Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia

The ERG considered the trials identified for evolocumab to be relevant, good-quality RCTs. It noted that the patient and disease characteristics at baseline were generally well-balanced across treatment arms. However, all 4 trials excluded patients with type 1 diabetes, or newly diagnosed or poorly controlled type 2 diabetes. The ERG questioned whether this could affect the generalisability of the trials because, in clinical practice, these patients are likely to present with co-morbid hypercholesterolaemia or mixed dyslipidaemia.

The ERG pointed out that the change in LDL‑C concentration is clinically important if it can be used as a surrogate for cardiovascular disease (CVD). Although the effect of statins on cardiovascular (CV) events is established, that of evolocumab has not been robustly shown in purposely designed clinical trials. The ERG noted that the ongoing FOURIER RCT will test whether LDL‑C is a valid surrogate for CV outcomes for evolocumab, which it considered to be a key area of uncertainty in the current evidence.

All efficacy and safety analyses were based on the modified intention-to-treat populations, that is, all patients who had at least 1 dose of study treatment. The results for the primary end points are shown in table 2 and table 3.

The company presented subgroup analyses. It stated that in all of these evolocumab, compared with placebo or ezetimibe, was consistently effective in lowering LDL‑C, with no notable differences between subgroups.

The company presented interim results from 2 ongoing, long-term, extension studies, OSLER and OSLER‑2, which compared evolocumab plus standard of care (defined according to local guidelines) with standard of care alone. Eligible patients were those who completed treatment in a 'parent' study, including the RCTs identified for evolocumab. The company stated that OSLER and OSLER‑2 showed that the effect of evolocumab continued for over 2 years. It also presented a pre-specified exploratory analysis, which combined data from OSLER and OSLER‑2 (n=4,465) on adjudicated CV events including death, myocardial infarction, unstable angina, coronary revascularisation, stroke, transient ischaemic attack, and heart failure. The rate of CV events at 1 year was 0.95% and 2.18% among patients randomised to evolocumab or standard of care respectively (hazard ratio 0.47, 95% CI 0.28 to 0.78; p=0.003).

TAUSSIG is an ongoing non-randomised, non-controlled, 5‑year extension study of evolocumab for severe familial hypercholesterolaemia. Among 142 patients with severe heterozygous-familial hypercholesterolaemia, the percent reduction from baseline in LDL‑C level at week 36 was 50.5%, with reductions ranging from 42.0% to 54.3% at earlier time points.

In addition to the data on adverse effects from the individual studies for evolocumab, the company presented integrated analyses of safety data from 6,026 patients with primary hypercholesterolaemia or mixed dyslipidaemia who had any dose of evolocumab. The key results of these analyses are summarised below:

• Overall, evolocumab had a safety profile similar to the control treatment (placebo or ezetimibe) arms, with the incidence of adverse events being 51.1% compared with 49.6%. Most adverse events were mildly to moderately severe.

• Serious adverse events occurred in 2.8% and 2.1% of patients who had evolocumab or any control treatment (placebo or ezetimibe) respectively.

• Of patients who had evolocumab, 1.9% stopped treatment because of an adverse event compared with 2.3% of those who had placebo or ezetimibe.

• The most common adverse events for evolocumab compared with placebo or ezetimibe were: nasopharyngitis (5.9% compared with 4.8%), upper respiratory tract infection (3.2% compared with 2.7%), headache (3.0% compared with 3.2%) and back pain (3.0% compared with 2.7%).

• The company stated that anti-evolocumab antibodies were infrequent, non-neutralising, and not associated with clinically relevant adverse events.

The company modelled 3 separate subpopulations:

• non-familial hypercholesterolaemia without CVD

• non-familial hypercholesterolaemia with CVD

• heterozygous-familial hypercholesterolaemia (with or without CVD).
  
