Long-term outcomes of elderly patients with CYP2C9 and VKORC1 variants treated with vitamin K antagonists.

Essentials The long-term effects of VKORC1 and CYP2C9 variants on clinical outcomes remains unclear. We followed 774 patients ≥65 years with venous thromboembolism for a median duration of 30 months. Patients with CYP2C9 variants are at increased risk of death and non-major bleeding. Patients with genetic variants have a slightly lower anticoagulation quality only. SUMMARY: Background The long-term effect of polymorphisms of the vitamin K-epoxide reductase (VKORC1) and the cytochrome P450 enzyme gene (CYP2C9) on clinical outcomes remains unclear. Objectives We examined the association between CYP2C9/VKORC1 variants and long-term clinical outcomes in a prospective cohort study of elderly patients treated with vitamin K antagonists for venous thromboembolism (VTE). Methods We followed 774 consecutive patients aged ≥ 65 years with acute VTE from nine Swiss hospitals for a median duration of 30 months. The median duration of initial anticoagulant treatment was 9.4 months. The primary outcome was the time to any clinical event (i.e. the composite endpoint of overall mortality, major and non-major bleeding, and recurrent VTE. Results Overall, 604 (78%) patients had a CYP2C9 or VKORC1 variant. Three hundred and thirty-four patients (43.2%) had any clinical event, 119 (15.4%) died, 100 (12.9%) had major and 167 (21.6%) non-major bleeding, and 100 had (12.9%) recurrent VTE. After adjustment, CYP2C9 (but not VKORC1) variants were associated with any clinical event (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.08-1.66), death (HR, 1.74; 95% CI, 1.19-2.52) and clinically relevant non-major bleeding (sub-hazard ratio [SHR], 1.39; 95% CI, 1.02-1.89), but not with major bleeding (SHR, 1.03; 95% CI, 0.69-1.55) or recurrent VTE (SHR, 0.95; 95% CI, 0.62-1.44). Patients with genetic variants had a slightly lower anticoagulation quality. Conclusions CYP2C9 was associated with long-term overall mortality and non-major bleeding. Although genetic variants were associated with a slightly lower anticoagulation quality, there was no relationship between genetic variants and major bleeding or VTE recurrence.

Association between thyroid dysfunction and venous thromboembolism in the elderly: a prospective cohort study.

BACKGROUND: Venous thromboembolism (VTE) and subclinical thyroid dysfunction (SCTD) are both common in elderly patients. SCTD has been related to a hypercoagulable state and an increased thromboembolic risk. However, prospective data on the relationship between SCTD and VTE are lacking. OBJECTIVES: To investigate the relationship between SCTD and recurrent VTE (rVTE), all-cause mortality, and thrombophilic biomarkers. Patients Elderly patients with VTE were studied. METHODS: In a prospective multicenter cohort, thyroid hormones and thrombophilic biomarkers were measured 1 year after acute VTE, as both may be influenced by acute thrombosis. We defined subclinical hypothyroidism (SHypo) as elevated thyroid-stimulating hormone (TSH) levels (4.50-19.99 mIU L(-1) ), and subclinical hyperthyroidism (SHyper) as TSH levels of < 0.45 mIU L(-1) , both with normal free thyroxine levels. Outcomes were incidence of rVTE and overall mortality during follow-up starting after the 1-year blood sampling. RESULTS: Of 561 participants (58% with anticoagulation), 6% had SHypo and 5% had SHyper. After 20.8 months of mean follow-up, 9% developed rVTE and 10% died. The rVTE incidence rate was 7.2 (95% confidence interval [CI] 2.7-19.2) per 100 patient-years in SHypo participants, 0.0 (95% CI 0.0-7.6) in SHyper participants, and 5.9 (95% CI 4.4-7.8) in euthyroid participants. In multivariate analyses, the sub-hazard ratio for rVTE was 0.00 (95% CI 0.00-0.58) in SHyper participants and 1.50 (95% CI 0.52-4.34) in SHypo participants as compared with euthyroid participants, without increased levels of thrombophilic biomarkers. SHyper (hazard ratio [HR] 0.80, 95% CI 0.23-2.81) and SHypo (HR 0.99, 95% CI 0.30-3.29) were not associated with mortality. CONCLUSION: In elderly patients, SHyper may be associated with lower rVTE risks. SHypo showed a non-statistically significant pattern of an association with rVTE, without increased mortality or differences in thrombophilic biomarkers.

