Edoxaban for treating and for preventing deep vein thrombosis and pulmonary embolism

The company did a systematic review of the literature to identify studies evaluating the clinical effectiveness and safety of edoxaban for the treatment and secondary prevention of venous thromboembolism (VTE). It identified 1 relevant randomised clinical trial (Hokusai‑VTE). The company did not find any head‑to‑head studies, so it conducted a network meta‑analysis that compared edoxaban against treatment with rivaroxaban, dabigatran etexilate, and warfarin. The company did not find any relevant non‑randomised studies.

Hokusai‑VTE was an international (37 countries including the UK) randomised, double‑blind, non‑inferiority trial. It compared initial treatment with heparin followed by edoxaban or warfarin for treating acute symptomatic VTE or preventing symptomatic recurrent VTE. Eligible adults were randomised in a 1:1 ratio with stratification by presenting diagnosis, temporary baseline risk factors (such as trauma, surgery or immobilisation) and the dose of edoxaban (which was reduced for patients with moderate renal impairment, those who were having concomitant treatment with potent permeability glycoprotein [P‑glycoprotein] inhibitors, or those who weighed 60 kg or less). A total of 8,292 patients were randomly assigned to either the edoxaban group (n=4,143) or the warfarin group (n=4,149).

All patients had initial therapy with open‑label heparin for at least 5 days. Edoxaban or warfarin was administered in a double‑blind, double‑dummy fashion:

• Patients in the edoxaban group had placebo warfarin during initial heparin therapy. After stopping heparin, they continued placebo warfarin (adjusted to maintain a sham international normalised ratio [INR] of 2.0 to 3.0) and started 60 mg of edoxaban once daily (or 30 mg once daily in patients who needed dose reduction at randomisation or during the study).

• Patients in the warfarin group started warfarin during initial heparin therapy. After stopping heparin, they continued warfarin (adjusted to maintain an INR of 2.0 to 3.0) and started placebo edoxaban.
  
  Treatment with edoxaban or warfarin continued for at least 3 months and up to a maximum of 12 months, with treatment duration based on risk of recurrent VTE, risk of bleeding, and patient preference. The company noted that people who stayed in the trial for longer than 3 months were mostly those identified as being at higher risk of recurrence. In both groups, the median duration of treatment was about 260 days (8.5 months). Around 60% of patients had treatment for more than 6 months; 40% of patients continued treatment for 12 months.

Patient characteristics were similar between the treatment groups: mean age was 56 years, the majority of patients were male (57%) and patient ethnicity was reported as white (70%), Asian (21%), black (4%) or 'other' (5%). A total of 4,921 patients presented with deep vein thrombosis (DVT) only, and 3,319 with pulmonary embolism (PE; with or without DVT).

The primary efficacy outcome measure in the trial was the incidence of symptomatic recurrent VTE (a composite measure of recurrent DVT, new non‑fatal symptomatic PE, and fatal PE) during the 12‑month study period. Secondary outcomes included clinically relevant bleeding during treatment or within 3 days of interrupting or stopping the study drug (this was referred to by the company as the primary safety outcome; a composite of major bleeding and clinically relevant non‑major bleeding), and a composite clinical efficacy outcome of recurrent VTE and all‑cause mortality during the 12‑month study period.

The trial included 3 analysis sets (modified intention to treat, per protocol analysis, and safety analysis) and 2 study periods (overall study period and on‑treatment period). The primary efficacy analyses were done in the modified intention to treat population (analyses based on randomised treatment, even if the patient did not receive this) for the overall study period, which included 4,118 patients randomised to edoxaban and 4,122 randomised to warfarin. Summary statistics were provided for the on‑treatment period. The safety population (analyses based on treatment received) was used for outcomes related to safety; this population was identical to the modified intention to treat population, because all patients had the treatment to which they were randomised. The company did pre‑specified subgroup analyses for the primary efficacy outcome for various patient and disease characteristics, including whether the presenting diagnosis was PE with or without DVT (n=1,650 in the edoxaban group; n=1,669 in the warfarin group), or DVT only (n=2,468 in the edoxaban group; n=2,453 in the warfarin group).

