Abstract
Patients with heart failure (HF) are frequently anti-coagulated with vitamin K-antagonists (VKAs). The use of long-acting VKA may be preferable for HF patients due to higher stability of ...plasma concentrations. However, evidence on phenprocoumon-based oral anti-coagulation (OAC) therapy in HF is scarce. The aim of this study was to assess the impact of the presence of HF on quality of phenprocoumon-based OAC and the subsequent clinical outcome. Quality of OAC therapy and the incidence of adverse events were analysed in a cohort of regular care (
n
= 2,011) from the multi-centre thrombEVAL study program (NCT01809015) stratified by the presence of HF. To assess the modifiability of outcome, results were compared with data from individuals receiving specialized care for anti-coagulation (
n
= 760). Overall, the sample comprised of 813 individuals with HF and 1,160 subjects without HF in the regular care cohort. Quality of OAC assessed by time in therapeutic range (TTR) was 66.1% (47.8%/82.8%) for patients with HF and 70.6% (52.1%/85.9%) for those without HF (
p
= 0.0046). Stratification for New York Heart Classification (NYHA)-class demonstrated a lower TTR with higher NYHA classes: TTR
NYHA-I
69.6% (49.4%/85.6%), TTR
NYHA-II
66.5% (50.1%/82.9%) and TTR
NYHA-≥III
61.8% (43.1%/79.9%). This translated into a worse net clinical benefit outcome for HF (hazard ratio HR 1.63 1.31/2.02;
p
< 0.0001) and an increased risk of bleeding (HR 1.40 1.04/1.89;
p
= 0.028). Management in a specialized coagulation service resulted in an improvement of all, TTR (∆+12.5% points), anti-coagulation-specific and non-specific outcome of HF individuals. In conclusion, HF is an independent risk factor for low quality of OAC therapy translating into an increased risk for adverse events, which can be mitigated by specialized care.
Background
Experimental data indicate that direct acting oral anticoagulants (DOAC) and vitamin K antagonists (VKA) may exert differential effects on cardiovascular disease.
Methods
Data from the ...prospective, observational, single-center MyoVasc Study were used to examine associations of DOAC as compared to VKA with subclinical markers of cardiovascular disease, cardiac function, and humoral biomarkers in heart failure (HF).
Results
Multivariable analysis adjusted for age, sex, traditional cardiovascular risk factors, comorbidities, and medications with correction for multiple testing demonstrated that DOAC therapy was among all investigated parameters an independent significant predictor of better diastolic function (
E
/
E
′:
β
− 0.24 − 0.36/− 0.12;
P
< 0.0001) and higher levels of ApoA1 (
β
+ 0.11 g/L 0.036/0.18;
P
= 0.0038) compared to VKA therapy. In propensity score-weighted analyses, the most pronounced differences between DOAC and VKA-based therapy were also observed for
E
/
E
′ (∆ − 2.36) and ApoA1 (∆ + 0.06 g/L). Sensitivity analyses in more homogeneous subsamples of (i) individuals with AF and (ii) individuals with asymptomatic HF confirmed the consistency and robustness of these findings. In the comparison of factor IIa and Xa-directed oral anticoagulation, no differences were observed regarding cardiac function (
E
/
E
′ ratio:
β
IIa inhibitor
− 0.22 − 0.36/− 0.08 vs.
β
Xa inhibitor
− 0.24 − 0.37/− 0.11) and lipid metabolism (ApoA1:
β
IIa inhibitor
0.10 0.01/0.18 vs.
β
Xa inhibitor
0.12 0.04/0.20) compared to VKA therapy.
Conclusion
This study provides the first evidence for differential, non-conventional associations of oral anticoagulants on cardiac function and lipid metabolism in humans. The potentially beneficial effect of DOACs in the highly vulnerable population of HF individuals needs to be further elucidated and may have implications for individually tailored anticoagulation therapy.
Background
Oral anticoagulation therapy in individuals with atrial fibrillation (AF) reduces the risk of thromboembolic events at cost of an increased bleeding risk. Whether anticoagulation-related ...outcomes differ between patients with paroxysmal and sustained AF receiving anticoagulation is controversially discussed.