Physical activity and risk of bleeding in elderly patients taking anticoagulants.

BACKGROUND: Although the possibility of bleeding during anticoagulant treatment may limit patients from taking part in physical activity, the association between physical activity and anticoagulation-related bleeding is uncertain. OBJECTIVES: To determine whether physical activity is associated with bleeding in elderly patients taking anticoagulants. PATIENTS/METHODS: In a prospective multicenter cohort study of 988 patients aged ≥ 65 years receiving anticoagulants for venous thromboembolism, we assessed patients' self-reported physical activity level. The primary outcome was the time to a first major bleeding, defined as fatal bleeding, symptomatic bleeding in a critical site, or bleeding causing a fall in hemoglobin or leading to transfusions. The secondary outcome was the time to a first clinically relevant non-major bleeding. We examined the association between physical activity level and time to a first bleeding by using competing risk regression, accounting for death as a competing event. We adjusted for known bleeding risk factors and anticoagulation as a time-varying covariate. RESULTS: During a mean follow-up of 22 months, patients with a low, moderate, and high physical activity level had an incidence of major bleeding of 11.6, 6.3, and 3.1 events per 100 patient-years and an incidence of clinically relevant non-major bleeding of 14.0, 10.3, and 7.7 events per 100 patient-years, respectively. A high physical activity level was significantly associated with a lower risk of major bleeding (adjusted sub-hazard ratio 0.40, 95% confidence interval 0.22-0.72). There was no association between physical activity and non-major bleeding. CONCLUSIONS: A high level of physical activity is associated with a decreased risk of major bleeding in elderly patients receiving anticoagulant therapy.

Risk of falls and bleeding in elderly patients with acute venous thromboembolism.

OBJECTIVE: Whether or not a high risk of falls increases the risk of bleeding in patients receiving anticoagulants remains a matter of debate. METHODS: We conducted a prospective cohort study involving 991 patients ≥ 65 years of age who received anticoagulants for acute venous thromboembolism (VTE) at nine Swiss hospitals between September 2009 and September 2012. The study outcomes were as follows: the time to a first major episode of bleeding; and clinically relevant nonmajor bleeding. We determined the associations between the risk of falls and the time to a first episode of bleeding using competing risk regression, accounting for death as a competing event. We adjusted for known bleeding risk factors and anticoagulation as a time-varying covariate. RESULTS: Four hundred fifty-eight of 991 patients (46%) were at high risk of falls. The mean duration of follow-up was 16.7 months. Patients at high risk of falls had a higher incidence of major bleeding (9.6 vs. 6.6 events/100 patient-years; P = 0.05) and a significantly higher incidence of clinically relevant nonmajor bleeding (16.7 vs. 8.3 events/100 patient-years; P < 0.001) than patients at low risk of falls. After adjustment, a high risk of falls was associated with clinically relevant nonmajor bleeding [subhazard ratio (SHR) = 1.74, 95% confidence interval (CI) = 1.23-2.46], but not with major bleeding (SHR = 1.24, 95% CI = 0.83-1.86). CONCLUSION: In elderly patients who receive anticoagulants because of VTE, a high risk of falls is significantly associated with clinically relevant nonmajor bleeding, but not with major bleeding. Whether or not a high risk of falls is a reason against providing anticoagulation beyond 3 months should be based on patient preferences and the risk of VTE recurrence.

Prospective, multicenter validation of prediction scores for major bleeding in elderly patients with venous thromboembolism.

