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NOACs for thromboprophylaxis in medical patients
Best Practice & Research Clinical Haematology 26 (2013) 183–190
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NOACs for thromboprophylaxis in medical patients Alexander (Ander) T. Cohen, MBBS, MSc, MD, FRACP a, *, Tom Rider, MBBS b a b
Vascular Medicine, Department of Surgery, King’s College Hospital, London, London SE5 9RS, UK Royal Sussex County Hospital, Brighton, Eastern Road, East Sussex BN2 5BE, UK
Keywords: venous thrombosis prevention medical patients new oral anticoagulants
The risk of venous thrombosis extends for an indeterminate length of time following admission to hospital with a medical or surgical condition. Observational studies in surgery show this risk extends for months and perhaps more than one year, for medical patients the risk extends for at least several weeks. Large bodies of evidence support the heightened risk status of hospitalised surgical and medical patients, and that prophylactic measures significantly reduce the risk of thrombosis. Extending thromboprophylaxis for 4–6 weeks with anticoagulants both old and new has been shown to be efficacious and safe in surgical patients. However in populations of medical patients although prolonged anticoagulant thromboprophylaxis has been shown to be efficacious it also results in more bleeding and the risk benefit is not clear. Hence no therapies are approved for prolonged thromboprophylaxis in medical patients. In this area there have been one phase III study of low molecular weight heparin and two completed phase III studies of NOACs. This article briefly summarises our understanding of the background to preventing venous thromboembolism in hospitalised medical patients and reviews the details of the studies using NOACs. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Venous thromboembolism (VTE), defined as deep venous thrombosis (DVT) or pulmonary embolism (PE), following illness or hospitalisation is associated with a significant disease burden worldwide.
* Corresponding author. Tel.: þ44 20 3299 3015; Fax: þ44 20 3299 3927. E-mail addresses: [email protected] (A.(Ander)T. Cohen), [email protected] (T. Rider). 1521-6926/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.beha.2013.07.002
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The risk of venous thrombosis continues following admission to hospital with a medical or surgical condition, usually long after discharge [1,2]. Clinical and observational studies in surgery show this risk extends for months and perhaps more than one year, for medical patients the risk extends for at least several weeks. Hospitalised medical patients face a significant risk of VTE, with 42% at moderate or high risk according to American College of Chest Physicians (ACCP) criteria [3–5]. As many as 10–20% of hospitalised medical patients can be expected to develop a VTE secondary to hospitalisation [3,5]. Autopsy data suggest VTE contributes to more than 10% of deaths among hospitalised medical patients [6,7]. VTE prophylaxis can at least halve the risk of VTE in medical patients [8–10]. While increasing adoption of VTE prevention strategies appears to have caused a decline in VTE incidence over time, this has disproportionately benefited surgical rather than medical patients. The period 1966–2000 saw a 71% reduction in autopsy-detected fatal PE rates among surgical patients, while among medical patients this decline was only 18% [11,12]. Meta-analyses have shown that short-term (1–2 weeks) thromboprophylaxis with anticoagulants has resulted in a reduction of both non-fatal and fatal PE in medical and surgical patients, reduction of total mortality in surgical patients and shown a strong indication of reducing total mortality in medical patients [9,13,14]. Therefore thromboprophylaxis is important in these patients and extending the length of thromboprophylaxis was expected to have additional benefits. Extended-duration thromboprophylaxis regimens in surgical patients have successfully reduced the incidence of VTE compared with placebo with using heparins [15] or NOACs compared with low molecular weight heparins (LMWH) [16–18], and their use is recommended in clinical guidelines [19]. The new drugs (apixaban, dabigatran, and rivaroxaban) seemed to be the ideal agents for extendedduration prophylaxis in medical patients [20]. However extended-duration regimens in medical patients with LMWH and NOACs have not replicated the success found with surgical patients [21–23]. The EXCLAIM study demonstrated that extended-duration enoxaparin (38 4 days), compared with placebo after open-label standard-duration enoxaparin (10 4 days), significantly reduced the overall incidence of VTE (absolute risk difference, 1.53% [95.8% CI, 2.54% to 0.52%]) in acutely ill medical patients with reduced mobility, but with a significant increase in the incidence of major bleeding (absolute risk difference, 0.51% [95% CI, 0.12–0.89%]) [21]. When reviewing these studies it is necessary to consider the variations in the definition of medical patients and the inclusion criteria. Acute medical illness populations may include: Acute congestive heart failure (NYHA class III or IV), acute respiratory disease (acute respiratory failure or an acute exacerbation of chronic obstructive pulmonary disease (COPD) or other chronic lung diseases), medical conditions associated with an inflammatory response such as acute infectious diseases (most commonly respiratory, urinary tract, or severe cellulitis), rheumatological disorders (acute polyarthropathies, osteoporotic vertebral crush fractures, severe back pain and sciatica), and inflammatory bowel disease. Ischaemic stroke, lower limb paralysis and cancer patients have also been included in some studies. The degree of immobility must also be considered. Immobility has long been associated with VTE, and yet remains poorly defined, partially because of the great