  The company modelled the 2 non-familial hypercholesterolaemia populations based on the characteristics of the respective populations in LAPLACE‑2 with or without CVD. However, it only used data from the subset of patients who had an LDL‑C concentration over 2.5 mmol/litre to represent a population at high risk of CVD. For patients with heterozygous-familial hypercholesterolaemia, the company used the modified intention-to-treat population in RUTHERFORD‑2.

The intervention modelled in the base case was evolocumab 140 mg every 2 weeks; the company explored using the monthly dosage of evolocumab in scenario analyses (see section 3.48). For each population modelled, the company presented separate results for 4 treatment comparisons; 2 relevant to patients who can tolerate statins (who had atorvastatin as background therapy), and 2 relevant to those who cannot (who did not have any background lipid-lowering therapy):

• For patients who can tolerate statins:

  • evolocumab plus atorvastatin compared with ezetimibe plus atorvastatin

  • evolocumab plus ezetimibe plus atorvastatin compared with ezetimibe plus atorvastatin.

• For patients who cannot tolerate statins:

  • evolocumab compared with ezetimibe

  • evolocumab plus ezetimibe compared with ezetimibe.
    
    The company represented statins with atorvastatin because this is the statin recommended in NICE's previous guideline on cardiovascular disease for people with or without CVD (now replaced by NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification).

The company's model consisted of 24 mutually exclusive states:

• 3 acute states (in which the patient could stay for a maximum of 1 year unless the same event occurred in the next cycle)

  • acute coronary syndrome (including myocardial infarction and unstable angina)

  • ischaemic stroke

  • heart failure

• 5 chronic states

  • no CVD

  • established CVD (including patients who had a history of stable angina, transient ischaemic attack, carotid stenosis, revascularisation without a history of myocardial infarction, abdominal aortic aneurism, or peripheral vascular disease)

  • 3 post-event states

    • post-acute coronary syndrome

    • post-ischaemic stroke

    • post-heart failure

• 13 composite CVD states (formed of a combination of 2 or 3 acute and post-event states; these were used to remember the history of CV events and model the corresponding outcomes of recurring CV events)

• 3 death states: death from coronary heart disease, death from stroke and death from other causes.
  
  Patients who had CVD could have either 1 of the events modelled separately (acute coronary syndrome, ischaemic stroke or heart failure), or 1 of the events in the established CVD state. This was because the events in the established CVD state were less severe than those modelled separately, and so would be associated with lower costs and better health outcomes. The company assumed that patients who started treatment in the model had it continuously over their lifetime.

Patients entered the model in different states depending on the population to which they belonged:

• All patients with non-familial hypercholesterolaemia who did not have CVD entered the model in the no CVD state.

• Patients with non-familial hypercholesterolaemia who had CVD entered the model in one of the 3 post-event states, or the established CVD state.

• Patients with heterozygous-familial hypercholesterolaemia (with or without CVD) entered the model in one of the 3 post-CVD event states, the established CVD state, or the no CVD state.
  
  Patients who entered the model in the no CVD state stayed in this state until they had CVD (that is, acute coronary syndrome, ischaemic stroke, heart failure, or one of the events in the established CVD state), or died. After the first CV event, patients could have no further CV events and move to the corresponding post-event state, have the same event again and stay in the same acute event state, have a different acute event and move to a composite state representing the post-event state for previous events and the new event, or die. Patients in a post-event state could have the same acute event and move to the corresponding acute state or composite state (if the patient had had other CV events), a different acute event and move to the relevant composite state, or die.

To estimate the risk of CVD in the model, the company used a 3‑step approach. First, it predicted the risk of CVD before treatment in patients in LAPLACE‑2 with an LDL‑C concentration at baseline over 2.5 mmol/litre (non-familial hypercholesterolaemia), and the modified intention-to-treat population in RUTHERFORD‑2 (heterozygous-familial hypercholesterolaemia). To do so, the company used published risk equations from the Framingham Heart Study for patients without CVD, and the REACH registry for patients with CVD. Second, the company estimated calibration (adjustment) factors from an analysis of data from the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES). Third, it adjusted the predicted risks of CVD based on the Framingham and REACH registry equations using these calibration factors to reflect real‑world data (CPRD and HES data). Because there was no CV risk equation specifically for patients with heterozygous-familial hypercholesterolaemia, the company adjusted the predicted risks of CVD in this population using a rate ratio of 7.1 (relative to patients without heterozygous-familial hypercholesterolaemia) derived from a study by Benn et al. (2012).

