Luise Tittl

Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry

Worldwide, rivaroxaban is increasingly used for stroke prevention in atrial fibrillation and treatment of venous thromboembolism, but little is known about rivaroxaban-related bleeding complications in daily care. Using data from a prospective, noninterventional oral anticoagulation registry of daily care patients (Dresden NOAC registry), we analyzed rates, management, and outcome of rivaroxaban-related bleeding. Between October 1, 2011, and December 31, 2013, 1776 rivaroxaban patients were enrolled. So far, 762 patients (42.9%) reported 1082 bleeding events during/within 3 days after last intake of rivaroxaban (58.9% minor, 35.0% of nonmajor clinically relevant, and 6.1% major bleeding according to International Society on Thrombosis and Haemostasis definition). In case of major bleeding, surgical or interventional treatment was needed in 37.8% and prothrombin complex concentrate in 9.1%. In the time-to-first-event analysis, 100-patient-year rates of major bleeding were 3.1 (95% confidence interval 2.2-4.3) for stroke prevention in atrial fibrillation and 4.1 (95% confidence interval 2.5-6.4) for venous thromboembolism patients, respectively. In the as-treated analysis, case fatality rates of bleeding leading to hospitalizations were 5.1% and 6.3% at days 30 and 90 after bleeding, respectively. Our data indicate that, in real life, rates of rivaroxaban-related major bleeding may be lower and that the outcome may at least not be worse than that of major vitamin K antagonist bleeding, and probably better. This trial was registered at www.clinicaltrials.gov as identifier #NCT01588119.

Effectiveness and safety of rivaroxaban therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry.

The effectiveness and safety of rivaroxaban for stroke prevention in atrial fibrillation (SPAF) demonstrated in ROCKET AF needs to be confirmed in daily care. To evaluate effectiveness and safety of rivaroxaban therapy in SPAF patients in daily care, we used data from an ongoing, prospective, non-interventional registry of more than 2700 patients on novel oral anticoagulants in daily care. Between October 1, 2011 and February 28, 2013, a total of 1204 SPAF patients receiving rivaroxaban were enrolled. During a mean follow-up of 796.2 ± 207.3 days, the combined endpoint of stroke/transient ischaemic attack/systemic embolism occurred at a rate of 2.03/100 patient-years in the intention-to-treat analysis (95 % confidence interval [CI] 1.5-2.7) and at 1.7/100 patient-years in the on-treatment analysis (events within 3 days after last intake). On-treatment rates were higher in patients selected for 15 mg rivaroxaban (n=384) once daily [OD] compared with the 820 patients selected for 20 mg OD (2.7 [95 % CI 1.6-4.2] vs 1.25/100 patient-years [95 % CI 0.8-1.9]). On treatment, major bleeding occurred at a rate of 3.0/100 patient-years and significantly more often in patients receiving the 15 mg OD dose compared with the 20 mg OD dose (4.5 vs 2.4/100 patient-years). Rivaroxaban treatment discontinuation occurred in a total of 277 patients during follow-up (12.0/100 patient-years in Kaplan-Meier analysis). Our data contribute to the confirmation of effectiveness and relative safety of rivaroxaban in daily-care patients. Furthermore, rivaroxaban discontinuation rates were considerably lower than those reported for vitamin K antagonists.

Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation

The effectiveness and safety of dabigatran for stroke prevention in atrial fibrillation (SPAF) demonstrated in RE-LY needs to be confirmed in daily care. To evaluate treatment persistence, effectiveness and safety of dabigatran therapy in SPAF patients in daily care, we used data from an ongoing, prospective, non-interventional registry of more than 2,500 patients on novel oral anticoagulants in daily care. Between October 1, 2011 and February 28, 2013, a total of 341 SPAF patients receiving dabigatran were enrolled. The combined endpoint of stroke/transient ischaemic attack/systemic embolism occurred at a rate of 2.93/100 patient-years in the intention-to-treat analysis (95%-CI 1.6-4.9) and at 1.9/100 patient-years in the on treatment analysis (events within three days after last intake). On-treatment rates were higher in patients selected for 110 mg dabigatran (n=183) BID compared to the 158 patients selected for 150 mg BID (2.88 [95% CI 1.16- 5.93] vs 0.86/100 patient-years [95% CI 0.10, 3.12]). On treatment, major bleeding occurred at a rate of 2.3/100 patient-years and numerically more often in patients receiving the 110 mg BID dose compared to the 150 mg BID dose (2.9 vs 1.7/100 patient-years). Dabigatran treatment discontinuation occurred in a total of 124 patients during follow-up (25.8 per 100 patient-years in Kaplan Meier analysis). Main reasons for treatment discontinuation were non-bleeding side effects. Our data contribute to the confirmation of effectiveness and relative safety of dabigatran in unselected patients in daily care. However, discontinuation rates are not lower than those reported for patients treated with vitamin K antagonists.

