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Background There is a paucity of data on the long-term clinical outcomes according to the severity of pulmonary embolism (PE) at initial diagnosis. Methods The COMMAND VTE Registry is a multicenter registry enrolling 3027 consecutive patients with acute symptomatic venous thromboembolism (VTE). After excluding 1312 patients without PE, the current study population consisted of 1715 patients with PE, who were divided into 3 groups according to the clinical severity; massive PE, sub-massive PE and low-risk PE. Results There were 179 patients (10%) with massive PE, 742 patients (43%) with sub-massive PE, and 794 patients (46%) with low-risk PE. By the landmark analysis at 3 months, the cumulative incidences of recurrent VTE were similar among the 3 groups both within and beyond 3 months (Massive PE: 2.9%, Sub-massive PE: 4.2%, and Low-risk PE: 3.3%, P = 0.61, and 4.3%, 8.8%, and 7.8% at 5 years, P = 0.47, respectively). After adjusting confounders, the risk of massive PE relative to low-risk PE for recurrent VTE beyond 3 months remained insignificant (adjusted HR 0.54, 95% CI: 0.13–1.51, P = 0.27). Patients with massive PE at initial diagnosis more often presented as severe recurrent PE events than those with sub-massive and low-risk PE. Conclusions In the current real-world large registry, the long-term risk of overall recurrent VTE in patients with massive PE at initial diagnosis did not significantly differ from those with sub-massive and low-risk PE beyond 3 months, although patients with massive PE at initial diagnosis more frequently developed recurrent VTE as PE with severe clinical presentation.

Anticoagulation therapy is prescribed for the prevention of recurrence in patients with venous thromboembolism, which could be temporarily interrupted during invasive procedures. The COMMAND VTE Registry is a multicenter registry enrolling 3027 consecutive patients with acute symptomatic VTE in Japan between January 2010 and August 2014. We identified patients who underwent invasive procedures during the entire follow-up period and evaluated periprocedural managements and clinical outcomes at 30 days after invasive procedures. During a median follow-up period of 1213 (IQR: 847–1764) days, 518 patients underwent invasive procedures with the cumulative incidences of 5.8% at 3 months, 11.1% at 1 year, and 24.0% at 5 years. Among 382 patients in high bleeding-risk category of invasive procedures, anticoagulation therapy had been discontinued already in 62 patients (16%) and interrupted temporarily in 288 patients (75%) during the invasive procedures with bridging anticoagulation therapy with heparin in 214 patients (56%). Among 80 patients in low bleeding-risk category, anticoagulation therapy had been already discontinued in 15 patients (19%) and interrupted temporarily in 31 patients (39%) during invasive procedure with bridging anticoagulation therapy with heparin in 17 patients (21%). At 30 days after the invasive procedures, 14 patients (2.7%) experienced recurrent VTE, while 28 patients (5.4%) had major bleeding. This study elucidated the real-world features of peri-procedural management and prognosis in patients with VTE who underwent invasive procedures during follow-up in the large multicenter VTE registry. The 30-day incidence rates of recurrent VTE and major bleeding events were 2.7% and 5.4%.

Prolonged anticoagulation therapy is recommended for patients with intermediate-risk for recurrence of venous thromboembolism (VTE). The current study aimed to identify risk factors of VTE recurrence and major bleeding in intermediate-risk patients. The COMMAND VTE Registry is a multicenter registry enrolled consecutive 3027 patients with acute symptomatic VTE among 29 centers in Japan. The current study population consisted of 1703 patients with intermediate-risk for recurrence. The primary outcome measure was recurrent VTE during the entire follow-up period, and the secondary outcome measures were recurrent VTE and major bleeding during anticoagulation therapy. In the multivariable Cox regression model for recurrent VTE incorporating the status of anticoagulation therapy as a time-updated covariate, off-anticoagulation therapy was strongly associated with an increased risk for recurrent VTE (HR 9.42, 95% CI 5.97–14.86). During anticoagulation therapy, the independent risk factor for recurrent VTE was thrombophilia (HR 3.58, 95% CI 1.56–7.50), while the independent risk factors for major bleeding were age ≥ 75 years (HR 2.04, 95% CI 1.36–3.07), men (HR 1.52, 95% CI 1.02–2.27), history of major bleeding (HR 3.48, 95% CI 1.82–6.14) and thrombocytopenia (HR 3.73, 95% CI 2.04–6.37). Among VTE patients with intermediate-risk for recurrence, discontinuation of anticoagulation therapy was a very strong independent risk factor of recurrence during the entire follow-up period. The independent risk factors of recurrent VTE and those of major bleeding during anticoagulation therapy were different: thrombophilia for recurrent VTE, and advanced age, men, history of major bleeding, and thrombocytopenia for major bleeding. Unique identifier: UMIN000021132. COMMAND VTE Registry: http://www.umin.ac.jp/ctr/index.htm .

