PMID- 27868321 OWN - NLM STAT- MEDLINE DCOM- 20171109 LR - 20211204 IS - 1879-0844 (Electronic) IS - 1388-9842 (Print) IS - 1388-9842 (Linking) VI - 19 IP - 1 DP - 2017 Jan TI - Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction. PG - 129-137 LID - 10.1002/ejhf.687 [doi] 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-beta 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. CI - (c) 2016 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. FAU - Cannon, Jane A AU - Cannon JA AD - BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK. FAU - Shen, Li AU - Shen L AD - BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK. FAU - Jhund, Pardeep S AU - Jhund PS AD - BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK. FAU - Kristensen, Soren L AU - Kristensen SL AD - Rigshospitalet Copenhagen University Hospital, Copenhagen. FAU - Kober, Lars AU - Kober L AD - Rigshospitalet Copenhagen University Hospital, Copenhagen. FAU - Chen, Fabian AU - Chen F AD - Novartis Pharmaceutical Corporation, East Hanover, NJ, USA. FAU - Gong, Jianjian AU - Gong J AD - Novartis Pharmaceutical Corporation, East Hanover, NJ, USA. FAU - Lefkowitz, Martin P AU - Lefkowitz MP AD - Novartis Pharmaceutical Corporation, East Hanover, NJ, USA. FAU - Rouleau, Jean L AU - Rouleau JL AD - Institut de Cardiologie, Universite de Montreal, Montreal, Canada. FAU - Shi, Victor C AU - Shi VC AD - Novartis Pharmaceutical Corporation, East Hanover, NJ, USA. FAU - Swedberg, Karl AU - Swedberg K AD - Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London. FAU - Zile, Michael R AU - Zile MR AD - Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC, USA. FAU - Solomon, Scott D AU - Solomon SD AD - Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA. FAU - Packer, Milton AU - Packer M AD - Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX, USA. FAU - McMurray, John J V AU - McMurray JJ AD - BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK. CN - PARADIGM-HF Investigators and Committees LA - eng GR - R01 HL123478/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Randomized Controlled Trial DEP - 20161120 PL - England TA - Eur J Heart Fail JT - European journal of heart failure JID - 100887595 RN - 0 (Aminobutyrates) RN - 0 (Angiotensin Receptor Antagonists) RN - 0 (Angiotensin-Converting Enzyme Inhibitors) RN - 0 (Biphenyl Compounds) RN - 0 (Drug Combinations) RN - 0 (Tetrazoles) RN - 69PN84IO1A (Enalapril) RN - 80M03YXJ7I (Valsartan) RN - EC 3.4.24.11 (Neprilysin) RN - WB8FT61183 (sacubitril and valsartan sodium hydrate drug combination) SB - IM MH - Aged MH - Aminobutyrates/*therapeutic use MH - Amnesia/epidemiology MH - Angiotensin Receptor Antagonists/*therapeutic use MH - Angiotensin-Converting Enzyme Inhibitors/*therapeutic use MH - Biphenyl Compounds MH - Confusion/epidemiology MH - Delirium/epidemiology MH - Dementia/*epidemiology MH - Disorders of Excessive Somnolence/epidemiology MH - Drug Combinations MH - Enalapril/*therapeutic use MH - Female MH - Heart Failure/*drug therapy/physiopathology MH - Humans MH - Male MH - Middle Aged MH - Neprilysin/antagonists & inhibitors MH - Proportional Hazards Models MH - Stroke Volume MH - Tetrazoles/*therapeutic use MH - Valsartan PMC - PMC5248626 OTO - NOTNLM OT - ARNI OT - Dementia OT - Heart failure OT - Neprilysin inhibition EDAT- 2016/11/22 06:00 MHDA- 2017/11/10 06:00 PMCR- 2017/01/20 CRDT- 2016/11/22 06:00 PHST- 2016/05/26 00:00 [received] PHST- 2016/09/14 00:00 [revised] PHST- 2016/10/07 00:00 [accepted] PHST- 2016/11/22 06:00 [pubmed] PHST- 2017/11/10 06:00 [medline] PHST- 2016/11/22 06:00 [entrez] PHST- 2017/01/20 00:00 [pmc-release] AID - EJHF687 [pii] AID - 10.1002/ejhf.687 [doi] PST - ppublish SO - Eur J Heart Fail. 2017 Jan;19(1):129-137. doi: 10.1002/ejhf.687. Epub 2016 Nov 20.