The objective of the model was to capture the lifetime progression of CVD among adults with primary hypercholesterolaemia (heterozygous-familial and non-familial) or mixed dyslipidaemia. Because none of the clinical trials for evolocumab had data on the direct effect of evolocumab on CVD, the company used estimates from the Cholesterol Treatment Trialists' (CTT) meta-analysis to convert the surrogate outcomes measured in the trials (LDL‑C concentration) to 'real‑world' outcomes (CV events).

The company used the estimates of treatment effect on LDL‑C concentrations from the head-to-head RCTs comparing evolocumab with ezetimibe. The data on other lipid parameters were not included in the model. For patients with non-familial hypercholesterolaemia, the company used LAPLACE‑2 for the treatment comparisons relevant to patients who can tolerate statins, and GAUSS‑2 for the comparisons relevant to those who cannot (see section 3.18). To source the clinical effectiveness in patients with heterozygous-familial hypercholesterolaemia who can tolerate statins, the company used RUTHERFORD‑2 for evolocumab and LAPLACE‑2 for ezetimibe because RUTHERFORD‑2 compared evolocumab with placebo only. For patients with heterozygous-familial hypercholesterolaemia who cannot tolerate statins, the company used GAUSS‑2. The company assumed that the treatment effect in the model lasted throughout the time horizon.

To populate the base-case model with utility data, the company used the utility values informing the model developed for NICE's previous guideline on cardiovascular disease for people with or without CVD (now replaced by NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification), with some adjustments to match the states in the model:

• Established CVD: in the company's model, this state included various CV events, 1 of which was stable angina. The original utility value for stable angina was 0.808 (for both acute and post event). This was unexpectedly lower than the value for post myocardial infarction (0.880) and post unstable angina (0.880), which are considered more severe than stable angina. Because of this, the company used the utility value for the post-acute coronary syndrome state (0.880) for the established CVD state.

• Acute states: in the model, the acute coronary syndrome state included myocardial infarction and unstable angina. The original utility values for the acute events of these 2 diseases were 0.760 and 0.77 respectively. The company chose the higher utility value (0.77) for the acute coronary syndrome state. The utility values for the ischaemic stroke and heart failure were 0.63 and 0.68 respectively.

• Post-event states: the utility value was 0.88 for acute coronary syndrome, 0.63 for ischaemic stroke, and 0.68 for heart failure.

• Composite states: the company assumed the lowest utility value in the individual acute or post-event states included in that composite state.
  
  In line with NICE's previous guideline on cardiovascular disease for people with or without CVD (now replaced by NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification), the company assumed that the utility depends on age, and so it multiplied the utility values (multipliers) by age-adjusted utility values for the general population based on a study by Dolan et al. (1996). The company also gave details of a company-sponsored study that used the time trade-off method to estimate utility values for patients with CVD. It explored using utility values from this study in scenario analyses (see section 3.48).

The company's model included treatment and monitoring costs, and those associated with the model health states. The cost of evolocumab in the model included the patient access scheme discount. The company assumed that patients who started treatment with evolocumab had 1‑hour training by a nurse to self-administer the treatment at a cost of £84.00; no additional monitoring was assumed for patients having evolocumab compared with those having ezetimibe. The company equated the costs in the composite states to the highest cost in the individual states included in that state.

In its patient access scheme submission accompanying the original submission, the company presented incremental cost-effectiveness analyses for all 3 populations. The original base-case ICERs, including the patient access scheme, are shown in table 4. All of these ICERs are based on the every 2 weeks dosage of evolocumab 140 mg.

