Sebastian Werth

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.

Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry

AIMS Patients receiving novel oral anticoagulants (NOACs) frequently undergo interventional procedures. Short half-lives and rapid onset of action allow for short periods of NOAC interruption without heparin bridging. However, outcome data for this approach are lacking. We evaluated the peri-interventional NOAC management in unselected patients from daily care. METHODS AND RESULTS Effectiveness and safety data were collected from an ongoing, prospective, non-interventional registry of >2100 NOAC patients. Outcome events were adjudicated using standard event definitions. Of 2179 registered patients, 595 (27.3%) underwent 863 procedures (15.6% minimal, 74.3% minor, and 10.1% major procedures). Until Day 30 ± 5 post-procedure, major cardiovascular events occurred in 1.0% of patients [95% confidence interval (95% CI) 0.5-2.0] and major bleeding complications in 1.2% (95% CI 0.6-2.1). Cardiovascular and major bleeding complications were highest after major procedures (4.6 and 8.0%, respectively). Heparin bridging did not reduce cardiovascular events, but led to significantly higher rates of major bleeding complications (2.7%; 95% CI 1.1-5.5) compared with no bridging (0.5%; 0.1-1.4; P = 0.010). Multivariate analysis demonstrated diabetes [odds ratio (OR) 13.2] and major procedures (OR 7.3) as independent risk factors for cardiovascular events. Major procedures (OR 16.8) were an independent risk factor for major bleeding complications. However, if major and non-major procedures were separately assessed, heparin bridging was not an independent risk factor for major bleeding. CONCLUSION Continuation or short-term interruption of NOAC is safe strategies for most invasive procedures. Patients at cardiovascular risk undergoing major procedures may benefit from heparin bridging, but bleeding risks need to be considered.

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.

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.

Bleeding Risk, Management and Outcome in Patients Receiving Non-VKA Oral Anticoagulants (NOACs).

Modern direct-acting anticoagulants are rapidly replacing vitamin K antagonists (VKA) in the management of millions of patients worldwide who require anticoagulation. These drugs include agents that inhibit activated factor X (FXa) (such as apixaban and rivaroxaban) or thrombin (such as dabigatran), and are collectively known today as non-VKA oral anticoagulants (NOACs). Since bleeding is the most common and most dangerous side effect of long-term anticoagulation, and because NOACs have very different mechanisms of action and pharmacokinetics compared with VKA, physicians are naturally concerned about the lack of experience regarding frequency, management and outcome of NOAC-associated bleeding in daily care. This review appraises trial and registry (or “real-world”) data pertaining to bleeding complications in patients taking NOACs and VKA and provides practical recommendations for the management of acute bleeding situations.

Efficacy and safety of venous thromboembolism prophylaxis with fondaparinux or low molecular weight heparin in a large cohort of consecutive patients undergoing major orthopaedic surgery - findings from the ORTHO-TEP registry.

