Mixed Benefits Seen Following Sacubitril/Valsartan Use Among Patients With HFrEF

Recent study findings highlight mixed results following use of this medication among Mississippi and Massachusetts Medicaid beneficiaries.

Entresto (sacubitril/valsartan) was approved by the FDA on July 8, 2015,1 for use among patients with New York Heart Association class II through IV heart failure (HF), meaning these patients have reduced or no physical activity and mild to severe symptoms of congestive HF.2 Evidence shows the medication can reduce the risk of cardiovascular death and hospitalization among patients with chronic HF with reduced ejection fraction (HFrEF), through its combination of the angiotensin II receptor blocker (ARB) valsartan and the neprilysin inhibitor sacubitril.3

Results from 2 investigations highlight the mixed cost-related benefits of this medication among individuals in Mississippi and Massachusetts, respectively, with Medicaid coverage. Prior to these findings, few data were available on sacubitril/valsartan’s real-world impact, specifically that among Medicaid beneficiaries.

The American Heart Association defines the heart’s ejection fraction as “a measurement, expressed as a percentage, of how much blood the left ventricle pumps out with each contraction.”4 Essentially, it is a comparison of how much blood is pumped out vs that inside the chamber.

A detailed medical history, physical examination, and evaluation of risk factors are used to reach the correct diagnosis, in addition to any, or all, of the following assessments5 as necessary:

  • Blood tests
  • Chest x-ray
  • Electrocardiogram
  • Echocardiogram
  • Stress test
  • Cardiac CT scan
  • MRI
  • Coronary angiogram
  • Myocardial biopsy

Three groupings help to further define this classification of heart disease, and they are used to first diagnose, then treat, the condition by enabling the treating physicians to design the appropriate program to treat the failure in the patient, which typically includes a combination of exercise, medication, and regular check-ups with health care providers:

  1. HFrEF, or systolic HF (≤40%)
  2. HF with preserved ejection fraction, or diastolic HF6 (≥50%)
  3. HF with borderline ejection fraction7 (41%-49%)

Among these 3 types of HF, the focus of the recent study results is on HFrEF and the use of Entresto (sacubitril/valsartan) to treat patients with Medicaid coverage. An abstract from a team of investigators at the University of Mississippi and the Mississippi Division of Medicaid,8 which was presented at this year’s Academy of Managed Care Pharmacy (AMCP) Nexus 2020 Virtual meeting in October, show the results of an investigation into adherence to and the cost-effectiveness of 3 doses of the medication. A poster from Commonwealth Medicine in Massachusetts,9 presented at this year’s AMCP eLearning Days in April, displays findings from an investigation into the cost-benefit ratio of sacubitril/valsartan.

Despite this combination medication being approved for and available at 3 dosing levels, there are few real-world data on its economic impact among patients with HF, especially those with Medicaid coverage.

A previous study investigated the medication’s cost-effectiveness among hospitalized patients who have HFrEF,10 but an editorial accompanying those findings noted that “equitable access remains a challenge for many patients with HFrEF. Careful ongoing analyses are required to further validate these assumptions in real-world applications, evaluate their generalizability, and consider the individual, health system, and societal value for this indication.”11

Cost-effectiveness of Sacubitril/Valsartan at 3 Dosing Levels8

The authors of this study abstract from Mississippi investigated the dose-specific impact of each of the 3 approved doses of sacubitril/valsartan:

  • Low: 24/26 mg
  • Medium: 49/51 mg
  • High: 97/103 mg

“One of our Medicaid providers reported to us that upward titration of dosage was not to be feasible for many patients in routine clinical practice and he questioned the cost-effectiveness of the product at the lower dose,” stated the poster’s authors in an interview with AJMC®. “Our main goal, in this study, was to explore the cost impact of 3 dosing levels of sacubitril/valsartan and whether lower doses of sacubitril/valsartan had comparable cost-benefit as its high dose.”

The findings show that patients on the high dose had the highest adherence rate, followed by those on the low and medium doses: 58.5% vs 53.7% and 50.4%, respectively. “The variation in adherence rates was small and would not be considered to have clinically significant implications,” explained the authors. “We measured treatment adherence to account for it in the final statistical models measuring the association between sacubitril/valsartan dose and health care costs since adherence could significantly impact drug costs and outcomes.”

Potential adverse effects include hypotension, hyperkalemia, angioedema, and risk of renal injury, they added in the interview, “but evaluation of specific adverse events associated with sacubitril/valsartan treatment was beyond the scope of this study and is difficult to evaluate using clinical data.”

Conversely, the patients taking the lowest dose also had the highest increase in unadjusted pharmacy costs post treatment compared with patients taking the medium and high doses: $1434 vs $1180 (P < .001) and $1113 (P = .002), respectively. The authors determined this finding to be significant.

Following adjustment for demographics (age, race, sex, adherence), the low-dose group was the only one to experience a posttreatment cost increase, at 25% (P = .157). The medium- and high-dose groups, meanwhile, had reductions in total costs of 52% (P < .001) and 25% (P = .061), respectively, compared with the low-dose group in the post treatment period.

