Wysokinski, Waldemar

Abstract Aims Echocardiographic assessment of cancer-associated non-bacterial thrombotic endocarditis (Ca-NBTE) is limited to case reports and small clinical series. The study aimed to identify heart valve abnormalities and its relation to embolic complications and cancer types. Methods and results Manual review of echocardiographic images and medical records of Mayo Clinic patients (31 March 2002–30 June 2022) was performed. Ca-NBTE in 111 patients (mean age 63.2 ± 9.7 years, 66.7% female) predominantly affected mitral valves (MV) (69), 56 aortic (AV), 8 tricuspid (TV), and rarely pulmonic (PV) (1). In 18 patients, 2 valves were involved, 3 and 4 valve involvement in only a single patient each. Embolic complications were prevalent (n = 102, 91.9%). Ca-NBTE affected MV more frequently on the upstream (atrial) (90% vs. 49.3%) and TV downstream (ventricular) side (75% vs. 37.5%). NBTE size (cm) varied significantly among valves, with TV hosting the largest masses (0.63–2.40 × 0.39–1.77), compared with MV [(0.11–1.81 × 0.11–1.62), (length P = 0.001; width P = 0.03)] and AV [(0.20–2.70 × 0.11–1.51), (length P = 0.001; width P = 0.056)]; MV masses were borderline longer in systemic compared with cerebral emboli (P = 0.057). Majority of MV (79.6%) and AV (69.6%) had thickened leaflets. NBTE lesions commonly affected closing margins (73.9% MV, 85.7% AV, and 62.5% of TV) but rarely commissures of MV (8.7%), yet fairly frequently of AV (41.1%). Five patients had severe regurgitation of MV and 5 AV. Conclusion Ca-NBTE manifests mainly as thrombotic mobile masses attached to thickened MV and AV, with distinct variations in size based on valve type. Embolic destination but not cancer type is associated with NBTE mass size and location.

Abstract Premortem clinical presentation of cancer‐associated non‐bacterial thrombotic endocarditis (Ca‐NBTE), therapy, and the clinal course is limited to case reports and small clinical series. An electronic search of Mayo Clinic records (03/31/2002–06/30/2022) with a subsequent manual review was performed to identify adult patients with echocardiographically detected NBTE and active malignancy, excluding those with infectious endocarditis or lupus anticoagulant/antiphospholipid antibodies. In this retrospective cohort study, we analyzed 115 Ca‐NBTE patients (mean age 63.2 ± 9.7 years, 66.1% female) involving 71 (61.7%) mitral, 58 (50.4%) aortic, 8 (6.9%) tricuspid, and 1 (0.9%) pulmonary valve. The most common cancer was lung ( n = 45 cases (39.1%), followed by pancreatic ( n = 19, 16.5%), gynecological (17, 14.8%), gastrointestinal ( n = 10, 8.7%), and 10 (8.7%) with hematologic malignancy; 6 patients had two active cancers. Embolic complications at presentation were frequent: 94 (81.7%) brain, 11 splenic, 10 renal, 6 coronary, and 4 to the extremities. Of 104 anticoagulated patients, 60 received low molecular weight heparin, 17 unfractionated heparin, 16 apixaban, 8 warfarin, and 3 rivaroxaban. There were 18 arterial thromboembolisms; the Kaplan–Meier estimates of the incidence at 2 years were consistent with a rate of 15.9% [95% Confidence Interval (CI) 9.9–23.3], including 14 strokes (12.4%, 95%CI, 7.1–19.2), and 8 other arterial emboli (10.5%, 95%CI, 4.7–18.9); there were 10 venous thromboembolisms (8.9%, 95%CI, 4.5–15.0). Fourteen major bleedings occurred (12.8%, 95%CI, 7.3–19.9) and 94 patients died during follow‐up (77.9%, 95%CI, 71.1–85.8). Ca‐NBTE predominantly affected women with lung adenocarcinoma or digestive tract cancers and manifested by stroke with high mortality and frequent embolic and bleeding complications during anticoagulation therapy.

AbstractPatients with thrombophilia remain concerned about venous thromboembolism (VTE) risk with COVID‐19 vaccinations. The aim of this study was to examine VTE outcomes in patients with inherited or acquired thrombophilia who were vaccinated for COVID‐19. Vaccinated patients ≥18 years between November 1, 2020 and November 1, 2021 were analyzed using electronic medical records across the Mayo Clinic enterprise. The primary outcome was imaging confirmed acute VTE occurring 90 days before and after the date of the first vaccine dose. Thrombophilia patients were identified through laboratory testing results and ICD‐10 codes. A total of 792 010 patients with at least one COVID‐19 vaccination were identified. Six thousand sixty‐seven of these patients were found to have a thrombophilia, among whom there was a total of 39 VTE events after compared to 51 VTE events before vaccination (0.64% vs. 0.84%, p = .20). In patients with Factor V Leiden or prothrombin gene mutation, VTE occurred in 27 patients before and in 29 patients after vaccination (0.61 vs. 0.65%, p = .79). In patients with antiphospholipid syndrome, VTE occurred in six patients before and four patients after vaccination (0.59% vs. 0.39%, p = .40). No difference was observed in the overall VTE rate when comparing the postvaccination 90 days to the prevaccination 90 days, adjusted hazard ratio 0.81 (95% confidence interval: 0.53–1.23). In this subgroup of COVID‐19 vaccinated patients with thrombophilia, there was no increased risk for acute VTE postvaccination compared to the prevaccination timeframe. These results are consistent with prior studies and should offer additional reassurance to patients with inherited or acquired thrombophilia.