AIMS In large randomized trials, thromboprophylaxis with fondaparinux in major orthopaedic surgery (MOS) has been shown to be superior to low molecular weight heparin (LMWH) prophylaxis with comparable safety. However, patients treated under trial conditions are different from unselected patients and efficacy and safety outcomes may be different in unselected patients in daily practice. We performed a retrospective cohort study to compare the efficacy and safety of venous thromboembolism (VTE) prophylaxis with fondaparinux or LMWH in 3896 consecutive patients undergoing major orthopaedic surgery at our centre. METHODS All patients undergoing MOS between January 2006 and December 2009 were retrospectively analyzed using patient charts, hospital admission and discharge database, quality management database, transfusion unit database and VTE event documentation. VTE standard prophylaxis at our institution was LMWH (3000-6000 aXa units once daily) from January 2006 to December 2007 or fondaparinux 2.5 mg from January 2008 to December 2009. In these two large cohorts of unselected consecutive patients, in-hospital incidences of VTE, surgical complications, severe bleeding and death were evaluated. RESULTS Symptomatic VTE was found in 4.1% of patients in the LMWH group (62/1495 patients; 95% CI 0.032, 0.052) compared with 5.6% of patients receiving fondaparinux (112/1994 patients, 95% CI 0.047, 0.067; P= 0.047). Distal deep vein thrombosis (DVT) was significantly more frequent in the fondaparinux group (3.9%, 95% CI 0.031, 0.048; vs. 2.5%; 95% CI 0.018, 0.034; P= 0.021). No significant differences in the rates of major VTE or death were found. Rates of severe bleeding, transfusion of RBC concentrates, plasma and platelet concentrates were comparable between both treatment groups. However, patients receiving fondaparinux had significantly lower rates of surgical revisions (1.6%, 95% CI 0.011, 0.022 vs. 3.7%, 95% CI 0.028, 0.047; P < 0.001). Multivariate analysis revealed previous VTE (HR 18.2, 95% CI 11.6, 28.5; P < 0.001) and female gender (HR 1.9, 95% CI 1.3, 2.7; P < 0.001), but not fondaparinux prophylaxis (HR1.3, 95% CI 0.9, 1.7; P= 0.184) to be associated with significantly increased VTE risk. DISCUSSION Thromboprophylaxis with fondaparinux is less effective to prevent distal VTE than LMWH in unselected patients undergoing MOS, but is equally effective with regard to rates of major VTE and death. However, differences in efficacy of LMWH or fondaparinux are of little relevance compared with a history of VTE or female gender, which were found to be the main VTE risk factors in MOS. The safety profile of fondaparinux was comparable with LMWH with regard to rates of severe bleeding complications, but patients receiving fondaparinux had significantly less surgical complications requiring surgical revisions. Both our efficacy and safety findings differ from data derived from large phase III trials testing fondaparinux against LMWH in MOS, where overall rates of symptomatic VTE were lower and the safety profile of fondaparinux was different. CONCLUSION We conclude that the strict patient selection and surveillance in phase-III trials results in lower VTE and bleeding event rates compared with unselected routine patients. Consequently, the efficacy and safety profile of thromboprophylaxis regimens needs to be confirmed in large registries or phase IV trials of unselected patients.

Efficacy and safety of venous thromboembolism prophylaxis with apixaban in major orthopedic surgery

Over the last 15 years, low-molecular-weight heparins (LMWHs) have been accepted as the “gold standard” for pharmaceutical thromboprophylaxis in patients at high risk of venous thromboembolism (VTE) in most countries around the world. Patients undergoing major orthopedic surgery (MOS) represent a population with high risk of VTE, which may remain asymptomatic or become symptomatic as deep vein thrombosis or pulmonary embolism. Numerous trials have investigated LMWH thromboprophylaxis in this population and demonstrated high efficacy and safety of these substances. However, LMWHs have a number of disadvantages, which limit the acceptance of patients and physicians, especially in prolonged prophylaxis up to 35 days after MOS. Consequently, new oral anticoagulants (NOACs) were developed that are of synthetic origin and act as direct and very specific inhibitors of different factors in the coagulation cascade. The most developed NOACs are dabigatran, rivaroxaban, and apixaban, all of which are approved for thromboprophylaxis in MOS in a number of countries around the world. This review is focused on the pharmacological characteristics of apixaban in comparison with other NOACs, on the impact of NOAC on VTE prophylaxis in daily care, and on the management of specific situations such as bleeding complications during NOAC therapy.

Trousseau's syndrome in a patient with adenocarcinoma of unknown primary and therapy-resistant venous thrombosis treated with dabigatran and fondaparinux

