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VTE Real-World Studies

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Real World Evidence and Claims Databases – a Guide for Healthcare Professionals
Prof. Craig I. Coleman gives an appreciation of the methodology used to perform Real World Evidence studies, particularly those investigating the effectiveness and safety, of non-vitamin K antagonist oral anticoagulants (or NOACs) in non-valvular atrial fibrillation patients. He also provides some key insights on what real world evidence and specifically claims databases can - and cannot - tell us. Approval number: PP-XAR-ALL-0036-2

  • Objective: to provide additional information on the benefit–risk assessment of rivaroxaban compared with standard care treatment for VTE prophylaxis
  • This non-interventional study enrolled 17,701 patients in 37 countries between February 2009 and August 2011 from approximately 252 centres worldwide1
  • Enrolled patients were scheduled to undergo elective hip or knee replacement (or hip fracture surgery where indicated) and receive pharmacological VTE prophylaxis
  • During an observation period of 3 months, data was collected on the following outcomes reported as serious or non-serious adverse events:
    • Bleeding events
    • Symptomatic thromboembolic events (DVT, PE)
    • Uncommon adverse events (incidence rates between 0.1% and 1.0%)
    • All-cause mortality
  • Compared with standard of care1
    • Rivaroxaban was associated with a significantly lower incidence of symptomatic thromboembolic events (odds ratio [OR] =0.65; 95% confidence interval [CI] 0.49–0.87)
    • Rates of any bleeding event were increased with rivaroxaban, but major bleeding was similar between the treatment arms (OR=1.19; 95% CI 0.73–1.95)
    • Similar incidences of serious adverse events were observed in both treatment arms, and all-cause mortality was ~0.1% in both treatment arms
  • The non-interventional study approach of XAMOS:
    • Confirmed the results of the RECORD clinical trial programme
    • Demonstrated that in routine clinical practice rivaroxaban has a favourable benefit–risk profile in comparison with current standard of care
    • Provided useful additional information additional to that obtained from the RECORD clinical trial programme
  • Subsequent analyses of data subsets from XAMOS have demonstrated:
    • Effectiveness and safety of rivaroxaban in patients undergoing major orthopaedic surgery in routine clinical practice was maintained irrespective of timing of the first postoperative dose within 24 hours after surgery, the type of anaesthesia, and the additional use of mechanical thromboprophylaxis2
    • Use of non-steroidal anti-inflammatory drugs in addition to an anticoagulant in XAMOS was common and associated with a higher frequency of bleeding events than in patients receiving rivaroxaban [OR=1.50; 95% CI 1.06–2.13] or standard of care [OR=1.70; 95% CI 1.16–2.49]3
    • Rivaroxaban provided effective thromboprophylaxis after fracture-related orthopaedic surgery of the lower limb with a favourable safety profile4

 

For more information visit:

Clinicaltrials.gov study record (Accessed 9 November 2020

 

Related key publications:

Haas S, Holberg G, Kreutz R et al. 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. Vasc Health Risk Manag 2016;12:209−218.

Kreutz R, Haas S, Holberg G et al. Rivaroxaban compared with standard thromboprophylaxis after major orthopaedic surgery: co-medication interactions. Br J Clin Pharmacol 2016;81:724−734.

Lassen MR, Haas S, Kreutz R et al. Rivaroxaban for thromboprophylaxis after fracture-related orthopedic surgery in routine clinical practice. Clin Appl Thromb Hemost 2016;22:138−146.

Turpie AGG, Haas S, Kreutz R et al. A non-interventional comparison of rivaroxaban with standard of care for thromboprophylaxis after major orthopaedic surgery in 17,701 patients with propensity score adjustment. Thromb Haemost 2014;111:94–102.

Turpie AGG, Schmidt AC, Kreutz R et al. Rationale and design of XAMOS: noninterventional study of rivaroxaban for prophylaxis of venous thromboembolism after major hip and knee surgery. Vasc Health Risk Manag 2012;8:363–370.

