THIEME Original Article e67 Direct Oral Anticoagulants or Standard Anticoagulant Therapy in Fragile Patients with Venous Thromboembolism Juan J. López-Núñez1 Ricard Pérez-Andrés2 Pierpaolo Di Micco3 Sebastian Schellong4 Covadonga Gómez-Cuervo5 Joan Carles Sahuquillo6 Maurizio Ciammaichella7 Maria del Valle Morales8 Marijan Bosevski9 Manuel Monreal1 and the RIETE Investigators 1 Department of Internal Medicine, Hospital Universitari Germans Address for correspondence Juan José López-Núñez, MD, Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain Department of Internal Medicine, Universitari Germans Trias i Pujol 2 Department of Radiology, Hospital Universitari Germans Trias i This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Hospital, Universitat Autònoma de Barcelona, Badalona, Spain Pujol, Universitat Autònoma de Barcelona, Badalona, Spain (e-mail: jjlopez.germanstrias@gencat.cat). 3 Department of Internal Medicine and Emergency Room, Ospedale Buon Consiglio Fatebenefratelli, Naples, Italy 4 Department of Medical Clinic, Municipal Hospital of Dresden Friedrichstadt, Dresden, Germany 5 Department of Internal Medicine, Hospital Universitario 12 de Octubre, Madrid, Spain 6 Department of Internal Medicine, Hospital Municipal de Badalona, Barcelona, Spain 7 Department of Emergency Internal Medicine, Ospedale St. John, Rome, Italy 8 Department of Internal Medicine, Hospital del Tajo, Madrid, Spain 9 University Cardiology Clinic, Faculty of Medicine, Skopje, Republic of Macedonia TH Open 2019;3:e67–e76. Abstract Background The efficacy and safety of the direct oral anticoagulants (DOACs) in fragile patients (age  75 years and/or creatinine clearance levels  50 mL/min and/or body weight  50kg) with venous thromboembolism (VTE) has not been evaluated. Methods We used the RIETE database to compare the rates of the composite of VTE recurrences or major bleeding during anticoagulation in fragile patients with VTE, according to the use of DOACs or standard anticoagulant therapy. Results From January 2013 to April 2018, 24,701 patients were recruited. Of these, 10,054 (41%) were fragile. Initially, 473 fragile patients (4.7%) received DOACs and 8,577 (85%) low-molecular-weight heparin (LMWH). For long-term therapy, 1,298 patients (13%) received DOACs and 5,038 (50%) vitamin K antagonists (VKAs). Overall, Keywords 95 patients developed VTE recurrences and 262 had major bleeding. Patients initially ► venous receiving DOACs had a lower rate of the composite outcome (hazard ratio [HR]: 0.32; thromboembolism 95% confidence interval [CI]: 0.08–0.88) than those on LMWH. Patients receiving ► fragile patients DOACs for long-term therapy had a nonsignificantly lower rate of the composite ► direct oral outcome (HR: 0.70; 95% CI: 0.46–1.03) than those on VKAs. On multivariable analysis, anticoagulants patients initially receiving DOACs had a nonsignificantly lower risk for the composite  A full list of RIETE investigators is given in ►Appendix A. received DOI https://doi.org/ © 2019 Georg Thieme Verlag KG December 8, 2018 10.1055/s-0039-1683970. Stuttgart · New York accepted ISSN 2512-9465. February 6, 2019 e68 DOACs in Fragile Patients with VTE López-Núñez et al. outcome (HR: 0.36; 95% CI: 0.11–1.15) than those on LMWH, while those receiving DOACs for long-term therapy had a significantly lower risk (HR: 0.61; 95% CI: 0.41– 0.92) than those on VKAs. Conclusions Our data suggest that the use of DOACs may be more effective and safe than standard therapy in fragile patients with VTE, a subgroup of patients where the risk for bleeding is particularly high. Introduction outcome was the composite of VTE recurrences or major bleeding events appearing during therapy. Comparisons Subgroup analyses from randomized clinical trials suggested were made separately for initial (DOACs vs. low-molecular- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. that the direct oral anticoagulants (DOACs) may have some weight heparin [LMWH]) and for long-term therapy (DOACs advantages over standard therapy in fragile patients with vs. vitamin K antagonists [VKAs]). venous thromboembolism (VTE). In the EINSTEIN trials, the For initial therapy, patients receiving DOACs were con- rate of major bleeding was much lower in fragile patients sidered to receive the recommended therapy if they started receiving rivaroxaban than in those on standard therapy.1 within the first 48 hours after VTE diagnosis and were This difference was not seen in nonfragile patients. Besides, prescribed rivaroxaban 15 mg twice daily for 21  2 days the HOKUSAI trial found a higher efficacy using edoxaban or apixaban 10 mg twice daily for 7  2 days. For long-term than warfarin in fragile patients, without any safety con- therapy, patients were