variation in medical and nursing practices. Marked immobility has been associated with VTE in medical studies examining short-term periods (6–14 days) [1,24]. This was also seen in the EXCLAIM study of prolonged thromboprophylaxis. Immobilisation for seven or more days has been linked with a HR of 1.9 (95% CI 1.3–2.7) for VTE [21]. Studies using NOACs for the prevention of VTE in medical patients Two studies have recently been reported and in both, as also seen in the EXCLAIM Study, safety has proven to be a concern. The ADOPT trial, comparing an extended course of apixaban to a standard course of enoxaparin in medical patients, reported a non-significant decrease in VTE related mortality but a significant increase in major bleeding risk (RR 2.6) [22]. The MAGELLAN trial evaluated an extended course of rivaroxaban against a standard course of enoxaparin among hospitalised medical patients. It revealed rivaroxaban was non-inferior at day 10 and superior at days 30–35 with regards to VTE prevention, however clinically relevant bleeding rates were increased in the rivaroxaban arm with
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a RR of 2.3 and 3.0 at day 10 and days 30–35, respectively [23]. Therefore new studies are required before clinical use of any of these newer agents among medical patients for either short-term or extended prophylaxis [25]. These studies are described in detail below. MAGELLAN study The MAGELLAN trial was a randomised, double-blinded, double-dummy trial that compared rivaroxaban with enoxaparin in the prevention of VTE in hospitalised adults with an acute medical illness [23]. Rivaroxaban is an orally active direct Xa inhibitor that is used for the prevention of VTE after elective hip or knee replacement surgery in adults, for prevention of stroke in patients with atrial fibrillation and for the treatment of acute coronary syndrome and PE. The initial phase of this trial compared oral rivaroxaban 10 mg once a day and subcutaneous enoxaparin 40 mg once a day for duration of 10 4 days. During the extended second phase the rivaroxaban group continued to take rivaroxaban 10 mg and the enoxaparin group discontinued the parenteraltreatment and continued with an oral placebo. Including the 10 4 day initial phase the extended phase lasted a total of 35 4 days. The study population was aged 40 and over who had been hospitalised with an acute medical illness for less than 72 h prior to randomisation and had reduced mobility as defined in Table 1. All patients underwent bilateral ultrasonography to detect asymptomatic DVT at day 10 and day 35. Clinically suspected DVT or PE was confirmed with the use of an appropriate imaging technique such as ultrasonography or computed tomography pulmonary angiography. The primary efficacy outcome measure was a composite of asymptomatic proximal DVT, symptomatic proximal or distal DVT, symptomatic non-fatal PE or VTE related death from day 1 to 10 for non-inferiority analysis and from day 1 to 35 for superiority analysis. The principal safety outcome was clinically relevant bleeding, defined as a composite of major bleeding or clinically relevant nonmajor bleeding. Major bleeding was defined as bleeding causing a 2 g/dl fall in haemoglobin or transfusion of two units of packed or whole blood, bleeding into a critical site or bleeding leading to death. Non-major clinically relevant bleeding was defined as overt bleeding not meeting the major bleeding criteria but associated with a medical intervention, unscheduled contact with a physician, temporary cessation of study treatment, impairing activities of daily living or causing discomfort to the participant. A modified intention-to-treat and per-protocol analysis was performed using data from day 10 and day 35. The median age of both the rivaroxaban and enoxaparin followed by placebo groups was 71 years and the median length of hospital admission was 11 days for both groups. Table 1 summarises the cause of hospitalisation for both groups with acute infection being the most common aetiology. At the day 10 analysis 2.7% of patients in both groups had a primary efficacy outcome event meeting non-inferiority criteria (RR with rivaroxaban 0.97, 95% CI 0.71–1.31, P ¼ 0.003 for non-inferiority). At the day 35 intention-to-treat analysis 4.4% in the extended rivaroxaban group had a primary efficacy outcome event in comparison with 5.7% in the enoxaparin followed by placebo group thus meeting superiority criteria (RR with rivaroxaban 0.77, 95% CI 0.62–0.96, P ¼ 0.02 for superiority). However, rivaroxaban also had higher safety outcome events. At day 10 2.8% of patients taking rivaroxaban experienced clinically relevant bleeding compared to 1.2% receiving enoxaparin (RR with rivaroxaban 2.3, 95% CI 1.63–3.17, P < 0.001). There were 5 fatal bleeds with rivaroxaban and 1 fatal bleed with enoxaparin during this interval. Between day 1 and 35 clinically relevant bleeding occurred in 4.1% of patients receiving extended rivaroxaban and this occurred in 1.7% of patients who received enoxaparin followed by placebo (RR 2.5, 95% CI 1.85–3.25, P < 0.001). A composite of the primary efficacy outcome and primary safety outcome was analysed to determine the net clinical benefit or harm. At day 10 both outcomes had occurred in 6.6% in the rivaroxaban group and 4.6% in the enoxaparin group (RR with rivaroxaban 1.44, 95% CI 1.18–1.77, P < 0.001). At day 35 both outcomes had occurred in 9.4% of the rivaroxaban group and 7.8% in the enoxaparin followed by placebo group (RR with rivaroxaban 1.21, 95% CI 1.03–1.43, P ¼ 0.02). A total of 7 fatal bleeds occurred in the rivaroxaban arm from day 1 to 35 and 1 in the enoxaparin followed by placebo group. Other adverse-event profiles including cardiovascular events, derangement of liver functions tests and death from any cause were similar in both groups.
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Table 1 Characteristics and results of the NOACs in medical thromboprophylaxis.
