Comparison of rivaroxaban and low molecular weight heparin in the treatment of cancer-associated venous thromboembolism: a Swedish national population-based register study.

BACKGROUND: Treating cancer-associated venous thromboembolism (CAT) with anticoagulation prevents recurrent venous thromboembolism (rVTE), but increases bleeding risk. OBJECTIVES: To compare incidence of rVTE, major bleeding, and all-cause mortality for rivaroxaban versus low molecular weight heparin (LMWH) in patients with CAT. METHODS: We developed a cohort study using Swedish national registers 2013-2019. Patients with CAT (venous thromboembolism within 6 months of cancer diagnosis) were included. Those with other indications or with high bleeding risk cancers were excluded (according to guidelines). Follow-up was from index-CAT until outcome, death, emigration, or end of study. Incidence rates (IR) per 1000 person-years with 95% confidence interval (CI) and propensity score overlap-weighted hazard ratios (HRs) for rivaroxaban versus LMWH were estimated. RESULTS: We included 283 patients on rivaroxaban and 5181 on LMWH. The IR for rVTE was 68.7 (95% CI 40.0-109.9) for rivaroxaban, compared with 91.6 (95% CI 81.9-102.0) for LMWH, with adjusted HR 0.77 (95% CI 0.43-1.35). The IR for major bleeding was 23.5 (95% CI 8.6-51.1) for rivaroxaban versus 49.2 (95% CI 42.3-56.9) for LMWH, with adjusted HR 0.62 (95% CI 0.26-1.49). The IR for all-cause mortality was 146.8 (95% CI 103.9-201.5) for rivaroxaban and 565.6 (95% CI 541.8-590.2) for LMWH with adjusted HR 0.48 (95% CI 0.34-0.67). CONCLUSIONS: Rivaroxaban performed similarly to LMWH for patients with CAT for rVTE and major bleeding. An all-cause mortality benefit was observed for rivaroxaban which potentially may be attributed to residual confounding. TRIAL REGISTRATION NUMBER: NCT05150938 (Registered 9 December 2021).

The Net Clinical Outcome of Dual-Pathway Inhibition in Clinical Practice: The "Xarelto plus Acetylsalicylic Acid: Treatment Patterns and Outcomes in Patients with Atherosclerosis" Registry.

Background: In the COMPASS trial, the combination of acetylsalicylic acid (ASA) plus 2.5 mg rivaroxaban twice daily (dual-pathway inhibition, DPI) has been shown to be superior to ASA monotherapy for the reduction in ischemic major adverse cardiovascular events (MACEs, i.e., cardiovascular death, stroke, or myocardial infarction). Methods: The international XATOA registry (Xarelto plus Acetylsalicylic acid: Treatment patterns and Outcomes in patients with Atherosclerosis) is a prospective post-approval registry that investigates the cardiovascular outcomes of patients taking ASA plus 2.5 mg rivaroxaban. The aim of this pre-specified analysis was to determine the net clinical outcome (NCO), i.e., a combination of MACEs and bleeding events, of DPI in patients from daily clinical practice. Results: Among the 5615 patients, the presence of multiple risk factors resulted in an increase in the total risk of experiencing an NCO event, e.g., from 1.27% (one risk factor) to 2.18% (two risk factors) and 4.07% (three or more risk factors), respectively, with ischemic MACE representing the primary driver of bleeding complications. Conclusions: In the real-world XATOA registry, the annual rate of NCO events was low and numerically similar to those seen in the treatment group in the randomized COMPASS trial.

Diagnosis and Treatment Patterns of Chronic Thromboembolic Pulmonary Hypertension in Russia, Kazakhstan, Turkey, Lebanon, and Saudi Arabia: A Registry Study.