AbstractBackgroundClinical picture and outcome of incidental pulmonary embolism (iPE) compared to symptomatic pulmonary embolism (sPE) remain unclear.MethodsDemographics, recurrent venous thromboembolism (VTE), mortality, major bleeding, and clinically relevant nonmajor bleeding (CRNMB) were compared between iPE and sPE patients who were followed prospectively at Mayo Thrombophilia Clinic (March 1, 2013 to August 1, 2020).ResultsOut of 3576 VTE patients, 1417 (39.6%) had PE: 562 (39.7%) iPE and 855 sPE. Patients with cancer were more likely to have iPE (400 iPE vs. 314 sPE) compared to those without cancer (162 iPE vs. 541 sPE). VTE recurrence rate (all per 100 person‐years) was similar in all iPE and sPE patients (3.34 vs. 3.68, p = .50), with cancer (4.16 vs. 4.89, p = .370), and without cancer patients (0.89 vs. 2.80, p = .25). Higher mortality observed in all patients with iPE compared to sPE (46.45 vs. 23.47, p < .001) and with cancer (56.41 vs. 45.77, p = .03) became not significant after adjustment for age, antiplatelet therapy, metastases, and cancer location. Noncancer iPE patients had higher mortality (15.95 vs. 7.18, p = .006) even after adjustment (p = .05). The major bleeding rate was also higher in all patients iPE compared to sPE (7.10 vs. 3.68, p = .03), but not after adjustment (p = .974); higher major bleeding rate in noncancer patients (6.49 vs. 1.25, p = .007) remained significant after adjustment (.02). CRNMB rate was similar to iPE and sPE patients.ConclusioniPE represents a more serious clinical condition compared to sPE as indicated by the higher mortality and major bleeding but these differences reflect underlying comorbidities rather than the seriousness of the embolic event.

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.

AbstractRandomized controlled trials leading to the approval of apixaban and rivaroxaban for venous thromboembolism (VTE) did not include patients with upper extremity deep vein thrombosis (UE‐DVT). We sought to evaluate the safety and effectiveness of rivaroxaban and apixaban for the treatment of acute UE‐DVT. Consecutive patients with VTE enrolled into the Mayo Clinic VTE Registry, between March 1, 2013 and December 31, 2019, were followed prospectively. Clinical, demographic and imaging data were collected at the time of study recruitment. Patients with a diagnosis of acute UE‐DVT who received rivaroxaban, apixaban, LMWH or warfarin were included. Recurrent VTE, major bleeding, clinical‐relevant non‐major bleeding (CRNMB), and death were assessed at 3‐month intervals. During the study period, 210 patients with acute UE‐DVT were included; 63 were treated with apixaban, 39 with rivaroxaban, and 108 with LWMH and/or warfarin. Overall 51% had catheter‐associated UE‐DVT, 60% had a diagnosis of malignancy, and 14% had concurrent pulmonary embolism. Malignancy was more common in patients treated with LMWH/warfarin (67% vs 52%, P = .03). At 3 months of follow up, one (0.9%) recurrent VTE occurred in a patient treated with LMWH/warfarin and one (1.0%) patient treated with apixaban or rivaroxaban (P = .97). Major bleeding occurred in three patients treated with LMWH/warfarin, and in none of those treated with apixaban or rivaroxaban (P = .09). Clinical‐relevant non‐major bleeding occurred in one patient (0.9%) treated with LWMH/warfarin and two patients (2.0%) treated with apixaban or rivaroxaban (P = .53). Treatment of UE‐DVT with apixaban or rivaroxaban appears to be as safe and effective as LMWH/warfarin.

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.

Abstract To provide direct comparison between apixaban and rivaroxaban in patients with acute cancer‐associated venous thromboembolism (Ca‐VTE), consecutive patients treated with apixaban, rivaroxaban, or enoxaparin at Mayo Thrombophilia Clinic (March 1, 2013 to January 31, 2018)) were followed prospectively. The primary effectiveness outcome was venous thromboembolism (VTE) recurrence, and the secondary was mortality. The primary safety outcome was major bleeding, the secondary clinically relevant safety outcome was non‐major bleeding (CRNMB), and the third a composite of major and CRNMB. There were 750 patients treated for acute Ca‐VTE with apixaban (n = 224), rivaroxaban (n = 163), and enoxaparin (n = 363) within 14 days of diagnosis and for at least 3 months, or until study event. Recurrent VTE was diagnosed in 11 receiving apixaban, 7 receiving rivaroxaban (apixaban vs rivaroxaban hazard ratio (HR) 1.31, 95% confidence interval (95% CI) 0.51‐3.36) and 17 in the enoxaparin receiving group (apixaban vs enoxaparin HR 1.14, 95% CI: 0.54, 2.42 and rivaroxaban vs enoxaparin HR 0.85, 95% Cl: 0.36, 2.06). There were 82 deaths in apixaban, 74 rivaroxaban (apixaban vs rivaroxaban HR 1.67, 95% Cl: 1.20, 2.33) and 171 in enoxaparin group (rivaroxaban vs enoxaparin HR 0.73, 95% Cl: 0.56, 0.96). Major bleeding occurred in 11 apixaban, 12 rivaroxaban (apixaban vs rivaroxaban HR 0.73, 95% Cl: 0.32, 1.66) and 21 enoxaparin group (apixaban vs enoxaparin HR 0.89, 95% Cl: 0.43, 1.84 and rivaroxaban vs enoxaparin HR 1.23, 95% Cl: 0.61, 2.50). The CRNMB rate was higher in rivaroxaban compared to apixaban ( P = .03) and LMWH ( P = .01) groups. Recurrence of VTE and major bleeding were similar in apixaban, rivaroxaban, and enoxaparin groups. Rivaroxaban was associated with higher CRNMB but lower mortality compared to apixaban and enoxaparin.

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.