Rivaroxaban for preventing adverse outcomes after acute management of acute coronary syndrome

Evidence-based recommendations on rivaroxaban (Xarelto) for preventing atherothrombotic events, such as heart attack and stroke, after acute coronary syndrome in adults.

# Guidance
Rivaroxaban is recommended as an option within its marketing authorisation, in combination with aspirin plus clopidogrel or aspirin alone, for preventing atherothrombotic events in people who have had an acute coronary syndrome with elevated cardiac biomarkers.
Clinicians should carefully assess the person's risk of bleeding before treatment with rivaroxaban is started. The decision to start treatment should be made after an informed discussion between the clinician and the patient about the benefits and risks of rivaroxaban in combination with aspirin plus clopidogrel or with aspirin alone, compared with aspirin plus clopidogrel or aspirin alone.
A decision on continuation of treatment should be taken no later than 12 months after starting treatment. Clinicians should regularly reassess the relative benefits and risks of continuing treatment with rivaroxaban and discuss them with the patient.# The technology
Rivaroxaban (Xarelto, Bayer), coadministered with aspirin alone or with aspirin plus clopidogrel or ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an acute coronary syndrome with elevated cardiac biomarkers. The licensed dose is 2.5 mg twice daily. Patients should also take a daily dose of 75100 mg aspirin or a daily dose of 75100 mg aspirin in addition to either a daily dose of 75 mg clopidogrel or a standard daily dose of ticlopidine. Ticlopidine is not listed in the British National Formulary (BNF).
Treatment with rivaroxaban should be evaluated regularly in the individual patient, weighing the risk for ischaemic events against the bleeding risks. Extension of treatment beyond 12 months should be done on an individual patient basis because experience up to 24 months is limited. Treatment with rivaroxaban should be started as soon as possible after stabilisation of the acute coronary syndrome event (including revascularisation procedures); at the earliest 24 hours after admission to hospital and at the time when parenteral anticoagulation therapy would normally be discontinued.
The summary of product characteristics includes the following adverse reactions for rivaroxaban: anaemia, dizziness, headache, fainting, bleeding events, tachycardia (rapid heartbeat), low blood pressure, haematoma, stomach pain, dyspepsia (heartburn), nausea, constipation, diarrhoea, vomiting, pruritus (itching), rash, bruising, pain in the extremities, fever, and swelling, especially of the ankles and feet. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The list price of rivaroxaban is 58.88 per 2.5 mg, 56 capsule pack (excluding VAT, company submission) The recommended dose is 2.5 mg twice daily which equates to a price of 2.10 per day. Total acquisition costs depend on the duration of therapy. Assuming a treatment duration of 12 months, total acquisition costs are 766.50. Costs may vary in different settings because of negotiated procurement discounts.# The company's submission
The Appraisal Committee (section 7) considered evidence submitted by the company that manufactures rivaroxaban and a review of this submission by the Evidence Review Group (ERG; section 8).
The main evidence in the company's submission came from ATLASACS 2TIMI 51. This was an international, multicentre (766 sites in 44 countries including the UK), randomised controlled trial (RCT) designed to evaluate whether rivaroxaban in addition to standardcare antiplatelet therapy reduced the risk of cardiovascular death, myocardial infarction or stroke in patients with recent acute coronary syndrome (unstable angina, nonST segment elevation myocardial infarction  or ST segment elevation myocardial infarction ). The company also provided supportive evidence from the ATLASACS TIMI 46 trial, which compared rivaroxaban oncedaily dosing with twicedaily dosing within the same total daily dose range (520 mg). This study was a safety and efficacy study to determine the most favourable dose and dosing regimen of rivaroxaban for ATLASACS 2TIMI 51.
The ATLASACS 2TIMI 51 trial had 3 phases: a 6day screening phase; a doubleblind treatment phase; and a followup phase. Patients were enrolled into the trial within 7 days of being admitted to hospital for acute coronary syndrome. After stabilisation of the acute coronary syndrome (and after completion of any initial management strategies such as revascularisation), patients were stratified on the basis of whether they were to have clopidogrel or ticlopidine in addition to aspirin as standard care (stratum 1: aspirin only ; stratum 2: aspirin plus clopidogrel or ticlopidine ). Patients were then randomised to 1 of 3 treatment groups; rivaroxaban 2.5 mg, rivaroxaban 5 mg or placebo (all taken twice daily). The dosage of clopidogrel or ticlopidine followed national or local prescribing information. Enrolment was neither capped nor fixed and depended on regional medical practice. The daily maintenance dose was not to exceed 75 mg a day for clopidogrel or 250 mg twice daily for ticlopidine. Approximately 99% of the patients in stratum 2 had clopidogrel. The duration of treatment was not fixed because the trial was eventdriven (that is, the time needed to obtain at least 983 primary efficacy endpoint events across both strata and at least 728 primary efficacy events in stratum 2). The mean duration of treatment was 13.1 months.
The company considered the baseline patient characteristics of those enrolled into ATLASACS 2TIMI 51 to be generally similar between the treatment groups. The mean age of the trial population was 61.8 years; 9.0% were aged over 75 years, and 74.7% were men. In the trial population, the index acute coronary syndrome event was 50.9% STEMI, 25.6% NSTEMI and 23.6% unstable angina. The company stated that baseline patient characteristics were representative of a moderate to highrisk population of patients with acute coronary syndrome, with the majority of all patients randomised having cardiovascular risk factors such as hypertension (67.4%), diabetes (32.0%), a history of myocardial infarction (26.9%) or hypercholesterolaemia (48.6%). Of the 60.5% of patients who had a revascularisation procedure for the index event; the vast majority of these were percutaneous coronary intervention. In the trial population 7.1% of patients had impaired renal function with creatinine clearance less than 50 ml/min.
The efficacy analysis was based on the modified intentiontotreat (mITT) analysis set, which included all randomised patients (except those from 3 excluded sites where trial misconduct was identified) and the end point events that occurred from randomisation up to the earlier date of the global treatment end date, or 30 days after last dose of study drug (for patients who discontinued the study drug prematurely), or 30 days after randomisation (for patients who were randomised but never treated). The exclusion of the data from the 3 sites was considered to be acceptable by the European Medicines Agency (EMA). The company presented the efficacy results for the 2.5 mg rivaroxaban twicedaily and 5 mg twicedaily doses separately and combined by strata (stratum 1, stratum 2 and combined ).