The company presented results for the primary efficacy outcome (symptomatic recurrent VTE) using a pre‑specified non‑inferiority margin of 1.5 for the upper 95% confidence interval (CI) of the hazard ratio (HR) (that is, the non‑inferiority analyses demonstrated statistically significant non‑inferiority if the upper boundary of the 95% CI for the outcome was below 1.5). Edoxaban demonstrated statistically significant non‑inferiority for the primary outcome when compared with warfarin (p<0.0001; see tables 1 and 2). Similar results were obtained for the on‑treatment period (HR, 0.82; 95% CI 0.60 to 1.14; p<0.0001 for non‑inferiority).

Some patients in Hokusai‑VTE completed EuroQoL‑5‑Dimensions (EQ‑5D) assessments and utility scores were determined for all patients using the UK time trade‑off (TTO) value set, at baseline and then at 3‑month intervals. The company reported that the results should be interpreted with caution because data were too limited to compare the effects of edoxaban and warfarin on health‑related quality of life.

The company presented the results of safety analyses, all of which related to adverse events, using the safety analysis set for the on‑treatment population. For the safety outcomes, results included:

• Bleeding (major or clinically relevant non‑major bleeding [CRNM], primary safety outcome): edoxaban was associated with fewer bleeding events (p=0.004 for superiority, see table 3). Major bleeding in critical sites included 5 intracranial haemorrhage events (none of which were fatal) in the edoxaban group, and 18 (6 fatal) in the warfarin group. Major bleeding in non‑critical sites included 27 gastrointestinal tract bleed events (1 fatal) in the edoxaban group and 18 (2 fatal) in the warfarin group.

• Mortality: the rate for VTE‑related death, cardiovascular death and other known causes (cancer, bleeding, infectious disease or other) was 0.8% in both groups (no statistical analyses presented).

The company did a Bayesian network meta‑analysis that compared edoxaban with warfarin, apixaban, dabigatran etexilate and rivaroxaban for the treatment and secondary prevention of VTE. The company stated that, to reduce heterogeneity between the trials, it included only trials from which it could derive data for a fixed 6‑month study period (that is, either the trial was fixed for 6 months or, if the trial was longer than 6 months, only data up to 6 months were extracted). This led to the inclusion of 6 randomised controlled trials, all of which compared the treatment of interest with low‑molecular‑weight heparin plus warfarin.

The company used a fixed‑effects Bayesian model to synthesise the results for each outcome, and used the posterior distribution to derive comparative treatment effects (shown in the company submission as odds ratios with 95% credible intervals [CrI] for ease of interpretation), using warfarin as the reference treatment. It did network meta‑analyses for the whole VTE population, and also secondary analyses for the PE population only, for the following outcomes:

• VTE recurrence

• Bleeding (major bleeding, non‑major bleeding and a composite of both outcomes)

• VTE‑related death

• Net clinical benefit (composite of VTE recurrence, major bleeding and all‑cause mortality).
  
  The base case network meta‑analysis was for the outcome of VTE recurrence at 6 months. The results demonstrated no large differences in treatment effects for the outcomes, and the odds ratios had wide credible intervals that approached or crossed '1' (that is, there was no difference in effect). Results for the PE subgroup were consistent with the main population.

The company did a qualitative assessment of the consistency of evidence generated by direct and indirect comparisons, and stated that the network meta‑analysis results for each oral anticoagulant compared with warfarin were generally consistent with the direct evidence from the original trials.

The company did not quantitatively measure heterogeneity between the trials, because a low number of the trials had similar designs or comparators. Instead, it did a qualitative analysis of heterogeneity and found that there was variance across the trials in blinding, heparin lead‑in time, duration of treatment and the proportion of patients with extensive PE. The company concluded that there were substantial differences between the trial designs and the populations used for the network meta‑analyses, which meant that any results should be interpreted with caution. For example, Hokusai‑VTE was designed differently to other studies because it:

• included initial heparin therapy for at least 5 days, whereas trials for rivaroxaban did not include initial heparin therapy

• allowed the dosage of edoxaban to be reduced at any point, which was not allowed in other trials

• was the only trial to have a flexible treatment duration (so that later data included more high‑risk patients who needed to remain on treatment for longer)

• did not allow for an extension, whereas patients in other trials were entered into extension studies

• was double‑blind, whereas trials for rivaroxaban had open‑label designs.