Drug persistence with rivaroxaban therapy in atrial fibrillation patients—results from the Dresden non-interventional oral anticoagulation registry

Aims Worldwide, rivaroxaban is increasingly used for stroke prevention in atrial fibrillation (SPAF) but little is known about the rates of or reasons for rivaroxaban discontinuations in daily care. Using data from a prospective, non-interventional oral anticoagulation (NOAC) registry, we analysed rivaroxaban treatment persistence. Methods and results Persistence with rivaroxaban in SPAF was assessed in an ongoing, prospective, non-interventional registry of >2600 NOAC patients from daily care using the Kaplan–Meier time-to-first-event analysis. Reasons for and management of rivaroxaban discontinuation were assessed. Potential baseline risk factors for treatment discontinuation were evaluated using Cox regression analysis. Between October 2011 and April 2014, 1204 rivaroxaban SPAF patients were enrolled [39.3% switched from vitamin K antagonists (VKAs) and 60.7% newly treated patients]. Of these, 223 patients (18.5%) stopped rivaroxaban during follow-up (median 544 days), which translates into a discontinuation rate of 13.6 (95% CI 11.8–15.4) per 100 patient-years. Most common reasons for treatment discontinuations were bleeding complications (30% of all discontinuations), followed by other side-effects (24.2%) and diagnosis of stable sinus rhythm (9.9%). A history of chronic heart failure (HR 1.43; 95% CI 1.09–1.87; P = 0.009) or diabetes (HR 1.39; 95% CI 1.06–1.82; P = 0.018) were the only statistically significant baseline risk factors for rivaroxaban discontinuation. After discontinuation of rivaroxaban, patients received antiplatelet therapy (31.8%), VKA (24.2%), another NOAC (18.4%), heparin (9.9%), or nothing (15.7%). Conclusion Our data indicate that overall persistence with rivaroxaban therapy is high, with a discontinuation rate of ∼15% in the first year of treatment and few additional discontinuations thereafter.

Safety of switching from vitamin K antagonists to dabigatran or rivaroxaban in daily care – results from the Dresden NOAC registry

AIM Vitamin-K antagonists (VKA) and non-vitamin-K dependent oral anticoagulants (NOAC) have been approved for anticoagulation in venous thromboembolism (VTE) and atrial fibrillation and patients previously treated with VKA are switched to NOAC therapy. Safety data for this switching are urgently needed. METHODS Using data from a large regional prospective registry of daily care NOAC patients, we evaluated the safety of switching anticoagulation from VKA to dabigatran or rivaroxaban. Switching procedures and cardiovascular and bleeding events occurring within 30 days after switching were centrally adjudicated. RESULTS Between 1 October 2011 and 18 June 2013, 2231 patients were enrolled. Of these, 716 patients were switched from VKA to NOAC. Only 410 of the 546 evaluable patients (75.1%) had a recorded INR measurement within the 10 days preceding or following the end of VKA treatment (mean INR 2.4). As of day 30, major bleeding complications were rare (0.3%; 95% CI 0.0, 1.0) with an overall bleeding rate of 12.2% (95% CI 9.8, 14.8). Major cardiovascular events occurred in 0.8% (95% CI 0.3, 1.8). There was no significant difference in outcome event rates between the subgroups of patients with or without INR testing. CONCLUSION In daily care, only 75% of VKA patients have an INR measurement documented before NOAC are started. On average, NOAC are started within 2 to 5 days after the last intake of VKA. However, at 30 days follow-up cardiovascular events or major bleedings were rare both in patients with and without INR testing. However, switching procedures need to be further evaluated in larger cohorts of patients.