Methods
In the present analysis of the prospective multi-center cohort study thrombEVAL, the incidence of anticoagulation-related adverse events was analyzed according to the AF phenotype. Information on outcome was centrally recorded over 3 years, validated via medical records and adjudicated by an independent review panel. Study monitoring was provided by an independent institution.
Results
Overall, the sample comprised 1089 AF individuals, of whom
n
= 398 had paroxysmal AF and
n
= 691 experienced sustained AF. In Cox regression analysis with adjustment for potential confounders, sustained AF indicated an independently elevated risk of clinically relevant bleeding compared to paroxysmal AF hazard ratio (HR) 1.40 (1.02; 1.93);
P
= 0.038. For clinically relevant bleeding, a significant interaction of the pattern of AF type with concomitant heart failure (HF) was detected: HR
HF
2.45 (1.51, 3.98) vs. HR
no HF
0.85 (0.55, 1.34);
P
interaction
= 0.003. In HF patients, sustained AF indicated also an elevated risk of major bleeding HR 2.25 (1.26, 4.20);
P
= 0.006. A simplified HAS-BLED score incorporating only information on age (> 65 years), bleeding history, and HF with sustained AF demonstrated better discriminative performance for clinically relevant bleeding than the original version: AUC
HAS-BLED
: 0.583 vs. AUC
simplifiedHAS-BLED
: 0.642 (
P
= 0.004).
Conclusions
In HF patients receiving oral anticoagulation, sustained AF indicates a substantially elevated risk of bleeding.
Clinical Trial Registration
https://clinicaltrials.gov
, identifier: NCT01809015.
Aims Although depressive symptoms are highly prevalent in patients receiving oral anticoagulation (OAC), the relevance of depression for the outcome of anticoagulated individuals is unknown. Methods ...and results We analysed data from the multicentre cohort study thrombEVAL (NCT01809015) investigating the efficacy of OAC with vitamin K antagonists. There was an independent study monitoring, and an independent review panel assessed the endpoints. Out of n= 1558 participants, information about depressive symptoms, as measured by the two-item screener of the patient health questionnaire (PHQ-2), was available in n=1405 individuals. The mean follow-up period was 28.04 months, with a standard deviation of 11.52 months. In multivariable Cox regression analysis, baseline PHQ-2 sum score was a strong and robust predictor of clinically relevant bleeding hazard ratio (HR) 1.13, 95% confidence interval 1.03-1.24; P= 0.011 and all-cause mortality (HR 1.18, 1.08-1.28; P= 0.001) independent of age, sex, high school graduation, partnership, clinical profile, intake of serotonin reuptake inhibitors, and quality of OAC therapy. Individuals with clinically significant depressive symptoms (PHQ-2 greater than or equal to 3) had a 57% increased risk for clinically relevant bleeding (fully adjusted HR 1.57, 1.08-2.28) and 54% greater risk for death (fully adjusted HR 1.54, 1.09-2.17). There was no association of depressive symptoms with thromboembolic events. For hospitalization, individuals with depressive symptoms (PHQ-2 greater than or equal to 3) did not experience an elevated risk in the fully adjusted model (HR 1.08, 0.86-1.35; P = 0.52). Conclusion Assessment of depression by the PHQ-2 provided independent long-term prognostic information beyond common biomedical risk factors. These findings highlight the need for targeting depressive symptoms in the management of patients receiving OAC therapy. Keywords Oral anticoagulation * Depression * Patient health questionnaire (PHQ) * Adverse events
Abstract
Aims
Although depressive symptoms are highly prevalent in patients receiving oral anticoagulation (OAC), the relevance of depression for the outcome of anticoagulated individuals is unknown.
...Methods and results
We analysed data from the multicentre cohort study thrombEVAL (NCT01809015) investigating the efficacy of OAC with vitamin K antagonists. There was an independent study monitoring, and an independent review panel assessed the endpoints. Out of n = 1558 participants, information about depressive symptoms, as measured by the two-item screener of the patient health questionnaire (PHQ-2), was available in n = 1405 individuals. The mean follow-up period was 28.04 months, with a standard deviation of 11.52 months. In multivariable Cox regression analysis, baseline PHQ-2 sum score was a strong and robust predictor of clinically relevant bleeding hazard ratio (HR) 1.13, 95% confidence interval 1.03–1.24; P = 0.011 and all-cause mortality (HR 1.18, 1.08–1.28; P = 0.001) independent of age, sex, high school graduation, partnership, clinical profile, intake of serotonin reuptake inhibitors, and quality of OAC therapy. Individuals with clinically significant depressive symptoms (PHQ-2 ≥ 3) had a 57% increased risk for clinically relevant bleeding (fully adjusted HR 1.57, 1.08–2.28) and 54% greater risk for death (fully adjusted HR 1.54, 1.09–2.17). There was no association of depressive symptoms with thromboembolic events. For hospitalization, individuals with depressive symptoms (PHQ-2 ≥ 3) did not experience an elevated risk in the fully adjusted model (HR 1.08, 0.86–1.35; P = 0.52).
