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Sacubitril-Valsartan for the Treatment of Heart Failure: Effectiveness and Value

Sacubitril-Valsartan for the Treatment of Heart Failure: Effectiveness and Value Source of Review The Institute for Clinical and Economic Review developed an evidence report, including a systematic review of the literature, a cost-effectiveness analysis, and a potential budget impact assessment, to support a public meeting of the California Technology Assessment Forum (CTAF) on October 29, 2015, on sacubitril-valsartan combination therapy (Entresto, Novartis AG) for heart failure (HF).1 Background The 5-year mortality rate for patients with chronic HF is similar to that for many cancers, and the disease is characterized by high rates of hospitalization and requirements for intensive outpatient care.2,3 In the United States, the lifetime risk of developing HF approaches 20%,2 and the disease currently affects more than 6 million Americans.4 For more than 2 decades, angiotensin-converting enzyme (ACE) inhibitors have been the cornerstone of pharmacologic treatment in patients with HF owing to reduced ejection fraction. Recent attempts to develop new drug options that bolster the effects of naturally occurring natriuretic peptides, a family of hormones that helps maintain fluid balance, have generally failed owing to lack of efficacy or the development of angioedema.5 A new product combination tablet of the neprilysin inhibitor sacubitril with the angiotensin receptor blocker valsartan represents an attempt to improve fluid balance while mitigating angioedema risks. Sacubitril-valsartan was approved by the US Food and Drug Administration (FDA) in July 2015 for the treatment of patients with New York Heart Association (NYHA) class II to IV HF and reduced ejection fraction. It carries a wholesale acquisition cost of $4560 annually.6 Because the current standard of care for HF involves mostly generic medications, there is interest among multiple stakeholders in understanding the clinical value of sacubitril-valsartan therapy in relation to its cost. Summary of Findings We found a single, good-quality randomized clinical trial of sacubitril-valsartan that focused on the key outcomes of mortality and HF-related hospitalization. This was the phase 3 PARADIGM-HF trial, in which a total of 8442 patients (mean age, 63.8 years; 78.2% were male) with reduced ejection fraction (≤35%) and NYHA class II to IV HF symptoms were randomly assigned to sacubitril-valsartan (200 mg twice a day) or enalapril (10 mg twice a day) in addition to other recommended therapy.7 Prior to randomization, patients underwent single-blind run-in treatment with enalapril (median duration of treatment, 15 days) followed by sacubitril-valsartan (median duration of treatment, 29 days) to ensure tolerability. Of the 10 513 patients initially enrolled, 2079 (19.8%) withdrew from the study during the run-in phase, 1138 of whom (10.8%) withdrew due to failure to tolerate treatment, with similar proportions withdrawing while on run-in treatment with enalapril and sacubitril-valsartan. After a median duration of 27 months of follow-up, the study’s executive committee voted to stop the trial because the prespecified boundary for benefit (a 1-sided P <.001 for reduction in both cardiovascular death as well as the composite of cardiovascular death and first hospitalization for worsening HF) had been crossed. In the PARADIGM-HF trial, the primary composite end point of death from cardiovascular causes or first hospitalization for worsening HF occurred in 21.8% of the sacubitril-valsartan group and 26.5% of the enalapril group (hazard ratio, 0.80; 95% CI, 0.73-0.87; P < .001); the number needed to treat (NNT) avoid either cardiovascular death or first hospitalization for chronic HF was 21. The NNT to avoid 1 cardiovascular death, death from any cause, or first hospitalization for worsening HF was similar; NNT was higher for emergency department visits for HF without subsequent hospitalization (83) due largely to the infrequency of this occurrence (2.4% and 3.6% of sacubitril-valsartan and enalapril patients respectively treated in the emergency department alone; P = .001).7 Sacubitril-valsartan had higher reported rates of hypotension and lower rates of cough and renal impairment relative to enalapril.7 Discontinuation of study medication owing to an adverse event was less frequent among patients in the sacubitril-valsartan group (10.7% vs 12.3%; P = .03). Nineteen patients (0.5%) in the sacubitril-valsartan group and 10 patients (0.2%) in the enalapril group