Optimal quality of vitamin K antagonist therapy in Japanese patients with venous thromboembolism.

BACKGROUND: 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. METHODS: 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) measurement >5 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. RESULTS: The group with TTR ≥70 % based on PT-INR range ≥1.5 and <2.0 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). CONCLUSIONS: The current VTE registry showed the optimal intensity of VKA therapy was target PT-INR range ≥1.5 and <2.0, 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.

Impact of no, distal, and proximal deep vein thrombosis on clinical outcomes in patients with acute pulmonary embolism: From the COMMAND VTE registry.

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.

Risk Factors for Major Bleeding During Anticoagulation Therapy in Cancer-Associated Venous Thromboembolism　- From the COMMAND VTE Registry.

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<0.001), chronic kidney disease (adjusted HR, 1.89; 95% CI 1.06-3.37, P=0.031), and gastrointestinal cancer (adjusted HR, 1.78; 95% CI, 1.04-3.04, P=0.037) were independently associated with an increased risk of major bleeding. CONCLUSIONS: Major bleeding events were common during anticoagulation therapy in real-world cancer-associated VTE patients. Terminal cancer, chronic kidney disease, and gastrointestinal cancer were the independent risk factors for major bleeding.

Predictive ability of modified Ottawa score for recurrence in patients with cancer-associated venous thromboembolism: From the COMMAND VTE Registry.

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.

Usefulness of Simplified Pulmonary Embolism Severity Index Score for Identification of Patients With Low-Risk Pulmonary Embolism and Active Cancer: From the COMMAND VTE Registry.

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.

Effect of Statins on Recurrent Venous Thromboembolism (from the COMMAND VTE Registry).

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, p <0.001), included more women (67% vs 60%, p = 0.008), and less frequently had active cancer (12% vs 25%, p <0.001). 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%, p <0.001). 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.

Clinical outcomes of patients with pulmonary embolism versus deep vein thrombosis: From the COMMAND VTE Registry.

INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Cancer-Associated Venous Thromboembolism in the Real World　- From the COMMAND VTE Registry.

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<0.001). The cumulative 5-year incidences of recurrent VTE, major bleeding, and all-cause death were higher in patients with active cancer (recurrent VTE: 17.7%, 10.2%, and 8.6%, P<0.001; major bleeding: 26.6%, 8.8%, and 9.3%, P<0.001; all-cause death: 73.1%, 28.6%, 14.6%, P<0.001). Among the 4 groups classified according to active cancer status, the cumulative 1-year incidence of recurrent VTE was higher in the metastasis group (terminal stage group: 6.4%, metastasis group: 22.1%, under chemotherapy group: 10.8%, and other group: 5.8%, P<0.001). CONCLUSIONS: In a current real-world VTE registry, patients with active cancer had higher risk for VTE recurrence, bleeding, and death, with variations according to cancer status, than patients without active cancer. Anticoagulation therapy was frequently discontinued prematurely in patients with active cancer in discordance with current guideline recommendations.

Thrombolysis with tissue plasminogen activator in patients with acute pulmonary embolisms in the real world: from the COMMAND VTE registry.

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.

Risk Factors for Major Bleeding during Prolonged Anticoagulation Therapy in Patients with Venous Thromboembolism: From the COMMAND VTE Registry.

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.

Sex Differences in Clinical Characteristics and Outcomes of Patients With Venous Thromboembolism　- From the COMMAND VTE Registry.

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<0.001), more often had prior VTE (7.2% vs. 5.1%, P=0.02), and less often had transient risk factors for VTE (30% vs. 40%, P<0.001). The proportions of active cancer and pulmonary embolism were comparable between men and women (24% vs. 22%, P=0.26; 56% vs. 57%, P=0.48, respectively). The cumulative 3-year incidences of recurrent VTE, major bleeding, and all-cause death were not significantly different between men and women (7.0% vs. 8.6%, P=0.47; 10.6% vs. 9.2%, P=0.25; 25.2% vs. 23.4%, P=0.35, respectively). The adjusted risks of men relative to women for recurrent VTE and for major bleeding remained insignificant (HR 0.83, 95% CI 0.63-1.09, P=0.17; HR 1.15, 95% CI 0.90-1.47, P=0.25, respectively). CONCLUSIONS: In real-world VTE patients, the clinical characteristics differed between men and women, but there was not a large sex-related difference in the risks for recurrent VTE or major bleeding.

Clinical Characteristics and Outcomes of Venous Thromboembolisms According to an Out-of-Hospital vs. In-Hospital Onset　- From the COMMAND VTE Registry.