 

  • Objective: to improve patient care through a better understanding of patient demographics, management and in-hospital and post-discharge outcomes in patients who underwent elective primary total hip or total knee replacement surgery5
  • Data was obtained from 15,020 prospectively enrolled patients from 100 participating hospitals across 13 countries worldwide between the years of 2001 and 2004, with follow-up visits at 3 and 12 months
  • The key findings of the study were:
    • Elective hip and knee replacement is a relatively safe surgical procedure, with very low mortality rates and good outcomes for most patients – outcomes that were consistent across all 13 countries involved, despite wide practice variations
    • Rates of symptomatic VTE were higher in this real-world registry than in clinical trials
    • Almost all patients received VTE prophylaxis; however, guideline compliance was suboptimal, with thromboprophylaxis use falling over time, despite patients still having an elevated risk of VTE
    • Improved education regarding the nature and content of evidence-based guidelines for VTE prophylaxis in patients who undergo total hip or total knee replacement surgery is required

 

For more information visit:

The Global Orthopaedic Registry (Accessed 9 November 2020)

 

Related key publications:
Wang Z, Anderson FA Jr, Ward M, Bhattacharyya T. Surgical site infections and other postoperative complications following prophylactic anticoagulation in total joint arthroplasty. PLoS One 2014;9:e91755.

Anderson FA, Jr, Agnelli G, FitzGerald G et al. Overview of the Global Orthopaedic Registry (GLORY). Am J Orthop 2010;39:2–4.

Cushner F, Agnelli G, FitzGerald G et al. Complications and functional outcomes after total hip arthroplasty and total knee arthroplasty: results from the Global Orthopaedic Registry (GLORY). Am J Orthop 2010;39:22–28.

Friedman RJ, Gallus A, Gil-Garay E et al. Practice patterns in the use of venous thromboembolism prophylaxis after total joint arthroplasty–insights from the multinational Global Orthopaedic Registry (GLORY). Am J Orthop 2010;39:14–21.

Waddell J, Johnson K, Hein W et al. Orthopedic practice in total hip arthroplasty and Total knee arthroplasty: results from the Global Orthopaedic Registry (GLORY) Am J Orthop 2010;39:5–13.

Warwick D, Agnelli G, Cushner F et al. Lessons learned from the Global Orthopaedic Registry (GLORY): study design, current practice patterns, and future directions. Am J Orthop 2010;39:29–31.

Friedman RJ, Gallus AS, Cushner FD et al. Physician compliance with guidelines for deep-vein thrombosis prevention in total hip and knee arthroplasty. Curr Med Res Opin 2008;24:87–97.

 

  • Objective: to assess physician practices in the provision of prophylaxis against VTE in acutely ill hospitalized medical patients
  • Prospective cohort study in a population of over 15,000 hospitalized acutely ill medical patients from 52 hospitals in 12 countries6
  • Between July 2002 and September 2006, IMPROVE collected, analysed and published data on:
    • Clinical incidence and risk factors for the development of VTE6,7
    • Provision of VTE prophylaxis6,7
    • Bleeding event incidence and risk factors for bleeding8
  • Key findings:
    • Only 60% of patients who should have received guideline-recommended VTE prophylaxis actually received it, which was suboptimal
    • Practices varied considerably, with intermittent pneumatic compression being the most commonly used form of VTE prophylaxis in the US (22% of patients), whereas this was rarely used (0.2%) in other countries
    • UFH was the most commonly used drug for VTE prophylaxis in the US (21% of patients), whereas in other countries, this was LMWH (40%)
    • The IMPROVE Bleeding Risk Score calculated at admission can be used to predict major bleeding in medical inpatients9

 

For more information visit:

International Medical Prevention Registry on VTE (Accessed 9 November 2020)

In-hospital VTE and bleeding risk model calculator (Accessed 9 November 2020)

 

Related key publications:
Hostler DC, Marx ES, Moores LK et al. Validation of the International Medical Prevention Registry on Venous thromboembolism bleeding risk score. Chest 2016;149:372−379.