experienced angioedema (P = .13).7 We used data from the PARADIGM-HF trial for an analysis of the lifetime cost-effectiveness of sacubitril-valsartan relative to ACE inhibitor therapy. The ACE inhibitor arm had averages of 5.56 quality-adjusted life years (QALYs) and total costs of $123 578. The sacubitril-valsartan arm produced an additional 0.57 QALY and an additional $29 138 in costs. The resulting cost per QALY gained with sacubitril-valsartan therapy was $50 915. Variations in the monthly cost of sacubitril-valsartan, the likelihood of HF-related hospitalization or death, and measures of quality of life had little impact on the cost-effectiveness. However, the model was sensitive to changes in the assumed duration of improved outcomes with sacubitril-valsartan. Cost-effectiveness would exceed $100 000 per QALY gained if the benefits of sacubitril-valsartan over enalapril persist for 3.3 years or less. We used the same model to estimate the potential 5-year budget impact on overall health care costs from the payer perspective. To evaluate whether the potential impact is substantial enough to strain health system budgets without tight policy restrictions on utilization, our calculations modeled an “unmanaged” utilization of sacubitril-valsartan—that is, without significant payer or pharmacy benefit management controls in place. After accounting for the proportion of the HF population that would have class II to IV disease (approximately 75%) and the percentage of these individuals with reduced ejection fraction (48%), the size of the target population was estimated to be 2.2 million. Based on patient, condition, and treatment factors, we estimated that by the end of 5 years, 75% of all patients in the FDA-approved population, or approximately 1.7 million individuals, would be prescribed sacubitril-valsartan therapy. Across the 5-year time frame, the total potential budget impact is approximately $15 billion, or $3 billion per year, despite cost offsets due to reduced rates of HF-related hospitalization and mortality (an average offset of $1462 per year of treatment). We also calculated the price at which the 5-year budget impact would not exceed an annual threshold for new prescription medications defined to keep health care cost growth in line with overall US economic growth ($904 million).8 The annual price for sacubitril-valsartan to keep within this threshold is $4168, a 9% discount from the wholesale acquisition cost. Limitations of the Evidence Important limitations of this evidence bear mentioning. Data are from a single phase 3 trial, albeit a large study with an active comparator. In addition, because there was no comparison to valsartan alone, the contribution of each component of the combination treatment cannot be quantified. Meanwhile, in the active control arm of the study, patients may have been suboptimally dosed with enalapril; while the 20-mg daily dose used in the study protocol was similar to that used in other trials, the maximum daily dose is 40 mg. In addition, the PARADIGM-HF trial enrolled only patients who tolerated run-in treatment phases with enalapril followed by sacubitril-valsartan. Approximately 11% of patients withdrew owing to tolerability issues with either drug, raising concerns about the generalizability of the findings to the broader population of patients with HF, because included patients may have been healthier with more stable disease than all candidates. Finally, there is a theoretical risk that chronic neprilysin inhibition might potentiate dementia from accumulation of amyloid plaques in the brain. The FDA has required sacubitril-valsartan’s manufacturer to conduct a multicenter, randomized, double-blind, active-controlled trial to examine its effects compared with valsartan on cognitive function.9 Policy Discussions Votes by the CTAF Panel indicated that most (78%) felt that sacubitril-valsartan therapy had either high or intermediate long-term care value as reflected in a cost-effectiveness ratio near $50 000 per QALY. However, owing to the high-potential short-term budget impact, most of the CTAF panel voted that the provisional health system value at the current drug price was “low.” Participants in a multi-stakeholder policy roundtable discussion indicated that many payers and purchasers routinely achieve discounts through negotiation that would moderate the budget impact of sacubitril-valsartan and are therefore placing sacubitril-valsartan in “preferred” formulary tiers, reflecting the combination of clinical effectiveness and pricing aligned with patient benefit. Key roundtable recommendations