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Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Background Preclinical data have indicated a link between use of vitamin K antagonists (VKA) and detrimental effects on vascular structure and function. The objective of the present study was to determine the relationship between VKA intake and different phenotypes of subclinical cardiovascular disease in the population. Methods and Results Clinical and laboratory data, as well as medical–technical examinations were assessed from 15 010 individuals aged 35 to 74 years during a highly standardized 5‐hour visit at the study center of the population‐based Gutenberg Health Study. In total, the study sample comprised 287 VKA users and 14 564 VKA nonusers. Multivariable analysis revealed an independent association between VKA intake and stiffness index (β=+2.54 m/s; [0.41/4.66]; P=0.019), ankle‐brachial index (β=−0.03; [−0.04/−0.01]; P<0.0001), intima‐media thickness (β=+0.03 mm [0.01/0.05]; P=0.0098), left ventricular ejection fraction (β=−4.02% [−4.70/−3.33]; P<0.0001), E/E′ (β=+0.04 [0.01/0.08]; P=0.014) left ventricular mass (β=+5.34 g/m2.7 [4.26/6.44]; P<0.0001), and humoral markers of cardiac function and inflammation (midregional pro‐atrial natriuretic peptide: β=+0.58 pmol/L [0.50/0.65]; P<0.0001; midregional pro‐adrenomedullin: β=+0.18 nmol/L [0.14/0.22]; P<0.0001; N‐terminal pro B‐type natriuretic peptide: β=+1.90 pg/mL [1.63/2.17]; P<0.0001; fibrinogen: β=+143 mg/dL [132/153]; P<0.0001; C‐reactive protein: β=+0.31 mg/L [0.20/0.43]; P<0.0001). Sensitivity analysis in the subsample of participants with atrial fibrillation stratified by intake of VKA demonstrated consistent and robust results. Genetic variants in CYP2C9,CYP4F2, and VKORC1 were modulating effects of VKA on subclinical markers of cardiovascular disease. Conclusions These data demonstrate negative effects of VKA on vascular and cardiac phenotypes of subclinical cardiovascular disease, indicating a possible influence on long‐term disease development. These findings may be clinically relevant for the provision of individually tailored antithrombotic therapy.

Cardiac function was assessed by biplane LV ejection fraction (LVEF in %) according to the modified Simpson method in 4-and 2-chamber views. The E/E' ratio as surrogate for diastolic function was calculated by dividing the early filling velocity of transmitral Doppler (E) by the early relaxation velocity on tissue Doppler (E').

Definitions of Cardiovascular Risk Factors and Comorbidities
Arterial hypertension was stated for participants, who at least hold one of the following conditions: a) Intake of hypertensive drugs b) mean systolic blood pressure ≥ 140 mm Hg c) mean diastolic blood pressure ≥ 90 mm Hg or d) definite diagnosis of hypertension by physician. Antidiabetic drug treatment, a fasting blood glucose level ≥ 126 mg/dl after overnight fasting of at least 8 hours, a blood glucose level of ≥ 200 mg/dl after a fasting period of at least 8 hours at the baseline examination or a physician diagnosis of diabetes lead to the diagnosis of diabetes. Dyslipidemia was defined on intake of lipid lowering drugs, a LDL / HDL-ratio of ≥ 3.5 or a definite diagnosis of dyslipidemia by a physician. Smoking was dichotomized into smokers (occasional smokers and smokers) and non-smokers (never smokers and ex-smokers). Anthropometric measurements were taken with calibrated digital scales (Seca 862, Seca, Hamburg, Germany), a measuring stick (Seca 220, Seca, Hamburg, Germany) and a non-stretching waist measuring tape. Waist circumference was measured midway between the lower rib margin and the superior anterior iliac spine. Body height and weight were measured without shoes in underwear and the body mass index (BMI) was calculated as weight in kilograms divided by the scare of height in meters. Obesity was determined as BMI ≥ 30 kg/ m² according to WHO criteria. A positive family history of myocardial infarction or stroke was defined as at least one myocardial infarction or stroke in a female first-degree relative before 65 years of age and in a male first-degree relative before 60 years of age.
The diagnosis of Atrial Fibrillation (AF) was based on the history of AF reported by the participant during the computer assisted interview and/or the evidence of AF on the resting electrocardiogram (ECG) and/or the documentation of AF on the echocardiogram performed during the study. At least two physicians with training and experience in ECG reading had to confirm the diagnosis. Cancer, chronic obstructive pulmonary disease, congestive heart failure, coronary artery disease, deep vein thrombosis, liver disease, myocardial infarction, peripheral arterial disease, pulmonary embolism, and stroke were assessed by self-report of the participants and were collected by computer-assisted personal interviews. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 ml/min/1.73m² assess by a urine sample taken at the study center.

Genotyping and imputation of single nucleotide polymorphism
The search in the GWAS catalogue, accessed on 25th July 2015, resulted in four studies with 11 warfarin metabolism related SNPs. The genetic variants have been investigated in detail; inconsistent results were identified and not considered for further analysis. Two SNPs were present on the Affymetrix array used in this study. The other eight SNPs were tested with SNP Annotation and Proxy Search (http://www.broadinstitute.org/mpg/snap/ldsearch.php) for one or several proxies in linkage disequilibrium (LD) on the array. The following search options were used: r2 threshold = 0.9, distance limit = 500, population panel = CEU, SNP data set = 1000 Genomes Pilot 1.
Overlapping SNPs were excluded from the analysis. For two GWAS SNPs no matching proxy could be found on the Affymetrix 6.0 Array, resulting in five warfarin maintenance dose related SNPs (Table 7). Data are expressed as median with 25th/75th percentile. The prevalence ratio was calculated as the ratio of the frequency for "Intake of VKA" to the one for "No VKA intake". Data are expressed as median with 25 th /75 th percentile. Significant difference between the groups (P <0.0001) was detected for all outcomes. The percentage differences represent the change between "Intake of VKA" compared to "No VKA intake". MR-proANP, Mid-regional Pro-Atrial Natriuretic Peptide; MR-proADM, Midregional Pro-Adrenomedullin; Nt-proBNP, N-terminal pro-brain natriuretic peptide; vWF, von Willebrand factor; hs-CRP, high sensitivity C-reactive protein; IL-18, interleukin-18; IL-1RA, interleukin-1 receptor antagonist; MPO, myeloperoxidase; Data are expressed as median with 25 th /75 th percentile. The percentage differences represent the change between "Intake of VKA" compared to "No VKA intake". All biomarkers were measured in a sample set of the first 5,000 participants, unless otherwise indicated. * measured in a sample set of 15,010 participants

Table S5. Baseline characteristic in the subgroup of participants with atrial fibrillation and indication for oral anticoagulation stratified for VKA use (diagnosis of atrial fibrillation and CHA2DS2-VASc Score of ≥ 1)
Data are expressed as the relative and absolute frequencies for binary variables, for continuous variables as median with 25 th /75 th percentiles. The prevalence ratio was calculated as the ratio of the frequency for "Intake of VKA" to the one for "No VKA intake".   Inverse probability of treatment weighting using the propensity score was applied. The underlying propensity model included age, sex, diabetes mellitus, obesity, smoking, arterial hypertension, dyslipidemia, family history of stroke or myocardial infarction and history of cardiovascular diseases. All standardized differences for those variables between treatment groups after weighting were <0.1.