The primary efficacy end point in ATLASACS 2TIMI 51 was the composite of death from cardiovascular causes (cardiovascular  death), myocardial infarction (MI) or stroke (ischaemic, haemorrhagic or stroke of uncertain cause). A range of secondary composite end points were also included. These were:
composite of death from any cause, MI or stroke
net clinical outcome (composite of CV death, MI, ischaemic stroke and nonCABG TIMI major bleeding )
composite of CV death, MI, stroke or severe recurrent ischaemia needing revascularisation
composite of CV death, MI, stroke or severe recurrent ischaemia leading to hospitalisation.
The results for the primary efficacy end point for the total trial population in ATLASACS 2TIMI 51 are provided in table 1.

# Table 1 Effect of rivaroxaban compared with placebo on the primary efficacy end point (total population, mITT analysis )
Stratum
mg rivaroxaban bd vs placebo
mg rivaroxaban bd vs placebo
Combined rivaroxaban dose vs placebo
HR
(95% CI)
p value
HR
(95% CI)
p value
HR
(95% CI)
p value
ALL strata
(n=15,342)
Stratum 1*
(n=1050)
Stratum 2
(n=14,292)
bd, twice daily; CI: confidence interval; HR: hazard ratio, mITT, modified intention to treat
- stratum 1: aspirin alone
 stratum 2: aspirin plus clopidogrel or ticlopidine
In its submission, the company provided results on the primary efficacy end point across a number of subgroups for the whole trial population only (combined 2.5 mg twice daily and 5 mg twice daily doses of rivaroxaban). These included age, sex, creatinine clearance, previous MI, stroke or transient ischaemic attack (TIA) and index event (STEMI, NSTEMI or unstable angina). The company stated that in general, rivaroxaban treatment was consistently associated with improved outcomes across all major subgroups (with the exception of the subgroup analysis of prior history of stroke or TIA ). The company stated that during the marketing authorisation process, the EMA requested that a narrower population of patients with acute coronary syndrome be identified with a more favourable benefitrisk balance obtained from treatment with rivaroxaban in addition to dual antiplatelet therapy. The population identified by the company, and accepted by the EMA, was patients who had acute coronary syndrome with elevated cardiac biomarkers (that is patients with STEMI and NSTEMI), excluding patients with a history of stroke or TIA.
The company presented a post hoc subgroup analysis of patients in ATLASACS 2TIMI 51 who had acute coronary syndrome with elevated cardiac biomarkers, excluding those with a history of stroke and TIA. The company referred to this subgroup as the licensed population because it is the population of patients for whom the drug is indicated in the marketing authorisation. It consisted of 12,353 patients in ATLASACS 2TIMI 51 (ALL strata, 80% of the total trial population). Results for the primary efficacy end point and components for the licensed population in ATLASACS 2TIMI 51 are provided in table 2. Table 2 presents only the results for ALL strata because the results for strata 1 (aspirin alone) and strata 2 (aspirin plus clopidogrel or ticlopidine) are considered to be confidential by the company and so cannot be reported. The company explained that its submission focused on the results for the 2.5 mg twicedaily dose because this is the licensed dose.

# Table 2 Effect of rivaroxaban compared with placebo on the primary efficacy end point and components (licensed population, mITT analysis )
mg Rivaroxaban bd vs placebo
mg Rivaroxaban bd vs placebo
Combined rivaroxaban dose vs placebo
HR
(95% CI)
p value
HR
(95% CI)
p value
HR
(95% CI)
p value
ALL strata n=12,353
Primary end point
CV death
MI
Stroke
bd, twice daily; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; mITT, modified intention to treat
The company did not report any results in relation to treatment compliance or premature discontinuation of study treatments for the licensed population because data were not available at the time of submission. For the total trial population, among patients who had at least 1 dose of a study drug, premature discontinuation of treatment occurred in 26.9% (1376/5115) of patients having the 2.5 mg twicedaily dose of rivaroxaban, 29.4% (1504/5110) of patients having the 5 mg twicedaily dose of rivaroxaban and 26.4% (1351/5125) of patients having placebo. No statistical comparisons were reported for these differences. The most common reasons for discontinuation of study treatment were adverse events (rivaroxaban 2.5 mg twice daily 8.8%; rivaroxaban 5 mg twice daily 10.9%; placebo 7.3%), consent withdrawal (rivaroxaban 2.5 mg twice daily 4.7%; rivaroxaban 5 mg twice daily 4.3%; placebo 4.3%) and 'other' (rivaroxaban 2.5 mg twice daily 11.5%; rivaroxaban 5 mg twice daily 11.3%; placebo 11.8%).
Of the 15,526 patients randomised to ATLASACS 2TIMI 51, 13,124 (84.5%) patients were alive at the end of the trial followup period and 537 patients (3.5%) had died. The remaining 1865 (12.0%) of patients were categorised as having 'incomplete followup'. 11,026 (71.0%) of randomised patients completed both the doubleblind treatment period and the followup period. At the end of the trial, of the 1294 patients who withdrew consent, vital status was unknown for 1117 (86.3%) patients. During discussions with the US Food and Drug Administration (FDA), concerns were raised about the level of missing data as a result of the incomplete follow up of patients who withdrew from the trial. The company therefore made extensive efforts to obtain vital status information on patients who withdrew consent. This reduced the proportion of patients with unknown vital status to 3.2% (495 patients) in the intention to treat (ITT) analysis set and 1.8% (278 patients) in the mITT analysis set.
Healthrelated quality of life was assessed in ATLASACS 2TIMI 51 using the EuroQoL (EQ5D) utility index. EQ5D data were collected from sites in 8 countries including the UK at baseline, 4 weeks, 24 weeks, 48 weeks, 72 weeks and 96 weeks. Healthrelated quality of life data were collected for all of the participants in the trial. The company stated that the utility values obtained from the trial were not used in the economic model.
The primary safety analysis set was the treatmentemergent safety analysis set, which included all patients who were randomised and who had at least 1 dose of the study drug. For each patient, all events were included from the first dose of the study drug up to the date of the last dose of study drug plus 2 days. This analysis set was used for the primary safety end point of nonCABG TIMI major bleeding events, key adverse event summaries and for the benefitrisk analysis.
The company presented results on the primary safety end point and other bleedingrelated end points based on the whole trial population and for the licensed population (that is, adult patients after an acute coronary syndrome with elevated cardiac biomarkers without a history of stroke or TIA). The total number of patients included in the safety analysis from ATLASACS 2TIMI 51 in the licensed population was 12,325 (ALL strata n=4096; rivaroxaban 2.5 mg twice daily n=4072; rivaroxaban 5 mg twice daily n=4157; placebo). The results for the licensed population showed a dosedependent increase in the rate of nonCABG TIMI major bleeding events for rivaroxaban added to antiplatelet therapy compared with antiplatelet therapy alone. In 'ALL strata' in the treatmentemergent safety analysis set, the primary safety end point occurred in 1.3% of patients in the rivaroxaban 2.5 mg twicedaily group, 1.6% of patients in the rivaroxaban 5 mg twicedaily group and 0.4% of patients in the placebo group. The hazard ratio (HR) for the primary safety end point was 3.44 (95% confidence interval : 1.97, 6.01) for the 2.5 mg rivaroxaban twicedaily group, 4.4 (95% CI 2.55 to 7.60) for the rivaroxaban 5 mg twicedaily group and 3.91 (95% CI 2.32 to 6.59) for the rivaroxaban combineddose group.

