Empagliflozin for treating chronic heart failure with reduced ejection fraction

3.1 Heart failure with reduced ejection fraction is a chronic condition that affects survival and quality of life. The patient experts highlighted the psychological effects of a diagnosis. They explained that breathlessness, extreme fatigue and fluid accumulation in particular can be debilitating. Clinical expert submissions to NICE confirmed that heart failure with reduced ejection fraction is associated with high rates of death and hospitalisation. They also stated that there is an unmet need for new treatment options. Current treatments aim to manage symptoms and stabilise the disease to prevent further decline in quality of life and to keep people alive longer. The clinical experts explained that, despite optimising therapies, many people still have symptoms, including breathlessness. The patient experts said that they would welcome a new treatment option, especially if it could be used early in the treatment pathway. The committee concluded that there is an unmet need for a new treatment option for symptomatic chronic heart failure with reduced ejection fraction. It also concluded that people with the condition and healthcare professionals would welcome a new treatment option.

3.2 NICE's guideline on diagnosing and managing chronic heart failure in adults recommends a range of drug treatments for newly diagnosed heart failure with reduced ejection fraction. These are separated into first-line and specialist treatments. First-line treatments include angiotensin-converting enzyme (ACE) inhibitors, or angiotensin 2 receptor blockers (ARBs) when an ACE inhibitor is not tolerated. Beta blockers can also be offered and a mineralocorticoid receptor antagonist (MRA) can be offered if appropriate and tolerated. The company's submission had suggested that empagliflozin should be positioned as an add-on to first-line treatment in people with heart failure with reduced ejection fraction who may or may not have comorbidities. The committee understood that this is narrower than the marketing authorisation, which does not specify use as an add-on treatment for heart failure with reduced ejection fraction. The clinical experts said the company's positioning was now in line with the European Society of Cardiology guidelines on the diagnosis and treatment of acute and chronic heart failure. These guidelines recommend that empagliflozin or dapagliflozin (another SGLT2 inhibitor) could be started earlier in the care pathway for heart failure with reduced ejection fraction. The committee noted this was not directly in line with NICE's technology appraisal guidance on dapagliflozin for treating chronic heart failure with reduced ejection fraction. This recommends that dapagliflozin is used after standard care is optimised. The committee noted that there are a range of treatments for heart failure with reduced ejection fraction. It concluded that empagliflozin was an appropriate treatment that should be used as an add-on to optimised standard care.

3.3 The final scope for this appraisal listed 2 comparators: individually optimised standard care without empagliflozin, and dapagliflozin as an add-on to standard care. The company stated that individually optimised standard care was the most relevant comparator. That is, people should have the most appropriate treatments used for standard care before starting treatment with empagliflozin. This was because most people with heart failure with reduced ejection fraction in England and Wales would have at least one of these treatment options. It did not consider dapagliflozin to be a relevant comparator because it considered that this was not standard care in the NHS. It cited recent market data suggesting that dapagliflozin is used by very few people with heart failure alone, and is most frequently used by people with heart failure and type 2 diabetes. The committee noted that NICE's technology appraisal guidance on dapagliflozin for treating chronic heart failure with reduced ejection fraction had only been published in February 2021 so there had been a relatively short period of time to consider uptake. The clinical experts stated uptake had increased widely since publication of the guidance and that it would now be considered as standard care. The committee considered whether empagliflozin and dapagliflozin would likely be used interchangeably in the same place in the treatment pathway for chronic heart failure with reduced ejection fraction. The clinical experts said that the European Society of Cardiology guidelines on the diagnosis and treatment of acute and chronic heart failure did not distinguish between the 2 SGLT2 inhibitors. For this reason, they would also consider that empagliflozin and dapagliflozin would be used in the same groups of people. They further noted that it would be unlikely that someone who is not eligible for treatment with dapagliflozin would be eligible for treatment with empagliflozin. This was because the technologies are considered to work in the same way. The committee concluded that dapagliflozin was the most appropriate comparator for this appraisal.

3.4 EMPEROR-Reduced was a double-blind randomised clinical trial comparing empagliflozin plus standard care with placebo plus standard care. Standard care could include medical therapy with an ACE inhibitor, an ARB, a beta blocker or an MRA. The trial included people aged at least 18 who had had a diagnosis of chronic heart failure for at least 3 months. They had moderate to severe heart failure with reduced ejection fraction. This was defined by a left ventricular ejection fraction of 40% or less based on the New York Heart Association functional class 2 to 4. The clinical experts said that the trial findings were generalisable to NHS clinical practice. However, they highlighted several differences between the population in EMPEROR-Reduced and people having treatment in the NHS:

3.5 The primary efficacy outcome in EMPEROR-Reduced was a composite of cardiovascular death and hospitalisation for heart failure. Intention-to-treat analyses showed that empagliflozin plus standard care reduced the incidence of the primary outcome by 25.0% compared with placebo plus standard care (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.65 to 0.86; p<0.0001). At a median follow up of 16 months, results showed that 19.4% of people having empagliflozin plus standard care had an event compared with 24.7% in the placebo group. The committee concluded that empagliflozin is clinically effective compared with placebo and that it reduces the risk of cardiovascular events when added to standard care.