Almost 10% of cancer patients develop venous thromboembolism (VTE), an association known as Trousseaus syndrome. Treatment of VTE increases survival of cancer patients [1], but recurrent VTE despite therapeutic anticoagulation is common in Trousseaus syndrome and contributes to increased mortality [2]. We report an individualized treatment approach using dabigatran 150 mg twice daily and fondaparinux 7.5 mg once daily in a patient with therapy-resistant VTE. The patient, a 53-year-old female, was diagnosed with an unprovoked calf deep vein thrombosis (DVT) and treated with vitamin K antagonist (VKA) and 6 days of weight-adjusted doses of enoxaparin (60 mg twice daily), until the VKA therapy reached therapeutic INR levels above 2.0. Ten days later the patient was re-admitted with symptomatic submassive pulmonary embolism (PE) and DVT progression despite adequate anticoagulation (INR value of 2.9). Thorough examination ruled out malignant disease, VKA was stopped and enoxaparin 60 mg twice daily restarted. Four months later VKA was re-initiated (target INR 2.5 to 3.5), which could not prevent disease progression to bilateral recurrent DVT despite an INR of 3.6. Enoxaparin was restarted and the patient transferred to our centre. Heparin-induced thrombocytopenia (HIT), antiphospholipid syndrome and malignant disease were ruled out, but heterozygosity for Factor V-Leiden mutation was found. On day 157 an acute right subclavian DVT occurred and anticoagulation was changed to fondaparinux 7.5 mg OD. In the following period, unprovoked thrombophlebitis of left cephalic vein, minor bleedings (nose, gingiva) and recurrent PE, complicated by significant haemoptysis, occurred. Coagulation parameters were monitored and treatment repeatedly adapted according to the clinical situation (see Table S1). On day 307, recurrent subclavian and upper caval DVTs and bulky cervical metastases of a low-differentiated adenocarcinoma were found. Due to recurrent VTE and overwhelming thrombin activation anticoagulant treatment was changed from fondaparinux to argatroban, since direct thrombin inhibition (DTI) is known to be effective in highly coagulable states such as HIT. A short interruption of argatroban during lymph node biopsy for histology led to an acute right iliac DVT. Palliative chemotherapy with carboplatin and paclitaxel was started on day 323. Since DTI with argatroban effectively prevented recurrent VTE, anticoagulant therapy was switched from argatroban to a combination of fondaparinux 7.5 mg once daily and the DTI dabigatran in a prophylactic dose of 75 mg once daily for discharge. However, only 6 days later the patient was re-admitted to our intensive care unit with acute submassive PE with severe right heart strain. The patient consented to fibrinolytic therapy with alteplase together with argatroban, but developed clinically relevant haemoptysis after 50 mg alteplase. Later on, the patients condition improved and, to allow discharge, therapy was changed to therapeutic fondaparinux together with escalated dosages of the oral DTI dabigatran (150 mg twice daily) to block the coagulation cascade both at the level of factor Xa and thrombin to control the severe procoagulatory state. The patient and her husband were informed about the experimental nature of such treatment and the risks of thromboembolic and bleeding complications and written informed consent was obtained. The patient was discharged on day 368. The patient developed slow tumour progression despite five cycles of radio-chemotherapy, but remained free of VTE recurrence for more than 180 days. However, the patient died on day 566 due to final stage cancer and a haemodynamically relevant malignant pericardial effusion. To our knowledge, this is the first published case of a successful anticoagulant treatment with DTI in combination with fondaparinux in paraneoplastic VTE refractory to conventional anticoagulation. Within 333 days, our patient experienced seven thromboembolic events as well as bleeding complications, which are also more common in paraneoplastic VTE [3]. During an individualized treatment with fondaparinux and dabigatran in therapeutic dosages, our patient remained free of VTE recurrence over a period of more than 180 days and survived more than 550 days after the first VTE event despite the progression of malignant disease, demonstrating the beneficial effect of the combined anticoagulant treatment. Clearly, it has to be considered that the stabilization in our patient may partly be attributable to cancer therapy [4]. However, the patient showed progressive malignant disease and died of a terminal complication despite radiation and chemotherapy, indicating that cancer treatment alone does not account for the control of paraneoplastic coagulation activation. We conclude that patients with recurrent paraneoplastic VTE and massive hypercoagulability untreatable with conventional anticoagulation may benefit from treatment with DTI in combination with selective factor Xa inhibition. DTI seems to be an option in recurrent paraneoplastic VTE, since prothrombotic states are often due to increased thrombin generation. It has to be stressed, however, that dabigatran is currently not approved for treatment of VTE and thorough information of patients as well as close monitoring are required for this off-label use.