Background The majority of acute pulmonary embolism (PE) is caused by thrombus developed from leg veins. However, impact of concomitant deep venous thrombosis (DVT) on clinical outcomes has not been fully evaluated in patients with acute PE. Methods The COMMAND VTE Registry is a multicenter registry enrolling consecutive 3027 patients with acute symptomatic venous thromboembolism (VTE) in Japan. The current study population consisted of 655 acute PE patients who underwent lower extremities ultrasound examination at diagnosis for the assessment of concomitant DVT status. Results There were 424 patients with proximal DVT (64.7%), 162 patients with distal DVT (24.7%), and 69 patients with no DVT (10.5%). The cumulative 90-day incidence of all-cause death was higher in proximal DVT patients than in distal DVT and no DVT patients (7.9%, 2.5%, and 1.4%, p = 0.01). Regarding the causes of death, the cumulative 90-day incidence of PE-related death was low, and not significantly different across the 3 groups (1.4%, 0.6%, and 1.7%, p = 0.62). The most frequent cause of death was cancer in proximal and distal DVT patients. There were no significant differences in 90-day rates of recurrent VTE and major bleeding, regardless of the status of concomitant DVT (2.9%, 3.2%, and 2.2%, p = 0.79, and 1.5%, 4.4%, and 4.9%, p = 0.46, respectively). Conclusions Acute PE with proximal DVT at diagnosis was associated with a higher risk for short-term mortality than in patients without DVT, while the risk for short-term mortality was not significantly different between distal DVT patients and patients without DVT.

There are uncertainties on the influence of the days of diagnosis in a week (weekends versus weekdays) on clinical outcomes in patients with acute venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT). The COMMAND VTE registry is a multicenter cohort study enrolling 3027 consecutive patients with acute symptomatic VTE. The current study population consisted of 337 patients diagnosed on weekends and 2690 patients diagnosed on weekdays. We compared the clinical characteristics, management strategies and 30-day outcomes between the 2 groups. The patients diagnosed on weekends more often presented with PE (72% vs. 55%, P

Background The simplified Pulmonary Embolism Severity Index (sPESI) score is a practical score for identification of patients with low-risk pulmonary embolism (PE), although it has not been applied in patients with active cancer. The current study aimed to evaluate the usefulness of the sPESI score in patients with PE and active cancer. Methods The COMMAND VTE Registry is a multicenter registry enrolling consecutive patients with acute symptomatic VTE. The current study population consisted of 368 patients with PE and active cancer. The 30-day clinical outcomes were compared between patients with sPESI score = 1 and patients with sPESI scores ≥ 2. Results Overall, 37 patients (10%) died during the 30 days after diagnosis. The cumulative 30-day incidences of mortality, and PE-related death, were lower in patients with sPESI score = 1 than in patients with sPESI scores ≥ 2 (6.3% vs 13.1%; log-rank P = .03; and 0.7% vs 3.9%; log-rank P = .046). Among patients with sPESI score = 1, the predominant cause of death was cancer. There were no significant differences in the cumulative 30-day incidence of recurrent VTE and major bleeding between the two groups (3.9% vs 5.6%; log-rank P = .46; and 6.4% vs 4.5%; log-rank P = .45). Conclusions Among patients with PE and active cancer, patients with sPESI score = 1 had a lower 30-day mortality rate compared with patients with sPESI scores ≥ 2, and they showed very low PE-related mortality risk, although the overall mortality rate remained high because of cancer-related mortality. They also showed relatively high risks for recurrence and major bleeding, suggesting the need for careful follow-up. Trial Registry UMIN Clinical Trials Registry; No.: UMIN000021132; URL: http://www.umin.ac.jp/ctr/index.htm

Vitamin K antagonist (VKA) remains an essential option for venous thromboembolism (VTE), although direct oral anticoagulants have become available. However, there is a paucity of data on the optimal intensity and quality of control for VKA in Japanese.The COMMAND VTE Registry is a multicenter registry enrolling consecutive 3027 patients with acute symptomatic VTE among 29 centers in Japan. The current study population consisted of 1938 patients who received VKA with prothrombin time-international normalized ratio (PT-INR) measurement5 times. The primary outcome measure was a composite of symptomatic VTE recurrence or major bleeding at 1 year. The presumed optimal quality of VKA therapy was defined as the combination of PT-INR range and time in therapeutic range (TTR) with the numerically lowest event rate.The group with TTR ≥70 % based on PT-INR range ≥1.5 and2.0 showed the lowest cumulative incidence rate. The cumulative 1-year incidence and the adjusted risk for the primary outcome measure were significantly lower in the optimal quality group than in the non-optimal quality group (5.2 % vs. 11.7 %, p = 0.001, and HR 0.49, 95%CI 0.28-0.81). Similarly, the cumulative 1-year incidences of a recurrent VTE, major bleeding, and all-cause death were significantly lower in the optimal quality group (recurrent VTE: 2.5 % vs. 6.0 %, p = 0.02; major bleeding: 2.8 % vs. 7.0 %, p = 0.008; and all-cause death: 2.8 % vs. 12.6 %, p 0.0001). The lower risk of the optimal quality group relative to non-optimal quality group for the clinical outcomes was consistent regardless of the etiology of VTE (active cancer, transient risk factor, and unprovoked).The current VTE registry showed the optimal intensity of VKA therapy was target PT-INR range ≥1.5 and2.0, which could support the current Japanese guideline recommendation, and the good quality of control for VKA therapy of TTR ≥70 % was independently associated with better outcomes.

