Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction

Jane A. Cannon; Li Shen; Pardeep S. Jhund; Søren L. Kristensen; Lars Køber; Fabian Chen; Jianjian Gong; Martin P. Lefkowitz; Jean L. Rouleau; Victor C. Shi; Karl Swedberg; Michael R. Zile; Scott D. Solomon; Milton Packer; John J.V. McMurray; PARADIGM-HF Investigators and Committees

doi:10.1002/ejhf.687

Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction

Jane A. Cannon, Li Shen, Pardeep S. Jhund, Søren L. Kristensen, Lars Køber, Fabian Chen, Jianjian Gong, Martin P. Lefkowitz, Jean L. Rouleau, Victor C. Shi, Karl Swedberg, Michael R. Zile, Scott D. Solomon, Milton Packer, John J.V. McMurray^*, PARADIGM-HF Investigators and Committees

^*Corresponding author for this work

Department of Clinical Medicine

60 Citations (Scopus)

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Abstract

Aims: Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction (HFrEF), as shown in PARADIGM-HF which compared the angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan with enalapril. As neprilysin is also one of many enzymes clearing amyloid-β peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials. Methods and results: In PARADIGM-HF, patients with symptomatic HFrEF were randomized to sacubitril/valsartan 97/103 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with ‘broad’ and ‘narrow’ preferred terms related to dementia. In PARADIGM-HF, 8399 patients aged 18–96 years were randomized and followed for a median of 2.25 years (up to 4.3 years). The narrow SMQ search identified 27 dementia-related AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/valsartan [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.33–1.59]. The broad search identified 97 (2.30%) and 104 (2.48%) AEs (HR 1.01, 95% CI 0.75–1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF. Conclusion: We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment. Further studies to address this question are warranted.

Original language	English
Journal	European Journal of Heart Failure
Volume	19
Issue number	1
Pages (from-to)	129-137
ISSN	1388-9842
DOIs	https://doi.org/10.1002/ejhf.687
Publication status	Published - 2017

Keywords

ARNI
Dementia
Heart failure
Neprilysin inhibition

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10.1002/ejhf.687Licence: CC BY-NC-ND

Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fractionFinal published version, 134 KBLicence: CC BY-NC-ND

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Cannon, J. A., Shen, L., Jhund, P. S., Kristensen, S. L., Køber, L., Chen, F., Gong, J., Lefkowitz, M. P., Rouleau, J. L., Shi, V. C., Swedberg, K., Zile, M. R., Solomon, S. D., Packer, M., McMurray, J. J. V., & PARADIGM-HF Investigators and Committees (2017). Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction. European Journal of Heart Failure, 19(1), 129-137. https://doi.org/10.1002/ejhf.687

Cannon, JA, Shen, L, Jhund, PS, Kristensen, SL, Køber, L, Chen, F, Gong, J, Lefkowitz, MP, Rouleau, JL, Shi, VC, Swedberg, K, Zile, MR, Solomon, SD, Packer, M, McMurray, JJV & PARADIGM-HF Investigators and Committees 2017, 'Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction', European Journal of Heart Failure, vol. 19, no. 1, pp. 129-137. https://doi.org/10.1002/ejhf.687

@article{765aec22b0cb4e2ca862b9ab17f87cfe,

title = "Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction",

abstract = "Aims: Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction (HFrEF), as shown in PARADIGM-HF which compared the angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan with enalapril. As neprilysin is also one of many enzymes clearing amyloid-β peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials. Methods and results: In PARADIGM-HF, patients with symptomatic HFrEF were randomized to sacubitril/valsartan 97/103 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with {\textquoteleft}broad{\textquoteright} and {\textquoteleft}narrow{\textquoteright} preferred terms related to dementia. In PARADIGM-HF, 8399 patients aged 18–96 years were randomized and followed for a median of 2.25 years (up to 4.3 years). The narrow SMQ search identified 27 dementia-related AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/valsartan [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.33–1.59]. The broad search identified 97 (2.30%) and 104 (2.48%) AEs (HR 1.01, 95% CI 0.75–1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF. Conclusion: We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment. Further studies to address this question are warranted.",

keywords = "ARNI, Dementia, Heart failure, Neprilysin inhibition",

author = "Cannon, {Jane A.} and Li Shen and Jhund, {Pardeep S.} and Kristensen, {S{\o}ren L.} and Lars K{\o}ber and Fabian Chen and Jianjian Gong and Lefkowitz, {Martin P.} and Rouleau, {Jean L.} and Shi, {Victor C.} and Karl Swedberg and Zile, {Michael R.} and Solomon, {Scott D.} and Milton Packer and McMurray, {John J.V.} and {PARADIGM-HF Investigators and Committees}",

year = "2017",

doi = "10.1002/ejhf.687",

language = "English",

volume = "19",

pages = "129--137",

journal = "European Journal of Heart Failure, Supplement",

issn = "1567-4215",

publisher = "JohnWiley & Sons Ltd",

number = "1",

}

TY - JOUR

T1 - Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction

AU - Cannon, Jane A.

AU - Shen, Li

AU - Jhund, Pardeep S.

AU - Kristensen, Søren L.

AU - Køber, Lars

AU - Chen, Fabian

AU - Gong, Jianjian

AU - Lefkowitz, Martin P.

AU - Rouleau, Jean L.

AU - Shi, Victor C.

AU - Swedberg, Karl

AU - Zile, Michael R.

AU - Solomon, Scott D.

AU - Packer, Milton

AU - McMurray, John J.V.

AU - PARADIGM-HF Investigators and Committees

PY - 2017

Y1 - 2017

N2 - Aims: Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction (HFrEF), as shown in PARADIGM-HF which compared the angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan with enalapril. As neprilysin is also one of many enzymes clearing amyloid-β peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials. Methods and results: In PARADIGM-HF, patients with symptomatic HFrEF were randomized to sacubitril/valsartan 97/103 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with ‘broad’ and ‘narrow’ preferred terms related to dementia. In PARADIGM-HF, 8399 patients aged 18–96 years were randomized and followed for a median of 2.25 years (up to 4.3 years). The narrow SMQ search identified 27 dementia-related AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/valsartan [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.33–1.59]. The broad search identified 97 (2.30%) and 104 (2.48%) AEs (HR 1.01, 95% CI 0.75–1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF. Conclusion: We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment. Further studies to address this question are warranted.

AB - Aims: Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction (HFrEF), as shown in PARADIGM-HF which compared the angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan with enalapril. As neprilysin is also one of many enzymes clearing amyloid-β peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials. Methods and results: In PARADIGM-HF, patients with symptomatic HFrEF were randomized to sacubitril/valsartan 97/103 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with ‘broad’ and ‘narrow’ preferred terms related to dementia. In PARADIGM-HF, 8399 patients aged 18–96 years were randomized and followed for a median of 2.25 years (up to 4.3 years). The narrow SMQ search identified 27 dementia-related AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/valsartan [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.33–1.59]. The broad search identified 97 (2.30%) and 104 (2.48%) AEs (HR 1.01, 95% CI 0.75–1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF. Conclusion: We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment. Further studies to address this question are warranted.

KW - ARNI

KW - Dementia

KW - Heart failure

KW - Neprilysin inhibition

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U2 - 10.1002/ejhf.687

DO - 10.1002/ejhf.687

M3 - Journal article

C2 - 27868321

AN - SCOPUS:85006136299

SN - 1567-4215

VL - 19

SP - 129

EP - 137

JO - European Journal of Heart Failure, Supplement

JF - European Journal of Heart Failure, Supplement

IS - 1

ER -

Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction

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