Increased Risk of Adverse Neurocognitive Outcomes with Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors

Circulation: Cardiovascular Quality and Outcomes

Volumn 10, Issue 1, 2017, Pages

  Khan, Abdur Rahman ^a   Bavishi, Chirag ^c   Riaz, Haris ^d   Farid, Talha A ^a   Khan, Sobia ^a   Atlas, Michel ^b   Hirsch, Glenn ^a   Ikram, Sohail ^a   Bolli, Roberto ^a  

^a University of Louisville School of Medicine   (United States)

^b UNIVERSITY OF LOUISVILLE   (United States)

^c ST LUKE S ROOSEVELT HOSPITAL CENTER   (United States)

^d LERNER RESEARCH INSTITUTE   (United States)

Author keywords

cognitive impairment; meta analysis; proprotein convertases; stroke; subtilisins

Indexed keywords

PROPROTEIN CONVERTASE 9; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9 INHIBITOR; SERINE PROTEINASE INHIBITOR; UNCLASSIFIED DRUG; ANTILIPEMIC AGENT; BIOLOGICAL MARKER; LIPID; PCSK9 PROTEIN, HUMAN;

ADVERSE OUTCOME; ARTICLE; CEREBROVASCULAR ACCIDENT; DISORDERS OF HIGHER CEREBRAL FUNCTION; DRUG SAFETY; HUMAN; META ANALYSIS; MUSCULOSKELETAL DISEASE; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); TREATMENT OUTCOME; ADOLESCENT; ADULT; AGED; ANTAGONISTS AND INHIBITORS; BLOOD; CHEMICALLY INDUCED; CHI SQUARE DISTRIBUTION; CLINICAL TRIAL (TOPIC); COGNITION; COGNITION DISORDERS; DRUG EFFECTS; DYSLIPIDEMIAS; ENZYMOLOGY; FEMALE; INCIDENCE; MALE; METABOLISM; MIDDLE AGED; ODDS RATIO; PATHOPHYSIOLOGY; PSYCHOLOGY; RISK ASSESSMENT; RISK FACTOR; STROKE; YOUNG ADULT;

ADOLESCENT; ADULT; AGED; BIOMARKERS; CHI-SQUARE DISTRIBUTION; CLINICAL TRIALS AS TOPIC; COGNITION; COGNITION DISORDERS; DYSLIPIDEMIAS; FEMALE; HUMANS; HYPOLIPIDEMIC AGENTS; INCIDENCE; LIPIDS; MALE; MIDDLE AGED; ODDS RATIO; PROPROTEIN CONVERTASE 9; RISK ASSESSMENT; RISK FACTORS; SERINE PROTEINASE INHIBITORS; STROKE; TREATMENT OUTCOME; YOUNG ADULT;

EID: 85009986038     PISSN: 19417713     EISSN: 19417705     Source Type: Journal    
DOI: 10.1161/CIRCOUTCOMES.116.003153     Document Type: Article

References (42)

