D-dimer and reduced-dose apixaban for extended treatment after unprovoked venous thromboembolism: the Apidulcis study.

D-dimer assay is used to stratify patients with unprovoked venous thromboembolism (VTE) for the risk of recurrence. However, this approach was never evaluated since direct oral anticoagulants are available. With this multicenter, prospective cohort study, we aimed to assess the value of an algorithm incorporating serial D-dimer testing and administration of reduced-dose apixaban (2.5 mg twice daily) only to patients with a positive test. A total of 732 outpatients aged 18 to 74 years, anticoagulated for ≥12 months after a first unprovoked VTE, were included. Patients underwent D-dimer testing with commercial assays and preestablished cutoffs. If the baseline D-dimer during anticoagulation was negative, anticoagulation was stopped and testing repeated after 15, 30, and 60 days. Patients with serially negative results (286 [39.1%]) were left without anticoagulation. At the first positive result, the remaining 446 patients (60.9%) were given apixaban for 18 months. All patients underwent follow-up planned for 18 months. The study was interrupted after a planned interim analysis for the high rate of primary outcomes (7.3%; 95% confidence interval [CI], 4.5-11.2), including symptomatic proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) recurrence, death for VTE, and major bleeding occurring in patients off anticoagulation vs that in those receiving apixaban (1.1%; 95% CI, 0.4-2.6; adjusted hazard ratio [HR], 8.2; 95% CI, 3.2-25.3). In conclusion, in patients anticoagulated for ≥1 year after a first unprovoked VTE, the decision to further extend anticoagulation should not be based on D-dimer testing. The results confirmed the high efficacy and safety of reduced-dose apixaban against recurrences. This trial was registered at www.clinicaltrials.gov as #NCT03678506.

The risk of post-thrombotic syndrome in patients with proximal deep vein thrombosis treated with the direct oral anticoagulants.

The novel direct oral anticoagulants (DOAC) have been shown to be at least as effective as and safer than conventional anticoagulants for the initial and long-term treatment of venous thromboembolic disorders. However, the rate of post-thrombotic syndrome (PTS) in patients with deep-vein thrombosis (DVT) treated with the DOACs is unknown. With the adoption of the Villalta scale, we assessed the rate of PTS at the end of the follow-up period in a consecutive series of 309 outpatients with acute proximal DVT who had received at least 3 months of treatment with a DOAC and had been followed-up for up to 3 years. The rate of PTS development was compared with that recorded in a historical cohort of 1036 consecutive patients who had been treated with vitamin K antagonists (VKA) and had received a similar follow-up examination. Logistic regression analysis, including propensity scoring to adjust for differing probabilities of undergoing VKA/DOAC, was used to identify predictors of PTS. PTS developed in 87 patients (28.2%) treated with the DOACs (severe in 12), and in 443 patients (42.8%) treated with VKAs (severe in 61). After adjusting for estimated propensity score, age, gender, concomitant symptoms of pulmonary embolism, duration of anticoagulation and development of residual vein thrombosis, the risk of PTS in the DOAC-treated patients was reduced by 54% in comparison to patients treated with conventional anticoagulation (odds ratio 0.46; 95% CI 0.33 to 0.63). We conclude that in comparison to VKAs, the use of the direct oral anticoagulants has the potential to offer a more favorable prognosis in terms of PTS development.

An association between residual vein thrombosis and subclinical atherosclerosis: Cross-sectional study.

BACKGROUND: The association between venous and arterial thrombotic disorders is still unclear. We assessed the association between residual vein thrombosis (RVT) and subclinical atherosclerosis in a cohort of patients with unprovoked (or associated with weak risk factors) proximal deep-vein thrombosis (DVT). METHODS: In a multicenter cross-sectional study, consecutive patients over 40years free from atherosclerotic disorders received the ultrasound assessment of the leg vein system and that of carotid arteries approximately three months after an episode of proximal DVT. In each center the evaluation was done by two independent assessors. The presence of RVT was defined as the incompressibility of at least 4mm in either the popliteal or the common femoral vein, and that of subclinical atherosclerosis as the presence of increased (>0.9mm) intima-media tickness (IMT) and/or carotid plaques. RESULTS: Out of 252 patients (mean age, 67; males, 53%; unprovoked, 77%), the presence of RVT was found in 139 (55.2%). An increased IMT was shown in 76 (54.7%) patients with and in 35 (31.0%) without RVT (p<0.001). At least one carotid plaque was found in 80 (57.6%) patients with and in 36 (31.9%) without RVT (p<0.001). After adjusting for the baseline characteristics, the odds ratio of subclinical atherosclerosis (increased IMT and/or carotid plaques) was 2.8 (95% CI, 1.6 to 4.7). CONCLUSION: The ultrasound detection of RVT after an episode of proximal DVT that is either unprovoked or triggered by weak risk factors is associated with a higher prevalence of subclinical atherosclerosis. These findings may have implications for patient prognosis.

Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism.

The impact of residual pulmonary obstruction on the outcome of patients with pulmonary embolism is uncertain.We recruited 647 consecutive symptomatic patients with a first episode of pulmonary embolism, with or without concomitant deep venous thrombosis. They received conventional anticoagulation, were assessed for residual pulmonary obstruction through perfusion lung scanning after 6 months and then were followed up for up to 3 years. Recurrent venous thromboembolism and chronic thromboembolic pulmonary hypertension were assessed according to widely accepted criteria.Residual pulmonary obstruction was detected in 324 patients (50.1%, 95% CI 46.2-54.0%). Patients with residual pulmonary obstruction were more likely to be older and to have an unprovoked episode. After a 3-year follow-up, recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension developed in 34 out of the 324 patients (10.5%) with residual pulmonary obstruction and in 15 out of the 323 patients (4.6%) without residual pulmonary obstruction, leading to an adjusted hazard ratio of 2.26 (95% CI 1.23-4.16).Residual pulmonary obstruction, as detected with perfusion lung scanning at 6 months after a first episode of pulmonary embolism, is an independent predictor of recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension.

Recanalization rate in patients with proximal vein thrombosis treated with the direct oral anticoagulants.

BACKGROUND: The recanalization rate in patients with deep venous thrombosis (DVT) of the legs treated with the direct oral anticoagulants (DOAC) is unknown. METHODS: In an Italian cohort, we investigated the rate of residual vein thrombosis (RVT) after three and/or six months in 352 patients with proximal DVT who had been treated with the DOACs as a stand-alone therapy or lead-in parenteral anticoagulants, and compared it to that recorded in a historical cohort of 1094 patients in which vitamin K antagonists (VKAs) had been employed. In both cohorts, RVT was defined as the ultrasound persistence of thrombotic material resulting in a diameter of at least 4mm of incompressibility of the proximal veins. RESULTS: RVT was detected in 143 patients treated with DOACs (41.2%) after three months and in 58 patients (21.1%) after six months; the corresponding figure in patients treated with conventional anticoagulation was 52.3% and 54.5%, respectively. After adjusting for the baseline characteristics, the odds ratio of RVT in patients treated with the DOACs as compared with those treated with conventional anticoagulation was 0.63 (95% CI, 0.48-0.81) after three months, and 0.17 (95% CI; 0.11-0.26) after six months. CONCLUSIONS: In patients with proximal DVT treated with the DOACs, the persistence of ultrasound detectable RVT is likely to occur less frequently than in patients treated with conventional anticoagulation. These results may have implications for the prognosis of patients with DVT.

Residual vein thrombosis and serial D-dimer for the long-term management of patients with deep venous thrombosis.

BACKGROUND: The optimal long-term strategy for preventing recurrent venous thromboembolism (VTE) in patients with deep-vein thrombosis (DVT) is uncertain. METHODS: In 620 consecutive outpatients with a first proximal DVT who had completed at least three months of anticoagulation (unprovoked in 483, associated with minor risk factors in 137), the ultrasound presence of residual vein thrombosis (RVT) was assessed and defined as an incompressibility of at least 4mm. In 517 patients without RVT and with negative D-dimer, anticoagulation was stopped and D-dimer was repeated after one and three months. Anticoagulation was resumed in 63 of the 72 patients in whom D-dimer reverted to positivity. RESULTS: During a mean follow-up of three years, recurrent VTE developed in 40 (7.7%) of the 517 patients, leading to an annual rate of 3.6% (95% CI, 2.6 to 4.9): 4.1% (95% CI, 2.9 to 5.7) in individuals with unprovoked DVT, and 2.2% (95% CI, 1.1 to 4.5) in those with DVT associated with minor risk factors. Of the 233 males with unprovoked DVT, 17 (7.3%) developed events in the first year of follow-up. Major bleeding complications occurred in 8 patients while on anticoagulation, leading to an annual rate of 1.2% (95% CI, 0.6 to 2.4). CONCLUSIONS: Discontinuing anticoagulation in patients with a first episode of proximal DVT based on the assessment of RVT and serial D-dimer leads to an overall annual rate of recurrent VTE lower than 5.0%, which is the rate deemed as acceptable by the Subcommittee on Control of Anticoagulation of the ISTH. However, in males with unprovoked DVT there is room for further improving the long-term strategy of VTE prevention. (ClinicalTrials.gov number, NCT01285661).