considered to receive the recom- cern.2 Fragile patients are underrepresented in clinical trials, mended doses if they were prescribed rivaroxaban 20 mg and these favorable results have not been validated yet in real once daily; apixaban 5 mg twice daily; dabigatran 150 mg life. In a recent study, we found that 42% of VTE patients in twice daily or edoxaban 60 mg once daily. real life are fragile,3 and that during anticoagulation they had fewer VTE recurrences and more major bleeding events than Definitions the nonfragile. Fragile patients were defined as those having age 75 years, The RIETE (Registro Informatizado de Enfermedad Trom- creatinine clearance (CrCl) levels 50 mL/min, or body boEmbólica) registry is an ongoing, multicenter registry of weight 50 kg, as previously reported. Immobilized patients consecutive patients with acute VTE with 223 collaborating were defined as nonsurgical patients who had been immo- centers in the Americas, Asia, and Europe (ClinicalTrials.gov bilized (i.e., total bed rest with bathroom privileges) for identifier: NCT02832245). Since its inception in 2001, the 4 days in the 2-month period prior to VTE. Surgical patients aim of RIETE was to record data including the clinical were defined as those who underwent a surgical interven- characteristics, treatment patterns, and outcomes in tion in the 2 months prior to VTE. Active cancer was defined patients diagnosed with VTE.4–7 Using the RIETE database, as newly diagnosed cancer, metastatic cancer, or cancer that the current study aimed to compare the outcomes during was being treated (i.e., surgery, chemotherapy, radiotherapy, anticoagulation in fragile patients with VTE, according to the support therapy). Recent bleeding was defined as any major use of DOACs or standard anticoagulant therapy. bleeding episode <30 days prior to VTE. Initial therapy was defined as any therapy administered during the first week in the case of LMWH or apixaban, and during the first 3 weeks Patients and Methods in the case of rivaroxaban. Long-term therapy was defined as Consecutive patients presenting with symptomatic, acute any therapy administered after the end of initial therapy. deep vein thrombosis (DVT) or pulmonary embolism (PE) Bleeding events were classified as “major” if they were overt confirmed by objective tests (compression ultrasonography and required a transfusion of two units or more of blood, or or contrast venography for DVT; helical computed tomogra- were retroperitoneal, spinal or intracranial, or when they phy [CT] scan, ventilation-perfusion lung scintigraphy, or were fatal. Fatal bleeding was defined as any death occurring angiography for PE) were enrolled in RIETE. Patients were within 10 days of a major bleeding episode, in the absence of excluded if they were currently participating in a therapeutic an alternative cause of death. Fatal PE, in the absence of clinical trial with a blinded therapy. The rationale, design, autopsy, was defined as any death appearing within 10 days and methodology of RIETE have been reported elsewhere.8 after symptomatic PE diagnosis, in the absence of any alter- native cause of death. Study Design We conducted a retrospective study of prospectively col- Treatment and Follow-up lected data from consecutive patients with acute VTE Patients were managed according to each participating enrolled in the RIETE registry. Data were collected from hospital’s clinical practice, and there were no standardized January 2013 to April 2018, corresponding to the time or recommended duration of therapy or follow-up. All when the prescription of DOACs was allowed. The major patients had to be followed up for at least 3 months in the TH Open Vol. 3 No. 1/2019 DOACs in Fragile Patients with VTE López-Núñez et al. e69 outpatient clinic or physician’s office. During each visit, any Role of the Funding Source signs or symptoms suggesting VTE recurrences or bleeding The sponsors of the RIETE registry (Sanofi and Bayer) had no complications were noted. Each episode of clinically sus- role in study design, data collection, data analysis, data pected recurrent VTE was investigated by repeat compres- interpretation, or writing of the report. The corresponding sion ultrasonography, lung scanning, helical CT scan, or author had full access to all the data in the study and had final pulmonary angiography, as appropriate. Most outcomes responsibility for the decision to submit for publication. were classified as reported by the clinical centers. However, if staff at the coordinating center were uncertain how to Results classify a reported outcome, that event was reviewed by a central adjudicating committee (less than 10% of events). From January 2013 to April 2018, 24,701 patients with acute