BACKGROUND: Patients with chronic thromboembolic pulmonary hypertension (CTEPH) in countries with limited resources have, to date, been poorly represented in registries. OBJECTIVE: This work assesses the epidemiology, diagnosis, hemodynamic and functional parameters, and treatment of CTEPH in Russia, Kazakhstan, Turkey, Lebanon, and Saudi Arabia. METHODS: A prospective, cohort, phase IV, observational registry with 3-year follow-up (n = 212) in patients aged ≥ 18 years diagnosed with CTEPH was created. Clinical, hemodynamic, and functional parameters were obtained at an initial visit, follow-up visits, and a final visit at the end of 3 years' observation or end of follow-up. Data were recorded on electronic case report forms. Parameters evaluated included 6-minute walking distance (6MWD), use of pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA), pulmonary hypertension (PH)-targeted therapy, and survival. All statistical analyses were exploratory and descriptive, and were performed in the overall population. RESULTS: The most common symptoms were typical of those expected for CTEPH. Almost 90% of patients underwent right heart catheterization at diagnosis or initial study visit. In total, 66 patients (31%) underwent PEA before the initial visit; 95 patients (45%) were considered operable, 115 (54%) were inoperable, and two (1%) had no operability data. Only 26 patients (12%) had been assessed for BPA at their initial visit. PH-targeted therapy was documented at diagnosis for 77 patients (36%), most commonly a phosphodiesterase type 5 inhibitor (23%). Use of PH-targeted therapy increased to 142 patients (67%) at the initial visit, remaining similar after 3 years. Use of riociguat increased from 6% of patients at diagnosis to 38% at 3 years. Between baseline and end of observation, results for patients with paired data showed an increase in 6MWD. Survival at the end of observation was 88%. CONCLUSIONS: These data highlight the current diagnosis and management of CTEPH in the participating countries. They show that early CTEPH diagnosis remains challenging, and use of off-label PH-targeted therapy is common. CLINICALTRIALS: gov: NCT02637050; registered December 2015.

Identifying the highest risk vascular patients: Insights from the XATOA registry.

BACKGROUND: Patients with coronary and peripheral artery disease (PAD) have a residual risk of major adverse cardiovascular and limb events despite standards of care. Among patients with coronary artery disease (CAD) and/or PAD selected for low dose rivaroxaban (2.5 mg BID) and aspirin, we sought to determine the highest risk vascular patients. METHODS: Xarelto pluc Acetylsalicylic acid: Treatment patterns and Outcomes in patients with Atherosclerosis (XATOA) is a single-arm registry of CAD and/or PAD patients. All participants were initiated on low dose rivaroxaban (2.5 mg BID) and aspirin. We report the incidence risk of major adverse cardiovascular events (MACE) or major adverse limb events (MALE) and major bleeding. A classification and regression tree analysis determined independent subgroups. RESULTS: Between November 2018 and May 2020, 5,808 participants were enrolled in XATOA; 5,532 were included in the full analysis. The median follow-up (interquartile range) was 462 (371-577) days. The incidence risk per 100 patient-years of MACE or MALE was highest among participants with polyvascular disease (2 or more vascular beds affected, n = 2,889). The incidence risk was 9.16 versus 2.48 per 100 patient-years in polyvascular and nonpolyvascular patients respectively. Other subgroups of high-risk patients included participants 75 years or older, with a history of diabetes, heart failure, or chronic renal insufficiency (CRI). Rates of major bleeding were low overall. A classification and regression tree analysis showed that polyvascular disease was the most dominant factor separating higher from lower risk participants, and this was heightened with CRI or diabetes. CONCLUSION: Patients with polyvascular disease represent a substantial subset of patients in clinical practice and should be prioritized to receive maximal medical therapy including low dose rivaroxaban (2.5 mg BID) and aspirin.

Assessment for residual disease after pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension.

Objectives: Pulmonary endarterectomy (PEA) is recommended for eligible patients with chronic thromboembolic pulmonary hypertension (CTEPH) and is potentially curative. However, persistent/recurrent CTEPH post-PEA can occur. Here we describe symptom and diagnostic assessment rates for residual disease post-PEA and longitudinal diagnostic patterns before and after riociguat approval for persistent/recurrent CTEPH after PEA. Methods: This US retrospective cohort study analysed MarketScan data (1 January 2002-30 September 2018) from patients who underwent PEA following a CTEPH/pulmonary hypertension (PH) claim with at least 730 days of continuous enrolment post-PEA. Data on pre-specified PH symptoms and the types and timings of diagnostic assessments were collected. Results: Of 103 patients (pre-riociguat approval, n=55; post-riociguat approval, n=48), residual PH symptoms >3 months after PEA were reported in 89% of patients. Overall, 89% of patients underwent one or more diagnostic tests (mean 4.6 tests/patient), most commonly echocardiography (84%), with only 5% of patients undergoing right heart catheterisation (RHC). In the post- versus pre-riociguat approval subgroup, assessments were more specific for CTEPH with an approximately two-fold increase in 6-min walk distance and N-terminal prohormone of brain natriuretic protein measurements and ventilation/perfusion scans, and a four-fold increase in RHCs. Conclusions: Low RHC rates suggest that many patients with PH symptoms post-PEA are not being referred for full diagnostic workup. Changes to longitudinal diagnostic patterns may indicate increased recognition of persistent/recurrent CTEPH post-PEA; however, there remains a need for greater awareness around the importance of continued follow-up for patients with residual PH symptoms post-PEA.

