable pharmacology, routine laboratory monitoring of new OACs is deemed unnecessary. Under special circumstances, however, understanding the extent of thrombin or factor (F) Xa inhibition may aid in evaluating compliance and handling emergency interventions, bleeding complications, or overdoses. Although commonly available global coagulation-time assessments (prothrombin time and activated partial thromboplastin time) are insensitive, they may assist clinical management by indicating a severe accumulation of OACs; moreover, a normal thrombin time (TT) excludes a thrombin-inhibitor effect. In particular circumstances, specific assays (diluted TT, Ecarin clotting time, anti-FIIa or anti-FXa activity) may quantify the anticoagulant effect, but therapeutic ranges for dose adjustment are not yet established. Laboratory results are also influenced by clinical situation: e.g. bleed (consumption of coagulation factors) versus postoperative state (activation of coagulation). Without specific antidotes and evidence-based treatment strategies, new OACs are clinically worrisome in patients with impaired renal or liver function. Postmarketing surveillance and recording of bleeding complications (ICD-10 D68.32) are therefore of major importance.

Comparison of monitoring methods for lepirudin: impact of warfarin and lupus anticoagulant.

INTRODUCTION: Appropriate monitoring methods are needed for lepirudin, a direct thrombin inhibitor, as activated partial thromboplastin time (APTT) may under- or overestimate lepirudin. We compared APTT with thrombin-specific methods, also in the presence of warfarin and lupus anticoagulant (LA). MATERIALS AND METHODS: Lepirudin i.v. was assessed in five patients (35 samples) and in vitro spiked plasma pools: normal control and plasma containing warfarin and LA. Wide dose-responses to lepirudin (0-4.0microg/ml) were studied with APTT (Actin FSL), Ecarin Chromogenic Assay (ECA), chromogenic Anti-Factor IIa (Anti-FIIa, Hirudin Activity Assay), Prothrombinase-induced Clotting Time (PiCT), and plasma diluted Thrombin Time (dTT). RESULTS: APTT both under- and overestimated in vivo lepirudin doses according to ECA) and Anti-FIIa, which matched completely in various plasma pools at all lepirudin doses (r=0.99). APTT and PiCT) underestimated high lepirudin concentrations in normal plasma, and in LA-positive plasma they were invalid. In all plasma pools, dTT (1:16) indicated lepirudin well up to 1.0microg/ml. CONCLUSIONS: ECA or Anti-FIIa are preferable for lepirudin monitoring, because neither warfarin nor LA, interfered with them, and they were the most precise methods even for supratherapeutic doses. PiCT reflected co-inhibition of FIIa and FXa, but was disturbed, like APTT, by LA and high lepirudin. Further experience of laboratory monitoring is valuable in this era of new anticoagulants.