McBane, Robert

Calf muscle pump (CMP) promotes venous return from the lower extremity and contributes to preload and cardiac output. Impaired CMP function may reflect a measure of frailty or cumulative disease burden or may impede cardiac function. The study objective was to test the hypothesis that impaired CMP negatively impacts survival. Consecutive adult patients who underwent venous strain gauge plethysmography at the Mayo Clinic Gonda Vascular Laboratory (January 1, 1998 – December 31, 2011) were assessed for overall survival. Patients with venous incompetence, venous obstruction or unilateral calf pump dysfunction were excluded. Risk of mortality was assessed with Cox proportional hazard ratios and after adjusting for Charlson Comorbidity Index variables. Over the study period, 2728 patients were included in the analysis. Compared to patients with normal CMP, those with impaired CMP were older ( p < 0.001), predominantly female ( p = 0.01) and had higher mean Charlson scores ( p < 0.001). Patients with impaired CMP had a higher mortality rate at 5 (8.9% vs 2.4%), 10 (17.5% vs 5.9%), and 15 years (22.8% vs 8.3%) compared to those with normal CMP ( p < 0.001 for each comparison). Of patients with heart failure, those with impaired CMP had worse survival at each 5-year increment compared to those with normal CMP ( p < 0.05 at each increment). In conclusion, impaired CMP appears to be an independent predictor of poor outcomes after adjusting for variables within the Charlson Comorbidity Index. The association between impaired CMP, heart failure, and mortality may represent a negative impact on circulatory function or a surrogate measure of frailty.

Abstract Objectives To investigate the association of extremes in bodyweight (EBW) and outcomes in patients with acute venous thromboembolism (VTE). Recurrent VTE, major bleeding, and clinically relevant non‐major bleeding were compared between patients with bodyweight <60 kg, 60‐120 kg, and >120 kg. Methods Consecutive patients enrolled in the Mayo Clinic VTE Registry (03/28/2013‐8/31/2019) with acute VTE were followed prospectively. Patient status was assessed in person, by mailing a written questionnaire, or by a scripted phone interview. Results Among 2577 patients with weight ranging from 27.0 kg to 263.2 kg, 2123 (82%) had a bodyweight between 60 and 120 kg, 223 (8.7%) had bodyweight < 60 kg, and 230 (8.9%) had bodyweight >120 kg. Patients with bodyweight <60 kg treated with DOACs had higher 3‐ and 6‐month incidence of major bleeding compared to the bodyweight 60‐120kg group (4.4% vs 1.1%, P = .03, and 4.4% vs 1.4%, P = .05, respectively). Patients with bodyweight >120 kg and cancer on rivaroxaban had higher VTE recurrence compared to bodyweight 60‐120kg group ( P = .01). Conclusions Treatment of acute VTE is associated with a higher incidence of bleeding in patients with bodyweight <60 kg. A higher VTE recurrence rate occurred only in cancer patients with bodyweight >120 kg on rivaroxaban.

Abstract Direct oral anticoagulants (DOACs) are an emerging treatment option for patients with cancer and acute venous thromboembolism (VTE), but studies have reported inconsistent results. This systematic review and meta-analysis compared the efficacy and safety of DOACs and low-molecular-weight heparins (LMWHs) in these patients. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and conference proceedings were searched to identify relevant randomized controlled trials. Additional data were obtained from the original authors to homogenize definitions for all study outcomes. The primary efficacy and safety outcomes were recurrent VTE and major bleeding, respectively. Other outcomes included the composite of recurrent VTE and major bleeding, clinically relevant nonmajor bleeding (CRNMB), and all-cause mortality. Summary relative risks (RRs) were calculated in a random effects meta-analysis. In the primary analysis comprising 2607 patients, the risk of recurrent VTE was nonsignificantly lower with DOACs than with LMWHs (RR, 0.68; 95% CI, 0.39-1.17). Conversely, the risks of major bleeding (RR, 1.36; 95% CI, 0.55-3.35) and CRNMB (RR, 1.63; 95% CI, 0.73-3.64) were nonsignificantly higher. The risk of the composite of recurrent VTE or major bleeding was nonsignificantly lower with DOACs than with LMWHs (RR, 0.86; 95% CI, 0.60-1.23). Mortality was comparable in both groups (RR, 0.96; 95% CI, 0.68-1.36). Findings were consistent during the on-treatment period and in those with incidental VTE. In conclusion, DOACs are an effective treatment option for patients with cancer and acute VTE, although caution is needed in patients at high risk of bleeding.