Patients selected for dual pathway inhibition in clinical practice have similar characteristics and outcomes to those included in the COMPASS randomized trial: The XATOA Registry.

AIMS: To determine the characteristics of patients with coronary artery disease (CAD), peripheral artery disease (PAD), or both, initiating dual pathway inhibition (DPI) using rivaroxaban 2.5 mg twice daily plus aspirin, and to report their clinical outcomes and bleeding rates in clinical practice compared to the COMPASS randomized trial, which provided the basis for using DPI in this patient population. METHODS AND RESULTS: XATOA is a prospective registry of 5532 patients: of which, 72.7% had CAD, 58.9% had PAD, and 31.6% had both. The mean age of patients was 68 years and 25.5% were women. The mean follow-up period was 15 months. The most frequently reported reason for initiating DPI was the presence of existing, worsening or newly diagnosed risk characteristics (n = 4753, 85.9%). Before initiating DPI, 75.3% received a single antiplatelet and 18.3% received various antiplatelet combinations. The incidence of major adverse cardiovascular events (MACE), major adverse limb events (MALE) and acute or severe limb ischaemia was 2.26, 3.57, and 1.54 per 100 patient-years, respectively, among the 5532 patients in XATOA. Corresponding rates in COMPASS were 2.18, 0.19, and 0.12 per 100 patient-years, respectively. Major bleeding rates were 0.95 and 1.67 per 100 patient-years in XATOA and COMPASS, respectively. CONCLUSION: High-risk vascular patients are prioritized for DPI in clinical practice, and rates of MACE are similar to COMPASS, but MALE rates are higher in XATOA, consistent with the greater proportion of PAD patients. Major bleeding rates were lower in XATOA. The findings provide support for favourable net clinical benefit of DPI in high-risk vascular patients. ONE-SENTENCE SUMMARY: The characteristics of patients initiated on dual pathway inhibition (DPI: rivaroxaban 2.5  mg twice daily plus aspirin) have not previously been defined in clinical practice and the XATOA registry findings demonstrate patient outcomes are consistent with those of the COMPASS trial, despite geographic differences in recruitment and the higher proportion of PAD patients.

Xarelto plus Acetylsalicylic acid: Treatment patterns and Outcomes in patients with Atherosclerosis (XATOA): Rationale and design of a prospective registry study to assess rivaroxaban 2.5 mg twice daily plus aspirin for prevention of atherothrombotic events in coronary artery disease, peripheral artery disease, or both.

Patients with coronary artery disease (CAD), peripheral artery disease (PAD), or both remain at risk of cardiovascular events (including peripheral ischemic events), even when they receive the current guideline-recommended treatment. The phase III COMPASS trial demonstrated that treatment with rivaroxaban vascular dose 2.5 mg twice daily plus aspirin (dual pathway inhibition [DPI] regimen) significantly reduced the risk of major adverse cardiovascular events (including peripheral ischemic events) and increased the risk of major bleeding, but not fatal bleeding or intracranial hemorrhage, versus aspirin alone in patients with CAD, PAD, or both. The results of the COMPASS trial supported the regulatory approval of the DPI regimen in several geographic regions. However, it is unclear whether the patients selected for treatment with the DPI regimen in clinical practice will have a similar risk profile and event rates compared with the COMPASS trial population. The prospective post-approval XATOA registry study aims to assess treatment patterns, as well as ischemic and bleeding outcomes in patients with CAD, PAD, or both, who receive DPI therapy in routine clinical practice. Up to 10,000 patients from at least 400 centers in 22 countries will be enrolled and followed up for a minimum of 12 months, and all treatment will be at the discretion of the prescribing physician. The primary objective of the XATOA study will be to describe early treatment patterns, while ischemic and bleeding outcomes will be described as a secondary objective. TRIAL REGISTRATION NUMBER: NCT03746275.