VTE were recruited in RIETE. Of these, 10,054 (41%) were Statistical Analysis fragile (►Fig. 1). Initially, 473 fragile patients (4.7%) received Categorical variables were compared using the chi-square test DOACs (rivaroxaban 382, apixaban 91) and 8,577 (85%) were (two-sided) and Fisher’s exact test (two-sided). Continuous prescribed LMWH. Then, 1,298 patients (13%) switched to This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. variables were compared using Student t-test. Hazard ratios DOACs for long-term therapy (rivaroxaban 844, apixaban (HRs) and corresponding 95% confidence intervals (CIs) were 344, dabigatran 69, edoxaban 41) and 5,038 (50%) to VKAs. calculated. Incidence rates were calculated as cumulative For initial therapy, patients receiving DOACs were 2 years incidence (events/100 patient-years) and compared using younger than those treated with LMWH, less likely presented the HRs and 95% CI. Cox proportional hazard models were with PE (as compared with DVT), and were less likely to have used to compare the rates of the composite outcome of VTE cancer, anemia, or renal insufficiency, but were more likely recurrences or major bleeding occurring during initial and to have unprovoked VTE, prior VTE, chronic heart failure, or long-term therapy, separately. Crude and adjusted HRs as well to receive corticosteroids at baseline (►Table 1). Median as their 95% CIs were estimated. Covariates included in the duration of initial therapy with rivaroxaban, apixaban, or adjusted model were those for which a statistically significant LMWH was 23, 9, and 10 days, respectively (►Table 2). Most difference (a threshold p-value of 0.1 was set to assess sig- patients received the recommended doses of DOACs (rivar- nificance of differences) was found between the different oxaban 91%, apixaban 74%). Many patients receiving non- drugs, and a backward selection was used for the covariate recommended doses had recent major bleeding, severe renal selection in the multivariable model. Statistical analyses were insufficiency, liver failure, or thrombocytopenia. For long- conducted with SPSS for Windows Release 20.0 (SPSS Inc., term therapy, patients receiving DOACs were less likely to Chicago, Illinois, United States). have renal insufficiency and more likely to have prior VTE, Fig. 1 Flowchart of the patients. TH Open Vol. 3 No. 1/2019 e70 DOACs in Fragile Patients with VTE López-Núñez et al. Table 1 Clinical characteristics of the patients, according to initial therapy with LMWH or DOACs Initial therapy Long-term therapy DOACs LMWH DOACs VKAs Patients, N 473 8,577 1,298 5,038 Clinical characteristics Male gender 176 (37%) 3,291 (38%) 481 (37%) 1,917 (38%) a Mean age (years  SD) 78  11 80  10 79  9.9 80  9.6 Age  75 y 417 (88%) 7,539 (88%) 1,170 (90%) 4,497 (89%) Body weight (kg  SD) 72  14 71  14 72  15 72  14 Body weight  50 kg 36 (7.6%) 780 (9.1%) 103 (7.9%) 324 (6.4%) Initial VTE presentation This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. a Pulmonary embolism 242 (51%) 4,932 (58%) 795 (61%) 3,156 (63%) Risk factors for VTE Immobilization  4 d 133 (28%) 2,229 (26%) 307 (24%) 1,162 (23%) Surgery 40 (8.5%) 661 (7.7%) 103 (7.9%) 361 (7.2%) b Cancer 66 (14%) 2,168 (25%) 157 (12%) 626 (12%) Estrogen use 12 (2.5%) 292 (3.4%) 41 (3.2%) 129 (2.6%) Pregnancy/postpartum 0 14 (0.16%) 1 (0.08%) 6 (0.12%) c None of the above 251 (53%) 4,060 (47%) 755 (58%) 3,011 (60%) c a Prior VTE 83 (18%) 1,143 (13%) 232 (18%) 739 (15%) Underlying diseases b b Chronic heart failure 79 (17%) 932 (11%) 184 (14%) 543 (11%) Chronic lung disease 77 (16%) 1,288 (15%) 183 (14%) 786 (16%) b Recent major bleeding 9 (1.9%) 215 (2.5%) 38 (2.9%) 56 (1.1%) Blood tests at baseline b Anemia 144 (31%) 3,488 (41%) 420 (32%) 1,649 (33%) c Platelet count < 100,000/µL 5 (1.1%) 238 (2.8%) 17 (1.3%) 109 (2.2%) b b CrCl levels (mL/min  SD) 60  21 55  24 59  21 54  23 b b CrCl levels 50 mL/min 169 (36%) 4,185 (49%) 496 (38%) 2,479 (49%) Concomitant drugs a Corticosteroids 74 (16%) 977 (11%) 135 (10%) 512 (10%) Antiplatelets 134 (28%) 2,300 (27%) 340 (26%) 1,362 (27%) NSAIDs 38 (8.1%) 665 (7.8%) 98 (7.6%) 390 (7.7%) Abbreviations: CrCl, creatinine clearance; DOACs, direct oral anticoagulants; LMWH, low-molecular-weight heparin; NSAIDs, nonsteroidal anti- inflammatory drugs; SD, standard deviation; VKAs, vitamin K antagonists; VTE, venous thromboembolism. Comparisons between DOACs versus standard therapy: ap < 0.01; bp < 0.001; cp < 0.05. chronic heart failure, or recent major bleeding than those on therapy had a significantly lower rate of the composite out- long-term VKAs (►Table 1). Median duration of therapy with come (HR: 0.32; 95% CI: 0.08–0.88) and a lower mortality rate DOACs was half that of VKAs (96 vs. 172 