3.6 There were no trials directly comparing empagliflozin with dapagliflozin so the company presented an indirect treatment comparison using the Bucher method. This compared the results from EMPEROR-Reduced with those from DAPA‑HF. DAPA‑HF was a phase 3 multinational double-blind randomised controlled trial. It compared dapagliflozin plus standard care with placebo plus standard care in people with stable symptoms of heart failure with reduced ejection fraction. The company supported the indirect comparison with the results from a published pooled meta-analysis reported by Zannad et al. (2020). This pooled data for dapagliflozin and empagliflozin to create class effect estimates for SGLT2 inhibitors compared with placebo. The ERG broadly agreed that the results from the meta-analyses suggested there was a statistically significant benefit with SGLT2 inhibitors compared with placebo for all outcomes. However, the ERG noted that the results of the meta-analysis were only based on 1 trial of empagliflozin and 1 trial of dapagliflozin. It therefore considered the Bucher comparison was a more appropriate method of assessing the comparative efficacy of empagliflozin compared with dapagliflozin. The results of the indirect treatment comparison suggested there was no difference between empagliflozin and dapagliflozin in any of the outcomes (all results are confidential and cannot be reported here). However, the results suggested a trend towards possible differences in cardiovascular deaths, all-cause mortality and renal function. The committee was aware that the ERG had explored this uncertainty in the cost–utility analysis (see section 3.8). The committee noted that there were some baseline differences in the Bucher indirect treatment comparison between people in EMPEROR-Reduced and DAPA‑HF. People in EMPEROR-Reduced may have had a more severe renal impairment than people in DAPA‑HF. This meant that people in EMPEROR-Reduced may have been more likely to have a hospitalisation for heart failure or mortality event compared with those in DAPA‑HF. The committee acknowledged the limitations of the comparison but agreed it was appropriate for decision making. The committee concluded that the results of the Bucher indirect treatment comparison showed that the clinical outcomes between empagliflozin and dapagliflozin are similar.

3.7 The company modelled cost effectiveness using a state transition model with 5 states (4 based on symptom severity plus 1 for death). It captured disease severity using the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS). This is a disease-specific measure of quality of life. People transitioned through quartiles based on KCCQ‑CSS (0 to 100, with high scores indicating lower symptom burden), and a specific utility and cost associated with each state. The committee considered whether the KCCQ is an appropriate measure to capture quality-of-life outcomes. It noted that there may be some inconsistencies in how the size of effect translates from trial data to modelled quality-of-life effects. The clinical experts explained that the KCCQ is a well-validated comprehensive quality-of-life and symptom questionnaire for heart failure. The ERG stated that it was satisfied with the company's choice of KCCQ‑CSS states in the model. The committee concluded that the company's model structure was appropriate for decision making.

3.8 The company considered that a cost-comparison was the most appropriate way to estimate the cost effectiveness of empagliflozin compared with dapagliflozin. This was based on an assumption of equivalent effectiveness between empagliflozin and dapagliflozin. It noted that both drugs had the same list price, dosing frequency and method of administration, and that available evidence suggested the treatments were clinically equivalent. The ERG suggested that a cost–utility analysis may have been more appropriate. This was because the company's assumption of equal effectiveness was based on only 2 trials and ignored potential uncertainty (see section 3.6). After technical engagement, the company provided a cost–utility analysis to help with decision making. However, it argued that this type of analysis would amplify any uncertainty in the results of the indirect treatment comparison. The company's base-case cost–utility analysis assumed there was no survival benefit with empagliflozin over dapagliflozin. However, it assumed that taking empagliflozin would lead to improvements in renal function and reduced hospitalisations for heart failure. This was based on the results of the Bucher indirect treatment comparison (see section 3.6). The company's probabilistic and deterministic cost-effectiveness estimates suggested that empagliflozin dominated dapagliflozin (meaning it was less costly and at least equally effective). The ERG did additional scenario analyses to show the effect of adding the different outcomes included in the Bucher indirect treatment comparison. These scenarios included the following assumptions:

3.9 The committee recalled that people with heart failure with reduced ejection fraction have a poor prognosis and that there is an unmet need for treatment options (see section 3.1). It noted that empagliflozin is not the first drug of its class to gain regulatory approval for use in heart failure. So, it could not be considered a step-change in treatment. However, the committee concluded that it could be considered a relevant addition to current treatments and increase clinical choice.

3.10 The committee noted that the meta-analysis by Zannad et al. (2020; see section 3.6) suggested that SGLT2 inhibitors were most effective in people with a black or Asian family background. It noted that EMPEROR-Reduced mainly included people with a white family background. The committee noted that neither EMPEROR-Reduced or DAPA‑HF was powered to show difference between subgroups of different ages or people from a different family background. The clinical experts said that there is no reason to restrict empagliflozin use in adults based on age or family background. The committee noted that its recommendations applied to all people regardless of family background. It recognised that there were no ongoing clinical trials or data collection to validate the possibility of differences in treatment effect because of family background. But it considered that there may be the potential to explore this issue further in future research.

3.11 NICE's guideline on chronic heart failure in adults: diagnosis and management recommends that a specialist heart failure multidisciplinary team should work in collaboration with the primary care team to start new medicines that need specialist supervision. The committee noted that people taking empagliflozin for heart failure who also have diabetes might need adjustments in their diabetes medication for safety reasons because of an increased risk of ketoacidosis. The committee considered that risk factors should be identified, and some increased monitoring may be needed for treating heart failure with empagliflozin. So, it considered that a heart failure specialist was the most appropriate clinician to advise on starting treatment. The committee also noted that the summary of product characteristics states an assessment of renal function is recommended before starting empagliflozin and this should be done periodically during treatment. So, the committee considered that monitoring should be done by the most appropriate healthcare professional. The committee further noted that NICE's technology appraisal guidance on dapagliflozin for treating chronic heart failure with reduced ejection fraction included recommendations on who should advise on starting treatment and appropriate monitoring. The committee concluded that a heart failure specialist should advise on starting empagliflozin and monitoring should be done by the most appropriate healthcare professional.