BACKGROUND: The Outpatient Bleeding Risk Index (OBRI) and the Kuijer, RIETE and Kearon scores are clinical prognostic scores for bleeding in patients receiving oral anticoagulants for venous thromboembolism (VTE). We prospectively compared the performance of these scores in elderly patients with VTE. METHODS: In a prospective multicenter Swiss cohort study, we studied 663 patients aged ≥ 65 years with acute VTE. The outcome was a first major bleeding at 90 days. We classified patients into three categories of bleeding risk (low, intermediate and high) according to each score and dichotomized patients as high vs. low or intermediate risk. We calculated the area under the receiver-operating characteristic (ROC) curve, positive predictive values and likelihood ratios for each score. RESULTS: Overall, 28 out of 663 patients (4.2%, 95% confidence interval [CI] 2.8-6.0%) had a first major bleeding within 90 days. According to different scores, the rate of major bleeding varied from 1.9% to 2.1% in low-risk, from 4.2% to 5.0% in intermediate-risk and from 3.1% to 6.6% in high-risk patients. The discriminative power of the scores was poor to moderate, with areas under the ROC curve ranging from 0.49 to 0.60 (P = 0.21). The positive predictive values and positive likelihood ratios were low and varied from 3.1% to 6.6% and from 0.72 to 1.59, respectively. CONCLUSION: In elderly patients with VTE, existing bleeding risk scores do not have sufficient accuracy and power to discriminate between patients with VTE who are at a high risk of short-term major bleeding and those who are not.

Prospective comparison of clinical prognostic scores in elder patients with a pulmonary embolism.

BACKGROUND: The Geneva Prognostic Score (GPS), the Pulmonary Embolism Severity Index (PESI) and its simplified version (sPESI) are well-known clinical prognostic scores for a pulmonary embolism (PE). OBJECTIVES: To compare the prognostic performance of these scores in elderly patients with a PE. PATIENTS AND METHODS: In a multicenter Swiss cohort of elderly patients with venous thromboembolism, we prospectively studied 449 patients aged ≥ 65 years with a symptomatic PE. The outcome was 30-day overall mortality. We dichotomized patients as low vs. higher risk in all three scores using the following thresholds: GPS scores ≤ 2 vs. > 2, PESI risk classes I-II vs. III-V and sPESI scores 0 vs. ≥ 1. We compared 30-day mortality in low- vs. higher-risk patients and the areas under the receiver-operating characteristic curve (ROC). RESULTS: Overall, 3.8% of patients (17/449) died within 30 days. The GPS classified a greater proportion of patients as low risk (92% [413/449]) than the PESI (36.3% [163/449]) and the sPESI (39.6% [178/449]) (P < 0.001 for each comparison). Low-risk patients based on the sPESI had a mortality of 0% (95% confidence interval [CI] 0-2.1%) compared with 0.6% (95% CI 0-3.4%) for low-risk patients based on the PESI and 3.4% (95% CI 1.9-5.6%) for low-risk patients based on the GPS. The areas under the ROC curves were 0.77 (95% CI 0.72-0.81), 0.76 (95% CI 0.72-0.80) and 0.71 (95% CI 0.66-0.75), respectively (P = 0.47). CONCLUSIONS: In this cohort of elderly patients with PE, the GPS identified a higher proportion of patients as low risk but the PESI and sPESI were more accurate in predicting mortality.

Decreased umbilical artery compliance and igf-I plasma levels in infants with intrauterine growth restriction - implications for fetal programming of hypertension.

Epidemiological studies link intrauterine growth restriction (IUGR) to arterial hypertension in adulthood. We compared umbilical arteries from IUGR (n=12, <5th weight percentile) vs. appropriate for gestational age (AGA) infants (n=12) using structural and functional analyses. The vessel wall area of umbilical arteries in the IUGR group was significantly smaller than in the AGA group (2.8 vs. 3.8mm(2), P<0.05). Myographic measurements showed that maximal tension [mN/mm] as well as maximal force [mN] were both significantly increased in IUGR arteries compared with AGA arteries (P<0.05). Serum levels of IGF-I, a regulator of elastin synthesis, were significantly lower in IUGR cord blood (P<0.01) than in AGA cord blood. These IGF-I serum levels correlated significantly with maximum tension in umbilical arteries (P<0.01). Low intrauterine IGF-I serum levels may account for thinner and stiffer umbilical arteries in IUGR infants in comparison to AGA infants thereby providing a potential link to arterial hypertension in adulthood.