Objectives: The aim of this study was to investigate the prognostic impact of the decline in left ventricular ejection fraction (LVEF) at 1-year follow-up in patients with severe aortic stenosis (AS) managed conservatively. Background: No previous study has explored the association between LVEF decline during follow-up and clinical outcomes in patients with severe AS. Methods: Among 3, 815 patients with severe AS enrolled in the multicenter CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry in Japan, 839 conservatively managed patients who underwent echocardiography at 1-year follow-up were analyzed. The primary outcome measure was a composite of AS-related deaths and hospitalization for heart failure. Results: There were 91 patients (10.8%) with >10% declines in LVEF and 748 patients (89.2%) without declines. Left ventricular dimensions and the prevalence of valve regurgitation and atrial fibrillation or flutter significantly increased in the group with declines in LVEF. The cumulative 3-year incidence of the primary outcome measure was significantly higher in the group with declines in LVEF than in the group with no decline (39.5% vs. 26.5%; p < 0.001). After adjusting for confounders, the excess risk of decline in LVEF over no decline for the primary outcome measure remained significant (hazard ratio: 1.98; 95% confidence interval: 1.29 to 3.06). When stratified by LVEF at index echocardiography (≥70%, 60% to 69%, and 10% declines in LVEF at 1 year after diagnosis had worse AS-related clinical outcomes than those without declines in LVEF under conservative management. (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis Registry; UMIN000012140)

The duration of anticoagulation therapy after venous thromboembolism (VTE) should be based on the balance between risks of recurrent VTE and bleeding. However, there is uncertainty about the impact of these events on subsequent mortality.We evaluated the association of recurrent VTE and major bleeding events with mortality among 3026 patients in the COMMAND VTE Registry. We estimated the risks of the recurrent VTE events and the major bleeding events for subsequent mortality by the time-updated multivariable Cox proportional hazard model.During the median follow-up period of 1218 days, 225 patients developed recurrent VTE events, 274 patients developed major bleeding events, and 763 patients died. The multivariable Cox proportional hazard model revealed that both the recurrent VTE and major bleeding events were strongly associated with subsequent mortality risk (recurrent VTE: HR 3.24, 95%CI 2.57-4.08, P 0.001; major bleeding: HR 3.53, 95%CI 2.88-4.31, P 0.001). Both the recurrent pulmonary embolism (PE) and recurrent deep vein thrombosis (DVT) events were associated with subsequent mortality risk (recurrent PE events: HR 4.42, 95%CI 3.28-5.95, P 0.001; recurrent DVT events: HR 2.42, 95%CI 1.75-3.36, P 0.001).In the real-world patients with VTE, both the recurrent VTE events and the major bleeding events were strongly associated with subsequent mortality risk with the comparable effect size. The recurrent PE and recurrent DVT events were also associated with increased risks for mortality, although the magnitude of the effect on mortality was numerically greater with the recurrent PE events than with the recurrent DVT events.

The relationship between D-dimer level at diagnosis and long-term clinical outcomes has not been fully evaluated in venous thromboembolism (VTE). The COMMAND VTE Registry is a multicenter registry enrolling consecutive acute symptomatic VTE patients in Japan. Patients with available D-dimer levels at diagnosis (N = 2852) were divided into 4 groups according to the D-dimer levels; Quartile 1 (0.0–4.9 µg/mL): N = 682, Quartile 2 (5.0–9.9 µg/mL) N = 694, Quartile 3 (10.0–19.9 µg/mL) N = 710, and Quartile 4 (≥ 20.0 µg/mL): N = 766. The cumulative incidence of all-cause death was higher in Quartile 4 throughout the entire follow-up period (19.9%, 24.9%, 28.8%, and 41.5% at 5-year, P

Background There are limited data assessing the risk for bleeding on anticoagulation therapy beyond the acute phase in patients with venous thromboembolism (VTE). The present study aimed to identify risk factors for major bleeding during prolonged anticoagulation therapy in VTE patients. Patients and Methods The COMMAND VTE Registry is a multicenter registry enrolling 3,027 consecutive patients with acute symptomatic VTE. The current study population consisted of 2,728 patients who received anticoagulation therapy beyond the acute phase, after excluding those patients with major bleeding events (n = 48), death (n = 66), or loss to follow-up (n = 32) during the initial parenteral anticoagulation period within 10 days after diagnosis, and those without anticoagulation therapy beyond 10 days after diagnosis (n = 153). Results During the median follow-up period of 555 days, major bleeding occurred in 189 patients (70 patients within 3 months; 119 patients beyond 3 months) with fatal bleeding in 24 patients (13%). The cumulative incidence of major bleeding was 2.7% at 3 months, 5.2% at 1 year, and 11.8% at 5 years. Active cancer (hazard ratio [HR], 3.06, 95% confidence interval [CI], 2.23–4.18), previous major bleeding (HR, 2.38, 95% CI, 1.51–3.59), anemia (HR, 1.75, 95% CI, 1.27–2.43), thrombocytopenia (HR, 2.11, 95% CI, 1.27–3.33), and age ≥75 years (HR, 1.64, 95% CI, 1.22–2.20) were independently associated with an increased risk for major bleeding by the multivariable Cox regression model. Conclusion Major bleeding events were not uncommon during prolonged anticoagulation therapy in real-world VTE patients. Active cancer, previous major bleeding, anemia, thrombocytopenia, and old age were the independent risk factors for major bleeding.