# Cost effectiveness
The company submitted a de novo Markov cohort model comparing rivaroxaban 2.5 mg twice daily with standard care (clopidogrel plus aspirin or aspirin alone) in adults who had a recent acute coronary syndrome with elevated cardiac biomarkers and who had not had a previous stroke or TIA. The model used a time horizon of 40 years that was divided into 2 periods: an observation period, which was intended to replicate the duration of the trial data, and an extrapolation period. The extrapolation period started after 96 weeks and had a cycle length of 6 months. In the observation period the initial 2 cycles had a cycle length of 4 weeks and 8 weeks respectively and the remaining cycles used a cycle length of 12 weeks. The company based the analysis from an NHS and personal social services perspective, and costs and benefits were discounted at an annual rate of 3.5%. Halfcycle correction was performed on the Markov trace.
The company's model consisted of a number of health states corresponding to whether or not the hypothetical patient had another acute coronary syndrome event. The acute coronary syndrome events considered in the model were: MI, ischaemic stroke, haemorrhagic stroke or intracranial haemorrhage (HS/ICH); a bleeding event measured on the TIMI scale; and revascularisation. These acute coronary syndrome events fell into 2 broad categories: those with longer term implications for the relative risks of developing further conditions, utility and costs and those deemed to be transient events where the impacts were limited to 1 model cycle. Patients could die at any time in the model and there were multiple causes of death simulated in the model. Patients could die from an MI, ischaemic stroke or HS/ICH or other CV death, which included deaths related to bleeding. Patients could also die from nonCV causes at any time point in the model.
The longterm acute coronary syndrome events included the MI, ischaemic stroke and HS/ICH conditions. The longterm events had 2 subsequent tunnel states to allow for the patient's healthrelated quality of life to improve over time, and for the cost of treatment and the relative risk of having a subsequent event to fall over time. Patients could have up to 3 acute coronary syndrome events; the specific types of event were recorded when patients had 2 or fewer events. When 3 events happened, it was assumed that there was 1 event of each type (that is an MI, an ischaemic stroke and a HS/ICH).
The health states corresponding to bleeding and revascularisations were assumed to be transient health states and when a patient entered these states a oneoff cost and utility decrement was applied. These transient health states were applied to only the patients in the observation period of the model, implicitly assuming that the bleeding and revascularisation rates for the 2 interventions were comparable after rivaroxaban treatment was discontinued for all patients at the end of the second year.
The population modelled was the subgroup of patients who had acute coronary syndrome with elevated cardiac biomarkers and had not experienced a prior stroke or TIA in the ATLASACS 2TIMI 51 trial. The data were not pooled from both rivaroxaban trial arms; the model was based on the subgroup data from patients who had 2.5 mg rivaroxaban twice daily only. Data from both trial strata were used to inform the model. In accordance with ATLASACS 2TIMI 51, it was assumed that in the base case 93% of patients had clopidogrel plus aspirin and 7% of patients had aspirin alone. A scenario analysis was presented considering only those patients who had clopidogrel and aspirin.
In the base case the transition probabilities for future acute coronary syndromerelated events in the observation period (2 years) were determined by fitting a Weibull distribution to the trial data. This was undertaken for both the rivaroxaban 2.5 mg twicedaily arm and for the placebo arm. The company stated that because patient numbers diminished over time, particularly visible towards the end of ATLASACS 2TIMI 51, it was difficult to estimate transition probabilities directly from the data for the later cycles within the observation period. The company commented that by fitting a Weibull distribution to the ATLASACS 2TIMI 51 trial data, it was able to remove the data fluctuations caused by a decline in the numbers of observations over the trial.
The company's model assumed that patients could discontinue treatment in the observation period after they had an acute coronary syndrome event. The probability of discontinuation following an event was obtained from ATLASACS 2TIMI 51. This was calculated by using the total trial population, not the licensed population.
The UK marking authorisation for rivaroxaban states that 'extension of treatment beyond 12 months should be done on an individual patient basis as experience up to 24 months is limited'. To reflect this, the company adjusted the proportion of patients who continued on rivaroxaban treatment in the second year (that is from 4860 weeks on wards). The proportion of patients selected was to allow an overall continuation rate of 19% after 12 months and that this would decline to 0% at the end of the second year. No treatment effect or cost was applied to those patients who discontinued rivaroxaban treatment.
In the model patients had clopidogrel 75 mg once a day, aspirin 75 mg once a day and rivaroxaban 2.5 mg twice daily as appropriate. Because rivaroxaban entered the treatment pathway after stabilisation of an acute coronary syndrome event, any further differences in costs between the intervention and the comparator were a result of acute coronary syndrome events and discontinuations related to an acute coronary syndrome event.
Costs of acute coronary syndrome events were determined by the NHS reference costs (201213) of treating the event and the cost of follow up for the patient. An assumption was made that if a patient had multiple acute events in the long term, then the cost of hospitalisation and the follow up of two events were applied. This was the case irrespective of the time between the events. It was assumed that, on average, patients experienced 5, 14 and 28 days rehabilitation after MI, ischaemic stroke and HS/ICH respectively. These rehabilitation costs occurred in the first 3 months after the event. Transient event costs were also included in the model.
The utility values associated with longterm health states were obtained from the literature, primarily from NICE's technology appraisal guidance on ticagrelor for the treatment of acute coronary syndromes. A study by Ara and Brazier was used to calculate the improvement in healthrelated quality of life that patients would experience in the stroke health states. The study was used to obtain the utility values of patients with stroke in the UK at baseline and at 12 months after the stroke occurred. Based on the utility values from these 2 time points, a 33% improvement in healthrelated quality of life over 12 months was calculated for patients who had strokes. To calculate the utility values for patients who had a stroke 6 months after a previous stroke, the average of the stroke first 6 months and the stroke (post 12 months) health states was taken. Utility values were assumed to be the same for both rivaroxaban and standard care following any event. For multiple event states, the utility values of two events that had occurred were multiplied together. The company stated that this allowed for worsening healthrelated quality of life following multiple events to be taken into account. The utility value for the eventfree health state was assumed to remain constant over time. The resulting utility estimates were 0.842 for no event, 0.779 for nonfatal MI, 0.821 for after MI, 0.703 for nonfatal stroke, and 0.703 for after stroke.