Duration Inclusion criteria Exclusion criteria
Study population
Acute medical condition
Outcomes
N Age Length of hospitalisation Infectious disease Heart failure (NYHA class III or IV) Respiratory insufficiency Ischaemic stroke Active cancer Inflammatory or rheumatic disease Primary efficacy outcome Major bleeding and clinically relevant non-major bleeding Fatal bleeding
MAGELLAN
ADOPT
VTE prophylaxis when hospitalised with acute medical illness 10 mg rivaroxaban once daily Initially enoxaparin, then placebo during extended phase Multicentre randomised double-blinded trial, non-inferiority during initial phase and superiority during extension phase 10 4 days initial phase then 35 4 days extended phase 40 years of age with reduced mobilitya and an acute medical illness requiring hospitalisation Conditions that contraindicate use of enoxaparin or rivaroxaban, recent surgery or head injury, history of haemorrhagic stroke, high bleeding risk, sustained uncontrolled hypertension, alcohol or drug abuse, pregnant or breastfeeding, co-administration of cytochrome P450 3A4 inhibitors and severe renal impairment 8101 Median 71 days for both arms Median 11 days for both arms
VTE prophylaxis when hospitalised with acute medical illness 2.5 mg apixaban twice daily Initially enoxaparin, then placebo during extended phase Multicentre randomised double-blinded trial, non-inferiority during initial phase and superiority during extension phase Initial phase 6–14 days then 30 days extended phase 40 years of age, an acute medical illness requiring hospitalisation with one additional VTE risk factor (except heart failure or respiratory failure patients) and reduced mobilityb Confirmed VTE on admission, co-morbities requiring on-going anti-coagulation, active liver disease, severe renal impairment, anaemia or thrombocytopenia, contra-indication to enoxaparin, co-administration of two or more antiplatelet agents, recent surgery, pregnancy or breastfeeding 6528 Median 67 for both arms Unknown
46% rivaroxaban arm, 45% enoxaparin arm 32% rivaroxaban arm, 32% enoxaparin arm
22% apixaban arm, 23% placebo arm 38% for both arms
27% rivaroxaban arm, 29% enoxaparin arm 17% rivaroxaban arm, 17% enoxaparin arm 7% rivaroxaban arm, 7% enoxaparin arm 4% rivaroxaban arm, 4% enoxaparin arm
37% for both arms Unknown 4% apixaban arm, 3% placebo arm 2% for both arms
Rivaroxaban group 4.4% at day 35, enoxaparin then placebo 5.7% at day 35 (RR 0.77, 95% CI 0.0.62–0.96, P ¼ 0.02) 2.8% with rivaroxaban and 1.2% with enoxaparin at day 10 (P < 0.001). 4.1% with rivaroxaban and 1.7% with enoxaparin then placebo at day 35 (P < 0.001) 7 in the extended rivaroxaban group and 1 in the enoxaparin then placebo group
Apixaban group 2.7% at day 30, enoxaparin then placebo 3.1% (RR with apixaban 0.87, 95% CI 0.62–1.23, P ¼ 0.44) 2.67% with apixaban at day 30 and 2.08% with enoxaparin then placebo (RR 1.28, 95% CI 0.93–1.76, P ¼ 0.12) 0 in the apixaban group and 2 in the enoxaparin then placebo group
a Defined as at least one day of complete immobility followed by at least 4 days of decreased mobility. Complete immobilisation defined as being totally confined to bed or chair but allowing use a bedside commode or assistance to the bathroom. Decreased mobility causing >50% to be spent in bed or chair. b Defined as moderate or severe restriction in mobility. Moderately restricted allowed for walking within hospital room or to the bathroom, severely restricted mobility defined as confined to bed or to a bedside chair.
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Indications Drug Comparator Design
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ADOPT study The ADOPT trial was a randomised, double-blinded, double-dummy trial that compared apixaban with enoxaparin in the prevention of VTE in hospitalised adults with an acute medical illness [22]. The objectives were to determine whether oral apixaban is non-inferior to standard-duration (minimum 6 days) subcutaneous enoxaparin for the prevention of VTE in acutely ill medical patients, and whether extended-duration apixaban is superior to standard-duration enoxaparin. Apixaban is also an orally active direct Xa inhibitor which is effective in the prevention of VTE after elective hip or knee replacement surgery in adults and the prevention of stroke in patients with atrial fibrillation. The ADOPT trial and the MAGELLAN trial were similar in design. The initial phase of the ADOPT trial lasted a minimum of 6 days in which patients either received oral apixaban 2.5 mg twice daily or subcutaneous enoxaparin 40 mg once a day. After the 6 day period enoxaparin was stopped at the discretion of the investigator and placebo was taken for the remainder of the extended phase which ceased at day 30. The study population was also aged 40 and over who had been hospitalised with an acute medical illness less than 72 h prior to randomisation. Table 1 also summarises the characteristics of the trial population. Patients also underwent ultrasonography twice to detect asymptomatic DVT between days 5–14 and at day 30. An intention-to-treat analysis was performed to determine noninferiority at day 10 and superiority at day 35. The primary efficacy outcome was the same as the MAGELLAN trial. The safety outcomes included major bleeding, clinically relevant non-major bleeding and all bleeding reported by investigators. Major bleeding was defined as per the MAGELLAN trial with the addition of bleeding that occurred into an operated joint that required reoperation or intramuscular bleeding with compartment syndrome. Clinically relevant non-major bleeding was defined as not meeting the criteria for major bleeding but at least one of the following were present: epistaxis for >5 min or requiring medical attention, gastrointestinal bleeding containing frank blood or coffee-ground material that tested positive for blood, endoscopically confirmed bleeding, spontaneous haematuria or haematuria persisting >24 h postcatheterisation, radiological confirmed haematoma or haemoptysis. The median age of the apixaban group was 68 years and 67 years for the enoxaparin followed by placebo group. The majority of patients was white, 76% for both groups. Table 1 summarise the aetiology of hospitalisation admission. The most common cause of hospitalisation was congestive heart failure at 39% apixaban arm and 38% enoxaparin followed by placebo arm. The ADOPT trial also included patients with NYHA class I and II heart failure unlike the MAGELLAN trial which only included class III and IV heart failure patients. The primary efficacy outcome was confirmed in 2.71% of patients assigned to the apixaban arm when analysed at day 30 in comparison with 3.06% in the enoxaparin followed by placebo group (RR with apixaban 0.87, 95% CI 0.62–1.23, P ¼ 0.44). Following the cessation of parenteral-treatment the primary efficacy outcome occurred in 31 patients in this arm and 18 patients in the apixaban arm (RR with apixaban 0.59, 95% CI 0.33–1.05). Major bleeding during the 30 days trial period occurred at 0.47% in the apixaban group and 0.19% in the enoxaparin followed by placebo group (RR with apixaban 2.58, 95% CI 1.02–7.24, P ¼ 0.04). The combination of major bleeding and non-major clinically relevant bleeding occurred in 2.67% of the apixaban group with 2.08% found in the enoxaparin followed by placebo group (RR 1.28, 95% CI 0.93–1.76, P ¼ 0.12). There were no fatal bleeds in the apixaban group and two in the enoxaparin group. There was no significant difference in overall death, rates of adverse events or rates of liver function test derangement between the apixaban and enoxaparin followed by placebo group. It must be noted that the ADOPT trial was underpowered therefore clinically no direct conclusions can be drawn. Only 64% of the patients had a follow-up ultrasonography to detect asymptomatic disease.