BACKGROUND Differences in the clinical characteristics and outcomes of venous thromboembolisms (VTEs) based on different clinical situations surrounding the onset might be important for directing appropriate treatment strategies, but have not yet been appropriately evaluated. Methods and Results: The COMMAND VTE Registry is a multicenter registry enrolling 3,027 consecutive patients with acute symptomatic VTEs in Japan between January 2010 and August 2014. We divided the study population into 3 groups: Out-of-hospital onset (n=2,308), In-hospital onset with recent surgery (n=310), and In-hospital onset without recent surgery (n=374). Active cancer was most prevalent in the In-hospital onset without recent surgery group, and least in the Out-of-hospital onset group (Out-of-hospital onset group: 20%, In-hospital onset with recent surgery group: 26%, and In-hospital onset without recent surgery group: 38%, P

Anticoagulation therapy is prescribed for the prevention of recurrence in patients with venous thromboembolism, which could be temporarily interrupted during invasive procedures. The COMMAND VTE Registry is a multicenter registry enrolling 3027 consecutive patients with acute symptomatic VTE in Japan between January 2010 and August 2014. We identified patients who underwent invasive procedures during the entire follow-up period and evaluated periprocedural managements and clinical outcomes at 30 days after invasive procedures. During a median follow-up period of 1213 (IQR: 847-1764) days, 518 patients underwent invasive procedures with the cumulative incidences of 5.8% at 3 months, 11.1% at 1 year, and 24.0% at 5 years. Among 382 patients in high bleeding-risk category of invasive procedures, anticoagulation therapy had been discontinued already in 62 patients (16%) and interrupted temporarily in 288 patients (75%) during the invasive procedures with bridging anticoagulation therapy with heparin in 214 patients (56%). Among 80 patients in low bleeding-risk category, anticoagulation therapy had been already discontinued in 15 patients (19%) and interrupted temporarily in 31 patients (39%) during invasive procedure with bridging anticoagulation therapy with heparin in 17 patients (21%). At 30 days after the invasive procedures, 14 patients (2.7%) experienced recurrent VTE, while 28 patients (5.4%) had major bleeding. This study elucidated the real-world features of peri-procedural management and prognosis in patients with VTE who underwent invasive procedures during follow-up in the large multicenter VTE registry. The 30-day incidence rates of recurrent VTE and major bleeding events were 2.7% and 5.4%.

BACKGROUND Patients with cancer-associated venous thromboembolism (VTE) are at high risk for recurrent VTE and are recommended to receive prolonged anticoagulation therapy if they are at a low risk for bleeding. However, there are no established risk factors for bleeding during anticoagulation therapy.Methods and Results:The COMMAND VTE Registry is a multicenter retrospective registry enrolling 3,027 consecutive patients with acute symptomatic VTE among 29 Japanese centers. The present study population consisted of 592 cancer-associated VTE patients with anticoagulation therapy. We constructed a multivariable Cox proportional hazard model to estimate the hazard ratio (HR) and 95% confidence interval (CI) of the potential risk factors for major bleeding. During a median follow-up period of 199 days, major bleeding occurred in 72 patients. The cumulative incidence of major bleeding was 5.8% at 3 months, 13.8% at 1 year, 17.5% at 2 years, and 28.1% at 5 years. The most frequent major bleeding site was gastrointestinal tract (47%). Terminal cancer (adjusted HR, 4.17; 95% CI, 2.22-7.85, P

Introduction The external validation of the modified Ottawa score to predict the risk of recurrence in patients with cancer-associated venous thromboembolism (VTE) has not yet been firmly established. The present study aimed to evaluate the utility and limitations of the modified Ottawa score in the risk stratification of recurrent VTE in patients with cancer-associated VTE. Materials and methods The COMMAND VTE Registry is a multicenter retrospective registry enrolling 3027 consecutive patients with acute symptomatic VTE among 29 Japanese centers. The present study population consisted of 614 cancer-associated VTE patients, who were divided into 3 groups; High-risk group: 202 patients (33%) with a modified Ottawa score ≥ 1, Intermediate-risk group: 269 patients (44%) with a score = 0, and Low-risk group: 143 patients (23%) with a score ≤ −1. Results Recurrent VTE occurred in 39 patients on anticoagulation therapy within 6 months. The cumulative incidence of recurrent VTE substantially increased in the higher risk categories by the modified Ottawa score (high-risk group: 13.6% [95%CI, 8.9%–20.2%], intermediate-risk group: 5.9% [95%CI, 3.5%–9.8%], and low-risk group: 3.0% [95%CI, 1.1%–7.8%], P = .02). The discriminating power of the score was modest with a C-statistic of 0.63. Each score component of the score had a different impact on recurrent events with a variable effect size. Conclusions The risks of recurrence in patients with cancer-associated VTE substantially increased in the higher risk categories by using the modified Ottawa score, but the discriminating power of the score for recurrence was modest with a variable impact of each score component on recurrent events.