For the licensed population, the company reported a deterministic incremental costeffectiveness ratio (ICER) of 6203 per qualityadjusted life year (QALY) gained (incremental costs 764, incremental QALYs 0.12) for a life time horizon of 40 years for rivaroxaban compared with clopidogrel plus aspirin or aspirin alone.
The company conducted a series of 1way deterministic sensitivity analyses. Changes to the cost parameters, discount rates, utility values and risk estimates for MI impacted on the base case ICER, but no factor increased the ICER to over 10,000 per QALY gained. The company's probabilistic analysis showed that rivaroxaban had a 99.9% probability of being cost effective compared with clopidogrel plus aspirin or with aspirin alone if the maximum acceptable amount for an additional QALY was 20,000.

# Evidence Review Group comments
The ERG stated that the company undertook a comprehensive systematic review of rivaroxaban for the prevention of adverse outcomes in patients after the acute management of acute coronary syndrome. The ERG considered ATLASACS 2 TIMI 51 to be a welldesigned, multicentre RCT of reasonable quality.
The ERG questioned the generalisability of the population enrolled in ATLASACS 2TIMI 51 to the population seen in clinical practice in England. The ERG noted that of all patients randomised in ATLASACS 2TIMI 51, 74% were men and the mean age was 61.8 years. The ERG commented that patients with acute coronary syndrome in England are usually older, with a mean age of 65 years and 72 years for patients with STEMI and NSTEMI respectively. It highlighted that the EMA's assessment report noted that patients in the trial were considered to be at low risk. Patients in the trial had little comorbidity, lower than usual use of percutaneous coronary intervention and included a relatively small proportion of people aged over 75 years or who had impaired renal impairment with creatinine clearance less than 50 ml/min. As a result, the findings from ATLASACS 2TIMI 51 may not be applicable to an older population or to those with a greater incidence of renal impairment and a higher baseline bleeding risk.
The ERG commented that mean treatment duration with rivaroxaban in ATLASACS 2TIMI 51 was 13.1 months. As a result, the evidence on efficacy and safety of rivaroxaban 2.5 mg twice daily beyond this time is limited. The ERG noted that this is reflected in the summary of product characteristics, which recommends that extension of treatment beyond 12 months should be done on an individual patient basis because experience up to 24 months is limited.
The ERG stated that the test 'elevated cardiac biomarker' is less sensitive than if a patient exhibits a rise or fall in their cardiac biomarkers (preferably troponins), because many patients have persistently elevated biomarkers outside the context of acute coronary syndrome. In current practice, the diagnosis of NSTEMI requires evidence of myocardial ischaemia with a rise or fall in the blood level of a cardiac biomarker (troponin). In addition, the sensitivity of biomarker assays has increased since the trial was conducted. If more sensitive assays had been available during ATLASACS 2TIMI 51, more patients might have been diagnosed with NSTEMI rather than unstable angina and therefore included in the licensed population.
The ERG noted that there were numerical inconsistencies between the 2 dose groups (2.5 mg twice daily and 5 mg twice daily) for the components of the composite efficacy end points in the licensed population (see table 2). When the components of the primary efficacy end points were analysed individually, rivaroxaban 2.5 mg twice daily significantly reduced the risk of death from CV causes compared with placebo, but did not reduce the risk of MI or stroke. In contrast, rivaroxaban 5 mg twice daily significantly reduced the risk of MI, but did not reduce the risk of CV death or stroke. The ERG noted that the numerical inconsistencies between the 2 dose groups had been extensively discussed in a US FDA briefing document (albeit in the whole trial population of ATLASACS 2TIMI 51, rather than the licensed population). This briefing document states that 'the proposition that a lower dose of an antithrombotic drug is significantly more effective than a higher dose lacks biological plausibility'. The ERG also noted that the EMA's assessment report concluded that these findings may partly have been due to chance. The ERG therefore considered the hazard ratios from the combined dose to be more plausible than those of the individual doses.
The ERG considered the validity of the results from the ATLASACS 2TIMI 51 study to be questionable as a result of the high discontinuation rates from the trial. The ERG noted that 15.5% of the total randomised population (n=15,526) withdrew from the trial (2.5 mg rivaroxaban twice daily 15%; 5 mg rivaroxaban twice daily 16.3%; placebo 15.1%). The ERG highlighted that the rates of premature withdrawal in the ATLASACS 2TIMI 51 trial were higher than other similar randomised trials in patients with acute coronary syndrome: APPRAISE2 (apixaban, 1.8% ); TRACER (vorapaxar, 5.9% ); PLATO (ticagrelor, 3.0% ) and TRITON (prasugrel, 5.9% ).
The ERG commented that because data were missing for people who withdrew from the trial (proportion of patients with unknown vital statistics 3.2% ) there was a potential risk that this may have led to informative censoring. That is, patients who drop out (and therefore are censored) are more or less likely to experience the primary outcome of interest compared with those remaining in the study, and this happens in a nonrandom manner. This may be compounded if the reason for, or frequency of, discontinuation differs between treatment groups. The ERG highlighted that no detailed discussion was provided in the EMA's assessment report regarding this issue. The ERG considered that the efficacy analyses were at risk of bias because prognoses may differ in those patients who withdrew from the trial. The ERG highlighted that the likely bias introduced by informative censoring in the clinical outcomes and costeffectiveness analyses was unknown.
The ERG stated that the structure of the company's model led to the potential for systematic errors to occur, because the time between multiple events is not tracked. This causes the potential for systematic errors in 3 ways. First, patients who had 2 events in 1 time cycle were not distinguished from those patients who had multiple events in separate time cycles. Second, for patients who had multiple events in separate time cycles any improvement over time that they may have experienced was ignored. Finally, for those patients who transition into the multiple event states from the single event states, the first event was not tracked. The ERG commented that there were 2 solutions to this problem. First, a more complicated state transition cohort model could be developed so that cost and utilities for each multiple event state can be varied by the preceding health state and by the time between the events. Second, a patientlevel simulation approach could be taken.
The ERG stated that the population modelled by the company was the patient subgroup who had elevated cardiac biomarkers and had not experienced a prior stroke or TIA. Therefore, all issues with the generalisability of the results of ATLASACS 2TIMI 51 (see sections 3.3 and 3.28) and informative censoring (see sections 3.10 and 3.33) also apply to the economic model results.