Future research Some factors to consider in future research in medical patients are the following: 1. Reducing the risk of bleeding 2. Finding patients at significant risk of VTE
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3. Omission of the mid-study routine venous ultrasonography 4. Choosing the right intensity (dose, regimen) of anti-coagulation 5. Choosing the correct time to start and stop prophylaxis
Reducing the risk of bleeding The primary adverse effect of anti-coagulation is the increased risk of major bleeding, as defined by fatal bleeding, symptomatic bleeding in a critical area or organ, or bleeding causing a decrease in haemoglobin concentration of more than 20 g/l or requiring transfusion of two or more units of blood [26]. An analysis of the IMPROVE registry of general medical patients resulted in a bleeding risk score, with the factors most predictive of bleeding being active gastroduodenal ulcer, bleeding in the preceding 3 months, thrombocytopenia (<50 109/l), and advanced age (>85 years) [27]. Bleeding risk was also significantly increased by hepatic failure (with INR > 1.5), renal failure (with GFR < 30 ml/ min/m2), admission to the intensive care unit, presence of a central venous catheter, rheumatic disease, cancer, and male gender. These and other factors, such as stricter criteria to exclude patients at risk of bleeding, need to be considered in future studies in this area. Finding patients at significant risk of VTE Two papers have described an association between elevated D-dimer levels around the time of admission and the subsequent development of VTE in this patient group [28,29]. We have described a strong independent association between D-dimer levels of greater than or equal to twice the upper limit of normal and the subsequent development of VTE in this patient group. This independent association was stronger than that seen for advanced age (>75) and cancer [30]. Advanced age has also been shown to have a strong independent association with the risk of VTE [24,31]. Omission of the mid-study routine venous US The inclusion or omission of a mid-study or “Day 10” venous ultrasonography is an important consideration in new studies. These ultrasound studies are not routinely performed in clinical practice and are performed to allow a comparison between two active treatment arms. However they alter the natural history of VTE in the middle of the study period and they are likely to reduce the overall symptomatic VTE rates as the potential clinical VTE are diagnosed early and treated as asymptomatic events. For these reasons, omitting this test is favoured by most trialists and clinicians to allow a realistic comparison of extended and short-term regimens. Choosing the right intensity (dose, regimen) of anti-coagulation A recent study has shown that lowering the dose of anticoagulant thromboprophylaxis in patients with renal impairment may not compromise efficacy [32]. A lower dose may lead to less bleeding, the “Achilles heel” of all three published studies, but lowering the dose may result in efficacy being compromised. Choosing the correct time to start and stop prophylaxis The previous studies have randomised patients to prolonged therapy at different times. In the Exclaim study patients received standard thromboprophylaxis for 6–14 days and were then randomised (typically at the time of hospital discharge) to a further 4 weeks of enoxaparin 40 mg daily or placebo. This allowed the exclusion patients with poor prognosis, early bleeding and early thrombosis. In the more recent studies (MAGELLAN and ADOPT) patients were randomised to either the NOAC for around 4–5 weeks or enoxaparin for 6–14 days as soon as possible, typically 1–3 days, following admission. This meant a more heterogeneous group of patients entered these studies. Future studies
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may opt to start the randomisation procedure later than 1–3 days, perhaps around the time of discharge to allow the recognition of a clinically stable group. The optimal length of therapy to achieve the maximal benefit risk relationship is unknown and may be the status quo of 6–14 days. Future studies may test shorter or longer periods of extra therapy than the 4–5 weeks tested in MAGELLAN and ADOPT. On-going studies There is one new on-going study in this field. The Apex Study is testing betrixaban regimens and this study takes account of many of the lessons learnt from previous studies as mentioned above, as well as some dose adjustments and flexible onset of therapy (NCT01583218) [33]. Much work is still to be done with NOACs in this potential indication of thromboprophylaxis in acutely ill hospitalised medical patients
Practice Point At this stage there is no indication to use NOACs for thromboprophylaxis in acutely ill hospitalised medical patients
Conflict of Interest A. Cohen is a medical consultant, and has received consultancy and clinical trial funding from pharmaceutical companies, including Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Daiichi, GSK, Janssen (formerly Johnson & Johnson), Mitsubishi Pharma, Pfizer, Portola, Sanofi-Aventis, Schering-Plough, and Takeda. He is an advisor to the UK Government Health Select Committee, the All-Party Working Group on Thrombosis, the Department of Health, and the NHS, on the prevention of VTE. He is also an advisor to Lifeblood: The Thrombosis Charity and is the founder of the European educational charity the Coalition to Prevent VTE. T Rider has no disclosures to declare.