Rosenberg D, Eichorn A, Alarcon M et al. External validation of the risk assessment model of the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) for medical patients in a tertiary health system. J Am Heart Assoc 2014;3:e001152.

Decousus H, Tapson VF, Bergmann JF et al. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest 2011;139:69–79.

Spyropoulos AC, Anderson FA Jr, Fitzgerald G et al. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest 2011;140:706–714.

Tapson VF, Decousus H, Pini M et al. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest 2007;132:936–945.

 

  • Objective: to evaluate the prevalence of VTE risk and thromboprophylaxis practices in the acute hospital care setting
  • ENDORSE was a cross-sectional observational registry involving 358 acute care hospitals in 32 countries between August 2006 and January 200710,11
  • Of the 68,183 patients enrolled into ENDORSE, 45% were admitted to a surgical ward, and the remaining 55% admitted to a medical ward
  • 64.4% of surgical patients and 41.5% of medical patients were at risk of VTE12
    • Of these patients, only 58.5% of surgical patients and 39.5% of medical patients received guideline-recommended VTE prophylaxis
  • 92.5% of patients who underwent major surgery were at risk of VTE – use of prophylaxis varied according to major surgery type, ranging from:
    • 86.0% for orthopaedic surgery
    • 53.8% in urologic/gynaecologic procedures
    • 53.6% in other procedures
  • In real-world clinical practice, VTE prophylaxis for surgical and medical patients is not always compliant with guidelines and could be improved

 

For more information visit:

Epidemiologic international day for the evaluation of patients at risk for VTE in the acute hospital care setting (Accessed 9 November 2020)

 

Related key publications:
Anderson FA Jr, Goldhaber SZ, Tapson VF et al. Improving practices in US hospitals to prevent venous thromboembolism: lessons from ENDORSE. Am J Med 2010;123:1099–1106.e8.

Bergmann JF, Cohen AT, Tapson VF et al. Venous thromboembolism risk and prophylaxis in hospitalized medically ill patients: the ENDORSE global survey. Thromb Haemost 2010;103:736–748.

Kakkar AK, Cohen AT, Tapson VF et al. Venous thromboembolism risk and prophylaxis in the acute care hospital setting (ENDORSE survey): findings in surgical patients. Ann Surg 2010;251:330–338.

Cohen AT, Tapson VF, Bergmann JF et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008;371:387–394.

 

  • Objective: to provide an evaluation of treatment options to aid physicians’ treatment decisions to specifically reduce mortality, VTE recurrence and bleeding complications
  • Initiated in March 2001, RIETE is an ongoing multidisciplinary project aimed at obtaining an extensive data registry of consecutive patients with symptomatic acute DVT or PE13 – more than 72,000 patients have been enrolled to date14
  • For each patient, the registry includes details of:
    • Clinical status, including any coexisting or underlying conditions
    • Type, dose, duration and outcome (during the first 3 months of therapy) of antithrombotic treatment
  • Study endpoints:
    • Clinically recognized (and objectively confirmed) recurrences of VTE
    • Major and minor bleeding complications
    • Death
  • Over 130 manuscripts have been published reporting data from the RIETE registry, or have used RIETE data for decision analysis or pharmacoeconomic modelling
  • Key data findings
    • Patients with intermediate/high probabilities of PE will benefit from pre-emptive (i.e. before diagnosis is confirmed) anticoagulant therapy15
    • The presence of silent PE in patients presenting with DVT is associated with an increased incidence of symptomatic PE in the first 15 days of anticoagulant therapy16
    • Patients who present with acute symptomatic PE and have concomitant DVT are twice as likely to die than patients presenting with symptomatic PE without concomitant DVT17
    • Patients who develop VTE as a hospital inpatient have a significantly higher risk of death from PE than patients who develop VTE as an outpatient18
    • RIETE data has been used to determine predictive variables for major bleeding events in patients who present with acute VTE19
    • NOAC use increased from 0.5% in 2010 to 13.4% in 2014 (p<0.001)20
    • The perceived increased risk of bleeding has an impact on anticoagulant treatment decision, although a significant proportion of patients did not receive the recommended treatment in real-life practice21