days, respectively) (HR: 0.29; 95% CI: 0.12–0.62) than those receiving LMWH and the proportion of patients receiving the recommended (►Table 3). No patient receiving DOACs initially developed VTE doses of DOACs was: rivaroxaban 65%, apixaban 68%, dabi- recurrences, and the rate of major bleeding was nonsignifi- gatran 55%, and edoxaban 61%. Again, many patients receiv- cantly lower (HR: 0.37; 95% CI: 0.09–1.04) than in those on ing nonrecommended doses had recent major bleeding, LMWH. All three major bleeding events occurring in patients severe renal insufficiency, liver failure, or thrombocytopenia. initially receiving DOACs appeared in patients aged 75 years, During the course of anticoagulation, 95 patients developed with CrCl levels >50 mL/min. None of the 169 patients with VTE recurrences (LMWH 85, DOACs 10), 262 had major CrCl levels 50 mL/min developed major bleeding during bleeding (VKAs 241, DOACs 21), and 595 died (standard initial therapy with DOACs. No patients initially receiving therapy 536, DOACs 59). Patients receiving DOACs for initial DOACs died of PE or bleeding. On multivariable analysis, TH Open Vol. 3 No. 1/2019 DOACs in Fragile Patients with VTE López-Núñez et al. e71 Table 2 Treatment strategies for initial and for long-term therapy Initial therapy Long-term therapy DOACs LMWH DOACs VKAs Initial therapy with LMWH, N 473 8,577 1,298 5,038 a Mean days of therapy (  SD) 20  16 13  16 149  156 251  248 a Median days of therapy (IQR) 23 (12–24) 10 (7–13) 96 (65–183) 172 (99–313) Mean LMWH doses (IU/kg/d) – 170  46 – – Rivaroxaban, N 382 844 Mean days of therapy (  SD) 21  17 – 144  163 – Median days of therapy (IQR) 23 (14–24) – 94 (42–172) – 30 mg daily 346 (91%) – 204 (24%) – This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 20 mg daily 10 (2.6%) – 547 (65%) – 15 mg daily 25 (6.5%) – 87 (10%) – Apixaban, N 91 344 Mean days of therapy (  SD) 10  11 – 162  147 – Median days of therapy (IQR) 9 (9–10) – 114 (85–191) – 20 mg daily 67 (74%) – 44 (13%) – 10 mg daily 13 (14%) – 233 (68%) – 5 mg daily 11 (12%) – 64 (19%) – Dabigatran, N 69 Mean days of therapy (  SD) – – 173  137 – Median days of therapy (IQR) – – 134 (93–203) – 220 mg daily – – 38 (55%) – Other doses/not reported – – 31 (45%) – Edoxaban, N 41 Mean days of therapy (  SD) – – 125  78 – Median days of therapy (IQR) – – 98 (88–170) – 60 mg daily – – 25 (61%) – 30 mg daily – – 16 (39%) – Abbreviations: DOACs, direct oral anticoagulants; IQR, interquartile range; LMWH, low-molecular-weight heparin; SD, standard deviation; VKAs, vitamin K antagonists. Comparisons between DOACs versus standard therapy: ap < 0.001. patients initially receiving DOACs had a nonsignificantly lower than in those receiving LMWH (HR: 0.14; 95% CI: 0.007– risk for the composite outcome (HR: 0.36; 95% CI: 0.11–1.15) 0.71), as shown in ►Table 6. The rate in patients receiving than those on LMWH. During long-term therapy, patients nonrecommended doses of DOACs was higher. During long- receiving DOACs had a nonsignificantly lower rate of the term therapy, patients receiving DOACs at recommended composite outcome (HR: 0.70; 95% CI: 0.46–1.03), VTE recur- doses (but not those on nonrecommended doses) had half rences (HR: 0.77; 95% CI: 0.38–1.45), or major bleeding (HR: the rate of the composite outcome (HR: 0.45; 95% CI: 0.23– 0.68; 95% CI: 0.41–1.10) than those on VKAs, and a similar 0.80) compared to those on VKAs. The rates of the composite mortality rate (HR: 1.03; 95% CI: 0.76–1.39) (►Fig. 2 outcome during long-term therapy with rivaroxaban, apix- and ►Tables 3 and 4). Most patients (17 of 18, 94%) presenting aban, or dabigatran were similar. with major bleeding during long-term therapy with DOACs were aged 75 years. Of these, eight patients had CrCl levels Discussion >50 mL/min and nine had levels 50 mL/min. On multi- variable analysis, patients receiving DOACs had a significantly Our data, obtained from a series of fragile patients with VTE lower risk for the composite outcome (HR: 0.61; 95% CI: 0.41– in real life, suggest that the use of DOACs may be more 0.92) than those on VKAs (►Table 5). effective and safe than standard therapy in this patient During initial therapy, the rate of major bleeding in population. No patient receiving DOACs for initial therapy patients receiving DOACs at recommended doses was lower in our cohort developed VTE recurrences, and their rate of TH Open Vol. 3 No. 1/2019 e72 DOACs in Fragile Patients with VTE López-Núñez et al. Table 3 Outcomes in fragile patients with VTE, according to initial therapy with LMWH or DOACs N N per 100 N N per 100 Hazard ratio patient-years patient-years (95% CI) Initial therapy DOACs LMWH Patients, N 473 8,577 Recurrent DVT 0 – 8 2.29 (1.07–4.36) – Recurrent PE 0 – 