Risk of Hypersensitivity Reactions to Iopromide After Intra-Arterial Versus Intravenous Administration: A Nested Case-Control Analysis of 133,331 Patients.

OBJECTIVE: The aim of this study was to compare the risk of hypersensitivity reactions to iopromide after intra-arterial (IA) administration and intravenous (IV) administration. MATERIALS AND METHODS: Four observational studies were pooled. Almost half of the study population (48.1%) was from Europe, and one quarter each from China (27.6%) and other Asia countries (24.1%). All patients received iopromide either intra-arterially or intravenously for angiographic procedures (mostly cardio-angiography) or contrast-enhanced computed tomography. A nested case-control analysis, including a multivariable logistic regression model, was performed. Cases were defined by patients with a typical and unequivocal hypersensitivity (assumed non-IgE-mediated) reaction; controls were patients without any recorded reaction. The primary target variable is the odds ratio of having a hypersensitivity reaction after IA versus IV administration. RESULTS: A total of 133,331 patients met the inclusion criteria, 105,460 and 27,871 patients received iopromide IV or IA, respectively. Hypersensitivity reactions were recorded for 822 patients, and 132,509 patients served as controls.Major risk factors for hypersensitivity reactions were method of injection (IV vs IA), age (18 to <50 years vs ≥65 years), history of allergy or previous contrast media reaction (all P < 0.001), and asthma (P = 0.005).A total of 766 patients (0.7%) and 56 patients (0.2%) were recorded with hypersensitivity reactions after IV or IA administration, respectively (P < 0.0001).Adjusted odds ratio (IA vs IV) was 0.23 (95% confidence interval, 0.16-0.32) for all countries together: for China only, 0.22 (0.11-0.44); for all countries without China, 0.36 (0.25-0.53).Most frequent reactions were erythema/urticaria/rash, pruritus, and cough/sneezing. CONCLUSIONS: Hypersensitivity reactions to iopromide were significantly less frequently recorded after IA administrations. This could be related to the delayed and diluted arrival of iopromide to the lungs.

Correction to: Real-World Switching to Riociguat: Management and Practicalities in Patients with PAH and CTEPH.

The original version of this article unfortunately contained a mistake. In the "Results" section, the percentage of patients with inoperable or persistent/recurrent CTEPH included in the study was reported as 85%. This has been corrected to 68% with this erratum.

Real-World Switching to Riociguat: Management and Practicalities in Patients with PAH and CTEPH.

PURPOSE: A proportion of patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) do not achieve treatment goals or experience side effects on their current therapy. In such cases, switching patients to a new drug while discontinuing the first may be a viable and appropriate treatment option. CAPTURE was designed to investigate how physicians manage the switching of patients to riociguat in real-world clinical practice. Observations from the study were used to assess whether recommendations in the riociguat prescribing information are reflected in clinical practice. METHODS: CAPTURE was an international, multicenter, uncontrolled, retrospective chart review that collected data from patients with PAH or inoperable or persistent/recurrent CTEPH who switched to riociguat from another pulmonary hypertension (PH)-targeted medical therapy. The primary objective of the study was to understand the procedure undertaken in real-world clinical practice for patients switching to riociguat. RESULTS: Of 127 patients screened, 125 were enrolled in CAPTURE. The majority of patients switched from a phosphodiesterase type 5 inhibitor (PDE5i) to riociguat and the most common reason for switching was lack of efficacy. Physicians were already using the recommended treatment-free period when switching patients to riociguat from sildenafil, but a slightly longer period than recommended for tadalafil. In line with the contraindication, the majority of patients did not receive riociguat and PDE5i therapy concomitantly. Physicians also followed the recommended dose-adjustment procedure for riociguat. CONCLUSION: Switching to riociguat from another PH-targeted therapy may be feasible in real-world clinical practice in the context of the current recommendations.