 

For more information visit:

Computerized registry of patients with venous thromboembolism (Accessed 9 November 2020)

 

Related key publications:
Bikdeli B, Jimenez D, Hawkins M et al. Rationale, Design and methodology of the computerized registry of patients with venous thromboembolism (RIETE). Thromb Haemost 2018;118:214–224.

Brenner B, Bikdeli B, Tzoran I et al. Arterial ischemic events are a major complication in cancer patients with venous thromboembolism. Am J Med 2018: doi:10.1016/j.amjmed.2018.04.037

Chai-Adisaksopha C, Iorio A, Crowther MA et al. Vitamin K antagonists after 6 months of low-molecular-weight heparin in cancer patients with venous thromboembolism. Am J Med 2018;131:430–437.

Frere C, Trujillo-Santos J, Font C et al. Clinical course of venous thromboembolism in patients with pancreatic cancer: insights from the RIETE registry. Thromb Haemost 2018;118:1119–1122.

Galanaud JP, Bertoletti L, Amitrano M et al. Predictors of post-thrombotic ulcer after acute DVT: the RIETE registry. Thromb Haemost 2018;118:320–328.

Jara-Palomares L, Otero R, Jimenez D et al. Validation of a prognostic score for hidden cancer in unprovoked venous thromboembolism. PLoS One 2018;13:e0194673.

Jiménez D, Bikdeli B, Barrios D et al. Management appropriateness and outcomes of patients with acute pulmonary embolism. Eur Respir J 2018;51:1800445.

Kuperman A, López-Reyes R, Bosco LJ et al. Anemia and bleeding in patients receiving anticoagulant therapy for venous thromboembolism. J Thromb Thrombolysis 2018;45:360–368.

Lobo JL, Garcia-Fuertes JA, Trujillo-Santos J et al. Anticoagulant therapy for venous thromboembolism in patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 2018;30:526–530.

Tufano A, Ageno W, Di Micco P et al. Outcomes during anticoagulation in patients with symptomatic vs. incidental splanchnic vein thrombosis. Thromb Res 2018;164:69–74.

Bustos Merlo AB, Arcelus Martínez JI, Turiño Luque JD et al. Form of presentation, natural history and course of postoperative venous thromboembolism in patients operated on for pelvic and abdominal cancer. Analysis of the RIETE registry. Cir Esp 2017;95:328–334.

Guy JB, Bertoletti L, Magné N et al. Venous thromboembolism in radiation therapy cancer patients: Findings from the RIETE registry. Crit Rev Oncol Hematol 2017;113:83–89.

Tafur AJ, Caprini JA, Cote L et al. Predictors of active cancer thromboembolic outcomes. RIETE experience of the Khorana score in cancer-associated thrombosis. Thromb Haemost 2017;117:1192–1198.

Merah A, Bertoletti L, Ginzarly M et al. Prior thromboprophylaxis and outcome in patients experiencing acute venous thromboembolism after an acute medical illness. Eur J Intern Med 2016;30:72–76.

Morillo R, Jiménez D, Aibar MÁ et al. Deep vein thrombosis management and outcome trends, 2001 to 2014. Chest. 2016;150:374–383.

Baumann Kreuziger L, Cote L, Verhamme P et al. A RIETE registry analysis of recurrent thromboembolism and hemorrhage in patients with catheter-related thrombosis. J Vasc Surg Venous Lymphat Disord 2015;3:243–250.