The evidence review group (ERG) stated that the systematic review done by the company was reasonable, and that the identified trial (Hokusai‑VTE) was well conducted and appropriately powered to demonstrate non‑inferiority. However, the ERG stated that while the trial population was similar to trials for other newer anticoagulants, the generalisability of the trial to the UK population was uncertain because it included more people who were reported as 'Asian' and a younger population than would be expected in UK clinical practice. The treatment duration also suggested a higher‑risk population (60% had treatment for longer than 6 months). The ERG noted that the design of Hokusai‑VTE was different from other trials evaluating newer anticoagulants for this condition because patients could have their drug dosage altered at the beginning of or during the trial. The ERG was unsure about whether the monitoring undertaken in the trial would be needed in clinical practice but it stated that, because the dose of edoxaban was related to variable patient factors, it should be expected that some periodic monitoring would be needed to check whether a patient's dose needed to be reduced.

The ERG noted that the company had not presented evidence for the subgroups of:

• people with active cancer: the ERG noted that Hokusai‑VTE included people with a diagnosis of active cancer and an analysis of this subgroup had been planned but not conducted, which may have been because of limited data (n=208)

• people for whom treatment with warfarin was not appropriate: the ERG agreed that this exclusion was legitimate because of a lack of data

• people with DVT: the ERG disagreed with the exclusion of this subgroup. Because trials in the network for rivaroxaban, warfarin and edoxaban included data for people with DVT, the ERG was able to conduct an analysis for this population.

The ERG noted that although health‑related quality‑of‑life data had been collected in the trial, the small number of respondents severely limited the usefulness of this information.

The ERG considered the results of the trial, noting that recurrent VTE was more frequent for edoxaban in the first 30 days of the trial (21 events in the edoxaban group compared with 15 events in the warfarin group, in the DVT subgroup; and 9 events in the edoxaban group compared with 7 events in the warfarin group, in the PE subgroup). However, this difference was not statistically significant. Overall, the trial demonstrated statistically significant non‑inferiority compared with warfarin for VTE recurrence. The company reported that edoxaban was statistically significantly superior (p=0.004) for the outcome of major and non‑major bleeding. However, the ERG noted that this difference was driven by non‑major bleeding events (major bleeding events were not statistically significantly different for edoxaban compared with warfarin).

The ERG considered the approaches taken by the company for different aspects of the network meta‑analysis. It stated that:

• the approach to reduce heterogeneity by including only trials with 6‑month data was reasonable

• the qualitative approach to considering heterogeneity was pragmatic, but the ERG would have preferred it if the company had performed 2 separate analyses based on the patient's initial diagnosis (DVT or PE)

• the use of a fixed‑effects model was reasonable because of the small number of studies included in the network and the lack of direct comparison of newer oral anticoagulants with any treatment other than warfarin

• the quality assessments of the trials included in the network were mostly adequate

• the indirect comparisons from the network meta‑analysis were consistent with the direct evidence from the individual trials.

The ERG stated that any differences in outcomes between the treatments in the network were small and more likely to be as a result of random chance. This is because the non‑inferiority design of the original studies limited the opportunity for any treatment in the network to have any statistically significant differences. Overall, there were no large differences in treatment effects for the outcomes and the odds ratios had wide credible intervals that approached or crossed '1' (that is, there was no difference in effect), indicating a large amount of uncertainty. The ERG noted that results for the subgroups of DVT (conducted by the ERG because the company had not included this) and PE showed results that were consistent with the main population.

The company's base-case results for edoxaban (based on a model updated with corrections advised by the ERG, including costs and utilities) were presented incrementally, and also as edoxaban compared with each comparator, and each comparator compared with warfarin. In the incremental analysis, edoxaban, and all other comparator treatments, were dominated by rivaroxaban (that is, all treatments were more expensive and less effective than rivaroxaban). Edoxaban had an incremental cost‑effectiveness ratio (ICER) of £2,451 per quality‑adjusted life year (QALY) gained (incremental costs £45.37, incremental QALYs 0.0185) compared with warfarin, and was dominant (that is, more effective and less costly) compared with dabigatran etexilate.

The ERG noted several concerns about the model structure, but it stated that most of these issues did not have a substantial impact on the cost‑effectiveness estimates. The ERG's concerns included:

• If patients had a recurrent VTE, they returned to their original therapy. However, clinical experts advised the ERG that patients would switch to a higher dosage or change treatment because their original treatment had not prevented recurrence.