The ERG stated that the approach used by the company to calculate the transition probabilities for the transient health states was inappropriate because the cost and QALYs of the events that occurred in the second year were not appropriately discounted. Also, there was no clear adjustment for the number of additional patients who were assumed to discontinue rivaroxaban in year 2 or for those patients who were assumed to discontinue clopidogrel or rivaroxaban treatment after an acute coronary syndrome event.
The ERG commented that it was not clear in the submission how the patients who continued rivaroxaban treatment after 1 year were selected from the rest of the patient population. The ERG stated that it was unknown whether the basecase parameters for the change in efficacy and costs represent patient discontinuation in the second year of treatment.
The ERG had concerns with the methodology used by the company to calculate the utility values for patients who had a stroke. The ERG stated that it was unclear why the values from Ara and Brazier were appropriate to calculate the improvement in healthrelated quality of life of patients who experienced a stroke, but not considered appropriate to be used as the utility values in the economic model.
The ERG had concerns about how the improvement in utility values over time was modelled in the multiple event states. If a hypothetical patient transitioned into the multiple event states from a single event state, their utility in the multiple event state could be understated, because improvement in utility after the first event had been ignored. The ERG stated that that this problem was again related to the inability of the model to distinguish when events had occurred. The ERG noted that this was not the only assumption that the company could have made to calculate the utility value in the multiple event states. It could have assumed that the lowest utility value of the 2 events applied to the patients or, if the model could track the chronicity of events, it could have assumed that the utility of the most recent event applied.
The ERG expressed concerns about the appropriateness of the methods used to model the costs of rivaroxaban, clopidogrel and aspirin and the efficacy data (shape and scale parameters of the Weibull curve) in the probabilistic sensitivity analysis. The ERG recalculated the probabilistic sensitivity analysis and found that the results were generally more favourable to rivaroxaban, producing more incremental QALYs at a lower incremental cost.
The ERG commented that there were a number of key parameters that could not be adjusted within the model, which may have changed the ICER to a greater extent. These included: amendments to the hazard ratio for fatal bleeds; using pooled efficacy data rather than the 2.5 mg rivaroxaban twicedaily dose alone; and adjusting for the possibility of informative bias.
The ERG conducted an exploratory probabilistic sensitivity analysis in which published levels of uncertainty around the utility value estimates and the reference costs, rather than an arbitrary range, were taken into account. The resulting probabilistic ICER was 6150 per QALY gained for rivaroxaban plus clopidogrel plus aspirin or rivaroxaban plus aspirin, compared with clopidogrel plus aspirin or aspirin alone. The ERG noted that its probabilistic ICER was similar to the company's deterministic ICER.
The ERG addressed its concerns about informative censoring (see section 3.33) by conducting a 'crude' exploratory sensitivity analysis, to explore the effects on the ICER of increasing the number of patients who experienced a fatal bleeding event with rivaroxaban (assuming that the event occurred immediately on taking rivaroxaban). The ERG considered a range of additional fatal bleeding events ranging from no additional fatal bleeding events (company's base case) to 20 additional bleeding events. Because there were 21 fatal bleeding events in the combined rivaroxaban treatment arms of the total population in ATLASACS 2TIMI 51, the ERG considered that 20 additional fatal bleeding events was an unfavourable scenario for the rivaroxaban 2.5 mg twicedaily dose. The result of the ERG's exploratory analysis showed that even if rivaroxaban 2.5 mg twice a day caused an additional 20 fatal bleeding events compared with the event rate observed in the trial, the ICER was not estimated to be greater than 10,000 per QALY gained.
The ERG also undertook a series of exploratory scenario analyses. When the following changes to the model were implemented, the ERG's preferred deterministic basecase ICER was 5622 per QALY gained (compared with the company's deterministic basecase ICER of 6203 per QALY gained):
The transition probabilities were estimated from the trial data rather than using the Weibull curves.
The treatment duration of rivaroxaban was limited to 1 year.
Ageadjusted utility values for the whole population from Ara and Brazier's formula were used to adjust the noevent health state.
Only 1 cost was applied to the multiple event states. Where there were 2 different costs added together in the company's base case, the maximum of the 2 costs was applied.
No improvement over time in the stroke utility was modelled.
The relative risk of having a subsequent event, given that an event had already occurred, was amended.
The lifeyears gained matrix and the costs were adjusted for the 12week cycle length in the observation period.
Full details of all the evidence are available.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rivaroxaban, having considered evidence on the nature of acute coronary syndrome and the value placed on the benefits of rivaroxaban by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee discussed the clinical management of acute coronary syndrome in England. The Committee understood that treatment options for people with ST segment elevation myocardial infarction (STEMI) include percutaneous coronary intervention followed by dual antiplatelet therapy, prasugrel in combination with aspirin (for people who have had percutaneous coronary intervention or in whom it is planned), ticagrelor in combination with lowdose aspirin, or clopidogrel in combination with lowdose aspirin. It also understood that people with nonST segment elevation myocardial infarction (NSTEMI) are offered treatments depending on their Global Registry of Acute Coronary Events (GRACE) or thrombolysis in myocardial infarction (TIMI) score and that these include a range of options from aspirin alone to percutaneous coronary intervention, depending on the risk of future events. The Committee heard from the clinical experts that ticagrelor and prasugrel have potential advantages over clopidogrel because of their faster antiplatelet action, although they are associated with higher bleeding risk. The Committee also heard from the clinical experts that the use of clopidogrel in clinical practice was generally decreasing as uptake of the newer agents increased, but that there was variation in practice with different centres often having their own local protocols for the treatment of acute coronary syndrome. The Committee heard from the clinical experts that because of its different mechanism of action, rivaroxaban could be a useful additional treatment option for some patients receiving clopidogrel plus aspirin or aspirin alone, although it was not possible to identify a particular subgroup of patients for whom it would be most suitable. However, the clinical experts highlighted that there is some uncertainty as to when and how it would be best incorporated into the treatment pathway. They explained that the mean time to start rivaroxaban in ATLASACS 2TIMI 51 was 4.6 days, but the majority of patients in England have been discharged from hospital by then. The clinical experts further explained that if rivaroxaban was started in secondary care this could result in patients staying in hospital longer, which would not happen if it was started in primary care. The Committee heard from its GP members that, after an acute coronary syndrome event, patients would usually be seen by their GP within 1 week of being discharged from hospital. The Committee considered that a discharge summary which is sent to the patient's GP at the time of discharge would give sufficient information for the GP to start treatment with rivaroxaban. The Committee recognised that rivaroxaban may be a useful additional treatment option for selected patients and noted that in the trial it was started between 17 days after acute coronary syndrome, but acknowledged that its introduction might have an effect on existing patient pathways.