AbstractBackgroundCancer‐associated venous thromboembolism (VTE) carries a high rate of recurrence and death. Guidelines recommend continued anticoagulation therapy as long as active cancer persists. Apixaban 2.5 mg twice daily is the FDA‐approved dose for secondary prevention regardless of VTE causation. Whether this apixaban dose is appropriate for secondary VTE prevention in cancer patients is not clear. The rationale and design of this investigator initiated phase III, multicenter, randomized, double‐blind, trial assessing apixaban 2.5 mg vs 5 mg twice daily for 12 months for the secondary VTE prevention in cancer patients (n = 370) who have completed 6 months (but no more than 12 months) of anticoagulation is provided (NCT03080883).Methods/DesignThe primary study objective is to estimate differences in the combined rate of major plus clinically relevant non‐major bleeding for apixaban 2.5 mg vs 5 mg twice daily. Secondary efficacy outcome is to assess rates of venous or arterial thromboembolism. Participating centers are chosen from the Academic and Community Cancer Research United (ACCRU) consortium.ConclusionWe anticipate these trial results to provide evidence supporting low‐dose apixaban as a safe agent for secondary prevention of cancer‐associated VTE for patients who have already completed 6‐12 months of anticoagulation.

AbstractBackgroundLow molecular weight heparin (LMWH) is the guideline‐endorsed treatment for cancer‐associated venous thromboembolism (cVTE). Study objectives were to compare the efficacy and safety of rivaroxaban and enoxaparin in cVTE.MethodsUsing a cohort study design, consecutive patients with cVTE (3/1/2013‐7/31/2016), enrolled in the Mayo Thrombophilia Clinic Direct Oral Anticoagulants Registry, were compared to contemporary cancer patients receiving enoxaparin. The cumulative incidence of venous thromboembolism (VTE) recurrence, major and clinically relevant non‐major bleeding, and survival were assessed at 3 and 12 months.ResultsNinety‐eight patients received rivaroxaban (51% female, mean age 63 ± 12 years) and 168 enoxaparin (34.5% female, mean age 62 ± 15 years). The most common cancers included gastrointestinal/pancreatic, genitourinary and hematologic cancers. More than half of patients had pulmonary emboli at presentation. More than half had metastases, and two‐thirds were receiving chemotherapy. At 3 months, there were no differences in VTE recurrence (rivaroxaban 1.0% vs enoxaparin 4.2%; P = .15), major bleeding (rivaroxaban 5.1% vs enoxaparin 3.6%; P = .55), or all‐cause mortality (rivaroxaban 4.1% vs enoxaparin 8.9%; P = .14). At 12 months, these outcomes did not differ by treatment strategy.ConclusionThe results of this “real‐world” experience with cVTE suggest that rivaroxaban may offer a safe and effective alternative to LMWH.

AbstractIntroductionReticulated platelet (RP) content is increased in nonvalvular atrial fibrillation (NVAF). The purpose of this study was to determine if platelet content, morphology, and RP proportion are modulated by platelet genes.Methods and resultsExpression of six platelet‐predominate genes impacting platelet formation and release, platelet count, and RP content was assessed in NVAF patients before and 3–4 months after pulmonary veins isolation (PVI) and compared to normal sinus rhythm (NSR) controls. RNA from isolated platelets was reverse‐transcribed assayed against selected genes utilizing real‐time qPCR, and expressed as mean cycle threshold (ΔCt) using beta‐2‐microglobulin as endogenous control. RP content was assessed by flow cytometry. A fourfold lower expression of CFL1 gene coding for nonmuscle cofilin (7.8 ± 0.9 vs. 5.7 ± 1.6, P < 0.001) and twofold lower expression of four other genes were associated with similar platelet counts but fourfold higher (28.7+7.0 vs. 6.7+5.4, P < 0.001) RP content (%) in 97 NVAF cases compared to 51 NSR controls. Three to 4 months after PVI, RP decreased by 28%, while CFL1 gene expression increased over twofold but TUBA4A gene expression decreased almost twofold; NFE2 and MYL6 gene expression remained unchanged.ConclusionsNVAF is associated with notable downregulation of genes directing platelet production and size but increased RP content. PVI impacts the expression of many of these genes, implying a direct relationship between atrial fibrillation and platelet biogenesis.