12 3.44 (1.86–5.84) – Recurrent VTE 0 – 20 5.74 (3.60–8.71) – Major bleeding 3 11.7 (2.98–31.9) 109 31.4 (25.9–37.7) 0.37 (0.09–1.04) Gastrointestinal 1 3.90 (0.20–19.2) 30 8.60 (5.91–12.1) 0.45 (0.02–2.38) Intracranial 1 3.90 (0.19–19.2) 9 2.58 (1.26–4.73) 1.52 (0.07–9.09) This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Composite outcome 3 11.7 (2.98–31.9) 128 36.9 (30.9–43.8) 0.32 (0.08–0.88) Death 6 23.4 (9.49–48.7) 277 79.7 (70.8–89.6) 0.29 (0.12–0.62) Causes of death Pulmonary embolism 0 – 54 15.5 (11.7–20.0) – Bleeding 0 – 16 4.58 (2.71–7.28) – Long-term therapy DOACs VKAs Patients, N 1,298 5,038 Recurrent DVT 3 0.40 (0.10–1.09) 31 0.82 (0.57–1.16) 0.49 (0.12–1.43) Recurrent PE 7 0.94 (0.41–1.85) 35 0.93 (0.66–1.28) 1.01 (0.41–2.17) Recurrent VTE 10 1.34 (0.68–2.39) 65 1.74 (1.35–2.20) 0.77 (0.38–1.45) Major bleeding 18 2.41 (1.47–3.74) 132 3.52 (2.95–4.16) 0.68 (0.41–1.10) Gastrointestinal 12 1.61 (0.87–2.73) 54 1.43 (1.09–1.86) 1.12 (0.57–2.04) Intracranial 2 0.27 (0.04–0.88) 20 0.53 (0.33–0.80) 0.51 (0.08–1.85) Composite outcome 27 3.63 (2.44–5.21) 193 5.19 (4.50–5.96) 0.70 (0.46–1.03) Death 53 7.09 (5.36–9.20) 259 6.86 (6.06–7.73) 1.03 (0.76–1.39) Causes of death Recurrent PE 3 0.40 (0.10–1.09) 2 0.05 (0.01–0.17) 7.69 (1.12–50.0) Bleeding 1 0.13 (0.01–0.66) 19 0.50 (0.31–0.77) 0.27 (0.01–1.45) Fatal PE or bleeding 4 0.53 (0.17–1.29) 21 0.56 (0.35–0.84) 0.96 (0.28–2.63) Abbreviations: DOACs, direct oral anticoagulants; DVT, deep vein thrombosis; LMWH, low-molecular-weight heparin; PE, pulmonary embolism; VKAs, vitamin K antagonists; VTE, venous thromboembolism. major bleeding was one-third the rate in patients on LMWH. On multivariable analysis, the risk for the composite out- come was not significantly lower, most likely since fragile patients on DOACs were younger and less likely to have cancer, anemia, or renal insufficiency than those on LMWH. During long-term therapy however, the clinical characteristics of patients receiving DOACs or VKAs were similar, and the use of DOACs was associated with a lower risk for the composite outcome after adjusting for potential confounders. In a previous study using the RIETE database, we found that fragile patients with VTE had a twofold higher rate of major bleeding and half the rate of VTE recurrences com- pared to the nonfragile.3 Thus, there are reasons to suggest Fig. 2 Cumulative rates of the composite outcome during the first that when choosing an anticoagulant drug for fragile patients 6 months of therapy. with VTE, safety is an important issue. The current findings TH Open Vol. 3 No. 1/2019 DOACs in Fragile Patients with VTE López-Núñez et al. e73 Table 4 Cumulative rates of the composite of VTE recurrences or major bleeding during the first 6 months of therapy Days 30 60 90 120 150 180 VKAs Patients at risk 4,988 4,827 4,616 3,935 3,176 2,767 Events 61 (1.22%) 81 (1.63%) 93 (1.88%) 106 (2.21%) 115 (2.48%) 127 (2.9%) DOACs Patients at risk 1,288 1,250 1,118 857 653 544 Events 8 (0.62%) 13 (1.02%) 14 (1.11%) 17 (1.51%) 18 (1.67%) 18 (1.67%) Table 5 Uni- and multivariable analyses for the composite outcome of VTE recurrences plus major bleeding Initial therapy Long-term therapy Univariable Multivariable Univariable Multivariable This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Events, N 131 Clinical characteristics Male gender 0.73 (0.51–1.06) 0.70 (0.48–1.02) 1.03 (0.78–1.35) – a Age > 80 y 1.16 (0.82–1.64) – 1.43 (1.09–1.87) 1.31 (0.99–1.73) b Body weight  70 kg 0.90 (0.64–1.27) – 1.32 (1.01–1.72) 1.25 (0.95–1.65) Initial VTE presentation Pulmonary embolism 1.34 (0.94–1.92) – 1.13 (0.85–1.50) – Risk factors for VTE c b c b Unprovoked Ref. Ref. Ref. Ref. a b a b Cancer 1.90 (1.23–2.95) 1.71 (1.09–2.69) 1.67 (1.15–2.44) 1.52 (1.04–2.23) c a c b Transient risk factors 2.17 (1.43–3.28) 1.80 (1.18–2.76) 1.65 (1.22–2.21) 1.36 (1.01–1.85) Prior VTE 1.11 (0.69–1.79) – 1.12 (0.80–1.58) – Underlying diseases b Chronic heart failure 1.21 (0.73–2.01) – 1.56 (1.08–2.23) 1.37 (0.94–1.98) Chronic lung disease 1.33 (0.86–2.06) – 1.26 (0.89–1.78) – c c a b Recent major bleeding 4.51 (2.59–7.86) 3.69 (2.09–6.54) 3.28 (1.62–6.65) 2.37 (1.15–4.88) Blood tests b c c Anemia 1.52 (1.08–2.14) 1.23 (0.86–1.76) 1.96 (1.50–2.55) 1.69 (1.28–2.23) Platelet count < 100,000/µL 1.52 (0.62–3.72) – 1.52 (0.72–3.23) – CrCl levels 50 mL/min 1.12 (0.79–1.58) – 1.26 (0.97–1.64) 1.02 (0.77–1.35) Concomitant drugs Corticosteroids 1.28 (0.79–2.08) – 1.47 (1.00–2.18) 1.26 (0.85–1.87) b b Antiplatelets 1.45 (1.01–2.09) 1.48 (1.03–2.13) 1.32 (0.99–1.75) 1.18 (0.88–1.57) a a NSAIDs 1.30 (0.73–2.30) – 1.78 (1.21–2.63) 1.70 (1.15–2.53) DOACs b b Yes 0.34 (0.11–1.06) 0.36 (0.11–1.15) 0.65 (0.43–0.97) 0.61 (0.41–0.92) Abbreviations: CrCl, creatinine