Background: The simplified pulmonary embolism severity index (sPESI) score has been reported to be useful in predicting 30-day mortality for patients with pulmonary embolism, which helps the identification of low-risk patients for early hospital discharge or home treatment. However, therapeutic decision-making should also be based on the risks of adverse events other than mortality. Methods: The COMMAND VTE Registry is a multicentre registry enrolling consecutive patients with acute symptomatic venous thromboembolism in Japan between January 2010 and August 2014, and the current study population consisted of 1715 patients with pulmonary embolism. We calculated the sPESI score for each patient, and compared 30-day rates of mortality, recurrent venous thromboembolism and major bleeding between sPESI scores of 0 and 1 or greater. Results: Patients with a sPESI score of 0 accounted for 383 (22%) patients, and 110 (6.4%) patients died within 30 days. The cumulative 30-day incidence of mortality was lower in patients with a sPESI score of 0 than those with a sPESI score of 1 or greater (0.5% vs. 8.1%, log rank PConclusions: In patients with a sPESI score of 0, the 30-day mortality, recurrent venous thromboembolism and major bleeding rates were reasonably low. The sPESI score could be useful to identify candidates for early hospital discharge or home treatment.

We herein report a case of congenital long QT syndrome (LQTS) in which the QT interval was prolonged by Takotsubo syndrome (TTS), inducing ventricular fibrillation (VF). The patient was a 55-year-old woman who had been diagnosed with LQTS. Cardiopulmonary arrest occurred while coughing during sleep. VF was observed, and her heartbeat returned after two defibrillations. An electrocardiogram showed marked QT prolongation and large negative T waves. Echocardiography demonstrated hyperkinesis at the base of the left ventricle and akinesis at the apex. As there was no significant stenosis in the coronary artery, she was diagnosed with TTS.

Background:There is a paucity of data on the management and prognosis of cancer-associated venous thromboembolism (VTE), leading to uncertainty about optimal management strategies. Methods and Results:The COMMAND VTE Registry is a multicenter registry enrolling 3, 027 consecutive acute symptomatic VTE patients in Japan between 2010 and 2014. We divided the entire cohort into 3 groups: active cancer (n=695, 23%), history of cancer (n=243, 8%), and no history of cancer (n=2089, 69%). The rate of anticoagulation discontinuation was higher in patients with active cancer (43.5%, 27.0%, and 27.0%, respectively, at 1 year, P

Pulmonary embolism (PE) and deep vein thrombosis (DVT) can be considered as one clinical entity, venous thromboembolism (VTE). However, the potential differences between PE and DVT might have to be taken into consideration for the decision-making of the optimal treatment strategies.The COMMAND VTE Registry is a multicenter registry enrolling 3027 consecutive patients with acute symptomatic VTE. The current study population consisted of 1715 PE patients with or without DVT and 1312 DVT only patients.The adjusted risk for recurrent VTE was not significantly different between the PE and DVT only groups (HR 1.22, 95%CI 0.93-1.60, P = 0.15). PE patients developed recurrent VTE events more often as PE than as DVT only (62% and 38%). The adjusted excess mortality risk of PE patients relative to DVT only patients was significant (HR 1.29, 95%CI 1.11-1.50, P 0.001), with markedly higher cumulative 30-day incidence of all-cause death in PE patients (6.4% and 1.4%, P 0.001). The most frequent cause of deaths was cancer death in both groups, and second most frequent cause of deaths in PE patients was fatal PE, most of which developed within 30 days.The risk for recurrent VTE was not significantly different between PE and DVT, although PE was more likely to develop recurrent VTE as PE. The mortality risk of PE seemed to be higher than that of DVT, which was more remarkable in the short term due to PE death, and less remarkable in the long term due to cancer death.

BACKGROUND The recently proposed VTE-BLEED score to predict the risk of major bleeding in patients with venous thromboembolisms (VTEs) on prolonged anticoagulation therapy was validated externally in randomized controlled trials and in a selected cohort, but not applied in non-selective cohorts. OBJECTIVES The present study aimed to evaluate the generalizability of the VTE-BLEED score in a non-selective cohort. PATIENTS/METHODS The COMMAND VTE Registry is a multicenter retrospective registry enrolling consecutive patients with acute symptomatic VTEs among 29 centers in Japan. The present study population consisted of 2124 patients with prolonged anticoagulation therapy beyond 30 days, including 2008 (95%) patients with a first VTE episode and 1075 (51%) with unprovoked VTEs, who were divided into 1445 patients (68%) with a VTE-BLEED score of ≥2 (high-risk group) and 679 (32%) with a VTE-BLEED score of

Statins, which are considered as essential for primary and secondary prevention of atherosclerotic diseases, were also reported to reduce first venous thromboembolism (VTE). However, the effect of statins on VTE recurrence remains conflicting. We aimed to examine the association between statin use and VTE recurrence in a large observational study in Japan. The COMMAND VTE Registry is a multicenter registry enrolling consecutive 3027 patients with acute symptomatic VTE in 29 centers in Japan between January 2010 and August 2014. In the current study, the entire cohort was divided into statin group (N = 437) and no-statin group (N = 2590) according to the status of statin use at baseline. The statin group as compared with the no-statin group was older (statin group 71.2 vs no-statin group 66.5 years, p0.001), included more women (67% vs 60%, p = 0.008), and less frequently had active cancer (12% vs 25%, p0.001). There was no significant difference in the clinical presentation of VTE (pulmonary embolism, 58% vs 56%, p = 0.44). The cumulative 3-year incidence of recurrent VTE was significantly lower in the statin group than the no-statin group (3.8% vs 8.8%, p0.001). After adjusting for confounders including active cancer, statin use was associated with significantly lower risk for recurrent VTE (Hazard ratio 0.49, 95% confidence interval 0.29 to 0.78, p = 0.002). The results were consistent in a sensitivity sub-group analysis with and without active cancer. In conclusion, statin use was associated with significantly lower risk for the recurrent VTE in patients with VTE.