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[26] Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. Journal of Thrombosis and Haemostasis 2005;3(4):692–4. Epub 2005/04/22. [27] 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(1):69–79. Epub 2010/05/11. [28] Fan J, Li X, Cheng Y, , et alInvestigators G. Measurement of D-dimer as aid in risk evaluation of VTE in elderly patients hospitalized for acute illness: a prospective, multicenter study in China. Clinical and Investigative Medicine, Medecine clinique et experimentale 2011;34(2):E96–104. Epub 2011/04/06. [29] Desjardins L, Bara L, Boutitie F, et al. Correlation of plasma coagulation parameters with thromboprophylaxis, patient characteristics, and outcome in the MEDENOX study. Archives of Pathology & Laboratory Medicine 2004;128(5):519–26. Epub 2004/04/17. [30] Cohen AT, Spiro TE, Burton P, et al. The MAGELLAN study: an analysis of outcomes utilizing D-dimer. In: Presented at the annual scientific session of the American Society of Haematology; December 12, 2011. San Diego, CA: Blood; 2011. [31] Alikhan R, Cohen AT, Combe S, et al. Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: analysis of the MEDENOX Study. Archives of Internal Medicine 2004;164(9):963–8. Epub 2004/05/12. [32] Ageno W, Riva N, Noris P, et al. for the FONDAIR study group. Safety and efficacy of low-dose fondaparinux (1.5 mg) for the prevention of venous thromboembolism in acutely ill medical patients with renal impairment: the FONDAIR study. Journal of Thrombosis and Haemostasis 2012;10:2291–7. Epub 2012/08/29. [33] Clinicaltrials.gov. Acute medically ill VTE prevention with extended duration betrixaban study (The APEX study) [cited 2013 3 June]; Available from: http://clinicaltrials.gov/ct2/show/NCT01583218; 2012.
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8
NOACs for thromboprophylaxis in medical patients Alexander (Ander) T. Cohen, MBBS, MSc, MD, FRACP a, *, Tom Rider, MBBS b a b
Vascular Medicine, Department of Surgery, King’s College Hospital, London, London SE5 9RS, UK Royal Sussex County Hospital, Brighton, Eastern Road, East Sussex BN2 5BE, UK
Keywords: venous thrombosis prevention medical patients new oral anticoagulants
The risk of venous thrombosis extends for an indeterminate length of time following admission to hospital with a medical or surgical condition. Observational studies in surgery show this risk extends for months and perhaps more than one year, for medical patients the risk extends for at least several weeks. Large bodies of evidence support the heightened risk status of hospitalised surgical and medical patients, and that prophylactic measures significantly reduce the risk of thrombosis. Extending thromboprophylaxis for 4–6 weeks with anticoagulants both old and new has been shown to be efficacious and safe in surgical patients. However in populations of medical patients although prolonged anticoagulant thromboprophylaxis has been shown to be efficacious it also results in more bleeding and the risk benefit is not clear. Hence no therapies are approved for prolonged thromboprophylaxis in medical patients. In this area there have been one phase III study of low molecular weight heparin and two completed phase III studies of NOACs. This article briefly summarises our understanding of the background to preventing venous thromboembolism in hospitalised medical patients and reviews the details of the studies using NOACs. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Venous thromboembolism (VTE), defined as deep venous thrombosis (DVT) or pulmonary embolism (PE), following illness or hospitalisation is associated with a significant disease burden worldwide.
* Corresponding author. Tel.: þ44 20 3299 3015; Fax: þ44 20 3299 3927. E-mail addresses: [email protected] (A.(Ander)T. Cohen), [email protected] (T. Rider). 1521-6926/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.beha.2013.07.002
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The risk of venous thrombosis continues following admission to hospital with a medical or surgical condition, usually long after discharge [1,2]. Clinical and observational studies in surgery show this risk extends for months and perhaps more than one year, for medical patients the risk extends for at least several weeks. Hospitalised medical patients face a significant risk of VTE, with 42% at moderate or high risk according to American College of Chest Physicians (ACCP) criteria [3–5]. As many as 10–20% of hospitalised medical patients can be expected to develop a VTE secondary to hospitalisation [3,5]. Autopsy data suggest VTE contributes to more than 10% of deaths among hospitalised medical patients [6,7]. VTE prophylaxis can at least halve the risk of VTE in medical patients [8–10]. While increasing adoption of VTE prevention strategies appears to have caused a decline in VTE incidence over time, this has disproportionately benefited surgical rather than medical patients. The period 1966–2000 saw a 71% reduction in autopsy-detected fatal PE rates among surgical patients, while among medical patients this decline was only 18% [11,12]. Meta-analyses have shown that short-term (1–2 weeks) thromboprophylaxis with anticoagulants has resulted in a reduction of both non-fatal and fatal PE in medical and surgical patients, reduction of total mortality in surgical patients and shown a strong indication of reducing total mortality in medical patients [9,13,14]. Therefore thromboprophylaxis is important in these patients and extending the length of thromboprophylaxis was expected to have additional benefits. Extended-duration thromboprophylaxis regimens in surgical patients have successfully reduced the incidence of VTE compared with placebo with using heparins [15] or NOACs compared with low molecular weight heparins (LMWH) [16–18], and their use is recommended in clinical guidelines [19]. The new drugs (apixaban, dabigatran, and rivaroxaban) seemed to be the ideal agents for extendedduration prophylaxis in medical patients [20]. However extended-duration regimens in medical patients with LMWH and NOACs have not replicated the success found with surgical patients [21–23]. The EXCLAIM study demonstrated that extended-duration enoxaparin (38 4 days), compared with placebo after open-label standard-duration enoxaparin (10 4 days), significantly reduced the overall incidence of VTE (absolute risk difference, 1.53% [95.8% CI, 2.54% to 0.52%]) in acutely ill medical patients with reduced mobility, but with a significant increase in the incidence of major bleeding (absolute risk difference, 0.51% [95% CI, 0.12–0.89%]) [21]. When reviewing these studies it is necessary to consider the variations in the definition of medical patients and the inclusion criteria. Acute medical illness populations