The company also presented sensitivity analyses (deterministic and probabilistic), scenario analyses, and subgroup analyses for selected populations and treatment comparisons. All the analyses presented in the company's patient access scheme submission accompanying the original submission were superseded by the company's new evidence in response to consultation (see sections 3.44 to 3.50).

At the start of treatment evolocumab is prescribed in specialist secondary care clinics, but people may move from secondary to primary care after 2 to 3 years because routine lipid management is an area of standard GP practice. This has potential implications for the proposed simple discount patient access scheme because simple discounts do not apply when drugs are prescribed by GPs using FP10 prescriptions. In response to a request from NICE, the company presented sensitivity analyses varying the proportion of patients who may move from secondary care to primary care (after which point the simple discount does not apply), and the time patients spend in secondary care before this happens.

In response to consultation on the first appraisal consultation document, in which evolocumab was not recommended for primary hypercholesterolaemia (heterozygous-familial and non-familial) or mixed dyslipidaemia, the company was permitted to submit revised cost-effectiveness analyses. These incorporated the following changes, which reflected the committee's preferred analyses in the first appraisal consultation document:

• Use of the baseline characteristics of the population in GAUSS‑2 to model patients with non-familial hypercholesterolaemia who cannot tolerate statins.

• Modelling of the heterozygous-familial hypercholesterolaemia population with or without CVD separately.

• Use of the QRISK2 assessment tool to estimate the level of CVD risk in people without CVD (non-familial or heterozygous-familial hypercholesterolaemia).

• Adjustment of the risk of CVD in the heterozygous-familial hypercholesterolaemia population using a rate ratio of 6.1 derived from Benn et al. (2012).

• Use of the equation from the Health Survey for England to inform the relationship between age and background health-related quality of life.

• Modelling of subgroups reflecting all the characteristics of the actual subgroup in clinical trials.

The company's revised base-case ICERs, including the patient access scheme, are presented in table 5. All of these ICERs are based on the every 2 weeks' dosage of evolocumab 140 mg.

The company revised its deterministic sensitivity analyses, varying the input values in the model for 1 parameter at a time. Among the most influential parameters were the treatment duration assumed in the model, the effect of reducing LDL‑C concentration on death from coronary heart disease or ischaemic stroke, and the heterozygous-familial hypercholesterolaemia calibration rate ratio.

The company revised its probabilistic sensitivity analyses, varying parameters simultaneously with values from a probability distribution. The probabilistic ICERs were slightly higher than the deterministic ones. The company reported the following probabilities of evolocumab being cost effective:

• Non-familial hypercholesterolaemia population without CVD: 0% compared with any comparator at a maximum acceptable ICER of £30,000 per QALY gained.

• Non-familial hypercholesterolaemia population with CVD: 0% compared with ezetimibe plus statin at a maximum acceptable ICER of £30,000 per QALY gained. Compared with ezetimibe alone, the probability was 5.4% when used as an add-on to ezetimibe, and 30.1% when used as an alternative to ezetimibe.

• Heterozygous-familial hypercholesterolaemia without CVD: there was a low probability of evolocumab being cost effective at a maximum acceptable ICER of £20,000 per QALY gained (less than 20%). At a maximum acceptable ICER of £30,000 per QALY gained, the probability exceeded 85% for all comparisons.

• Heterozygous-familial hypercholesterolaemia with CVD: there was a low probability of evolocumab being cost effective at a maximum acceptable ICER of £20,000 per QALY gained (less than 5%). At a maximum acceptable ICER of £30,000 per QALY gained, the probability ranged from 15% to 42% compared with ezetimibe plus statin, and from 69% to 84% compared with ezetimibe alone.

The company revised its scenario analyses, varying the input values for certain parameters. The model was most sensitive to applying alternative discount rates (0% for costs, and 0% or 6% for health effects), having evolocumab monthly (as opposed to every 2 weeks), having treatment for a shorter duration of 5 or 10 years, and using utility values from the company-sponsored time trade-off study.