There is still uncertainty about the optimal usage of thrombolysis for acute pulmonary embolisms (PEs), leading to a widely varying usage in the real world. The COMMAND VTE Registry is a multicenter retrospective registry enrolling consecutive patients with acute symptomatic venous thromboembolisms (VTEs) in Japan. The present study population consisted of 1549 patients with PEs treated with tissue plasminogen activator (t-PA) thrombolysis (N = 180, 12%) or without thrombolysis (N = 1369). Thrombolysis with t-PA was implemented in 33% of patients with severe PEs, and 9.2% of patients with mild PEs with a wide variation across the participating centers. Patients with t-PA thrombolysis were younger, and less frequently had active cancer, history of major bleeding, and anemia. At 30 days, t-PA thrombolysis as compared to no thrombolysis was associated with similar mortality rates (5.0% vs. 6.9%, P = 0.33), but a lower adjusted mortality risk (OR 0.41; 95% CI 0.18–0.90, P = 0.03), while it was associated with a trend for higher rates of major bleeding (5.6% vs. 2.9%, P = 0.06) and a significantly higher adjusted risk for major bleeding (OR 2.39; 95% CI 1.06–5.36, P = 0.03). In patients with severe PEs, the mortality rates at 30 days were significantly lower in the t-PA thrombolysis group than no thrombolysis group (15% vs. 37%, P = 0.006). In the present real-world VTE registry in Japan, t-PA thrombolysis was not infrequently implemented, not only in patients with severe PEs, but also in patients with mild PEs. A substantial mortality risk reduction might be suggested with t-PA thrombolysis in patients with severe PEs.

The simplified Pulmonary Embolism Severity Index (sPESI) score is a practical score for identification of patients with low-risk pulmonary embolism (PE), although it has not been applied in patients with active cancer. The current study aimed to evaluate the usefulness of the sPESI score in patients with PE and active cancer.The COMMAND VTE Registry is a multicenter registry enrolling consecutive patients with acute symptomatic VTE. The current study population consisted of 368 patients with PE and active cancer. The 30-day clinical outcomes were compared between patients with sPESI score = 1 and patients with sPESI scores ≥ 2.Overall, 37 patients (10%) died during the 30 days after diagnosis. The cumulative 30-day incidences of mortality, and PE-related death, were lower in patients with sPESI score = 1 than in patients with sPESI scores ≥ 2 (6.3% vs 13.1%; log-rank P = .03; and 0.7% vs 3.9%; log-rank P = .046). Among patients with sPESI score = 1, the predominant cause of death was cancer. There were no significant differences in the cumulative 30-day incidence of recurrent VTE and major bleeding between the two groups (3.9% vs 5.6%; log-rank P = .46; and 6.4% vs 4.5%; log-rank P = .45).Among patients with PE and active cancer, patients with sPESI score = 1 had a lower 30-day mortality rate compared with patients with sPESI scores ≥ 2, and they showed very low PE-related mortality risk, although the overall mortality rate remained high because of cancer-related mortality. They also showed relatively high risks for recurrence and major bleeding, suggesting the need for careful follow-up.UMIN Clinical Trials Registry; No.: UMIN000021132; URL: http://www.umin.ac.jp/ctr/index.htm.

BACKGROUND It remains controversial whether sex category is a risk for recurrent venous thromboembolism (VTE) and major bleeding among VTE patients.Methods and Results:The COMMAND VTE Registry is a multicenter registry enrolling 3,027 consecutive acute symptomatic VTE patients from 29 centers in Japan between January 2010 and August 2014. We compared the clinical characteristics and outcomes of men and women. Men accounted for 1,169 (39%) and women 1,858 (61%). Compared with women, men were younger (64.9±14.7 vs. 68.6±15.6 years old, P

Background Data are scarce on the role of aortic valve area (AVA) to identify those patients with asymptomatic severe aortic stenosis (AS) who are at high risk of adverse events. We sought to explore the prognostic impact of AVA in asymptomatic patients with severe AS in a large observational database. Methods and Results Among 3815 consecutive patients with severe AS enrolled in the CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry, the present study included 1309 conservatively managed asymptomatic patients with left ventricular ejection fraction ≥50%. The study patients were subdivided into 3 groups based on AVA (group 1: AVA >0.80 cm2, N=645; group 2: 0.8 cm2 ≥AVA >0.6 cm2, N=465; and group 3: AVA ≤0.6 cm2, N=199). The prevalence of very severe AS patients (peak aortic jet velocity ≥5 m/s or mean aortic pressure gradient ≥60 mm Hg) was 2.0%, 5.8%, and 26.1% in groups 1, 2, and 3, respectively. The cumulative 5‐year incidence of AVR was not different across the 3 groups (39.7%, 43.7%, and 39.9%; P=0.43). The cumulative 5‐year incidence of the primary outcome measure (a composite of aortic valve–related death or heart failure hospitalization) was incrementally higher with decreasing AVA (24.1%, 29.1%, and 48.1%; P, See Editorial by Tribouilloy et al