may include: Acute congestive heart failure (NYHA class III or IV), acute respiratory disease (acute respiratory failure or an acute exacerbation of chronic obstructive pulmonary disease (COPD) or other chronic lung diseases), medical conditions associated with an inflammatory response such as acute infectious diseases (most commonly respiratory, urinary tract, or severe cellulitis), rheumatological disorders (acute polyarthropathies, osteoporotic vertebral crush fractures, severe back pain and sciatica), and inflammatory bowel disease. Ischaemic stroke, lower limb paralysis and cancer patients have also been included in some studies. The degree of immobility must also be considered. Immobility has long been associated with VTE, and yet remains poorly defined, partially because of the great variation in medical and nursing practices. Marked immobility has been associated with VTE in medical studies examining short-term periods (6–14 days) [1,24]. This was also seen in the EXCLAIM study of prolonged thromboprophylaxis. Immobilisation for seven or more days has been linked with a HR of 1.9 (95% CI 1.3–2.7) for VTE [21]. Studies using NOACs for the prevention of VTE in medical patients Two studies have recently been reported and in both, as also seen in the EXCLAIM Study, safety has proven to be a concern. The ADOPT trial, comparing an extended course of apixaban to a standard course of enoxaparin in medical patients, reported a non-significant decrease in VTE related mortality but a significant increase in major bleeding risk (RR 2.6) [22]. The MAGELLAN trial evaluated an extended course of rivaroxaban against a standard course of enoxaparin among hospitalised medical patients. It revealed rivaroxaban was non-inferior at day 10 and superior at days 30–35 with regards to VTE prevention, however clinically relevant bleeding rates were increased in the rivaroxaban arm with
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a RR of 2.3 and 3.0 at day 10 and days 30–35, respectively [23]. Therefore new studies are required before clinical use of any of these newer agents among medical patients for either short-term or extended prophylaxis [25]. These studies are described in detail below. MAGELLAN study The MAGELLAN trial was a randomised, double-blinded, double-dummy trial that compared rivaroxaban with enoxaparin in the prevention of VTE in hospitalised adults with an acute medical illness [23]. Rivaroxaban is an orally active direct Xa inhibitor that is used for the prevention of VTE after elective hip or knee replacement surgery in adults, for prevention of stroke in patients with atrial fibrillation and for the treatment of acute coronary syndrome and PE. The initial phase of this trial compared oral rivaroxaban 10 mg once a day and subcutaneous enoxaparin 40 mg once a day for duration of 10 4 days. During the extended second phase the rivaroxaban group continued to take rivaroxaban 10 mg and the enoxaparin group discontinued the parenteraltreatment and continued with an oral placebo. Including the 10 4 day initial phase the extended phase lasted a total of 35 4 days. The study population was aged 40 and over who had been hospitalised with an acute medical illness for less than 72 h prior to randomisation and had reduced mobility as defined in Table 1. All patients underwent bilateral ultrasonography to detect asymptomatic DVT at day 10 and day 35. Clinically suspected DVT or PE was confirmed with the use of an appropriate imaging technique such as ultrasonography or computed tomography pulmonary angiography. The primary efficacy outcome measure was a composite of asymptomatic proximal DVT, symptomatic proximal or distal DVT, symptomatic non-fatal PE or VTE related death from day 1 to 10 for non-inferiority analysis and from day 1 to 35 for superiority analysis. The principal safety outcome was clinically relevant bleeding, defined as a composite of major bleeding or clinically relevant nonmajor bleeding. Major bleeding was defined as bleeding causing a 2 g/dl fall in haemoglobin or transfusion of two units of packed or whole blood, bleeding into a critical site or bleeding leading to death. Non-major clinically relevant bleeding was defined as overt bleeding not meeting the major bleeding criteria but associated with a medical intervention, unscheduled contact with a physician, temporary cessation of study treatment, impairing activities of daily living or causing discomfort to the participant. A modified intention-to-treat and per-protocol analysis was performed using data from day 10 and day 35. The median age of both the rivaroxaban and enoxaparin followed by placebo groups was 71 years and the median length of hospital admission was 11 days for both groups. Table 1 summarises the cause of hospitalisation for both groups with acute infection being the most common aetiology. At the day 10 analysis 2.7% of patients in both groups had a primary efficacy outcome event meeting non-inferiority criteria (RR with rivaroxaban 0.97, 95% CI 0.71–1.31, P ¼ 0.003 for non-inferiority). At the day 35 intention-to-treat analysis 4.4% in the extended rivaroxaban group had a primary efficacy outcome event in comparison with 5.7% in the enoxaparin followed by placebo group thus meeting superiority criteria (RR with rivaroxaban 0.77, 95% CI 0.62–0.96, P ¼ 0.02 for superiority). However, rivaroxaban also had higher safety outcome events. At day 10 2.8% of patients taking rivaroxaban experienced clinically relevant bleeding compared to 1.2% receiving enoxaparin (RR with rivaroxaban 2.3, 95% CI 1.63–3.17, P < 0.001). There were 5 fatal bleeds with rivaroxaban and 1 fatal bleed with enoxaparin during this interval. Between day 1 and 35 clinically relevant bleeding occurred in 4.1% of patients receiving extended rivaroxaban and this occurred in 1.7% of patients who received enoxaparin followed by placebo (RR 2.5, 95% CI 1.85–3.25, P < 0.001). A composite of the primary efficacy outcome and primary safety outcome was analysed to determine the net clinical benefit or harm. At day 10 both outcomes had occurred in 6.6% in the rivaroxaban group and 4.6% in the enoxaparin group (RR with rivaroxaban 1.44, 95% CI 1.18–1.77, P < 0.001). At day 35 both outcomes had occurred in 9.4% of the rivaroxaban group and 7.8% in the enoxaparin followed by placebo group (RR with rivaroxaban 1.21, 95% CI 1.03–1.43, P ¼ 0.02). A total of 7 fatal bleeds occurred in the rivaroxaban arm from day 1 to 35 and 1 in the enoxaparin followed by placebo group. Other adverse-event profiles including cardiovascular events, derangement of liver functions tests and death from any cause were similar in both groups.
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Table 1 Characteristics and results of the NOACs in medical thromboprophylaxis.