Conclusion
Assessment of depression by the PHQ-2 provided independent long-term prognostic information beyond common biomedical risk factors. These findings highlight the need for targeting depressive symptoms in the management of patients receiving OAC therapy.
The obesity paradox, the controversial finding that obesity promotes disease development but protects against sequelae in patients, has been observed in venous thromboembolism (VTE). The aim of this ...investigation was to identify a body mass–related proteomic signature in VTE patients and to evaluate whether this signature mediates the obesity paradox in VTE patients. Data from the Genotyping and Molecular Phenotyping in Venous ThromboEmbolism Project, a prospective cohort study of 693 VTE patients, were analyzed. A combined end point of recurrent VTE or all-cause death was used. Relative quantification of 444 proteins was performed using high-throughput targeted proteomics technology. Measurements were performed in samples collected during the acute VTE event and at 12-month follow-up. An 11-protein signature (CLEC4C, FABP4, FLT3LG, IL-17C, LEP, LYVE1, MASP1, ST2, THBS2, THBS4, TSLP) for body mass in VTE patients was identified. The signature did not significantly mediate the obesity paradox (change in hazard ratio HR: 0.04; likelihood ratio test of nested models = 7.7; P = .74), but its main constituent protein, leptin, was inversely associated with recurrent VTE or death (adjusted HR 95% confidence interval per standard deviation increase: 0.66 0.46-0.94). This relationship was significantly (P = .007) modified by markers of leptin resistance (ie, high body mass index and high circulating matrix metalloproteinase-2 levels). Although the signature did not substantially explain the obesity paradox, leptin appears to be protective against disease recurrence and death in VTE patients. This protective effect was abrogated under conditions of leptin resistance and hence was unrelated to the obesity paradox.
•The obesity paradox in VTE was not substantially explained by a body mass–associated protein signature.•Leptin, the main protein in the signature, was inversely related to recurrent VTE and death but only under leptin-sensitive conditions.
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The introduction of direct oral anticoagulants (DOAC) in addition to the established Vitamin K antagonist (VKA) has increased the complexity of antithrombotic therapy leading to numerous treatment ...options. Studies of the medical evaluation of the current treatment situation by health care providers, which are of great importance for the development of treatment strategies in addition to studies on pharmacovigilance, are limited in the literature.
11 700 physicians (Rhineland-Palatinate, Germany) were contacted to participate in the web-based survey on health care with oral anticoagulation (OAC). After detailed quality control, the study was analysed in synopsis with routine care data of VKA patients of the thrombEVAL study programme (N = 2.011).
In total, 512 physicians (mean age: 48.0 ± 9.6 years; 74.0 % male) participated in the study. In general, quality of OAC therapy was rated as "average/satisfactory" (2.9 ± 0.9). Comparison of physicians' perception with data from routine care highlighted marked differences regarding time in therapeutic range (+ 6.4 % 95 %-CI 2.7 %; 9.5 %), duration of control intervals (- 35.0 % 28.0 %; 41.4 %) and rate of OAC-related complications (+ 61.8 37.8 %; 83.3 %, which differed additionally and statistically-significant between physician groups. The willingness to use DOAC was approximately 50 % lower in general physicians as compared to specialists (36.6 % 25.4 %; 47.8 % vs. 72.4 % 66.0 %; 78.9 %; p < 0.0001). Regarding management of OAC therapy, 73.8 % 69.7 %; 77.9 % advocated the establishment of a service hotline and 67.3 % 62,9 %; 71.6 % a specialized coagulation service.
The present survey among physicians reveals a need for optimization of OAC therapy in daily practice. Specialized care models might facilitate optimized OAC therapy with both VKAs and DOACs.
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