Efficacy and safety of thromboprophylaxis with low-molecular-weight heparin or rivaroxaban in hip and knee replacement surgery

Prospective trials have shown that rivaroxaban thromboprophylaxis is superior over low-molecular-weight heparin (LMWH) in patients undergoing hip and knee replacement surgery. However, patients treated under trial conditions are different from unselected routine patients, which may affect efficacy and safety of thromboprophylaxis. The objective was to evaluate the efficacy and safety of rivaroxaban or LMWH thromboprophylaxis in unselected patients undergoing hip and knee replacement surgery in daily care. In a monocentric, retrospective cohort study in 5,061 consecutive patients undergoing hip and knee replacement surgery a comparison of LMWH (hospital standard in 2006-2007) and rivaroxaban (since 2009) was made with regard to rates of symptomatic VTE, bleeding and surgical complications and length of hospital stay. Rates of symptomatic VTE were 4.1 % (LMWH) and 2.1 % (rivaroxaban; p=0.005) with rates for distal DVT 2.5 vs. 1.1 % (p<0.001). Rates of major VTE were numerically higher with LMWH (1.7 vs. 1.1%, not statistically significant). Rates of major bleeding (overt bleeding leading to surgical revision or death, occurring in a critical site, or transfusion of at least two units of packed red blood cells) were statistically lower with rivaroxaban (2.9 vs. 7.0%; p<0.001). Rivaroxaban patients had fewer surgical complications (1.1 vs. 3.7%; p<0.001) and a shorter length of hospitalisation (8.3 days; 95% CI 8.1- 8.5 vs. 11.1 days; 10.7- 11.5; p< 0.001). We conclude that rivaroxaban thromboprophylaxis is more effective than LMWH in unselected patients undergoing hip and knee replacement surgery in daily care and that switching from LMWH to rivaroxaban could be beneficial. Prospective comparisons are warranted to confirm our findings.

Management and outcomes of vaginal bleeding and heavy menstrual bleeding in women of reproductive age on direct oral anti-factor Xa inhibitor therapy: a case series

BACKGROUND Observational data and results from post-hoc analyses in clinical trials suggest that direct oral factor Xa inhibitors might increase menstrual bleeding intensity in women of reproductive age, but the extent of this effect is unknown. We aimed to investigate the management and outcomes of vaginal bleeding complications during therapy with direct oral factor Xa inhibitors in a case series of women of reproductive age. METHODS To identify individuals for inclusion in this case series, we searched two sources of prospectively collected data from women of reproductive age treated with direct oral factor Xa inhibitors: the non-interventional Dresden NOAC Registry (NCT01588119), which is based in the administrative district of Dresden (Saxony, Germany), and all locally archived data from phase 3 trials of direct oral factor Xa inhibitors done at University Hospital Carl Gustav Carus Dresden. Vaginal bleeding events were defined as any vaginal bleeding complications as reported by the patient. We collected data on type and dosage of anticoagulation; suspected or confirmed bleeding events, hospital admissions, and mortality; and pattern and management of vaginal bleeding events. For all cases of bleeding identified, we reviewed all available source data to identify examination results suggesting potential underlying anatomical causes of bleeding. FINDINGS We identified 178 women of reproductive age who received direct oral factor Xa inhibitor therapy, of whom 57 had vaginal bleeding events, including 50 who received rivaroxaban, six who received apixaban, and one who received edoxaban. These 57 women had 72 vaginal bleeding events, including 59 cases of heavy menstrual bleeding and 13 bleeding events unrelated to the menstrual cycle. 51 (86%) of these heavy menstrual bleeding events (two major bleeding events, 17 clinically relevant non-major bleeding events, 32 minor bleeding events) were treated conservatively (eg, change of oral hormone therapy or reduction, temporary interruption, or discontinuation of direct oral factor Xa inhibitor) and the remaining eight (14%) events (three major bleeding events and five clinically relevant non-major bleeding events) required elective surgical or interventional treatment (hysterectomy, curettage, ovary excision, or excision of ovarian cysts). Of the 57 women, 13 (23%) had a second bleeding event and two (4%) had a third event. Nine patients had underlying anatomical abnormalities; compared with patients without abnormalities, these patients had more intense bleeding, more had recurrent bleeding (five [56%] of nine patients with abnormalities vs eight [17%] of 48 patients without abnormalities), and more needed surgical treatment for bleeding (eight [89%] of nine vs zero of 48). INTERPRETATION Vaginal bleeding, particularly heavy menstrual bleeding, is a common complication in women of reproductive age on direct oral factor Xa inhibitor therapy. Most cases can be treated conservatively, but patients with severe or recurrent vaginal bleeding complications should be assessed for underlying anatomical abnormalities, which might require surgical or interventional treatment. Further data are needed to provide guidance on prevention and treatment of vaginal bleeding complications in this patient population. FUNDING None.