A possible reason for the almost 4-fold greater difference of $254 between the low and medium doses compared with $67 between the medium and high doses is dose titration over a 90-day posttreatment period, the authors stated in the interview with AJMC®.

“For example, a patient uptitrated to a medium or high dose may still have leftover medicine from the previous lower dose. They may fill the prescription for a higher dose on the day the provider changed their dose and be advised to finish the remainder of the previous low dose. Since the beginning of the stable medication period and the follow-up period is defined as the date of the first fill for the stable dose, a slightly lower number of fills associated with medium and high doses could have occurred because of this titration period,” they said.

Their retrospective observational study gleaned insights from data on 475 Mississippi Medicaid beneficiaries, 179 (37.7%) of whom took the low dose, 125 (26.3%) took the medium dose, and 171 (36.0%) took the high dose. All filed Medicaid claims between January 1, 2015, and August 31, 2019, and had continuous enrollment for the 3 months prior to starting treatment with sacubitril/valsartan to 3 months after their stable dose was reached.

In fact, 3 months was used as a benchmark across this study. “A stable dose of [sacubitril/valsartan] was defined as 3 months of [sacubitril/valsartan] treatment without a dose change,” the authors noted. “[And] medical and pharmacy costs were calculated for the 3 months pre-treatment and [the] 3-month stable dose treatment period.”

The post-index date was defined as the first day on which the stable dose of sacubitril/valsartan was determined, and patients were classified as adherent to treatment if they had a proportion of days covered (PDC) of at least 80%.

“Cost savings occurred for beneficiaries maintained on a [medium dose or high dose of sacubitril/valsartan],” the authors concluded. “Although the increase in total cost for the [low-dose] group was not significant, additional research may be needed to determine if this dose is cost-effective.”

Cost-Benefit Ratio of Sacubitril/Valsartan9

Investigators from Commonwealth Medicine in Massachusetts addressed the need for more real-world data on sacubitril/valsartan by comparing cost outcomes related to HF hospitalizations and emergency department (ED) visits before and after treatment with this combination medication.

“While the PARADIGM-HF clinical trial found sacubitril/valsartan to be more effective than enalapril in reducing [cardiovascular]-related deaths and hospitalizations, real-world data on the economic impact of sacubitril/valsartan is limited, especially in a Medicaid population,” noted Pavel Lavitas, PharmD, BCPS, clinical consultant pharmacist team lead, Clinical Pharmacy Services, Commonwealth Medicine, University of Massachusetts Medical School, one of the poster’s authors. “Given fiscal constraints faced by many state Medicaid programs, we decided to assess the cost benefit of sacubitril/valsartan in this vulnerable population.”

They found a negative correlation between initiation of the treatment and its overall benefits, showing that although the cost and number of hospitalization and ED visits dropped, the cost of HF-related pharmacotherapies increased.

Using Massachusetts Medicaid data for July 7, 2014, through August 31, 2019—from pharmacy and medical claims, as well as prior authorization (PA) requests—the team investigated their outcomes among fee-for-service, primary care clinician, and primary care accountable care organization members. All had to have 1-year continuous coverage before (preindex period) and after (postindex period) treatment initiation with sacubitril/valsartan began; be 18 years or older; have at least 1 PA request for sacubitril/valsartan from July 7, 2015, to August 31, 2018; and have at least 2 pharmacy claims for the treatment in the postindex period.

Twenty-two patients were included in the final analysis, and their mean age was 50.3 (range, 22.0-73.0) years. Their most common HF pharmacotherapies in the pre- and postindex periods were β-blockers (20 patients in each period), loop diuretics (preindex, n = 18; postindex, n = 19), and potassium-sparing agents (preindex, n = 18; postindex, n = 16).

Similar to the previous study,8 individuals were considered adherent if they complied with their sacubitril/valsartan treatment regimen for a PDC of at least 80% in the postindex period. Close to 55% (n = 12) of the patients in the study were considered adherent.

Results show that costs for HF-associated hospitalizations and/or ED visits in the preindex period outweighed those in the postindex period, for both the overall study population and the 12 patients considered adherent. This was in stark contrast to costs for pharmacotherapies, which were exponentially higher in the postindex period for both groups:

  • Hospitalization/ED visits:
    • Overall population: $249,392 (pre) vs $170,125 (post), a 46.6% difference
    • Adherent group: $173,283 (pre) vs $80,470 (post), a 115.3% difference
  • Pharmacotherapies:
    • Overall population: $6196 (pre) vs $92,865 (post), a 1399.0% difference
    • Adherent group: $4327 (pre) vs $69,520 (post), 1506.6% difference

Some light can be seen in that the adherent group had higher mean per-member hospitalization/ED cost avoided, pharmacotherapy cost difference, net benefit, and benefit-cost ratio compared with the overall population:

  • Avoided cost: $7734 vs $3603
  • Pharmacotherapy cost: $5397 vs $3939
  • Net benefit: $2337 vs -$336
  • Ratio: 1.43 vs 0.91

For the ratio especially, the authors stated, “In the overall study population, the negative net benefit and the benefit-cost ratio being <1.0 demonstrated that the cost of HF pharmacotherapies was greater than the cost of avoided HF-related hospitalizations and ED visits.”