The influence of anemia on the long-term clinical outcomes has not been fully evaluated in patients with venous thromboembolism (VTE). We evaluated the influence of anemia among 3012 patients in the COMMAND VTE Registry with a median follow-up period of 1219 days. The outcomes measures were ISTH major bleeding, recurrent VTE and all-cause death. There were 1012 patients (34%) with moderate/severe anemia (Hb ≤ 10.9 g/dl), 615 patients (20%) with mild anemia (Hb 11.0–12.9 g/dl for men, and 11.0–11.9 g/dl for women), and 1385 patients (46%) without anemia. The cumulative 5-year incidence of major bleeding was significantly higher in patients with anemia (moderate/severe anemia: 17.6%, mild anemia: 12.1%, and no anemia: 8.7%, P

There is a paucity of data on patients with deep vein thrombosis (DVT) in upper extremities.The COMMAND VTE Registry is a retrospective multicenter registry enrolling 3027 consecutive patients with acute symptomatic venous thromboembolism (VTE) in Japan. The current study population included 2498 patients with upper or lower extremities DVT.There were 74 patients (3.0%) with upper extremities DVT and 2424 patients with lower extremities DVT. Patients with upper extremities DVT more often had active cancer (58%) and central venous catheter use (22%). The proportion of concomitant pulmonary embolism at diagnosis was lower in patients with upper extremities DVT than in those with lower extremities DVT (14% and 51%, P 0.001). Discontinuation of anticoagulation therapy was more frequent in patients with upper extremities DVT (63.8% and 29.8% at 1-year, P 0.001). The cumulative 3-year incidence of recurrent VTE was not different between the 2 groups (9.8% and 7.4%, P = 0.43). After adjusting confounders, the risks of upper extremities DVT relative to lower extremities DVT for recurrent VTE remained insignificant (HR 0.94, 95%CI 0.36-2.01, P = 0.89).The prevalence of patients with DVT in upper extremities was 3.0% in the current large-scale real-world registry. Patients with DVT in upper extremities more often had active cancer at diagnosis and central venous catheter use as a transient risk factor for VTE, and less often had concomitant PE. Patients with DVT in upper extremities had similar long-term risk for recurrent VTE as those with DVT in lower extremities despite shorter duration of anticoagulation.

The influence of thrombocytopenia on the long-term clinical outcomes has not been thoroughly evaluated in patients with venous thromboembolism (VTE). This study sought to elucidate association of baseline thrombocytopenia with bleeding, recurrent VTE, and mortality risk. We evaluated the influence of baseline thrombocytopenia among 3,012 patients whose baseline platelet counts were available in the COMMAND VTE Registry in Japan with a median follow-up period of 1,219 days. Baseline thrombocytopenia was classified as follows: mild: 100,000 to 150,000/μl; moderate: 50,000 to 99,999/μl; and severe

Post-thrombotic syndrome (PTS) is the most common chronic complication of deep vein thrombosis (DVT). Identifying high-risk patients for the development of PTS might be useful for its prevention. The COMMAND VTE Registry is a multicenter registry that enrolled 3027 consecutive patients with acute symptomatic venous thromboembolisms (VTEs) in Japan between January 2010 and August 2014. The current study population consisted of 1298 patients with lower extremities DVTs who completed 3-year follow-up for those who developed PTS and those without PTS. We investigated risk factors for the development of PTS at the time of DVT diagnosis, using a multivariable logistic regression analysis. Of the entire 1298 study patients, 169 (13%) patients were diagnosed with PTS within 3 years. The rate for anticoagulation discontinuation during follow-up was not significantly different between those with and without PTS. Chronic kidney disease (OR 2.21, 95% CI 1.45–3.39, P

[Aim]To investigate the effect of malignancy on the outcomes of patients with severe aortic stenosis (AS) and the management strategy for AS with malignancy. [Methods and results]Using data of 3815 patients with severe AS in a retrospective multicentre registry [CURRENT AS (Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis) registry], we compared 3-year clinical outcomes among three groups based on malignancy status: with malignancy currently under treatment including best supportive care (malignancy group), with a history of malignancy without any current treatment (past history group), or without history of malignancy (no malignancy group). Patients in the malignancy group (n = 124) were more often men and had higher prevalence of low body mass index, recurrence of malignancy, anaemia, and asymptomatic status, despite comparable surgical risks and echocardiographic parameters. The malignancy group or the past history group (n = 389) had significantly higher risk for all-cause death [hazard ratio (HR) 2.49, 95% CI (95% confidence interval) 1.98–3.14; HR 1.23, 95% CI 1.04–1.46] and for malignancy-related death (HR 16.2, 95% CI 10.64–24.54; HR 3.66, 95% CI 2.43–5.52) than that of the no malignancy group (n = 3302). The excess risk for aortic valve-related death was not observed in the malignancy group (HR 0.79, 95% CI 0.48–1.29) and was lower in the past history group (HR 0.72, 95% CI 0.53–0.96). In the malignancy group, the treatment strategy (surgery: n = 16, conservative management: n = 108) was determined based on the clinical status of AS or life expectancy. [Conclusions]Malignancy had marked effect on all-cause death and malignancy-related death in patients with severe AS. History of malignancy also had a smaller but significant effect on mortality.