included (1) restricting prescribing to cardiologists to best monitor and manage adverse effects during the transition to sacubitril-valsartan; and (2) prioritizing use of sacubitril-valsartan in younger patients better able to tolerate a change in therapy, patients with worsening disease on current therapy, and in patients for whom the pronounced reduction in blood pressure sometimes seen with sacubitril-valsartan would not be a major concern. Conclusions Evidence from 1 good-quality trial provides moderate certainty that sacubitril-valsartan therapy provides substantial clinical benefit compared with the current standard of care for HF, owing to reductions in cardiovascular mortality and HF-related hospitalization. Uncertainties remain, however, around the drug’s long-term safety and performance in more broadly representative populations. Findings from our cost-effectiveness analysis suggest that if the sacubitril-valsartan benefits seen in the trial persist over many years that its cost-effectiveness is quite favorable, and, with a relatively modest discount off of the list price, its budgetary impact could be absorbed by the health care system without contributing to overly rapid cost growth. Back to top Article Information Corresponding Author: Daniel A. Ollendorf, PhD, Institute for Clinical and Economic Review, One State St, Ste 1050, Boston, MA 02109 (dollendorf@icer-review.org). Published Online: December 21, 2015. doi:10.1001/jamainternmed.2015.7661. Date of Revision: November 19, 2015. Funding/Support: The California Technology Assessment Forum is a program of the Institute for Clinical and Economic Review and is supported by grants from the BlueShield of California Foundation, the California HealthCare Foundation, and the Laura and John Arnold Foundation. Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: The following individuals contributed to the development of this article: Richard Chapman, PhD, Elizabeth Russo, MD, Matthew Seidner, Karen Shore, PhD, Patricia Synnott, MALD, MS, Karin Travers, DSc, and Jed Weissberg, MD, FACP, of the Institute for Clinical and Economic Review; and Paul Heidenreich, MD, MS, FACC, and Jeremy Goldhaber-Fiebert, PhD, of Stanford University School of Medicine. They were not compensated for their input. References 1. Ollendorf DA, Sandhu AT, Chapman R, et al. CardioMEMS HF System (St. Jude Medical) and Sacubitril/Valsartan (Entresto, Novartis) for Management of Congestive Heart Failure: Effectiveness, Value, and Value-Based Price Benchmarks. Institute for Clinical and Economic Review. http://ctaf.org/sites/default/files/u148/CHF_Revised_Draft_Report_100915.pdf. Accessed October 10, 2015. 2. Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol. 2011;8(1):30-41.PubMedGoogle ScholarCrossref 3. Feltner C, Jones CD, Cene CW, et al. Transitional care interventions to prevent readmissions for persons with heart failure: a systematic review and meta-analysis. Ann Intern Med. 2014;160(11):774-784.Google ScholarCrossref 4. Heidenreich PA, Albert NM, Allen LA, et al; American Heart Association Advocacy Coordinating Committee; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Clinical Cardiology; Council on Epidemiology and Prevention; Stroke Council. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail. 2013;6(3):606-619.PubMedGoogle ScholarCrossref 5. Vardeny O, Miller R, Solomon SD. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure. JACC Heart Fail. 2014;2(6):663-670.PubMedGoogle ScholarCrossref 6. Entresto pricing information. 2015 Truven Health Analytics Micromedex Solutions: REDBOOK; 2015. http://micromedex.com/products/product-suites/clinical-knowledge/redbook. Accessed July 23, 2015. 7. McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004.PubMedGoogle ScholarCrossref 8. Institute for Clinical and Economic Review. Value assessment project: a framework to guide payer assessment of the value of medical services. http://www.icer-review.org/wp-content/uploads/2014/01/Slides-on-value-framework-for-national-webinar1.pdf. Accessed October 19, 2015. 9. US Food and Drug Administration. FDA approved drug products: Entresto. 2015; http://www.fda.gov/Drugs/InformationOnDrugs/ucm457521.htm. Accessed November 20, 2015. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Internal Medicine American Medical Association

Sacubitril-Valsartan for the Treatment of Heart Failure: Effectiveness and Value

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American Medical Association
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Copyright © 2016 American Medical Association. All Rights Reserved.
