Regulatory Decision Summary for ENTRESTO

The sponsor demonstrated that Entresto is effective in reducing the incidence of cardiovascular death and heart failure hospitalization in patients with heart failure with reduced ejection fraction (HFrEF). In PARADIGM-HF, Entresto reduced the risk of cardiovascular death by 20%, time-to-first heart failure hospitalization by 21%, and all-cause mortality by 16%, compared to the angiotensin-converting enzyme inhibitor (ACEi) enalapril, a standard pharmacologic treatment for this condition, all on top of other standard treatments for HFrEF. Each of these observations was clinically meaningful and highly statistically significant. Accordingly, one should have a very high degree of confidence that these reported results are valid and will be reproduced in the real world setting, should patients be selected to be eligible for treatment with Entresto as outlined in the Product Monograph.

The PARADIGM-HF trial contained two sequential run-in phases to ensure that patients tolerate the maximum dose of these two drugs to be evaluated. This allowed for a direct comparison of the effectiveness of Entresto with enalapril, without interference due to differing rates of patient tolerability of deemed optimal dosing of these agents. 

The results of the PARADIGM-HF trial apply, strictly speaking, only to those HFrEF patients who can successfully tolerate a two week course of enalapril at 10 mg taken twice daily, followed by four weeks of exposure to, first, one tablet of Entresto (48.6 mg sacubitril/51.4 mg valsartan) taken twice daily for two weeks, and then two weeks of one tablet of Entresto (97.2  mg sacubitril/102.8 mg valsartan) taken twice daily.

Given the strong demonstrated benefit-risk to HFrEF patients who were able to tolerate such strengths of these drugs, very careful patient selection prior to initiation of Entresto was addressed in the Entresto Product Monograph, as well as the use of a lower strength of Entresto (24.3 mg sacubitril/25.7 mg valsartan) in select patients and the limitation of initial prescribing of Entresto to physicians experienced in the treatment of heart failure. Further, attention needs to be given by prescribers to ensure that all patients starting Entresto treatment are clinically stable and receiving stable doses of other recommended heart failure medications beforehand. Also, prescribers need to ensure that patients to be treated with Entresto do not have excessively low blood pressure, excessively high serum potassium, or poor renal function, that is (i.e.) severe renal impairment.

Hypotension is the most common adverse reaction associated with Entresto use. Optimal patient selection prior to initiation of Entresto, and close monitoring by prescribers of patients taking Entresto who have risk factors for hypotension, along with adjusting heart failure medication doses, including that of Entresto, accordingly, will allow for many patients to take advantage of the demonstrated benefits of this therapy. Similarly, patient potential to develop hyperkalemia while on Entresto needs to be evaluated before treatment initiation, and patients need to be monitored for this adverse event while on treatment. The incidence of angioedema, an uncommon hypersensitivity reaction, is increased with Entresto, although most cases were not life-threatening.  Black patients appear to have an increased susceptibility to develop angioedema. The product monograph clearly advises prescribers of this observation in the Warnings and Precautions section, and patients in Part III.

In summary, the benefit-risk of Entresto is favourable in clinically stable patients with HFrEF who can be properly selected for the initiation of this mediation, taking into account the detailed considerations provided in the Entresto Product Monograph. However, in some HFrEF patients, uncertainty exists in respect of the degree of benefit that would accrue with Entresto treatment. To help further address these concerns, the sponsor has committed to conduct a patient registry to better characterize the safety and efficacy of Entresto when used in different clinical scenarios in the real world setting.

For more information on Health Canadas decision, please view the Summary Basis of Decision.