clearance; DOACs, direct oral anticoagulants; NSAIDs, nonsteroidal anti-inflammatory drugs; Ref., reference; VTE, venous thromboembolism. Comparisons: ap < 0.01; bp < 0.05; cp < 0.001. confirm that the rate of major bleeding during the course of more cost effective to prescribe safer drugs in patients at anticoagulation clearly outweighed the rate of VTE recur- increased risk for bleeding, as fragile patients are. As far as we rences (262 vs. 95 events, respectively). Unexpectedly how- know, no studies have compared yet the efficacy and safety of ever, only one in every 20 fragile patients was prescribed the DOACs versus standard therapy in fragile patients with DOACS initially, and only one in every eight for long-term VTE. In a recent study, Coleman et al compared rivaroxaban therapy. Data from the PREFER in VTE registry also showed versus VKAs in a cohort of frail patients with VTE.15 However, that the use of DOACs was less likely in elderly patients or in the term “fragile” has been recently incorporated into the those with renal insufficiency.1,9–14 It would seem to be literature to include VTE patients who are elderly, renally TH Open Vol. 3 No. 1/2019 e74 DOACs in Fragile Patients with VTE López-Núñez et al. Table 6 Rates of VTE recurrences, major bleeding, and the composite outcome, according to prescribed drugs and doses. Results expressed as number of events per 100 patient-years and 95% confidence intervals Initial therapy Long-term therapy N Events per N Events per 100 patient-years 100 patient-years Standard therapy, N 8,577 5,038 VTE recurrences 20 5.74 (3.60–8.71) 65 1.74 (1.35–2.20) Major bleeding 109 31.4 (25.9–37.7) 132 3.52 (2.85–4.16) Composite outcome 128 36.9 (30.9–43.8) 193 5.19 (4.50–5.96) DOACs, recommended doses, N 413 843 VTE recurrences 0 – 4 0.85 (0.27–2.06) This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Major bleeding 1 4.44 (0.22–21.9) 7 1.49 (0.65–2.95) Composite outcome 1 4.44 (0.22–21.9) 11 2.35 (1.23–4.08) DOACs, nonrecommended doses, N 60 455 VTE recurrences 0 – 6 2.19 (0.89–4.56) Major bleeding 2 65.4 (11.0–216.1) 11 4.02 (2.12–6.99) Composite outcome 2 65.4 (11.0–216.1) 16 5.88 (3.48–9.35) Rivaroxaban, N 382 844 VTE recurrences 0 – 9 1.85 (0.90–3.39) Major bleeding 3 13.2 (3.37–36.1) 10 2.05 (1.04–3.65) Composite outcome 3 13.2 (3.37–36.1) 18 3.71 (2.27–5.74) Apixaban, N 91 344 VTE recurrences 0 – 1 0.51 (0.03–2.50) Major bleeding 0 – 6 3.05 (1.24–6.34) Composite outcome 0 – 7 3.56 (1.56–7.04) Dabigatran, N 0 69 VTE recurrences 0 – 0 – Major bleeding 0 – 2 4.84 (0.81–16.0) Composite outcome 0 – 2 4.84 (0.81–16.0) Edoxaban, N 0 41 VTE recurrences 0 – 0 – Major bleeding 0 – 0 – Composite outcome 0 – 0 Abbreviations: DOACs, direct oral anticoagulants; VTE, venous thromboembolism. impaired, or with low body weight.1 This term should not be <50 mL/min. Unfortunately, randomized clinical trials to confused with “frail,” which usually refers to elderly people compare the DOACs versus standard therapy are not allowed with reduced physiologic reserve associated with increased in patients with CrCl levels <50 mL/min. susceptibility to disability.16–20 The present study has several potential limitations. First, During long-term therapy, only two in every three since RIETE is an observational registry (and not a rando- patients (65%) on DOACs received the recommended doses. mized trial) our data are hypothesis-generating. They might This is important since the use of DOACs at nonrecom- be a useful basis for future controlled clinical trials compar- mended doses has been associated with a much higher ing different therapeutic strategies, but we should be extre- rate of VTE recurrences and a similar rate of major bleeding mely cautious in suggesting changes in treatment strategies compared to those on recommended doses.21 One in every just because of uncontrolled registry data. Second, for long- six patients (496 of 2,975, 17%) with CrCl levels <50 mL/min term therapy we compared DOACs versus VKAs, but one in in our series was prescribed DOACs, a subgroup of patients at every eight such patients (12%) had active cancer, and they increased risk for bleeding.4,22,23 However, only six of these should have been compared rather with LMWH. Third, patients had major bleeding, thus suggesting that the DOACs treatment varied with local practice, and is likely to have might be at least as safe as VKAs in patients with CrCl levels been influenced by a physician’s assessment of a patient’s TH Open Vol. 3 No. 1/2019 DOACs in Fragile Patients with VTE López-Núñez et al. e75 risk of bleeding. Fourth, patients in the RIETE database were 4 Ruíz-Giménez N, Suárez C, González R, et al; RIETE Investigators. selected from several different countries. The variability