Madridano O, Del Toro J, Lorenzo A et al. Subsequent arterial ischemic events in patients receiving anticoagulant therapy for venous thromboembolism. J Vasc Surg Venous Lymphat Disord 2015;3:135–141.

Mahé I, Sterpu R, Bertoletti L et al. Long-term anticoagulant therapy of patients with venous thromboembolism. What are the practices? PLoS One 2015;10:e0128741.

Tzoran I, Brenner B, Papadakis M et al. VTE registry: what can be learned from RIETE? Rambam Maimonides Med J 2014;5:e0037.

Tzoran I, Brenner B, Sakharov G et al. Clinical outcome in patients with venous thromboembolism receiving concomitant anticoagulant and antiplatelet therapy. Eur J Intern Med 2014;25:821–825.

Blondon M, Righini M, Aujesky D et al. Usefulness of preemptive anticoagulation in patients with suspected pulmonary embolism: a decision analysis. Chest 2012;142:697–703.

Tzoran I, Saharov G, Brenner B et al. Silent pulmonary embolism in patients with proximal deep vein thrombosis in the lower limbs. J Thromb Haemost 2012;10:564–571.

Jiménez D, Aujesky D, Díaz G et al. Prognostic significance of deep vein thrombosis in patients presenting with acute symptomatic pulmonary embolism. Am J Respir Crit Care Med 2010;181:983–991.

Maestre A, Sánchez R, Rosa V et al. Clinical characteristics and outcome of inpatients versus outpatients with venous thromboembolism: findings from the RIETE registry. Eur J Intern Med 2010;21:377–382.

Ruíz-Giménez N, Suárez C, González R et al. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE registry. Thromb Haemost 2008;100:26–31.

 

  • Objective: to describe patterns of acute and long-term treatment and outcomes in global VTE patient populations that are representative of those encountered in daily clinical practice in more than 20 countries worldwide
  • The registry was launched in 2013 and is designed to describe:
    • Treatment duration and reasons for cessation of therapy
    • The incidence of complications, practical aspects of patient management, healthcare resource use and treatment satisfaction
    • Incidences of VTE recurrence, major bleeding, post-thrombotic syndrome, venous ulcers and CTEPH

 

For more information visit:

Global Anticoagulant Registry in the FIELD (GARFIELD-VTE) (Accessed 9 November 2020)

 

Related key publications:
Weitz JI, Haas S, Ageno W et al. Global Anticoagulant Registry in the Field - Venous Thromboembolism (GARFIELD-VTE). Rationale and design. Thromb Haemost 2016;116:1172–1179.

 

  • Objective: prospective, non-interventional, observational clinical study to investigate the incidence of recurrent of VTE, major bleeding and mortality, as well as other cardiac and symptomatic thromboembolic events, treatment satisfaction and adherence, in adult patients with a diagnosis of acute DVT treated with rivaroxaban or traditional standard of care22
  • Patients from Canada and Europe with an indication for anticoagulation for at least 12 weeks were eligible for inclusion22
  • The study duration was 12 months after the end of enrolment21
  • Key findings:23
    • 5142 patients were enrolled
    • In routine clinical practice, rivaroxaban-treated patients had a lower risk profile at baseline than those treated with standard anticoagulation therapy
    • Rates of major bleeding and recurrent VTE were low in rivaroxaban-treated patients, consistent with phase III findings from the EINSTEIN programme
    • Propensity score-adjusted results confirmed that rivaroxaban was a safe and effective alternative to standard anticoagulation therapy in a broad range of patients
  • Subgroup analysis of the XALIA study on patients who switched from parenteral therapy to rivaroxaban early in the treatment process (‘early switchers’), patients with cancer and satisfaction with treatment have been published24-26
    • Early switchers had a higher frequency of risk factors for bleeding and recurrent VTE than patients who received rivaroxaban, which was reflected in the increased incidence of adverse events in the former group during follow-up24
    • Various anticoagulant regimens were used to treat patients with cancer associated thrombosis, with LMWH being the most common. Furthermore, anticoagulant choice varied with cancer type. In patients treated with rivaroxaban, primary outcome rates were low, which suggests that patients given rivaroxaban comprised a group with a good prognosis26
    • The Anti-Clot Treatment Scale (ACTS), which is comprised of a 12-item ACTS Burdens subscale, a 3-item ACTS Benefits subscale and one global item for each scale, measures patient-reported experience with anticoagulant treatment based on its perceived burdens and benefits. Consistent with phase III analyses, rivaroxaban was associated with improved ACTS Burdens scale scores versus standard anticoagulation; ACTS Benefits scale scores were numerically in favour of rivaroxaban, but this difference did not reach statistical significance25