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2168-6106
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2168-6114
DOI
10.1001/jamainternmed.2015.7661
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Abstract

Source of Review The Institute for Clinical and Economic Review developed an evidence report, including a systematic review of the literature, a cost-effectiveness analysis, and a potential budget impact assessment, to support a public meeting of the California Technology Assessment Forum (CTAF) on October 29, 2015, on sacubitril-valsartan combination therapy (Entresto, Novartis AG) for heart failure (HF).1 Background The 5-year mortality rate for patients with chronic HF is similar to that for many cancers, and the disease is characterized by high rates of hospitalization and requirements for intensive outpatient care.2,3 In the United States, the lifetime risk of developing HF approaches 20%,2 and the disease currently affects more than 6 million Americans.4 For more than 2 decades, angiotensin-converting enzyme (ACE) inhibitors have been the cornerstone of pharmacologic treatment in patients with HF owing to reduced ejection fraction. Recent attempts to develop new drug options that bolster the effects of naturally occurring natriuretic peptides, a family of hormones that helps maintain fluid balance, have generally failed owing to lack of efficacy or the development of angioedema.5 A new product combination tablet of the neprilysin inhibitor sacubitril with the angiotensin receptor blocker valsartan represents an attempt to improve fluid balance while mitigating angioedema risks. Sacubitril-valsartan was approved by the US Food and Drug Administration (FDA) in July 2015 for the treatment of patients with New York Heart Association (NYHA) class II to IV HF and reduced ejection fraction. It carries a wholesale acquisition cost of $4560 annually.6 Because the current standard of care for HF involves mostly generic medications, there is interest among multiple stakeholders in understanding the clinical value of sacubitril-valsartan therapy in relation to its cost. Summary of Findings We found a single, good-quality randomized clinical trial of sacubitril-valsartan that focused on the key outcomes of mortality and HF-related hospitalization. This was the phase 3 PARADIGM-HF trial, in which a total of 8442 patients (mean age, 63.8 years; 78.2% were male) with reduced ejection fraction (≤35%) and NYHA class II to IV HF symptoms were randomly assigned to sacubitril-valsartan (200 mg twice a day) or enalapril (10 mg twice a day) in addition to other recommended therapy.7 Prior to randomization, patients underwent single-blind run-in treatment with enalapril (median duration of treatment, 15 days) followed by sacubitril-valsartan (median duration of treatment, 29 days) to ensure tolerability. Of the 10 513 patients initially enrolled, 2079 (19.8%) withdrew from the study during the run-in phase, 1138 of whom (10.8%) withdrew due to failure to tolerate treatment, with similar proportions withdrawing while on run-in treatment with enalapril and sacubitril-valsartan. After a median duration of 27 months of follow-up, the study’s executive committee voted to stop the trial because the prespecified boundary for benefit (a 1-sided P <.001 for reduction in both cardiovascular death as well as the composite of cardiovascular death and first hospitalization for worsening HF) had been crossed. In the PARADIGM-HF trial, the primary composite end point of death from cardiovascular causes or first hospitalization for worsening HF occurred in 21.8% of the sacubitril-valsartan group and 26.5% of the enalapril group (hazard ratio, 0.80; 95% CI, 0.73-0.87; P < .001); the number needed to treat (NNT) avoid either cardiovascular death or first hospitalization for chronic HF was 21. The NNT to avoid 1 cardiovascular death, death from any cause, or first hospitalization for worsening HF was similar; NNT was higher for emergency department visits for HF without subsequent hospitalization (83) due largely to the infrequency of this occurrence (2.4% and 3.6% of sacubitril-valsartan and enalapril patients respectively treated in the emergency department alone; P = .001).7 Sacubitril-valsartan had higher reported rates of hypotension and lower rates of cough and renal impairment relative to enalapril.7 Discontinuation of study medication owing to an adverse event was less frequent among patients in the sacubitril-valsartan group (10.7% vs 12.3%; P = .03). Nineteen patients (0.5%) in the sacubitril-valsartan group and 10 