Hyperglycemia inhibits vascular smooth muscle cell apoptosis through a protein kinase C-dependent pathway.

We hypothesized that the pathogenesis of diabetic vasculopathy involves the abnormal regulation of vascular smooth muscle cell (VSMC) apoptosis. In nondiabetic mice, a reduction in carotid artery blood flow resulted in a significant loss of medial VSMCs via apoptosis (normal flow 84+/-1 viable VSMCs, reduced flow 70+/-5 viable VSMCs; n=12, P:<0.01). In contrast, flow-induced VSMC apoptosis was markedly attenuated in streptozotocin-induced diabetic mice (normal flow 85+/-2 viable VSMC, reduced flow 82+/-4 viable VSMC; n=13, NS). In accord with our in vivo findings, the exposure of cultured rat and human VSMCs to high glucose (17.5 mmol/L) significantly attenuated the induction of apoptosis in response to serum withdrawal (rat VSMCs in normal [5.5 mmol/L] glucose 28+/-1%, high D-glucose 19+/-2%; P:<0.0001). High glucose also inhibited apoptosis induced by Fas ligand (100 ng/mL) (normal 23+/-2%, high D-glucose 13+/-2%; P:<0.006). Supplementation with the nonmetabolized enantiomer L-glucose had no effect. We confirmed reports that high glucose activates protein kinase C (PKC) and demonstrated that PKC blockade with long-term phorbol ester treatment or calphostin C prevented the antiapoptotic effect (P:<0. 001). Moreover, the upregulation of either PKCalpha or PKCbetaII expression was sufficient to inhibit serum withdrawal-induced apoptosis (control 25+/-2%, PKCalpha 11+/-2%, PKCbetaII 8+/-2%; P:<0. 0001), whereas the upregulation of PKCdelta had no significant effect. Taken together, these findings demonstrate that hyperglycemia inhibits VSMC apoptosis via a PKC-dependent pathway.

Effect of NO donors on LV diastolic function in patients with severe pressure-overload hypertrophy.

BACKGROUND: Previous experimental studies have shown that nitric oxide (NO) modulates cardiac function by an abbreviation of systolic contraction and an enhancement of diastolic relaxation. However, the response to NO donors of patients with severe pressure-overload hypertrophy and diastolic dysfunction is unknown. METHODS AND RESULTS: Intracoronary NO donors were given to 17 patients with severe aortic stenosis. A dose-response curve was obtained with nitroglycerin (30, 90, and 150 microg) in 11 patients and sodium nitroprusside (1, 2, and 4 microg/min) in 6. Left ventricular (LV) high-fidelity pressure measurements with simultaneous LV angiograms were performed at baseline and after the maximal dose of NO. The dose-response curve for intracoronary NO donors showed a marked fall in LV end-diastolic pressure, from 23 to 14 mm Hg (-39%; P<0.0001), whereas LV peak systolic pressure fell only slightly, from 206 to 196 mm Hg (-4%; P<0.01). End-diastolic chamber stiffness decreased from 0.12 to 0.07 mm Hg/mL (P<0.0001) and end-systolic stiffness from 1.6 to 1.3 mm Hg/mL (P<0.01). Heart rate, right atrial pressure, LV ejection fraction, the time constant of isovolumic pressure decay (tau), and LV filling rates remained unchanged. CONCLUSIONS: In patients with severe pressure-overload hypertrophy, intracoronary NO donors exert a marked decrease in LV end-diastolic pressure without affecting LV systolic pump function. Thus, the hypertrophied myocardium appears to be particularly susceptible to NO donors, with a marked improvement in diastolic function.