The Committee discussed the clinical need for treatment in people with acute coronary syndrome. The Committee heard that the symptoms of acute coronary syndrome vary according to the type and severity of the disease. It was highlighted that common symptoms of acute coronary syndrome are chest pain, breathlessness and anxiety, and that the experience is painful and frightening. It was also highlighted that acute coronary syndrome may have a negative impact on the quality of life of the person and their family, as a result of worries over their future health and capability. The Committee heard from the patient expert about the importance of having timely diagnosis and effective treatments available for acute coronary syndrome. The Committee also heard that people were generally prepared to accept a certain risk of bleeding associated with antiplatelet therapy or anticoagulant treatment such as rivaroxaban if the treatment lowered their risk of further cardiovascular events sufficiently, but the patient expert stressed the need for efficient symptom management with regular reviews. The Committee acknowledged the impact on patients and families of the symptoms of acute coronary syndrome and the increased risk of further events that followed it. The Committee concluded that an additional treatment to reduce the risk of further cardiovascular events would be useful, but that the additional bleeding risk should be taken into account for any individual when considering starting treatment.

# Clinical effectiveness
The Committee considered the clinicaleffectiveness data from the ATLASACS 2TIMI 51 trial comparing rivaroxaban in combination with aspirin plus clopidogrel or aspirin alone against aspirin plus clopidogrel or aspirin alone. It noted that this formed the basis of the clinicaleffectiveness evidence in the company's submission. The Committee considered that the ATLASACS 2TIMI 51 trial was of good quality but noted that a key issue highlighted by the ERG was the generalisability of the results to people diagnosed with acute coronary syndrome in England. The Committee noted that people with acute coronary syndrome in clinical practice are usually older than those patients who were recruited to ATLASACS 2TIMI 51. The Committee also noted that patients in the trial could be considered a relatively lowrisk population because they had little comorbidity, lower than usual use of percutaneous coronary intervention and included a relatively small proportion of people aged over 75 years or with impaired renal function. The Committee heard from the clinical experts that the average age difference between the trial population and patients seen in clinical practice was not likely to be clinically significant and that patients recruited to ATLASACS 2TIMI 51 were similar in terms of baseline characteristics to those recruited to other trials in acute coronary syndrome. The Committee was persuaded that the issue of generalisability was similar across all trials in this condition, and concluded that the results of ATLASACS 2TIMI 51 were relevant to routine clinical practice.
The Committee considered the results of the ATLASACS 2TIMI 51 trial. The Committee noted that the company had presented clinicaleffectiveness results for the overall trial population and also for a post hoc subgroup analysis of patients with elevated cardiac biomarkers (STEMI and NSTEMI) and no history of a stroke or TIA (80% of the total trial population). The Committee was aware from the company that this post hoc subgroup analysis was carried out at the request of the European Medicines Agency (EMA). The Committee noted that this post hoc subgroup analysis (referred to as the licensed population by the company) provided efficacy results that tended to be more favourable to rivaroxaban than the results from the overall trial population. However, it acknowledged that these differences were unlikely to be sufficiently large as to have an impact on the overall decision as to whether rivaroxaban was clinically and cost effective in its licensed indication.
The Committee discussed the numerical inconsistencies between the 2 dose groups in the trial (2.5 mg twice daily and 5 mg twice daily) for the individual components of the composite efficacy end point that had been identified by the ERG (see section 3.31). It was aware that for some individual outcomes the 2.5 mg twicedaily dose appeared to have a greater efficacy than the 5 mg twicedaily dose. The ERG considered that it was unlikely that the 2.5 mg twicedaily dose would be more clinically effective than 5 mg twice daily and suggested that the results from both doses combined were more plausible than those of the individual doses. The Committee heard from the company that the summary of product characteristics for rivaroxaban specified the 2.5 mg twicedaily dose and that the EMA had based its decision for this dose based on the balance of risk and benefits of the 2.5 mg twicedaily dose, compared with those of the 5 mg twicedaily dose. The Committee noted the lower bleeding risk associated with the 2.5 mg twicedaily dose compared with the 5 mg twicedaily dose. While it acknowledged that there were numerical inconsistencies in the efficacy results between the 2.5 mg and 5 mg twicedaily arms, it concluded that the efficacy data from the 2.5 mg twicedaily rivaroxaban arm were the most relevant for decisionmaking because it is the licensed dose of rivaroxaban for this indication.
The Committee discussed the high discontinuation rates from the trial (see section 3.10). The Committee was aware that 15.5% of the total randomised population prematurely discontinued from the trial and that the discontinuation rate was higher in ATLASACS 2TIMI 51 than in other similar randomised trials in patients with acute coronary syndrome. The Committee heard from the clinical experts that high discontinuation rates were common in trials in patients with acute coronary syndrome and that this is replicated in the adherence rates seen in clinical practice, because current treatment protocols mean that people who had acute coronary syndrome are already taking 5 separate medications. The clinical experts highlighted that clinicians are mindful of the effect on patient adherence of adding any additional treatments to those already prescribed. The Committee acknowledged that the discontinuation rates in ATLASACS 2TIMI 51 were high but that this was a concern for other trials carried out in people with acute coronary syndrome, and that it was also an issue that is seen in clinical practice.
The Committee discussed the missing data from people who withdrew or were lost from the trial (see section 3.10). The Committee was aware of the ERG's concerns that missing data may result in informative censoring (that is, patients who drop out, and whose data are therefore censored, have different outcomes to those who remain in the trial) leading to bias. The Committee was aware from the company that extensive efforts had been made to trace trial participants, to clarify reasons for withdrawal and to find out if they had died. The company stated that this had reduced the proportion of patients for whom vital status was unknown to 3.2% of people who had been recruited to the trial. The company explained that it had been unable to obtain the data for the remaining participants for whom vital status was unknown, because of restrictions imposed by the countries in which the people lived. The clinical experts acknowledged that this was a problem for many multinational trials in people with acute coronary syndrome but expressed their concern about the level of missing data, given the bleeding risks associated with rivaroxaban added to antiplatelet therapy. The Committee understood that the EMA's assessment report had not discussed this issue in detail but acknowledged the clinical experts' concerns regarding the missing data. The Committee concluded that the missing data from those who withdrew or were lost from the trial remained of concern, but the magnitude of any bias introduced by informative censoring was unknown.
