Rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rivaroxaban, having considered evidence on the nature of stroke and systemic embolism and the value placed on the benefits of rivaroxaban by people with atrial fibrillation, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Committee was aware that the main concerns for people with atrial fibrillation were fear of having a stroke and anxiety about the difficulty of keeping the INR within the therapeutic range. The Committee heard from the clinical specialists, patient experts and from comments received during consultation that the current standard treatment for preventing stroke and systemic embolism in people with atrial fibrillation is warfarin, and that because aspirin is less effective it is used only in people for whom warfarin is unsuitable. The Committee also heard that warfarin, although an effective treatment, it is associated with a number of problems. The Committee was aware from the patient expert and from comments received during consultation that taking warfarin adversely affects quality of life. This is because people taking warfarin often worry about their level of INR control and they might find regular GP and hospital visits disruptive and inconvenient. The Committee heard from the clinical specialists that a substantial proportion of people taking warfarin have poorly controlled INR and are often not within the target therapeutic range at any one time. In particular, older people with atrial fibrillation are more likely to have poorly controlled INR because of comorbidities. The clinical specialists also explained that the need for regular monitoring and dose adjustments, occasionally involving complicated regimens such as different doses on alternate days, can cause difficulties with adherence to treatment. The Committee recognised the potential benefits of alternatives such as rivaroxaban for people with atrial fibrillation, including the positive effect on quality of life of removing the restrictions and difficulties associated with taking warfarin.

4.3 The Committee considered the clinical-effectiveness data from the ROCKET-AF trial comparing rivaroxaban with warfarin. It noted that this study was the basis of the clinical-effectiveness evidence in the manufacturer's submission. The Committee noted that the efficacy analysis in the manufacturer's submission had been undertaken on three different populations in the ROCKET-AF trial, the intention-to-treat set (all randomised patients), the safety-on-treatment set (all intention-to-treat patients who had taken at least one dose of study drug and were followed for events) and the per-protocol set (all intention-to-treat patients excluding those who have major pre-defined protocol deviations). The Committee noted that the manufacturer had presented data from the safety-on-treatment population for its primary analyses. The Committee heard from the clinical specialists that using a trial intention-to-treat population was considered to be the gold standard for estimating clinical effectiveness in a superiority trial, but the primary objective of ROCKET-AF was to establish non-inferiority of rivaroxaban compared with warfarin so the primary analysis was different. The Committee noted the comments received during consultation that suggested that it would be more appropriate to consider the intention-to-treat population rather than the safety-on-treatment population. The Committee reconsidered which of the two study populations was the most appropriate. The Committee noted that the intention-to-treat population included people who had either had no treatment or switched treatment during the trial, and agreed that the estimates derived from the safety-on-treatment population of the ROCKET-AF trial provided an adequate basis for evaluating clinical effectiveness.

4.4 The Committee noted that a key uncertainty highlighted by the ERG was the generalisability of the results of ROCKET-AF to people diagnosed with atrial fibrillation in the NHS. The Committee noted that the mean time in therapeutic range for the INR range of 2.0–3.0 for warfarin was 55% for the safety-on-treatment population in the ROCKET-AF trial. The clinical specialists confirmed this could be considered to be around the lower end of the level of control that would be expected in UK clinical practice, but there is considerable variation between different centres and also between different settings, depending on the patient group. The Committee noted that the ROCKET-AF trial had been undertaken in a number of countries, which did not all achieve similar levels of time in therapeutic range. The majority (66.5%) of the participants were recruited from centres in eastern Europe, Latin America and Asia, and in these centres the proportion of time in therapeutic range was lower than in the centres in North America and western Europe. The Committee was concerned that the effectiveness of warfarin could be underestimated if the proportion of time in therapeutic range was low, and that the UK context might be better reflected by results from centres where the time in therapeutic range in the warfarin arm more closely matched the usual levels in the UK. The Committee concluded that the trial results were broadly applicable to a UK setting, but for those already taking warfarin the current level of INR control should be taken into account in any decision to switch to rivaroxaban.