Duration Inclusion criteria Exclusion criteria
Study population
Acute medical condition
Outcomes
N Age Length of hospitalisation Infectious disease Heart failure (NYHA class III or IV) Respiratory insufficiency Ischaemic stroke Active cancer Inflammatory or rheumatic disease Primary efficacy outcome Major bleeding and clinically relevant non-major bleeding Fatal bleeding
MAGELLAN
ADOPT
VTE prophylaxis when hospitalised with acute medical illness 10 mg rivaroxaban once daily Initially enoxaparin, then placebo during extended phase Multicentre randomised double-blinded trial, non-inferiority during initial phase and superiority during extension phase 10 4 days initial phase then 35 4 days extended phase 40 years of age with reduced mobilitya and an acute medical illness requiring hospitalisation Conditions that contraindicate use of enoxaparin or rivaroxaban, recent surgery or head injury, history of haemorrhagic stroke, high bleeding risk, sustained uncontrolled hypertension, alcohol or drug abuse, pregnant or breastfeeding, co-administration of cytochrome P450 3A4 inhibitors and severe renal impairment 8101 Median 71 days for both arms Median 11 days for both arms
VTE prophylaxis when hospitalised with acute medical illness 2.5 mg apixaban twice daily Initially enoxaparin, then placebo during extended phase Multicentre randomised double-blinded trial, non-inferiority during initial phase and superiority during extension phase Initial phase 6–14 days then 30 days extended phase 40 years of age, an acute medical illness requiring hospitalisation with one additional VTE risk factor (except heart failure or respiratory failure patients) and reduced mobilityb Confirmed VTE on admission, co-morbities requiring on-going anti-coagulation, active liver disease, severe renal impairment, anaemia or thrombocytopenia, contra-indication to enoxaparin, co-administration of two or more antiplatelet agents, recent surgery, pregnancy or breastfeeding 6528 Median 67 for both arms Unknown
46% rivaroxaban arm, 45% enoxaparin arm 32% rivaroxaban arm, 32% enoxaparin arm
22% apixaban arm, 23% placebo arm 38% for both arms
27% rivaroxaban arm, 29% enoxaparin arm 17% rivaroxaban arm, 17% enoxaparin arm 7% rivaroxaban arm, 7% enoxaparin arm 4% rivaroxaban arm, 4% enoxaparin arm
37% for both arms Unknown 4% apixaban arm, 3% placebo arm 2% for both arms
Rivaroxaban group 4.4% at day 35, enoxaparin then placebo 5.7% at day 35 (RR 0.77, 95% CI 0.0.62–0.96, P ¼ 0.02) 2.8% with rivaroxaban and 1.2% with enoxaparin at day 10 (P < 0.001). 4.1% with rivaroxaban and 1.7% with enoxaparin then placebo at day 35 (P < 0.001) 7 in the extended rivaroxaban group and 1 in the enoxaparin then placebo group
Apixaban group 2.7% at day 30, enoxaparin then placebo 3.1% (RR with apixaban 0.87, 95% CI 0.62–1.23, P ¼ 0.44) 2.67% with apixaban at day 30 and 2.08% with enoxaparin then placebo (RR 1.28, 95% CI 0.93–1.76, P ¼ 0.12) 0 in the apixaban group and 2 in the enoxaparin then placebo group
a Defined as at least one day of complete immobility followed by at least 4 days of decreased mobility. Complete immobilisation defined as being totally confined to bed or chair but allowing use a bedside commode or assistance to the bathroom. Decreased mobility causing >50% to be spent in bed or chair. b Defined as moderate or severe restriction in mobility. Moderately restricted allowed for walking within hospital room or to the bathroom, severely restricted mobility defined as confined to bed or to a bedside chair.
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Indications Drug Comparator Design
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ADOPT study The ADOPT trial was a randomised, double-blinded, double-dummy trial that compared apixaban with enoxaparin in the prevention of VTE in hospitalised adults with an acute medical illness [22]. The objectives were to determine whether oral apixaban is non-inferior to standard-duration (minimum 6 days) subcutaneous enoxaparin for the prevention of VTE in acutely ill medical patients, and whether extended-duration apixaban is superior to standard-duration enoxaparin. Apixaban is also an orally active direct Xa inhibitor which is effective in the prevention of VTE after elective hip or knee replacement surgery in adults and the prevention of stroke in patients with atrial fibrillation. The ADOPT trial and the MAGELLAN trial were similar in design. The initial phase of the ADOPT trial lasted a minimum of 6 days in which patients either received oral apixaban 2.5 mg twice daily or subcutaneous enoxaparin 40 mg once a day. After the 6 day period enoxaparin was stopped at the discretion of the investigator and placebo was taken for the remainder of the extended phase which ceased at day 30. The study population was also aged 40 and over who had been hospitalised with an acute medical illness less than 72 h prior to randomisation. Table 1 also summarises the characteristics of the trial population. Patients also underwent ultrasonography twice to detect asymptomatic DVT between days 5–14 and at day 30. An intention-to-treat analysis was performed to determine noninferiority at day 10 and superiority at day 35. The primary efficacy outcome was the same as the MAGELLAN trial. The safety outcomes included major bleeding, clinically relevant non-major bleeding and all bleeding reported by investigators. Major bleeding was defined as per the MAGELLAN trial with the addition of bleeding that occurred into an operated joint that required reoperation or intramuscular bleeding with compartment syndrome. Clinically relevant non-major bleeding was defined as not meeting the criteria for major bleeding but at least one of the following were present: epistaxis for >5 min or requiring medical attention, gastrointestinal bleeding containing frank blood or coffee-ground material that tested positive for blood, endoscopically confirmed bleeding, spontaneous haematuria or haematuria persisting >24 h postcatheterisation, radiological confirmed haematoma or haemoptysis. The median age of the apixaban group was 68 years and 67 years for the enoxaparin followed by placebo group. The majority of patients was white, 76% for both groups. Table 1 summarise the aetiology of hospitalisation admission. The most common cause of hospitalisation was congestive heart failure at 39% apixaban arm and 38% enoxaparin followed by placebo arm. The ADOPT trial also included patients with NYHA class I and II heart failure unlike the MAGELLAN trial which only included class III and IV heart failure patients. The primary efficacy outcome was confirmed in 2.71% of patients assigned to the apixaban arm when analysed at day 30 in comparison with 3.06% in the enoxaparin followed by placebo group (RR with apixaban 0.87, 95% CI 0.62–1.23, P ¼ 0.44). Following the cessation of parenteral-treatment the primary efficacy outcome occurred in 31 patients in this arm and 18 patients in the apixaban arm (RR with apixaban 0.59, 95% CI 0.33–1.05). Major bleeding during the 30 days trial period occurred at 0.47% in the apixaban group and 0.19% in the enoxaparin followed by placebo group (RR with apixaban 2.58, 95% CI 1.02–7.24, P ¼ 0.04). The combination of major bleeding and non-major clinically relevant bleeding occurred in 2.67% of the apixaban group with 2.08% found in the enoxaparin followed by placebo group (RR 1.28, 95% CI 0.93–1.76, P ¼ 0.12). There were no fatal bleeds in the apixaban group and two in the enoxaparin group. There was no significant difference in overall death, rates of adverse events or rates of liver function test derangement between the apixaban and enoxaparin followed by placebo group. It must be noted that the ADOPT trial was underpowered therefore clinically no direct conclusions can be drawn. Only 64% of the patients had a follow-up ultrasonography to detect asymptomatic disease.