The Committee considered the effectiveness of rivaroxaban in combination with aspirin plus clopidogrel or with aspirin alone, compared with aspirin plus clopidogrel or aspirin alone in the licensed population (that is, people with elevated cardiac biomarkers and without a history of stroke or TIA). The Committee noted that rivaroxaban 2.5 mg twice daily in combination with aspirin plus clopidogrel or with aspirin alone reduced the composite risk of myocardial infarction, stroke and death from cardiovascular causes by 20% compared with aspirin plus clopidogrel or with aspirin alone (see table 2: ALL strata, 2.5 mg twicedaily rivaroxaban dose). The Committee understood that this composite reduction in risk was driven by reductions in cardiovascular death and myocardial infarction. The Committee concluded that rivaroxaban 2.5 mg twice daily in combination with aspirin plus clopidogrel or with aspirin alone was more effective than aspirin plus clopidogrel or aspirin alone for preventing myocardial infarction and death from cardiovascular causes in people with acute coronary syndrome and elevated cardiac biomarkers.
The Committee discussed the concerns about safety and adverse effects associated with rivaroxaban. The Committee was aware that the results for the licensed population showed that there was a dosedependent increase in the rate of nonCABG TIMI major bleeds (major bleeding assessed using 'Thrombolysis in Myocardial Infarction' criteria not related to coronaryartery bypass grafting) for rivaroxaban added to antiplatelet therapy compared with antiplatelet therapy alone. It noted that in the 2.5 mg rivaroxaban twicedaily arm of the ATLASACS 2TIMI 51 study, there was a 3 times greater risk of nonCABG TIMI major bleeding with rivaroxaban in combination with aspirin plus clopidogrel or aspirin compared with these antiplatelet therapies alone. The Committee acknowledged that all antiplatelet and anticoagulant treatments have an associated risk of bleeding but noted the comments it had heard from the clinical and patient experts that the risk of bleeding was a key consideration when deciding on a particular treatment. The Committee was aware that no data had been presented by the company or other stakeholders comparing the risk of bleeding with rivaroxaban in combination with antiplatelet agents compared with other treatment regimens with antiplatelet agents such as ticagrelor and prasugrel, because these were not included in the final scope. The Committee was therefore unable to compare the effectiveness and safety profile of a treatment strategy in which rivaroxaban is added to clopidogrel and aspirin at least 24 hours after admission to hospital, with strategies in which ticagrelor and prasugrel are added to aspirin from the start of treatment. The Committee concluded that treatment with rivaroxaban resulted in more nonCABGrelated major bleeding than aspirin plus clopidogrel or aspirin alone, but also recognised the particular importance of the effects of rivaroxaban in reducing the risk of myocardial infarction and death from cardiovascular causes. The Committee also concluded that clinicians should undertake a careful assessment of whether the bleeding risk is outweighed by the benefits of rivaroxaban in preventing further ischaemic events for individual patients when deciding whether to start or continue treatment. The Committee noted that the summary of product characteristics states that treatment should be regularly evaluated and, in particular, that careful consideration should be given to whether treatment is continued beyond 12 months because experience of treatment with rivaroxaban up to 24 months is limited.

# Cost effectiveness
The Committee considered the company's economic model and the review and exploratory sensitivity analyses performed by the ERG. The Committee noted that the ICERs presented by the company in its basecase analysis and in the ERG's exploratory sensitivity analyses were all lower than 10,000 per QALY gained. The Committee was aware of the ERG's concerns about the structure of the company's economic model and, in particular, that the model is relatively inflexible. This meant that the ERG could not carry out all the exploratory analyses that it deemed potentially relevant. These included amendments to the hazard ratio for fatal bleeds and adjusting for the possibility of informative censoring. The Committee noted that, to explore its concerns about informative censoring, the ERG had undertaken a 'crude' exploratory analysis to explore the effects on the ICER of increasing the number of patients who experienced a fatal bleed with rivaroxaban. The Committee was aware that the analysis showed that even if rivaroxaban 2.5 mg twice daily caused as many as 20 more fatal bleeds than observed in the trial, the estimated ICER remained below 10,000 per QALY gained. The Committee concluded that despite the inflexibility of the company's economic model and the resulting constraints on the ERG's ability to undertake further exploratory analyses, the ICERs presented were a suitable basis for decisionmaking on the cost effectiveness of rivaroxaban in addition to clopidogrel plus aspirin or with aspirin alone.
The Committee considered the ICER for the 2.5 mg dose of rivaroxaban in combination with aspirin plus clopidogrel or with aspirin alone, compared with aspirin plus clopidogrel or aspirin alone in patients with acute coronary syndrome with elevated cardiac biomarkers (STEMI or NSTEMI) and no history of stroke or TIA. The Committee noted that the company's basecase ICER was 6203 per QALY gained, and the ERG's preferred basecase estimate was 5622 per QALY gained. It accepted that there is uncertainty about the validity of the results based on ATLASACS 2TIMI 51 because of the risk of bias resulting from missing data and informative censoring. However, the Committee considered that the ICERs presented were all within the range that could be considered cost effective and that the results of the ERG's exploratory sensitivity and scenario analyses suggested that the ICER was unlikely to increase to the extent that it would become unacceptable. It concluded that rivaroxaban can be considered a costeffective use of NHS resources.
The Committee was aware that there is an increased risk of bleeding when rivaroxaban is added to aspirin or aspirin plus clopidogrel and it would be important for clinicians to carefully assess a person's individual bleeding risk and for patients to have an informed discussion with their clinician about the potential risks and benefits before starting treatment with rivaroxaban. The Committee noted that the summary of product characteristics states that after initiation, there should be regular assessment of the risks and benefits of continuing treatment with rivaroxaban and extension of treatment beyond 12 months should be done on an individual patient basis as experience up to 24 months is limited. The Committee concluded that it was appropriate that a formal assessment of whether to continue treatment should be made no later than 12 months after starting rivaroxaban.

# Summary of Appraisal Committee's key conclusions
TA335
Appraisal title: Rivaroxaban for preventing adverse outcomes in patients after the acute management of acute coronary syndrome
Section
Key conclusion
Rivaroxaban is recommended as an option within its marketing authorisation, in combination with aspirin plus clopidogrel or aspirin alone, for preventing atherothrombotic events in people who have had an acute coronary syndrome with elevated cardiac biomarkers.
Clinicians should carefully assess the person's risk of bleeding before treatment with rivaroxaban is started. The decision to start treatment should be made after an informed discussion between the clinician and the patient about the benefits and risks of rivaroxaban in combination with aspirin plus clopidogrel or with aspirin alone, compared with aspirin plus clopidogrel or aspirin alone.
A decision on continuation of treatment should be taken no later than 12 months after starting treatment. Clinicians should regularly reassess the relative benefits and risks of continuing treatment with rivaroxaban and discuss them with the patient.
The Committee concluded that rivaroxaban 2.5 mg twice daily in combination with aspirin plus clopidogrel or with aspirin alone was more effective than aspirin plus clopidogrel or aspirin alone for preventing myocardial infarction and death from cardiovascular causes in people with acute coronary syndrome and elevated cardiac biomarkers.