4.5 The Committee also noted that patients in the ROCKET-AF trial had a mean CHADS₂ score of 3.47, and that an inclusion criterion of the trial was a baseline CHADS₂ score of 2 or more. The scope specified that the appraisal population would be people with a medium to high risk of stroke. The clinical specialists confirmed that people with a CHADS₂ score of 3 or more would be at high risk of stroke and that this population was typical of people seen in secondary care. However, this did not necessarily represent people with atrial fibrillation treated in primary care, who tended to have a lower risk of stroke. The Committee heard that people with atrial fibrillation treated with warfarin in primary care often have a CHADS₂ score of less than 2 and that it is estimated that between 20 and 75% of people with atrial fibrillation and a CHADS₂ score of less than 2 are prescribed warfarin in the UK. Only 0.02% of the trial population had a CHADS₂ score less than 2. The clinical specialists agreed that it was likely that although people with a CHADS₂ score of 2 or more would benefit similarly to those in the ROCKET-AF trial, this cannot be assumed for people with a CHADS₂ score of less than 2. The Committee noted the comments received during consultation that suggested that consultees and commentators had differing opinions on the generalisability of the results of ROCKET-AF to UK clinical practice. The Committee was made aware by the manufacturer that a systematic review of the literature had suggested that there does not appear to be an interaction between treatment effect and baseline CHADS₂ risk. The Committee heard from the manufacturer that rivaroxaban would be indicated for atrial fibrillation in people with one or more risk factors for stroke, which equates to a CHADS₂ score of 1 or more. The Committee noted that the European Medicines Agency had stated in the 'European public assessment report' for rivaroxaban that efficacy results were essentially consistent in important subgroups, such as different CHADS₂ scores (CHADS₂ scores 2 to 6).The Committee accepted that, given the broad spectrum of risk covered by the licensed indication for rivaroxaban, there was no plausible reason to expect that the results of ROCKET-AF would not translate to people with a lower CHADS₂ score. However the Committee was mindful of the very small number of patients recruited to the ROCKET-AF trial with a baseline CHADS₂ score of less than 2, but concluded that the results of the ROCKET-AF trial were generalisable to UK clinical practice.

4.6 The Committee discussed the safety data from the ROCKET-AF trial. It noted that analysis of the primary safety end point of all major and non-major clinically significant bleeding events showed no significant differences between rivaroxaban and warfarin. There was a significant reduction in the rate of fatal bleeds and intracranial haemorrhage with rivaroxaban compared with warfarin, but a higher rate of gastrointestinal bleeds. The Committee heard from the patient experts that intracranial bleeds were considered to be a more serious complication than gastrointestinal bleeds in clinical practice, because they were more difficult to treat and often result in permanent disability. The Committee noted that the possible uncertainty in these results related to the relatively low proportion of time in therapeutic range of 55% in the warfarin arm of the trial, but concluded that the primary safety end point showed no statistically significant difference between rivaroxaban and warfarin.

4.7 The Committee then discussed the indirect clinical-effectiveness evidence for rivaroxaban compared with dabigatran etexilate and aspirin. The Committee noted that the population in the study comparing dabigatran etexilate with warfarin (RE-LY) had a lower risk of stroke (mean CHADS₂ score 2.1) than the population in the ROCKET-AF trial (mean CHADS₂ score of 3.47). The Committee noted that the manufacturer's interpretation of its network meta-analysis was that there was no significant difference between rivaroxaban and dabigatran etexilate for any outcome. The Committee noted the ERG's concerns about the validity of the manufacturer's network meta-analysis because of the clinical heterogeneity of the included trials, and the different levels of time in therapeutic range in the warfarin arms of the rivaroxaban and dabigatran etexilate trials. The Committee also noted that both the manufacturer's and ERG's network meta-analyses contained wide confidence intervals, and therefore the resulting efficacy point estimates were subject to considerable uncertainty. The Committee noted the comments received during consultation suggesting that the Committee should reconsider the value of the network meta-analysis. The Committee also noted the additional indirect comparison submitted by the manufacturer during consultation comparing rivaroxaban with aspirin. The Committee reconsidered the data from the manufacturer's and ERG's network meta-analyses and considered the manufacturer's additional indirect comparison comparing rivaroxaban with aspirin. The Committee concluded that it would not consider further the clinical effectiveness of rivaroxaban compared with aspirin or dabigatran etexilate.