of Predictive variables for major bleeding events in patients present- practices in different countries could potentially affect the ing with documented acute venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008;100(01):26–31 study outcomes. Fifth, a variety of practitioners entered data 5 Muñoz-Torrero JF, Bounameaux H, Pedrajas JM, et al; Registro into the registry, which may lend itself to potential inac- Informatizado de la Enfermedad TromboEmbólica (RIETE) Inves- curacies in the data being reported. Finally, lack of central tigators. Effects of age on the risk of dying from pulmonary adjudication of the events is another limitation that is embolism or bleeding during treatment of deep vein thrombosis. impossible for us to overcome. The main strengths of our J Vasc Surg 2011;54(06, Suppl):26S–32S 6 Jiménez D, de Miguel-Díez J, Guijarro R, et al; RIETE Investigators. observation are the high number of included patients, the Trends in the management and outcomes of acute pulmonary strict diagnostic criteria, and the reporting of objectively embolism: Analysis from the RIETE Registry. J Am Coll Cardiol established outcomes (major bleeding and recurrent VTE). 2016;67(02):162–170 Additionally, the population-based sample we used 7 Muriel A, Jiménez D, Aujesky D, et al; RIETE Investigators. Survival describes the effects of anticoagulant therapy in “real-world” effects of inferior vena cava filter in patients with acute sympto- clinical care, as opposed to that in a protocol driven rando- matic venous thromboembolism and a significant bleeding risk. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. J Am Coll Cardiol 2014;63(16):1675–1683 mized trial, and enhances the generalizability of our findings. 8 Bikdeli B, Jimenez D, Hawkins M, et al; RIETE Investigators. In summary, in real life 41% of VTE patients were fragile, a Rationale, design and methodology of the computerized registry subgroup of patients where the risk for bleeding is particu- of patients with venous thromboembolism (RIETE). Thromb Hae- larly high. Our findings suggest that the use of DOACs may be most 2018;118(01):214–224 more effective and safe than standard therapy in this patient 9 Bauersachs R, Agnelli G, Gitt AK, et al; PREFER in VTE Scientific population. Intervention studies specifically designed to Steering Committee. The role of heparin lead-in in the real-world management of acute venous thromboembolism: the PREFER in confirm our findings and the potential role of the DOACs VTE registry. Thromb Res 2017;157:181–188 in fragile patients receiving anticoagulant therapy for VTE 10 Cohen AT, Gitt AK, Bauersachs R, et al. The management of acute are warranted. venous thromboembolism in clinical practice. Results from the European PREFER in VTE Registry. Thromb Haemost 2017;117 Authors’ Contributions (07):1326–1337 11 Schulman S, Kearon C, Kakkar AK, et al; RE-COVER Study Group. All the authors introduced patients in the database, Dabigatran versus warfarin in the treatment of acute venous performed the research, analyzed results, and reviewed thromboembolism. N Engl J Med 2009;361(24):2342–2352 the article. J. J. López-Núñez and M. Monreal designed the 12 Büller HR, Prins MH, Lensin AW, et al; EINSTEIN–PE Investigators. research and wrote the article. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366(14):1287–1297 Conflict of Interest 13 Agnelli G, Buller HR, Cohen A, et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. None declared. N Engl J Med 2013;369(09):799–808 14 Becattini C, Agnelli G. Treatment of venous thromboembolism with Acknowledgments new anticoagulant agents. J Am Coll Cardiol 2016;67(16):1941–1955 We express our gratitude to Sanofi Spain for supporting 15 Coleman CI, Turpie AGG, Bunz TJ, Beyer-Westendorf J. Effectiveness this registry with an unrestricted educational grant. We and safety of rivaroxaban versus warfarin in frail patients with also express our gratitude to Bayer Pharma AG for sup- venous thromboembolism. Am J Med 2018;131(08):933.e1–938.e1 16 Buchner DM, Wagner EH. Preventing frail health. Clin Geriatr Med porting this registry. Bayer Pharma AG’s support was 1992;8(01):1–17 limited to the part of RIETE outside Spain, which accounts 17 Rockwood K, Song X, MacKnight C, et al. A global clinical measure of for a 25.20% of the total patients included in the RIETE fitness and frailty in elderly people. CMAJ 2005;173(05):489–495 Registry. We also thank the RIETE Registry Coordinating 18 Robinson TN, Eiseman B, Wallace JI, et al. Redefining geriatric Center, S&H Medical Science Service, for their quality preoperative assessment using frailty, disability and co-morbid- control data, logistic and administrative support, and ity. Ann Surg 2009;250(03):449–455 19 