The Committee concluded that treatment with rivaroxaban resulted in more noncoronary artery bypass grafting (nonCABG) major bleeding than aspirin plus clopidogrel or aspirin alone, but also recognised the particular importance of the effects of rivaroxaban in reducing the risk of myocardial infarction and death from cardiovascular causes. The Committee also concluded that clinicians should undertake a careful assessment of whether the bleeding risk is outweighed by the benefits of rivaroxaban in preventing further ischaemic events for individual patients when deciding whether to start or continue treatment. The Committee noted that the summary of product characteristics states that treatment should be regularly evaluated and, in particular, careful consideration should be given to whether treatment is continued beyond 12 months because experience of treatment with rivaroxaban up to 24 months is limited.
The Committee considered that the ICERs presented were all within the range that could be considered cost effective and that the results of the ERG's exploratory sensitivity and scenario analyses suggested that the ICER was unlikely to increase to the extent that it would become unacceptable. It concluded that rivaroxaban can be considered a cost effective use of NHS resources.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee understood that, in England, treatment options for people with ST segment elevation myocardial infarction (STEMI) include percutaneous coronary intervention followed by dual antiplatelet therapy, prasugrel in combination with aspirin (for those who have undergone percutaneous coronary intervention or in whom it is planned), ticagrelor in combination with lowdose aspirin, or clopidogrel in combination with lowdose aspirin. The Committee heard from the clinical experts that ticagrelor and prasugrel have potential advantages over clopidogrel because of their faster antiplatelet action, although they are associated with higher bleeding risk.
The Committee heard from the patient expert about the importance of having timely diagnosis and effective treatments available for acute coronary syndrome. The Committee also heard that people were generally prepared to accept a certain risk of bleeding associated with antiplatelet therapy or anticoagulant treatment such as rivaroxaban if the treatment lowered their risk of further cardiovascular events sufficiently, but the patient expert stressed the need for efficient symptom management with regular reviews.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on healthrelated benefits?
The Committee heard from the clinical experts that because of its different mechanism of action, rivaroxaban could be a useful additional treatment option for some patients having clopidogrel plus aspirin or aspirin alone, although it was not possible to identify a particular subgroup of patients for whom it would be most suitable.
What is the position of the treatment in the pathway of care for the condition?
The Committee heard from the clinical experts that there is some uncertainty as to when and how rivaroxaban would be best incorporated into the treatment pathway.
The clinical experts explained that the mean time to start rivaroxaban in ATLASACS 2TIMI 51 was 4.6 days, but the majority of patients in England have been discharged from hospital by then. The clinical experts further explained that if rivaroxaban was started in secondary care this could result in patients staying in hospital longer, which would not happen if it was started in primary care. The Committee heard from its GP members that, after an acute coronary syndrome event, patients would usually be seen by their GP within 1 week of being discharged from hospital. The Committee considered that the discharge summary which is sent to the patient's GP at the time of discharge would give sufficient information for the GP to start treatment with rivaroxaban.
Adverse reactions
The Committee was aware that treatment with rivaroxaban resulted in more nonCABGrelated major bleeding than aspirin plus clopidogrel or aspirin alone.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee considered the clinicaleffectiveness data from the ATLASACS 2TIMI 51 trial comparing rivaroxaban in combination with aspirin plus clopidogrel or aspirin alone against aspirin plus clopidogrel or aspirin alone. It noted that this formed the basis of the clinicaleffectiveness evidence in the company's submission. The Committee considered that the ATLASACS 2TIMI 51 trial was of good quality.
Relevance to general clinical practice in the NHS
The Committee concluded that the results of the ATLASACS 2TIMI 51 trial were broadly relevant to routine clinical practice.
Uncertainties generated by the evidence
The Committee discussed the missing data from people who withdrew or were lost from the trial. The Committee was aware of the ERG's concerns that missing data may result in informative censoring (that is, the patients who drop out, and whose data are therefore censored, have different outcomes to those who remain in the trial) leading to bias. The Committee was aware from the company that extensive efforts had been made to trace trial participants, to clarify reasons for withdrawal and to find out if they had died. The company stated that this had reduced the proportion of patients for whom vital status was unknown to 3.2% of people who were recruited to the trial.
The Committee concluded that the missing data from those who withdrew or were lost from the trial remained of concern, but the magnitude of any bias introduced by informative censoring was unknown.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
No subgroups were identified.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that rivaroxaban 2.5 mg twice daily in combination with aspirin plus clopidogrel or with aspirin alone was more effective than aspirin plus clopidogrel or aspirin alone for preventing myocardial infarction and death from cardiovascular causes in people with acute coronary syndrome and elevated cardiac biomarkers.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee considered the company's economic model and the review and exploratory sensitivity analyses performed by the ERG.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee was aware of the ERG's concerns about the structure of the company's economic model and, in particular, that the model is relatively inflexible. This meant that the ERG could not carry out all the exploratory analyses that it deemed potentially relevant. These included amendments to the hazard ratio for fatal bleeds and adjusting for the possibility of informative censoring.
Incorporation of healthrelated quality of life benefits and utility values
Have any potential significant and substantial healthrelated benefits been identified that were not included in the economic model, and how have they been considered?
Not applicable. The Committee did not draw any specific conclusions about the healthrelated quality of life benefits and utility values.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee did not identify specific groups of people for whom the technology is particularly cost effective.
What are the key drivers of cost effectiveness?
Not applicable. The Committee did not draw any specific conclusions about the key drivers of cost effectiveness.
Most likely costeffectiveness estimate (given as an ICER)
The Committee noted that the company's base case ICER was 6203 per QALY gained, and the ERG's preferred base case estimate was 5622 per QALY gained. It accepted that there is uncertainty about the validity of the results based on ATLASACS 2TIMI 51 because of the risk of bias resulting from missing data and informative censoring. However, the Committee considered that the ICERs presented were all within the range that could be considered cost effective and that the results of the ERG's exploratory sensitivity and scenario analyses suggested that the ICER was unlikely to increase the ICER to the extent that it would become unacceptable.
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable.
Endoflife considerations
Not applicable.
Equalities considerations and social value judgements
No equality issues relevant to the Committee's recommendations were raised.

# Review of guidance
The guidance on this technology will be considered for review 3 years after publication of the guidance. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveMarch 2015# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS.
This guidance was developed using the NICE single technology appraisal process.
It has been incorporated into the NICE Pathway on myocardial infarction: rehabilitation and preventing further cardiovascular disease along with other related guidance and products.
We have produced information for the public explaining this guidance. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
NICE produces guidance, standards and information on commissioning and providing highquality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.
ISBN: 9781473110922