4.8 The Committee considered the manufacturer's updated base-case analysis for rivaroxaban compared with warfarin for the licensed population. The Committee noted the ERG's comments on the manufacturer's updated cost-effectiveness analyses and the ERG's revised base-case analysis. The Committee noted that the manufacturer presented an ICER of £2870 per QALY gained (see section 3.25) and the ERG presented an ICER of £29,500 per QALY gained (see section 3.29). The Committee was made aware by both the manufacturer and the ERG that the difference in the ICERs resulted from two main factors. One was the manufacturer's inclusion in its updated analysis of a disutility value associated with warfarin treatment. The second was the different costs included by the manufacturer and ERG for warfarin monitoring (£580 and £242 respectively).

4.9 The Committee discussed the disutility values used in the manufacturer's updated economic analyses. It noted that the manufacturer had used a small study of 57 patients to justify including a disutility associated with warfarin. The Committee acknowledged that comments received during consultation implied that warfarin was associated with disadvantages. However the Committee was mindful that the manufacturer had assumed that there was no disutility associated with rivaroxaban and had not provided any rationale for its exclusion. The Committee noted the comments from the ERG and consultees and commentators suggesting that there could be some disutility associated with newer anticoagulation therapy, including concerns about non-reversibility in the case of bleeding. However, the Committee noted that no specific evidence relating to disutility associated with anticoagulation therapy other than warfarin had been submitted by any consultees and commentators or by the ERG. The Committee therefore agreed that although it was appropriate to consider that there might be a disutility associated with warfarin treatment, it was not appropriate to assume that there was no disutility associated with rivaroxaban and other anticoagulant treatments. The Committee concluded that the disutility value used in the economic model for warfarin may have resulted in a bias in the manufacturer's economic analysis in favour of rivaroxaban.

4.10 The Committee discussed the costs associated with warfarin INR monitoring. The Committee noted that the manufacturer' model assumed an average annual anticoagulant monitoring cost of £580 per person in the year that treatment is first initiated and £535 once the person is stabilised on warfarin. The clinical specialists agreed that the annual cost of anticoagulant monitoring for each person treated with warfarin was likely to be lower than the manufacturer's estimate in clinical practice, but a precise estimate could not be given because costs varied considerably between people (for example, they are higher in those with poor INR control) and between centres. The Committee was aware of the uncertainty, but in the interests of consistency had requested that the manufacturer use £242 in its economic model, in line with what it had accepted for the ongoing appraisal of dabigatran etexilate for the same indication. However, the Committee noted the comments received during consultation, which suggested that significant numbers of people have difficulties managing their INR control and could therefore visit a clinic for monitoring up to once a week, making 30 visits a year not implausible. The Committee also noted the manufacturer's comments highlighting its concerns about the plausibility of a cost of £242 per person. The Committee therefore agreed that £242 per person was likely to be a conservative estimate of annual anticoagulant monitoring for warfarin if fixed costs were fully included, and that there was uncertainty about the cost of warfarin INR monitoring in clinical practice.

4.11 The Committee considered what the most plausible ICER would be for rivaroxaban compared with warfarin. It noted the ICERs of £2870 per QALY gained presented by the manufacturer (which included disutility associated with warfarin, and warfarin monitoring costs of £580) and £29,500 per QALY gained (which excluded disutility associated with warfarin, and used warfarin monitoring costs of £242) presented by the ERG. The Committee agreed that because there could be some degree of utility decrement associated with treatment, and the estimate of annual anticoagulation monitoring costs of £242 was likely to be conservative, the ICER for rivaroxaban compared with warfarin would be no more than £29,500 per QALY gained and would lie somewhere between £2870 and £29,500 per QALY gained. The Committee therefore concluded that the most plausible ICER for the whole population eligible for rivaroxaban was within the range that could be considered a cost-effective use of NHS resources.

4.12 The Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal that needed addressing in the guidance.