BackgroundPatients with heart failure (HF) have increased risk for thromboembolic events. Real‐world incidences of efficacy and safety outcomes of direct oral anticoagulants (DOACs) in patients with left ventricular systolic dysfunction (LVSD) are of growing clinical interest.HypothesisReal‐world efficacy and safety outcomes of DOACs in patients with LVSD will be similar to those of LVSD or HF subgroups in the RE‐LY, ROCKET‐AF, and ARISTOTLE trials.MethodsWe performed a retrospective review of adult patients with LVSD (left ventricular ejection fraction ≤40%) on DOAC therapy between 2010 and 2016. Incidences of safety and efficacy outcomes of anticoagulation with DOACs were extracted from primary and secondary hospital discharge diagnoses.ResultsDOACs were prescribed to 287 patients with LVSD over a mean follow‐up of 313.3 ± 52.3 days. Many patients had moderate and severe chronic kidney disease (28.9% and 10.1%, respectively) and indications for anticoagulation therapy other than atrial fibrillation (19.9%). For efficacy outcomes, the calculated incidence rates of ischemic stroke and systemic embolism were 1.2 (95% confidence interval [CI]: 0.25‐3.56) and 0.81 (95% CI: 0.10‐2.94) events per 100 person‐years, respectively. For the safety outcomes, incidence rates of GI bleeding and intracranial hemorrhage were 2.4 (95% CI: 0.8‐5.3) and 0.41 (95% CI: 0.1‐2.2) events per 100 patient‐years, respectively.ConclusionsOur findings are largely compatible with the results of LVSD or HF subgroups in RE‐LY, ROCKET‐AF, and ARISTOTLE trials and add to increasing confidence that DOACs can be safely used for stroke and systemic embolism prevention in patients with LVSD.

AbstractPurposeTesticular vein thrombosis (TVT) etiology, recurrence, and survival were compared with lower extremity deep vein thrombosis (DVT) in order to determine whether treatment guidelines for DVT could be applied to TVT.Patients and MethodsAn inception cohort of patients with confirmed TVT (January 1995‐October 2015) was compared to a control group of patients with lower extremity DVT matched by age, gender, and diagnosis date.ResultsThirty‐nine men with TVT were identified; 15 (38%) with isolated TVT. Left testicular vein was affected in 77% patients; there were no cases of bilateral TVT. Cancer was over twofold more common in TVT patients (59% vs 28%, P = .01). Most cancers (78%) involved organs in proximity to the testicular vein. Although TVT patients were less frequently treated with anticoagulants (49% vs 97%, P = .0001), recurrence rates were similar to DVT group (TVT 4.2 vs DVT 1.1 per 100 patient‐years, P = .11). Despite higher cancer prevalence, survival rates were similar between groups (31% vs 28%; P = .34). Major bleeding events were rare (one patient per group).ConclusionsIdentifying TVT should prompt a search for a regional malignancy. Despite the high cancer prevalence and low utilization of anticoagulants, recurrent venous thrombosis and mortality rates are similar to DVT patients.

AbstractAimsvon Willebrand factor (VWF) is an independent risk factor for adverse events in patients with non‐valvular atrial fibrillation (NVAF). However, it is unclear if VWF level remains elevated and predictive of stroke during entire course of NVAF.Methods and ResultsIn order to determine if VWF is a time‐dependent blood variable, VWF antigen measured by latex immunoassay in 425 NVAF patients and 100 controls with normal sinus rhythm (NSR) was analyzed according to NVAF duration (<1 month: n = 76, 1‐12 months: n = 98, and >12 months: n = 251). The mean VWF antigen level in NVAF patients with <1‐month duration (167 ± 59%) was not different compared to those with 1‐12 months (157 ± 50%, P = .24) and >12 months duration (156 ± 54%, P = .11) but higher compared to NSR controls (143 ± 48%, P = .003). Higher VWF level correlated with higher CHADS2 scores and with progressing intensity of blood stasis in the left atrium and thrombus formation in all three time periods of atrial fibrillation duration. Patients not treated with warfarin had VWF 30% higher in the first month compared to following months.Conclusionsvon Willebrand Factor is steadily elevated throughout the course of dysrhythmia in NVAF patients treated with warfarin and in those with higher intensity of left atrium blood stasis.