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<0.001). The cumulative 5-year incidence of recurrent VTEs did not significantly differ across the 3 groups (11.4%, 5.8%, and 8.7%, respectively; P=0.11). The cumulative 5-year incidences of major bleeding and all-cause death were highest in the In-hospital onset without recent surgery group (11.1%, 8.5%, and 23.3%, P<0.001; 26.8%, 24.9%, and 48.4%, P<0.001, respectively). CONCLUSIONS: In the real-world VTE registry, the clinical characteristics and long-term outcomes substantially differed according to the clinical situation of VTE onset, suggesting the need for different treatment strategies for VTEs in different clinical settings.

Deep vein thrombosis in upper extremities: Clinical characteristics, management strategies and long-term outcomes from the COMMAND VTE Registry.

INTRODUCTION: There is a paucity of data on patients with deep vein thrombosis (DVT) in upper extremities. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Risk factors for post-thrombotic syndrome in patients with deep vein thrombosis: from the COMMAND VTE registry.

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 < 0.001), leg swelling (OR 4.15, 95% CI 2.25-7.66, P < 0.001), absence of transient risk factors for VTEs (OR 2.39, 95% CI 1.55-3.67, P < 0.001), active cancer (OR 3.66, 95% CI 2.30-5.84, P < 0.001), and thrombophilia (OR 2.07, 95% CI 1.06-4.04, P = 0.03) were independent risk factors for the development of PTS. In this real-world Japanese DVT registry, we could identify several important risk factors for the development of PTS at the time of DVT diagnosis.

Anticoagulation Therapy for Venous Thromboembolism in the Real World　- From the COMMAND VTE Registry.

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<0.001). The cumulative 5-year incidences of recurrent VTE, major bleeding and all-cause death were highest in the cancer group (recurrent VTE: 7.9% vs. 9.3% vs. 17.7%, P<0.001; major bleeding: 9.0% vs. 9.4% vs. 26.6%, P<0.001; and all-cause death: 17.4% vs. 15.3% vs. 73.1%, P<0.001). After discontinuation of anticoagulation therapy, the cumulative 3-year incidence of recurrent VTE was lowest in the transient risk group (transient risk: 6.1% vs. unprovoked: 15.3% vs. cancer: 13.2%, P=0.001). The cumulative 3-year incidence of recurrent VTE beyond 1 year was lower in patients on anticoagulation than in patients off anticoagulation at 1 year in the unprovoked group (on: 3.7% vs. off: 12.2%, P<0.001), but not in the transient risk and cancer groups (respectively, 1.6% vs. 2.5%, P=0.30; 5.6% vs. 8.6%, P=0.44). CONCLUSIONS: The duration of anticoagulation therapy varied widely in discordance with current guideline recommendations. Optimal duration of anticoagulation therapy should be defined according to the risk of recurrent VTE and bleeding as well as death.

Impact of the left ventricular mass index on the outcomes of severe aortic stenosis.

OBJECTIVE: To elucidate the factors associated with high left ventricular mass index (LVMI) and to test the hypothesis that high LVMI is associated with worse outcome in severe aortic stenosis (AS). METHODS: We analysed 3282 patients with LVMI data in a retrospective multicentre registry enrolling consecutive patients with severe AS in Japan. The management strategy, conservative or initial aortic valve replacement (AVR), was decided by the attending physician. High LVMI was defined as LVMI >115 g/m2 for males and >95 g/m2 for females. We compared the risk between normal and high LVMI in the primary outcome measures compromising aortic valve-related death and heart failure hospitalisation. RESULTS: Age was mean 77 (SD 9.6) years and peak aortic jet velocity (Vmax) was 4.1 (0.9) m/s. The factors associated with high LVMI (n=2374) included female, body mass index ≥22, absence of dyslipidemia, left ventricular ejection fraction <50%, Vmax ≥4 m/s, regurgitant valvular disease, hypertension, anaemia and end-stage renal disease. In the conservative management cohort (normal LVMI: n=691, high LVMI: n=1480), the excess adjusted 5-year risk of high LVMI was significant (HR: 1.53, 95% CI 1.26 to 1.85, p<0.001). In the initial AVR cohort (normal LVMI: n=217, high LVMI: n=894), the risk did not differ significantly between the two groups (HR: 0.96, 95% CI 0.60 to 1.55, p=0.88). There was a significant interaction between the initial treatment strategy and the risk of high LVMI (p=0.016). CONCLUSIONS: The deleterious impact of high LVMI on outcome was observed in patients managed conservatively, but not observed in patients managed with initial AVR. TRIAL REGISTRATION NUMBER: UMIN000012140; Post-results.