patients (0.2%) in the enalapril group experienced angioedema (P = .13).7 We used data from the PARADIGM-HF trial for an analysis of the lifetime cost-effectiveness of sacubitril-valsartan relative to ACE inhibitor therapy. The ACE inhibitor arm had averages of 5.56 quality-adjusted life years (QALYs) and total costs of $123 578. The sacubitril-valsartan arm produced an additional 0.57 QALY and an additional $29 138 in costs. The resulting cost per QALY gained with sacubitril-valsartan therapy was $50 915. Variations in the monthly cost of sacubitril-valsartan, the likelihood of HF-related hospitalization or death, and measures of quality of life had little impact on the cost-effectiveness. However, the model was sensitive to changes in the assumed duration of improved outcomes with sacubitril-valsartan. Cost-effectiveness would exceed $100 000 per QALY gained if the benefits of sacubitril-valsartan over enalapril persist for 3.3 years or less. We used the same model to estimate the potential 5-year budget impact on overall health care costs from the payer perspective. To evaluate whether the potential impact is substantial enough to strain health system budgets without tight policy restrictions on utilization, our calculations modeled an “unmanaged” utilization of sacubitril-valsartan—that is, without significant payer or pharmacy benefit management controls in place. After accounting for the proportion of the HF population that would have class II to IV disease (approximately 75%) and the percentage of these individuals with reduced ejection fraction (48%), the size of the target population was estimated to be 2.2 million. Based on patient, condition, and treatment factors, we estimated that by the end of 5 years, 75% of all patients in the FDA-approved population, or approximately 1.7 million individuals, would be prescribed sacubitril-valsartan therapy. Across the 5-year time frame, the total potential budget impact is approximately $15 billion, or $3 billion per year, despite cost offsets due to reduced rates of HF-related hospitalization and mortality (an average offset of $1462 per year of treatment). We also calculated the price at which the 5-year budget impact would not exceed an annual threshold for new prescription medications defined to keep health care cost growth in line with overall US economic growth ($904 million).8 The annual price for sacubitril-valsartan to keep within this threshold is $4168, a 9% discount from the wholesale acquisition cost. Limitations of the Evidence Important limitations of this evidence bear mentioning. Data are from a single phase 3 trial, albeit a large study with an active comparator. In addition, because there was no comparison to valsartan alone, the contribution of each component of the combination treatment cannot be quantified. Meanwhile, in the active control arm of the study, patients may have been suboptimally dosed with enalapril; while the 20-mg daily dose used in the study protocol was similar to that used in other trials, the maximum daily dose is 40 mg. In addition, the PARADIGM-HF trial enrolled only patients who tolerated run-in treatment phases with enalapril followed by sacubitril-valsartan. Approximately 11% of patients withdrew owing to tolerability issues with either drug, raising concerns about the generalizability of the findings to the broader population of patients with HF, because included patients may have been healthier with more stable disease than all candidates. Finally, there is a theoretical risk that chronic neprilysin inhibition might potentiate dementia from accumulation of amyloid plaques in the brain. The FDA has required sacubitril-valsartan’s manufacturer to conduct a multicenter, randomized, double-blind, active-controlled trial to examine its effects compared with valsartan on cognitive function.9 Policy Discussions Votes by the CTAF Panel indicated that most (78%) felt that sacubitril-valsartan therapy had either high or intermediate long-term care value as reflected in a cost-effectiveness ratio near $50 000 per QALY. However, owing to the high-potential short-term budget impact, most of the CTAF panel voted that the provisional health system value at the current drug price was “low.” Participants in a multi-stakeholder policy roundtable discussion indicated that many payers and purchasers routinely achieve discounts through negotiation that would moderate the budget impact of sacubitril-valsartan and are therefore placing sacubitril-valsartan in “preferred” formulary tiers, reflecting the combination of clinical effectiveness