 

For more information visit:

Clinicaltrials.gov study record (Accessed 9 November 2020)

 

Related key publications:
Cano S, Mantovani LG, Folkerts K et al. Patient-reported treatment experience with oral rivaroxaban: results from the noninterventional XALIA study of deep-vein thrombosis. TH Open 2018;2:e139–e146.

Ageno W, Mantovani LG, Haas S et al. Subgroup analysis of patients with cancer in XALIA: A noninterventional study of rivaroxaban versus standard anticoagulation for VTE. TH Open 2017;1:e33–e42.

Turpie AGG, Mantovani LG, Haas S et al. Analysis of patients with deep vein thrombosis switched from standard therapy to rivaroxaban in the non-interventional XALIA study. Thromb Res 2017;155:23–27.

Ageno W, Mantovani LG, Haas S et al. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol 2016;3:e12–e21.

Ageno W, Mantovani LG, Haas S et al. XALIA: rationale and design of a non-interventional study of rivaroxaban compared with standard therapy for initial and long-term anticoagulation in deep vein thrombosis. Thromb J 2014;12:16.

 

  • Objectives were to:
    • Collect data on the quality of life and treatment satisfaction of patients with VTE
    • Gather insights into patient management in the acute phase and the prevention of recurrent thromboembolic events
    • Investigate the economic burden of VTE treatment
    • The PREFER in VTE registry was a prospective, observational, multicentre study conducted in seven European countries including Austria, France, Germany, Italy, Spain, Switzerland, and the UK, with a one-year follow-up.27 Overall, 381 centres participated, which enrolled 3455 patients during an observational period of 1 year
  • Key findings28
    • Patients had a mean age of 60.8±17.0 years, 52.0% were male and 59.5% had a diagnosis of DVT compared with 40.5% with PE
    • The most common co-morbidities were cardiovascular disease (excluding hypertension; 45.5%), hypertension (42.3%) and dyslipidaemia (21.1%)
    • After the index VTE, most patients received initial therapy with heparin (73.2%), 48.7% received a VKA, whereas 24.5% received a NOAC
    • Almost one-quarter of all presentations were for recurrent VTE, and over 80% of previous episodes occurred more than 12 months prior to baseline
    • Hospital admission occurred in 17.5% of patients overall, though greater numbers of patients with PE ± DVT were hospitalized (21.5%) compared with DVT-only patients (14.5%; p<0.0001)

 

For more information visit:

PR Newswire. European patient registry in venous thromboembolism (VTE) - PREFER in VTE - enrols first patient. 2013. (Accessed 9 November 2020)

 

Related key publications:
Agnelli G, Gitt AK, Bauersachs R et al. The management of acute venous thromboembolism in clinical practice – study rationale and protocol of the European PREFER in VTE registry. Thromb J 2015;13:41.

Bauersachs R, Gitt AK, Mismetti P et al. Readmittance to hospital within 6 months after a venous thromboembolism event: PREFER in VTE registry. Value Health 2014;17:A472–A473.

Willich SN, Bauersachs R, Gitt AK et al. Treatment satisfaction in patients with venous thromboembolism as measured with PACT-Q2: PREFER in VTE registry. Value Health 2014;17:A496–A497.

References

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