BACKGROUND Venous thromboembolism (VTE) has a long-term risk of recurrence, which can be prevented by anticoagulation therapy.Methods and Results:The COMMAND VTE Registry is a multicenter registry enrolling 3,027 consecutive patients with acute symptomatic VTE between January 2010 and August 2014. The entire cohort was divided into the transient risk (n=855, 28%), unprovoked (n=1,477, 49%), and cancer groups (n=695, 23%). The rate of anticoagulation discontinuation was highest in the cancer group (transient risk: 37.3% vs. unprovoked: 21.4% vs. cancer: 43.5% at 1 year, P

The aim of this study was to evaluate the prognostic impact of left ventricular ejection fraction (LVEF) in patients with severe aortic stenosis (AS).The prognostic impact of LVEF in severe AS remains controversial.Among 3,815 consecutive patients with severe AS enrolled in the CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry, the present study population consisted of 3,794 patients after excluding 21 patients without LVEF data. Patients were divided into 4 groups according to LVEF at index echocardiography (50%, 50% to 59%, 60% to 69%, and ≥70%; conservative strategy: n = 388, n = 390, n = 1,025, and n = 800; initial aortic valve replacement strategy: n = 206, n = 170, n = 375, and n = 440). Echocardiographic data were site reported, and there was no echocardiography core laboratory.In the conservative group, the cumulative 5-year incidence of the primary outcome measure (a composite of aortic valve-related death or heart failure hospitalization) was significantly higher in patients with LVEFs 50% and 50% to 59% than in those with LVEFs 60% to 69% and ≥70% (72.3%, 58.4%, 38.7%, and 35.0%, respectively, p 0.001), whereas in the initial aortic valve replacement group, the negative effect of low LVEF was markedly attenuated (20.2%, 20.3%, 17.7%, and 12.4%, respectively, p = 0.03). After adjusting for confounders, LVEF 50% (hazard ratio: 1.82; 95% confidence interval: 1.44 to 2.28; p 0.001) and 50% to 59% (hazard ratio: 1.77; 95% confidence interval: 1.42 to 2.20; p 0.001) but not 60% to 69% (hazard ratio: 1.14; 95% confidence interval: 0.94 to 1.39; p = 0.17) were independently associated with poorer outcomes compared with LVEF ≥70% (reference) in the conservative group. In the initial aortic valve replacement group, the adjusted risk for the primary outcome measure was not significantly different across the 4 LVEF groups.This study demonstrates that survival in patients with severe AS is impaired when LVEF is 60%, and these findings have implications for decision making with regard to the timing of surgical intervention.

Background There are limited data regarding the risk stratification based on peak aortic jet velocity (Vmax) in patients with severe aortic stenosis ( AS ). Methods and Results Among 3815 consecutive patients with severe AS enrolled in the CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry, the study population consisted of 1075 conservatively managed patients with Vmax ≥4.0 m/s and left ventricular ejection fraction ≥50%. The study patients were subdivided into 3 groups based on Vmax (group 1, 4.0 ≤ Vmax AS ‐related events (aortic valve–related death or heart failure hospitalization) was incrementally higher with increasing Vmax (entire population; 38.0%, 49.4%, and 62.8%, P P =0.008; and asymptomatic patients; 29.4%, 38.9%, and 47.7%, P =0.005). After adjusting for confounders, the excess risk of group 2 and group 3 relative to group 1 for AS ‐related events remained significant (hazard ratio, 1.39; 95% CI , 1.07–1.81; P =0.02, and hazard ratio, 1.53; 95% CI , 1.17–2.00; P =0.002, respectively). The effect size of group 3 relative to group 1 for AS ‐related events in asymptomatic patients (N=479) was similar to that in symptomatic patients (N=596; hazard ratio, 1.59; 95% CI , 1.01–2.52; P =0.047, and hazard ratio, 1.67; 95% CI , 1.16–2.40, P =0.008, respectively), and there was no significant overall interaction between the symptomatic status and the effect of the Vmax categories on AS ‐related events (interaction, P =0.88). Conclusions In conservatively managed severe AS patients with preserved left ventricular ejection fraction, increasing Vmax was associated with incrementally higher risk for AS ‐related events. However, the cumulative 5‐year incidence of the AS ‐related events remained very high even in asymptomatic patients with less greater Vmax.

ST-segment elevation (STE) in leads V1-2 is often observed in patients with severe aortic stenosis (AS), but its significance remains unknown.We retrospectively evaluated baseline ECGs and 5-year clinical outcomes in 211 consecutive patients with severe AS, defined as peak aortic jet velocity (Aortic Vmax)4.0 m/s, or mean aortic pressure gradient40 mmHg, or aortic valve area (AVA)1.0 cm(2). The primary outcome measure was a composite of death or surgical aortic valve replacement (AVR). Patients with STE in leads V1-2(≥0.15 mV) had greater Aortic Vmax and smaller AVA than patients without. With a median follow-up of 4.9 years, the cumulative 5-year incidence of death or AVR was significantly higher in patients with STE in leads V1-2 than in patients without (91.4% vs. 77.1%; P=0.003). After adjusting for confounders, STE in leads V1-2 was independently associated with higher risk for death or AVR (hazard ratio, 1.53; 95% confidence interval, 1.06-2.22; P=0.02). In 64 asymptomatic patients without any indication for AVR at initial diagnosis of severe AS, the cumulative incidence of AVR was significantly higher in patients with STE in leads V1-2 than in patients without (57.6% vs. 30.5%; P0.001).STE in leads V1-2 independently predicted poorer prognosis and more frequent need for AVR in patients with severe AS.