• If shorter cycles are used (in this instance a 2‑week cycle was used) then the use of health states that have a fixed cycle duration needs to be carefully considered, because this may incorrectly estimate the impact of certain events on quality of life and costs. To overcome this, the company could have increased the length of the cycle, modelled the event without a fixed cycle duration, or used more post‑event states (as it had done for chronic thromboembolic pulmonary hypertension).

• Patients were at risk of post‑thrombotic syndrome when on or off treatment, but only at risk of chronic thromboembolic pulmonary hypertension and stroke when on treatment. However, clinical experts advised the ERG that these are all VTE‑related complications. The ERG therefore stated that patients should be at risk of these outcomes at all times in the model.

• The inclusion of the stroke health state was methodologically flawed, so the ERG conducted a scenario analysis without this. Flaws noted were that:

  • the company had not included several equally relevant cardiovascular events; for example, myocardial infarction

  • it included both intracerebral haemorrhages and ischaemic stroke, which meant that intracerebral haemorrhages (also included in the major bleeding health state) were double counted

  • clinical experts advised the ERG that the type of stroke would affect whether treatment would be stopped (patients would temporarily stop after an ischaemic stroke, but permanently stop after intracerebral haemorrhage).

• In the major bleeding health state, the impact of intracerebral haemorrhage (which has a 40% mortality risk and a 60% disabling risk) on quality of life was underestimated.

The ERG considered the clinical‑effectiveness estimates used in the model. It noted that the odds ratios derived from the 6‑month meta‑analysis for VTE recurrence used in the model had not shown any statistically significant differences between treatments. To consider this, the ERG conducted a scenario analysis that assumed there were no differences between treatments in effectiveness for this outcome (that is, the odds ratios were set to '1'). The ERG also conducted an analysis setting the HR to '1' for bleeding.

The ERG raised several concerns with the disease‑specific mortality in the model. For example, the ERG noted that VTE recurrence data from the trial were used to model the initial event mortality, and not recurrence. For the recurrent‑VTE mortality rate, clinical experts advised the ERG that the rate used (13.7%) was overestimated, with the rate in practice being closer to 3%. The ERG concluded that the mortality estimates for both initial and recurrent VTE were not appropriate, and conducted 2 scenario analyses; 1 using trial data, and 1 using NICE's technology appraisal guidance on dabigatran etexilate for treating and secondary prevention of DVT and/or PE estimate of 3% that was more consistent with expert opinion. For stroke, the ERG noted that the health state included both intracerebral haemorrhage and ischaemic stroke, but the mortality was derived from ischaemic stroke only. Clinical experts advised the ERG that intracerebral haemorrhage has a mortality of around 40%, therefore the modelled mortality rate for stroke (3.85%) was an underestimate.

The ERG made some revisions to the quality‑of‑life estimates used in the model (see section 3.38).

The ERG considered monitoring costs, stating that they appeared to be overestimated for warfarin and underestimated for the other oral anticoagulants. For warfarin, the ERG stated that in clinical practice most visits for international normalised ratio (INR) monitoring occur within the first 3 months, but the company had used an average number of visits per cycle in the model, which did not capture this. Clinical experts also advised the ERG that after 3 months the monitoring schedule would be closer to 3 visits per quarter, not 5; after 12 months it would be approximately 10 visits per year. Follow‑up visits would likely be delivered by nurses. To consider the impact of this, the ERG conducted a scenario analysis to reduce the number of visits needed in the first year (for the base case) to 3 visits per quarter after the initial 3 months, and 10 visits per year after the first year when assuming lifelong treatment, with follow‑up visits based on non‑consultant‑led anticoagulation clinic attendance. For edoxaban, dabigatran etexilate and rivaroxaban, the ERG stated that in clinical practice there would be some monitoring costs expected beyond those considered standard monitoring for patients who have experienced VTE. The ERG conducted 3 scenario analyses to reflect different clinical opinions about monitoring of newer anticoagulants: a scenario in which patients have an annual visit where they have urea and electrolyte tests; a scenario in which patients have an annual appointment with their GP but they have no tests; and a scenario in which patients have an appointment twice a year where they have urea and electrolyte tests.