Continuation rates, bleeding profile acceptability, and satisfaction of women using an oral contraceptive pill containing estradiol valerate and dienogest versus a progestogen-only pill after switching from an ethinylestradiol-containing pill in a real-life setting: results of the CONTENT study.

BACKGROUND: Oral contraceptives are still associated with high discontinuation rates, despite their efficacy. There is a wide choice of oral contraceptives available, and the aim of this study was to assess continuation rates, bleeding profile acceptability, and the satisfaction of women in the first year of using a contraceptive pill containing estradiol valerate and dienogest (E2V/DNG) versus a progestogen-only pill (POP) in a real-life setting after discontinuing an ethinylestradiol-containing pill. METHODS AND RESULTS: In this prospective, noninterventional, observational study, 3,152 patients were included for the efficacy analyses (n=2,558 women in the E2V/DNG group and n=592 in the POP group (two patients fulfilled the criteria of the efficacy population, but the used product was not known). Women had been taking an ethinylestradiol-containing pill ≥3 months before deciding to switch to the E2V/DNG pill or a POP. Overall, 19.8% (n=506) of E2V/DNG users and 25.8% (n=153) of POP users discontinued their prescribed pill. The median time to discontinuation was 157.0 days and 127.5 days, respectively. Time to discontinuation due to bleeding (P<0.0001) or other reasons (P=0.022) was significantly longer in the E2V/DNG group versus the POP group. The E2V/DNG pill was also associated with shorter (48.7% vs 44.1%), lighter (54% vs 46.1%), and less painful bleeding (91.1% vs 73.7%) and greater user satisfaction (80.7% vs 64.6%) than POP use, within 3-5 months after switch. CONCLUSION: The E2V/DNG pill was associated with higher rates of continuation, bleeding profile acceptability, and user satisfaction than POP use and may be an alternative option for women who are dissatisfied with their current pill.

The effects of timing of prophylaxis, type of anesthesia, and use of mechanical methods on outcome in major orthopedic surgery - subgroup analyses from 17,701 patients in the XAMOS study.

PURPOSE: Real-world data on the use of rivaroxaban in the perioperative period in patients undergoing major orthopedic surgery are limited. Subsets of data from the Phase IV, non-interventional XAMOS study were analyzed to explore the potential influence of timing of the first thrombo prophylactic dose, type of anesthesia, and concomitant mechanical prophylaxis on clinical outcomes in patients undergoing major orthopedic surgery in routine clinical practice. PATIENTS AND METHODS: In XAMOS, 8,778 patients received rivaroxaban (10 mg once daily) and 8,635 received standard-of-care (SOC) pharmacological prophylaxis (safety population). Crude incidences of symptomatic thromboembolic and treatment-emergent bleeding events were analyzed according to timing of the first postoperative thromboprophylactic dose, use of general or neuraxial anesthesia, and use of mechanical prophylaxis with pharmacological thromboprophylaxis. RESULTS: In the rivaroxaban group, the incidences of symptomatic thromboembolic events were 0.7%, 1.0%, and 0.7% in patients receiving the first thromboprophylactic dose at ≤6 hours, >6 hours to ≤10 hours, and >10 hours to ≤24 hours after surgery, respectively. In the SOC group, the incidence of symptomatic thromboembolic events was slightly higher when the postoperative dose was given at >10 hours to ≤24 hours (1.8% vs 1.1% at ≤6 hours and 1.3% at >6 hours to ≤10 hours). The antithrombotic effect of rivaroxaban was maintained in comparison to the SOC group. The incidence of major bleeding (RECORD trial definition) was low and similar between the two treatment groups and was not influenced by timing of the first thromboprophylactic dose. Neuraxial anesthesia was used more than any other form of anesthesia for both hip and knee surgery; the effectiveness of rivaroxaban was not influenced by the type of anesthesia used. No spinal hematomas were reported in patients receiving neuraxial anesthesia in either treatment group. Use of mechanical thromboprophylaxis in addition to rivaroxaban or SOC pharmacological prophylaxis did not reduce the risk of thromboembolic events further. CONCLUSION: The effectiveness and safety of rivaroxaban in patients undergoing major orthopedic surgery in routine clinical practice were maintained irrespective of timing of the first postoperative dose within 24 hours after surgery, the type of anesthesia, and the additional use of mechanical thromboprophylaxis.