Effect on treadmill exercise capacity, myocardial ischemia, and left ventricular function as a result of repeated whole-body periodic acceleration with heparin pretreatment in patients with angina pectoris and mild left ventricular dysfunction.

Whole-body periodic acceleration (WBPA) has been developed as a passive exercise device capable of improving endothelial function by applying pulsatile shear stress to vascular endothelium. We hypothesized that treatment with WBPA improves exercise capacity, myocardial ischemia, and left ventricular (LV) function because of increased coronary and peripheral vasodilatory reserves in patients with angina. Twenty-six patients with angina who were not indicated for percutaneous coronary intervention and/or coronary artery bypass grafting were randomly assigned to remain sedentary (sedentary group) or undergo 20 sessions of WBPA with the motion platform for 4 weeks (WBPA group) in addition to conventional medical treatment. WBPA was applied at 2 to 3 Hz and approximately ±2.2 m/s² for 45 minutes. We repeated the symptom-limited treadmill exercise test and adenosine sestamibi myocardial scintigraphy. In the WBPA group, the exercise time until 0.1-mV ST-segment depression increased by 53% (p <0.01) and the double product at 0.1-mV ST-segment depression by 23% (p <0.001). Severity score of myocardial scintigraphy during adenosine infusion decreased from 20 ± 10 to 14 ± 8 (p <0.001) and severity score at rest also decreased from 13 ± 10 to 8 ± 10 (p <0.01). On scintigraphic images at rest, LV end-diastolic volume index decreased by 18% (p <0.01) with an augmentation of LV ejection fraction from 50 ± 16% to 55 ± 16% (p <0.01). In contrast, all studied parameters remained unchanged in the sedentary group. In conclusion, treatment with WBPA for patients with angina ameliorates exercise capacity, myocardial ischemia, and LV function.

Impact of aortic plaque morphology on survival rate and incidence of a subsequent embolic event ­ long-term follow-up data ­.

BACKGROUND: There are no reports about the long-term follow-up data of patients with aortic plaques among the Japanese population. The purpose of this study was to clarify the frequency of patients with severe aortic plaques and the impact of aortic plaque morphology on the prognosis. METHODS AND RESULTS: We retrospectively investigated 1,570 consecutive patients who underwent transesophageal echocardiography. Survival rate and subsequent embolic event rate were compared between patients with severe aortic plaque (>5 mm in thickness) and control patients. The relationship between aortic plaque morphology and prognosis was also estimated according to the presence of ulceration, calcification, hypoechoic plaques, and mobile plaques. The mean follow-up period was 8.7 years. Among 1,570 patients, severe aortic plaque was detected in 92 patients (5.9%). These 92 patients showed a significantly low survival rate and high subsequent embolic event rate compared to control patients (5-year survival rate: 69% vs 94%; 5-year embolic event free rate: 52% vs 95%). Among patients with severe aortic plaque, only ulceration was associated with a low survival rate (hazards ratio: 2.4, 95% confidence interval (CI): 1.1-5.2) and only mobile plaque was associated with a high embolic event rate (hazards ratio: 2.2; 95%CI: 1.1-5.1). CONCLUSIONS: Aortic plaque >5 mm in thickness was a predictor of poor prognosis. In the presence of aortic plaque >5 mm, ulceration was a predictor of a low survival rate and mobile plaque was a predictor of a high embolic event rate.

Increased expression of cardiotrophin-1 during ventricular remodeling in hypertensive rats.

Cardiotrophin-1 (CT-1) stimulates longitudinal myocardial cell hypertrophy. We examined the expression of CT-1, leukemia inhibitory factor (LIF), and gp130 by competitive RT-PCR and Western blotting in Dahl salt-sensitive (DS) rats with a high-salt diet, which showed a distinct transition from left ventricular hypertrophy (LVH) to congestive heart failure (CHF). The expression levels of CT-1 mRNA and protein were significantly increased at the CHF stage compared with the LVH stage and age-matched Dahl salt-resistant (DR) rats (n = 6 for each group). mRNA expression of LIF was not changed in the left ventricle at any stage by RT-PCR. gp130 mRNA and protein levels of DS rats at 11 and 17 wk were significantly increased compared with age-matched DR rats. The isolated myocyte length of DS rats at 17 wk was the longest among the four groups of rats. The LV end-diastolic dimension (LVDd) of DS rats, determined by echocardiography, was significantly increased at the CHF stage. There was a significant correlation between the CT-1 protein level and LVDd. CT-1 may play a role in ventricular remodeling during transition from LVH to CHF in the rat hypertensive model.