The ERG considered the 1‑way sensitivity analysis presented by the company, stating that it had concerns about its transparency, relevance and robustness. It stated that the company had not justified its choice of parameters and had presented only the 8 most influential parameters. The ERG stated that the analysis was rendered largely irrelevant because the company included clinically implausible scenarios. For example, the 3 inputs identified by the company as the key model drivers for edoxaban compared with warfarin (probability of stroke with warfarin, and probability of stroke and chronic thromboembolic pulmonary hypertension with the other oral anticoagulants) were based on the assumption that the probability of these events might be different depending on the type of treatment, which did not have face validity. For utility values and decrements, the company had estimated 95% confidence intervals as the high and low values. However, the ERG stated that the company had not reported how it obtained the standard deviations in the calculation. For costs, the company had varied overall health state costs by plus or minus 20%. However, the ERG noted that this meant it was not possible to identify specific costs or resource use within each health state. The ERG stated that the company should have explicitly varied the resource use associated with warfarin monitoring, because this was expected to be a key model parameter.

The ERG was concerned with the validity of the probabilistic results. It noted that the company had assigned a non‑parametric distribution to the odds ratios for newer anticoagulant treatment effectiveness (VTE recurrence and bleeding events) therefore they were not included in the probabilistic sensitivity analysis. The ERG stated that the exclusion of key clinical parameter estimates calculated in the network meta‑analysis considerably reduced the usefulness of the probabilistic results.

The ERG corrected technical errors in the company's model. After these corrections were applied the base case ICERs remained the same for edoxaban compared with warfarin, dabigatran etexilate and rivaroxaban. The ERG then provided scenario analyses based on this revised company base case. When compared with rivaroxaban, edoxaban was dominated in all scenarios. When compared with dabigatran etexilate, the key parameters were the odds ratio used to model the probability of VTE recurrence for dabigatran etexilate compared with warfarin (£9,678 per QALY gained) and the data used to model recurrent VTE‑related mortality (when using Hokusai‑VTE phase‑specific data the ICER was £15,111 per QALY gained and when using NICE's technology appraisal guidance on dabigatran etexilate for treating and secondary prevention of DVT and/or PE the ICER was £28,116 per QALY gained). When compared with warfarin, the main parameters were INR monitoring (assuming 2 less visits per quarter in the final 3 quarters of the year, the ICERs were £18,953 per QALY gained in the scenario base case and £40,359 per QALY gained in lifelong duration scenario) and the level of newer oral anticoagulant monitoring assumed (£4,780 to £7,315 per QALY gained depending on the level assumed).

The ERG presented exploratory analyses that compared edoxaban with warfarin, using data from Hokusai‑VTE rather than from the company's network meta‑analysis. The ERG stated that it considered this approach and the associated ICERs to be the most robust because they were derived from direct comparisons in a randomised controlled trial. The ERG presented ICERs for each individual change to the model, and the cumulative effect of each change (table 4), with a final ICER of £26,028 per QALY gained after all of the following changes were made:

• used VTE recurrence and bleeding odds ratios from Hokusai‑VTE

• used phase‑specific data for bleeding events and VTE‑related mortality (not time‑to‑event data)

• increased the duration of the decrement in quality of life after recurring VTE and MB

• removed the disutility associated with non‑major bleeding

• reduced the number of INR monitoring visits for warfarin from 24 visits in the first year to 18 visits, to reflect 3 instead of 5 visits per quarter (after the initial 9 visits in the first 3 months)

• revised the warfarin cost (£0.04)

• changed the duration of heparin treatment to reflect the Hokusai‑VTE trial (7.5 days for edoxaban and 8.5 days for warfarin)

• assumed that 30% of recurrent DVT cases and 50% of recurrent PE cases need hospitalisation

• applied initial and recurrent VTE diagnostic costs to 100% of patients, according to the type of VTE event: DVT, £143.23; PE, £307.23

• used the estimate from NICE's guidance on venous thromboembolism for the long-term chronic thromboembolic pulmonary hypertension cost (£1,280 at 2014 prices), combined with anticoagulation treatment costs

• removed the stroke health state from the model

• assumed that patients having oral anticoagulants (except warfarin) have an annual appointment where they have urea and electrolyte tests.

Full details of all the evidence for this guidance are available on the NICE website.