Isolated systolic hypertension of young-to-middle-age individuals implies a relatively low risk of developing hypertension needing treatment when central blood pressure is low.

OBJECTIVES: The clinical significance of isolated systolic hypertension (ISH) in the young is still controversial. Aim of the present study was to investigate whether prognosis of ISH in young-to-middle-age individuals differs according to central blood pressure (BP). DESIGN: We studied 354 participants screened for stage 1 hypertension and 34 normotensive controls to determine which individuals developed hypertension needing drug therapy. Among the hypertensive patients, 67 had ISH and were divided according to whether their central SBP, measured with applanation tonometry, was above (ISH-high) or below (ISH-low) the median (120.5 mmHg). Large artery (C1) and small artery (C2) compliance were also measured. RESULTS: Compared to normotensive individuals, ISH-high had decreased C1 (P = 0.02) and C2 (P = 0.01), and higher peripheral resistance (P = 0.01). In contrast, in ISH-low, all these variables were similar to those in normotensive individuals. During 9.5 years of follow-up, incident hypertension was more common among participants with systolic-diastolic hypertension (SDH) and ISH-high than the other two groups [odds ratio (OR) = 6.2, 95% confidence interval (CI) = 1.8-21.1, P = 0.003 for SDH; OR = 6.0, 95% CI = 1.5-24.0, P = 0.01 for ISH-high, versus normotensive individuals]. Among ISH-low, incidence of hypertension was only slightly higher than that in normotensive individuals (OR = 1.1, 95% CI 0.2-5.3, P = 0.90) and lower than that in ISH-high (P = 0.03). These associations remained significant when ambulatory BP was included in the models or when the 125 mmHg cut-off for central BP was used to identify ISH subgroups. CONCLUSION: These data show that young-to-middle-age ISH individuals with low central BP have a lower risk of hypertension needing treatment than those with high central BP. These results are applicable mainly to male individuals.

Resting heart rate as a predictor of body weight gain in the early stage of hypertension.

We did a prospective study to investigate whether clinic heart rate (HR) and 24-h ambulatory HR were independent predictors of subsequent increase in body weight (BW) in young subjects screened for stage 1 hypertension. The study was conducted in 1,008 subjects from the Hypertension and Ambulatory Recording Venetia Study (HARVEST) followed for an average of 7 years. Ambulatory HR was obtained in 701 subjects. Data were adjusted for lifestyle factors and several confounders. During the follow-up BW increased by 2.1 ± 7.2 kg in the whole cohort. Both baseline clinic HR (P = 0.007) and 24-h HR (P = 0.013) were independent predictors of BMI at study end. In addition, changes in HR during the follow-up either measured in the clinic (P = 0.036) or with 24-h recording (P = 0.009) were independent associates of final BMI. In a multivariable Cox regression, baseline BMI (P < 0.001), male gender (P < 0.001), systolic blood pressure (BP) (P = 0.01), baseline clinic HR (P = 0.02), and follow-up changes in clinic HR (P < 0.001) were independent predictors of overweight (Ov) or obesity (Ob) at the end of the follow-up. Follow-up changes in ambulatory HR (P = 0.01) were also independent predictors of Ov or Ob. However, when both clinic and ambulatory HRs were included in the same Cox model, only baseline clinic HR and its change during the follow-up were independent predictors of outcome. In conclusion, baseline clinic HR and HR changes during the follow-up are independent predictors of BW gain in young persons screened for stage 1 hypertension suggesting that sympathetic nervous system activity may play a role in the development of Ob in hypertension.

Regular physical activity attenuates the blood pressure response to public speaking and delays the development of hypertension.