Robinson TN, Wu DS, Pointer L, Dunn CL, Cleveland JC Jr, Moss M. Prof. Salvador Ortiz, Universidad Autónoma Madrid, and Simple frailty score predicts postoperative complications across Silvia Galindo, both Statistical Advisors in S&H Medical surgical specialties. Am J Surg 2013;206(04):544–550 Science Service, for the statistical analysis of the data 20 Perera V, Bajorek BV, Matthews S, Hilmer SN. The impact of frailty presented in this article. on the utilisation of antithrombotic therapy in older patients with atrial fibrillation. Age Ageing 2009;38(02):156–162 21 Trujillo-Santos J, Di Micco P, Dentali F, et al; RIETE Investigators. References Real-life treatment of venous thromboembolism with direct oral 1 Bauersachs R, Berkowitz SD, Brenner B, et al; EINSTEIN Investi- anticoagulants: the influence of recommended dosing and regi- gators. Oral rivaroxaban for symptomatic venous thromboembo- mens. Thromb Haemost 2017;117(02):382–389 lism. N Engl J Med 2010;363(26):2499–2510 22 Monreal M, Falgá C, Valle R, et al; RIETE Investigators. Venous 2 Büller HR, Décousus H, Grosso MA, et al; Hokusai-VTE Investigators. thromboembolism in patients with renal insufficiency: findings Edoxaban versus warfarin for the treatment of symptomatic venous from the RIETE Registry. Am J Med 2006;119(12):1073–1079 thromboembolism. N Engl J Med 2013;369(15):1406–1415 23 Moustafa F, Stehouwer A, Kamphuisen P, et al; RIETE Investigators. 3 Moustafa F, Pierfranceschi MG, Di Micco P, et al. Clinical outcomes Management and outcome of major bleeding in patients receiving during anticoagulant therapy in fragile patients with venous throm- vitamin K antagonists for venous thromboembolism. Thromb Res boembolism. Res Pract Thromb Haemost 2017;1(02):172–179 2018;171:74–80 TH Open Vol. 3 No. 1/2019 e76 DOACs in Fragile Patients with VTE López-Núñez et al. Appendix A López-Jiménez L, López-Miguel P, López-Núñez JJ, López- Reyes R, López-Sáez JB, Lorente MA, Lorenzo A, Loring M, Coordinator of the RIETE Registry: Manuel Monreal. Madridano O, Maestre A, Marchena PJ, Martín del Pozo M, RIETE Steering Committee Members: Paolo Prandoni, Martín-Fortea MP, Martín-Guerra JM, Martínez-González L, Benjamin Brenner, and Dominique Farge-Bancel. Mella C, Mellado M, Monreal M, Montesa C, Morales MV, Nieto RIETE National Coordinators: Raquel Barba (Spain), MA, Nieto JA, Núñez MJ, Olivares MC, Otero R, Pedrajas JM, Pierpaolo Di Micco (Italy), Laurent Bertoletti (France), Sebas- Pellejero G, Pérez-Ductor C, Pérez-Jacoiste A, Pérez-Rus G, tian Schellong (Germany), Inna Tzoran (Israel), Abilio Reis Peris ML, Porras JA, Rivas A, Rodríguez-Hernández A, Rubio (Portugal), Marijan Bosevski (R. Macedonia), Henri Bouna- CM, Ruiz-Artacho P, Ruiz-Ruiz J, Ruiz-Sada P, Sahuquillo JC, meaux (Switzerland), Radovan Malý (Czech Republic), Peter Sala-Sainz MC, Salazar V, Salgueiro G, Sampériz A, Sánchez- Verhamme (Belgium), Joseph A. Caprini (United States), Hanh Muñoz-Torrero JF, Sancho T, Soler S, Suriñach JM, Tolosa C, My Bui (Vietnam). Torres MI, Trujillo-Santos J, Uresandi F, Valle R, Vidal G, Villares RIETE Registry Coordinating Center: S&H Medical P. ARGENTINA: Gutiérrez P, Vázquez FJ, Vilaseca A. BELGIUM: This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Science Service. Vanassche T, Vandenbriele C, Verhamme P. CZECH REPUBLIC: Members of the RIETE Group: SPAIN: Adarraga MD, Agud Hirmerova J, Malý R. ECUADOR: Salgado E. FRANCE: Benzidia I, M, Aibar MA, Aibar J, Alcalde-Manero M, Amado C, Arcelus JI, Bertoletti L, Bura-Riviere A, Debourdeau P, Farge-Bancel D, Hij Ballaz A, Barba R, Barrón M, Barrón-Andrés B, Bascuñana J, A, Mahé I, Merah A, Moustafa F. GERMANY: Schellong S. Blanco-Molina A, Camon AM, Cañas I, Carrasco C, Castro J, de ISRAEL: Braester A, Brenner B, Ellis M, Tzoran I. IRAN: Ancos C, del Toro J, Demelo P, Díaz-Pedroche C, Díaz-Pero- Sharif-Kashani B. ITALY: Barillari G, Bilora F, Bortoluzzi C, mingo JA, Falgá C, Farfán AI, Fernández-Capitán C, Fernández- Brandolin B, Ceccanti G, Ciammaichella M, Dentali F, Di Micco Criado MC, Fidalgo MA, Font C, Font L, Furest I, García MA, P, Grandone E, Maida R, Mastroiacovo D, Pallotti G, Pace F, García-Bragado F, García-Morillo M, García-Raso A, García- Parisi R, Pesavento R, Prandoni P, Quintavalla R, Rocci A, Ródenas M, Gavín O, Gaya-Manso I, Gayol MC, Gil-Díaz A, Siniscalchi C, Tufano A, Visonà A, Vo Hong N, Zalunardo B. Gómez V, Gómez-Cuervo C, González-Martínez J, Grau E, LATVIA: Gibietis V, Kigitovica D, Skride A. REPUBLIC OF Gutiérrez J, Hernández-Blasco LM, Iglesias M, Jara-Palomares MACEDONIA: Bosevski M. SWITZERLAND: Bounameaux H, L, Jaras MJ, Jiménez D, Jou I, Joya MD, Lima J, Llamas P, Lobo JL, Mazzolai L. USA: Caprini J. VIETNAM: Bui HM, Pham KQ. TH Open Vol. 3 No. 1/2019