Future research Some factors to consider in future research in medical patients are the following: 1. Reducing the risk of bleeding 2. Finding patients at significant risk of VTE
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3. Omission of the mid-study routine venous ultrasonography 4. Choosing the right intensity (dose, regimen) of anti-coagulation 5. Choosing the correct time to start and stop prophylaxis
Reducing the risk of bleeding The primary adverse effect of anti-coagulation is the increased risk of major bleeding, as defined by fatal bleeding, symptomatic bleeding in a critical area or organ, or bleeding causing a decrease in haemoglobin concentration of more than 20 g/l or requiring transfusion of two or more units of blood [26]. An analysis of the IMPROVE registry of general medical patients resulted in a bleeding risk score, with the factors most predictive of bleeding being active gastroduodenal ulcer, bleeding in the preceding 3 months, thrombocytopenia (<50 109/l), and advanced age (>85 years) [27]. Bleeding risk was also significantly increased by hepatic failure (with INR > 1.5), renal failure (with GFR < 30 ml/ min/m2), admission to the intensive care unit, presence of a central venous catheter, rheumatic disease, cancer, and male gender. These and other factors, such as stricter criteria to exclude patients at risk of bleeding, need to be considered in future studies in this area. Finding patients at significant risk of VTE Two papers have described an association between elevated D-dimer levels around the time of admission and the subsequent development of VTE in this patient group [28,29]. We have described a strong independent association between D-dimer levels of greater than or equal to twice the upper limit of normal and the subsequent development of VTE in this patient group. This independent association was stronger than that seen for advanced age (>75) and cancer [30]. Advanced age has also been shown to have a strong independent association with the risk of VTE [24,31]. Omission of the mid-study routine venous US The inclusion or omission of a mid-study or “Day 10” venous ultrasonography is an important consideration in new studies. These ultrasound studies are not routinely performed in clinical practice and are performed to allow a comparison between two active treatment arms. However they alter the natural history of VTE in the middle of the study period and they are likely to reduce the overall symptomatic VTE rates as the potential clinical VTE are diagnosed early and treated as asymptomatic events. For these reasons, omitting this test is favoured by most trialists and clinicians to allow a realistic comparison of extended and short-term regimens. Choosing the right intensity (dose, regimen) of anti-coagulation A recent study has shown that lowering the dose of anticoagulant thromboprophylaxis in patients with renal impairment may not compromise efficacy [32]. A lower dose may lead to less bleeding, the “Achilles heel” of all three published studies, but lowering the dose may result in efficacy being compromised. Choosing the correct time to start and stop prophylaxis The previous studies have randomised patients to prolonged therapy at different times. In the Exclaim study patients received standard thromboprophylaxis for 6–14 days and were then randomised (typically at the time of hospital discharge) to a further 4 weeks of enoxaparin 40 mg daily or placebo. This allowed the exclusion patients with poor prognosis, early bleeding and early thrombosis. In the more recent studies (MAGELLAN and ADOPT) patients were randomised to either the NOAC for around 4–5 weeks or enoxaparin for 6–14 days as soon as possible, typically 1–3 days, following admission. This meant a more heterogeneous group of patients entered these studies. Future studies
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may opt to start the randomisation procedure later than 1–3 days, perhaps around the time of discharge to allow the recognition of a clinically stable group. The optimal length of therapy to achieve the maximal benefit risk relationship is unknown and may be the status quo of 6–14 days. Future studies may test shorter or longer periods of extra therapy than the 4–5 weeks tested in MAGELLAN and ADOPT. On-going studies There is one new on-going study in this field. The Apex Study is testing betrixaban regimens and this study takes account of many of the lessons learnt from previous studies as mentioned above, as well as some dose adjustments and flexible onset of therapy (NCT01583218) [33]. Much work is still to be done with NOACs in this potential indication of thromboprophylaxis in acutely ill hospitalised medical patients
Practice Point At this stage there is no indication to use NOACs for thromboprophylaxis in acutely ill hospitalised medical patients
Conflict of Interest A. Cohen is a medical consultant, and has received consultancy and clinical trial funding from pharmaceutical companies, including Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Daiichi, GSK, Janssen (formerly Johnson & Johnson), Mitsubishi Pharma, Pfizer, Portola, Sanofi-Aventis, Schering-Plough, and Takeda. He is an advisor to the UK Government Health Select Committee, the All-Party Working Group on Thrombosis, the Department of Health, and the NHS, on the prevention of VTE. He is also an advisor to Lifeblood: The Thrombosis Charity and is the founder of the European educational charity the Coalition to Prevent VTE. T Rider has no disclosures to declare.
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