OBJECTIVES: The objective of this study was to investigate the effect of regular physical activity on the haemodynamic response to public speaking and to evaluate the long-term effect of exercise on development of hypertension. PARTICIPANTS: We assessed 75 sedentary and 44 active participants screened for stage 1 hypertension with consistent activity habits and 63 normotensive individuals as control. METHODS: The blood pressure (BP) response to public speaking was assessed with beat-to-beat noninvasive recording. Definition of incident hypertension was based either on clinic or 24-h BP measurement. RESULTS: The BP response to public speaking was greater in the hypertensive than the normotensive participants (P=0.018/0.009). Among the former, sedentary participants showed increased BP reactivity to the speech test (45.2+/-22.6/22.2+/-11.5mmHg, P<0.01/<0.001 versus controls), whereas physically active participants had a response similar to that of controls (35.4+/-18.5/18.5+/-11.5mmHg, P=not significant). During a median follow-up of 71 months, ambulatory BP did not virtually change in the active participants (-0.9+/-7.8/-0.0+/-4.7mmHg) and increased in their sedentary peers (2.8+/-9.8/3.2+/-7.4mmHg, P=0.08/0.003 versus active). Active participants were less likely to develop incident hypertension than sedentary ones. After controlling for several confounders including baseline heart rate, the hazard ratio was 0.53 [95% confidence interval (CI) 0.31-0.94] for clinic hypertension and 0.60 (95% CI 0.37-0.99) for ambulatory hypertension. Inclusion of BP response to public speaking into the Cox model influenced the strength of the association only marginally [hazard ratio=0.55 (95% CI 0.30-0.97) and hazard ratio=0.59 (95% CI 0.36-0.99), respectively]. CONCLUSION: Regular physical activity attenuates the BP reaction to psychosocial stressors. However, this mechanism seems to be only partially responsible for the long-term effect of exercise on BP.

Serial 2-point ultrasonography plus D-dimer vs whole-leg color-coded Doppler ultrasonography for diagnosing suspected symptomatic deep vein thrombosis: a randomized controlled trial.

CONTEXT: Patients with suspected deep vein thrombosis (DVT) of the lower extremities are usually investigated with ultrasonography either by the proximal veins (2-point ultrasonography) or the entire deep vein system (whole-leg ultrasonography). The latter approach is thought to be better based on its ability to detect isolated calf vein thrombosis; however, it requires skilled operators and is mainly available only during working hours. No randomized comparisons are yet available evaluating the relative values of these 2 strategies. OBJECTIVE: To assess if the 2 diagnostic strategies are equivalent for the management of symptomatic outpatients with suspected DVT of the lower extremities. DESIGN, SETTING, AND PATIENTS: A prospective, randomized, multicenter study of consecutive symptomatic outpatients (n = 2465) with a first episode of suspected DVT of the lower extremities who were randomized to undergo 2-point or whole-leg ultrasonography. Data were taken from ultrasound laboratories of 14 Italian universities or civic hospitals between January 1, 2003, and December 21, 2006. Patients with normal ultrasound findings were followed up for 3 months, with study completion on March 20, 2007. MAIN OUTCOME MEASURE: Objectively confirmed 3-month incidence of symptomatic venous thromboembolism in patients with an initially normal diagnostic workup. RESULTS: Of 2465 eligible patients, 345 met 1 or more exclusion criteria and 22 refused to participate; therefore, 2098 patients were randomized to either 2-point (n = 1045) or whole-leg (n = 1053) ultrasonography. Symptomatic venous thromboembolism occurred in 7 of 801 patients (incidence, 0.9%; 95% confidence interval [CI], 0.3%-1.8%) in the 2-point strategy group and in 9 of 763 patients (incidence, 1.2%; 95% CI, 0.5%-2.2%) in the whole-leg strategy group. This met the established equivalence criterion (observed difference, 0.3%;95% CI, -1.4% to 0.8%). CONCLUSION: The 2 diagnostic strategies are equivalent when used for the management of symptomatic outpatients with suspected DVT of the lower extremities. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00353093.

[Appropriateness of requests of echo-color-Doppler tests]. / L'appropriatezza nelle richieste degli esami eco-color-doppler.

Technological development of ultrasound has allowed diagnosis of diseases that one would be able to see later. These easy and harmless examinations have produced an increasing in demand not always justified, as one could think to reach simply a shining diagnosis. The authors evaluated the appropriate use of each color-doppler sonography request in agreement with published guidelines. Nine hundred eighty six requests were examined in three months: 60.2% of them were not appropriate. Carotid-vertebral arteries were the group with higher inappropriate use (67.9%) and also the urgent exams have 21.9% of inappropriate use. When clinical reason was missing in the request, the inappropriate use reached 70%. The 52.9% of examinations have not revealed any vascular pathology and among appropriate exams the 31.7% was disease free. Although angiology clinical guidelines have been recently published in Italy, the data suggest a poor clinical valuation of suspected vascular patient (70% of not appropriate examination when clinical problem was lacking); this may be the answer for both the enormous color-doppler requests, high inappropriate use and normal results. Authors think that a way to lower this high grade of color-doppler exams may be to take in appropriate consideration clinical approach, fact that also permit a correct interpretation of ultrasonographic data.