Additionally, hospitalization and ED visits dropped in the postindex period compared with the preindex period: from 26 to 23 overall and from 12 to 10 in the adherent group. However, the median cost of avoided visits also dropped, from $21,301 to $12,552. In total, 89% of the pharmacy spend in the postindex period was because of sacubitril/valsartan.

“The results showed that the overall economic benefit, as demonstrated by the cost avoidance of HF-related hospitalizations and ED visits, did not outweigh the additional costs of sacubitril/valsartan,” Lavitas stated. “However, the benefit outweighed the cost for the subset of members who were adherent to the sacubitril/valsartan. Additional studies are needed to evaluate a larger population with HF for a longer time frame that extends beyond 1 year.”

A principal limitation to their findings is the risk of inaccurate or incomplete data often seen with retrospective claims analyses, despite the current findings mirroring those of previous studies, he added.

“A large retrospective, claims-based study by Albert et al12 of patients with HFrEF enrolled in commercial and Medicare Advantage health plans has found sacubitril/valsartan to be associated with lower hospitalization and healthcare costs than those treated with [angiotensin-converting enzyme inhibitors]/ARB,” Lavitas said. “Another recent study by Burke et al13 of commercially insured patients with HFrEF who initiated and adhered to their sacubitril/valsartan treatment for 1 year demonstrated lower total cost of care.”


1. FDA approves Estresto. Heart Failure Society of America. July 8, 2015. Accessed November 23, 2020. https://hfsa.org/fda-approves-entresto

2. Classes of heart failure. American Heart Association. Accessed November 23, 2020. https://www.heart.org/en/health-topics/heart-failure/what-is-heart-failure/classes-of-heart-failure

3. Entresto (sacubitril/valsartan). Prescribing information. Novartis; 2020. Accessed November 24, 2020. https://www.entresto.com/index.jsp

4. Ejection fraction heart failure measurement. American Heart Association. Accessed November 23, 2020. https://www.heart.org/en/health-topics/heart-failure/diagnosing-heart-failure/ejection-fraction-heart-failure-measurement

5. Heart failure. Mayo Clinic. May 29, 2020. Accessed November 23, 2020. https://www.mayoclinic.org/diseases-conditions/heart-failure/diagnosis-treatment/drc-20373148

6. Healthwise staff. Heart failure with preserved ejection fraction (diastolic heart failure). Michigan Medicine. Updated December 14, 2019. Accessed November 23, 2020. https://www.uofmhealth.org/health-library/tx4091abc

7. HF and your ejection fraction explained. American Heart Association. Accessed November 23, 2020. https://www.heart.org/-/media/files/health-topics/heart-failure/hf-and-your-ejection-fraction-explained-481884.pdf?la=en

8. Banahan B, Gangan N, Korgaonkar S, et al. Evaluation of treatment patterns for chronic heart failure and associated costs of different dosing levels of sacubitril/valsartan among Mississippi Medicaid beneficiaries. Presented at: AMCP Nexus 2020 Virtual; October 19-23, 2020. Abstract I6. https://www.jmcp.org/pb-assets/Poster%20Abstract%20Supplements/Oct2020Abstracts.pdf

9. Gabot A, Lavitas P, Bacon R, et al. Cost-benefit analysis of sacubitril/valsartan among patients with heart failure with reduced ejection fraction in a Medicaid population. Presented at: AMCP eLearning Days; April 20-24, 2020. Accessed November 23, 2020. https://commed.umassmed.edu/our-work/2020/04/22/cost-benefit-analysis-sacubitrilvalsartan-among-patients-heart-failure-reduced

10. Gaziano TA, Fonarow GC, Velazquez EJ, Morrow DA, Braunwald E, Solomon SD. Cost-effectiveness of sacubitril-valsartan in hospitalized patients who have heart failure with reduced ejection fraction. JAMA Cardiol. 2020;5(11):1236-1244. doi:10.1001/jamacardio.2020.2822

11. Yancy CW, Hernandez AF, Bonow RO. The use of sacubitril/valsartan for hospitalized heart failure—why do we care about cost and value? JAMA Cardiol. 2020;5(11):1244. doi:10.1001/jamacardio.2020.3108

12. Albert NM, Swindle JP, Buysman EK, Chang C. Lower hospitalization and healthcare costs with sacubitril/valsartan versus angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker in a retrospective analysis of patients with heart failure. J Am Heart Assoc. Published online April 26, 2019. doi:10.1161/JAHA.118.011089

13. Burke J, Sahli B, Gleason P. Sacubitril-valsartan real-world assessment of total cost of care and resource utilization pre/post initiation among commercially insured members with reduced ejection fraction heart failure. Presented at: Academy of Managed Care Pharmacy Nexus; October 19-23, 2020; Poster I9.

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