and pricing aligned with patient benefit. Key roundtable recommendations included (1) restricting prescribing to cardiologists to best monitor and manage adverse effects during the transition to sacubitril-valsartan; and (2) prioritizing use of sacubitril-valsartan in younger patients better able to tolerate a change in therapy, patients with worsening disease on current therapy, and in patients for whom the pronounced reduction in blood pressure sometimes seen with sacubitril-valsartan would not be a major concern. Conclusions Evidence from 1 good-quality trial provides moderate certainty that sacubitril-valsartan therapy provides substantial clinical benefit compared with the current standard of care for HF, owing to reductions in cardiovascular mortality and HF-related hospitalization. Uncertainties remain, however, around the drug’s long-term safety and performance in more broadly representative populations. Findings from our cost-effectiveness analysis suggest that if the sacubitril-valsartan benefits seen in the trial persist over many years that its cost-effectiveness is quite favorable, and, with a relatively modest discount off of the list price, its budgetary impact could be absorbed by the health care system without contributing to overly rapid cost growth. Back to top Article Information Corresponding Author: Daniel A. Ollendorf, PhD, Institute for Clinical and Economic Review, One State St, Ste 1050, Boston, MA 02109 (dollendorf@icer-review.org). Published Online: December 21, 2015. doi:10.1001/jamainternmed.2015.7661. Date of Revision: November 19, 2015. Funding/Support: The California Technology Assessment Forum is a program of the Institute for Clinical and Economic Review and is supported by grants from the BlueShield of California Foundation, the California HealthCare Foundation, and the Laura and John Arnold Foundation. Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: The following individuals contributed to the development of this article: Richard Chapman, PhD, Elizabeth Russo, MD, Matthew Seidner, Karen Shore, PhD, Patricia Synnott, MALD, MS, Karin Travers, DSc, and Jed Weissberg, MD, FACP, of the Institute for Clinical and Economic Review; and Paul Heidenreich, MD, MS, FACC, and Jeremy Goldhaber-Fiebert, PhD, of Stanford University School of Medicine. They were not compensated for their input. References 1. Ollendorf DA, Sandhu AT, Chapman R, et al. CardioMEMS HF System (St. Jude Medical) and Sacubitril/Valsartan (Entresto, Novartis) for Management of Congestive Heart Failure: Effectiveness, Value, and Value-Based Price Benchmarks. Institute for Clinical and Economic Review. http://ctaf.org/sites/default/files/u148/CHF_Revised_Draft_Report_100915.pdf. Accessed October 10, 2015. 2. Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol. 2011;8(1):30-41.PubMedGoogle ScholarCrossref 3. Feltner C, Jones CD, Cene CW, et al. Transitional care interventions to prevent readmissions for persons with heart failure: a systematic review and meta-analysis. Ann Intern Med. 2014;160(11):774-784.Google ScholarCrossref 4. Heidenreich PA, Albert NM, Allen LA, et al; American Heart Association Advocacy Coordinating Committee; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Clinical Cardiology; Council on Epidemiology and Prevention; Stroke Council. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail. 2013;6(3):606-619.PubMedGoogle ScholarCrossref 5. Vardeny O, Miller R, Solomon SD. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure. JACC Heart Fail. 2014;2(6):663-670.PubMedGoogle ScholarCrossref 6. Entresto pricing information. 2015 Truven Health Analytics Micromedex Solutions: REDBOOK; 2015. http://micromedex.com/products/product-suites/clinical-knowledge/redbook. Accessed July 23, 2015. 7. McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004.PubMedGoogle ScholarCrossref 8. Institute for Clinical and Economic Review. Value assessment project: a framework to guide payer assessment of the value of medical services. http://www.icer-review.org/wp-content/uploads/2014/01/Slides-on-value-framework-for-national-webinar1.pdf. Accessed October 19, 2015. 9. US Food and Drug Administration. FDA approved drug products: Entresto. 2015; http://www.fda.gov/Drugs/InformationOnDrugs/ucm457521.htm. Accessed November 20, 2015.

Journal

JAMA Internal MedicineAmerican Medical Association

Published: Feb 1, 2016

Keywords: combination drug therapy,angiotensin receptors,heart failure,cost effectiveness,budgets,drug costs,health expenditures,neprilysin,treatment outcome,drug effectiveness

References