Vaginal bleeding and heavy menstrual bleeding during direct oral anti-Xa inhibitor therapy

Vaginal bleeding and heavy menstrual bleeding during direct oral anti-Xa inhibitor therapy -

Venous thromboembolism therapy with rivaroxaban in daily-care patients: Results from the Dresden NOAC registry

The effectiveness and safety of acute venous thromboembolism (VTE) treatment with rivaroxaban, demonstrated in phase-III trials, needs to be confirmed in daily care. To confirm the positive results of phase-III VTE treatment trials with rivaroxaban in daily care, we used data from the ongoing, prospective, non-interventional Dresden NOAC Registry. For this analysis, only patients with acute VTE who started rivaroxaban within 14days after diagnosis of VTE and who were enrolled within these 14days were evaluated with regard to patient characteristics, treatment persistence and clinical outcomes. Between December 1st 2011 and 30th September 2016, 418 patients with acute VTE and rivaroxaban treatment were enrolled. During rivaroxaban treatment (median rivaroxaban exposure 206d; median follow-up 862d) rates of recurrent VTE and ISTH major bleeding were 1.9% and 3.8%, respectively. At 6months. 58.3% of patients were still taking rivaroxaban, 28.2% had a scheduled end of treatment, 7.2% were switched to other anticoagulants, 1.7% had withdrawn their consent and the remaining 3.6% of patients had unplanned complete discontinuation of anticoagulation. After permanent discontinuation of rivaroxaban, 20 patients experienced a recurrent VTE (7 pulmonary embolism±deep vein thrombosis, 13 deep vein thrombosis) with a mean time between last intake of rivaroxaban and VTE recurrence of 374.3±247.6days (range 28-927d). In daily care patients with acute VTE, rivaroxaban demonstrated high effectiveness with acceptable major bleeding rates. Initial dosing was according to label in over 90% of patients and persistence to rivaroxaban therapy was adequate with low rates of unplanned complete discontinuation.

Management and outcome of gastrointestinal bleeding in patients taking oral anticoagulants or antiplatelet drugs

BackgroundNon-vitamin K dependent oral anticoagulants (NOACs) significantly decrease overall major bleeding rates compared with vitamin K antagonists (VKAs) but there is conflicting evidence regarding the relative risk of gastrointestinal bleeding. Since data regarding the types, the management, and the outcome of NOAC-associated gastrointestinal bleeding are scarce, we aimed to fill this gap by comparing cases of gastrointestinal bleeding associated with NOAC, VKA, or antiplatelet therapy.MethodsAll major gastrointestinal bleeding events documented in the prospective Dresden NOAC registry were identified, and bleeding location, lesion type, endoscopic treatment, use of blood and coagulation factor transfusion, length of stay, and in-hospital mortality were compared with historical data from a large cohort of consecutive gastrointestinal bleeding patients.ResultsIn the 143 NOAC therapy cases, upper gastrointestinal tract bleeding was seen in 44.1%, lower gastrointestinal tract bleeding was seen in 42.0%, and no lesion could be identified in the remaining 14.0%. In contrast, upper gastrointestinal tract bleeding was commoner in the 185 VKA therapy cases (53.0%) and in the 711 antiplatelet therapy cases (68.1%). Among cases with upper gastrointestinal tract bleeding during VKA or antiplatelet therapy, 54.1% and 61.4% respectively presented with ulcers, compared with 27.0% for NOAC therapy. In contrast, hemorrhoid bleeding was the predominant lesion type for lower gastrointestinal tract bleeding with NOAC therapy, with a rate of 33.3%, compared with 10.6% with VKA therapy and 8.7% with antiplatelet therapy. NOAC-associated gastrointestinal bleeding resulted in comparatively low resource consumption, shorter hospitalization, and low in-hospital mortality (1.6%) compared with gastrointestinal bleeding historically seen with use of VKAs (in-hospital mortality 5.6%) or antiplatelet agents (in-hospital mortality 11.9%).ConclusionsGastrointestinal bleeding in NOAC recipients is different from that seen with VKA or antiplatelet therapy and has a better short-term prognosis.