1. Giugliano RP, Desai NR, Kohli P, Rogers WJ, Somaratne R, Huang F, Liu T, Mohanavelu S, Hoffman EB, McDonald ST, Abrahamsen TE, Wasserman SM, Scott R, Sabatine MS; LAPLACE-TIMI 57 Investigators. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012;380:2007-2017. doi: 10.1016/S0140-6736(12)61770-X
2. Hirayama A, Honarpour N, Yoshida M, Yamashita S, Huang F, Wasserman SM, Teramoto T. Effects of evolocumab (AMG 145), a monoclonal antibody to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk-primary results from the phase 2 YUKAWA study. Circ J. 2014;78:1073-1082
3. Koren MJ, Lundqvist P, Bolognese M, Neutel JM, Monsalvo ML, Yang J, Kim JB, Scott R, Wasserman SM, Bays H; MENDEL-2 Investigators. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2531-2540. doi: 10.1016/j.jacc.2014.03.018
4. Koren MJ, Scott R, Kim JB, Knusel B, Liu T, Lei L, Bolognese M, Wasserman SM. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, doubleblind, placebo-controlled, phase 2 study. Lancet. 2012;380:1995-2006. doi: 10.1016/S0140-6736(12)61771-1
5. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/ kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012;59:2344-2353. doi: 10.1016/j.jacc.2012.03.007
6. Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM, Stein EA. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation. 2012;126:2408-2417. doi: 10.1161/ CIRCULATIONAHA.112.144055
7. Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, Wasserman SM, Stein EA; TESLA Investigators. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:341-350. doi: 10.1016/S0140-6736(14)61374-X
8. Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L, Langslet G, Scott R, Olsson AG, Sullivan D, Hovingh GK, Cariou B, Gouni-Berthold I, Somaratne R, Bridges I, Scott R, Wasserman SM, Gaudet D; RUTHERFORD-2 Investigators. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:331-340. doi: 10.1016/S0140-6736(14)61399-4
9. Robinson JG, Nedergaard BS, Rogers WJ, Fialkow J, Neutel JM, Ramstad D, Somaratne R, Legg JC, Nelson P, Scott R, Wasserman SM, Weiss R; LAPLACE-2 Investigators. Effect of evolocumab or ezetimibe added to moderate-or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014;311:1870-1882. doi: 10.1001/jama.2014.4030
10. Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012;367:1891-1900. doi: 10.1056/NEJMoa1201832
11. Stein EA, Gipe D, Bergeron J, Gaudet D, Weiss R, Dufour R, Wu R, Pordy R. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. 2012;380:29-36. doi: 10.1016/S0140-6736(12)60771-5
12. Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF, Bruckert E, Cho L, Dent R, Knusel B, Xue A, Scott R, Wasserman SM, Rocco M; GAUSS-2 Investigators. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2541-2548. doi: 10.1016/j.jacc.2014.03.019
13. Sullivan D, Olsson AG, Scott R, Kim JB, Xue A, Gebski V, Wasserman SM, Stein EA. Effect of a monoclonal antibody to PCSK9 on lowdensity lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 2012;308:2497-2506. doi: 10.1001/ jama.2012.25790
14. Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott R, Koren MJ, Stein EA; Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500-1509. doi: 10.1056/NEJMoa1500858
15. Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, Ceska R, Roth E, Koren MJ, Ballantyne CM, Monsalvo ML, Tsirtsonis K, Kim JB, Scott R, Wasserman SM, Stein EA; DESCARTES Investigators. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370:1809-1819. doi: 10.1056/NEJMoa1316222
16. Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, Bruckert E, Jacobson TA, Kopecky SL, Baccara-Dinet MT, Du Y, Pordy R, Gipe DA; ODYSSEY ALTERNATIVE Investigators. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9:758-769. doi: 10.1016/j.jacl.2015.08.006
17. Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM. Efficacy and safety of the proprotein convertase subtilisin/ kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J. 2015;169:906-915.e13. doi: 10.1016/j.ahj.2015.03.004
18. Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM; ODYSSEY COMBO II Investigators. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36:1186-1194. doi: 10.1093/eurheartj/ehv028
19. Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, Blom D, Civeira F, Krempf M, Lorenzato C, Zhao J, Pordy R, Baccara-Dinet MT, Gipe DA, Geiger MJ, Farnier M. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36:2996-3003. doi: 10.1093/eurheartj/ehv370
20. Ginsberg HN, Rader DJ, Raal FJ, Guyton JR, Lorenzato C, Pordy R, Baccara-Dinet MT. ODYSSEY HIGH FH: Efficacy and safety of alirocumab in patients with severe heterozygous familial hypercholesterolemia. Presented at the American Heart Association Scientific Sessions, Chicago, IL, November 15-19, 2014. http://My.Americanheart. Org/Idc/Groups/Ahamah-Public/@Wcm/@Sop/@Scon/Documents/ Downloadable/Ucm-469651.Pdf. Accessed November 15, 2015
21. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, El Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ; ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489-1499. doi: 10.1056/ NEJMoa1501031
22. Roth EM, Taskinen MR, Ginsberg HN, Kastelein JJ, Colhoun HM, Robinson JG, Merlet L, Pordy R, Baccara-Dinet MT. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol. 2014;176:55-61. doi: 10.1016/j. ijcard.2014.06.049
23. Bays H, Gaudet D, Weiss R, Ruiz JL, Watts GF, Gouni-Berthold I, Robinson J, Zhao J, Hanotin C, Donahue S. Alirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I Randomized Trial. J Clin Endocrinol Metab. 2015;100:3140-3148. doi: 10.1210/jc.2015-1520
24. Farnier M, Jones P, Severance R, Averna M, Steinhagen-Thiessen E, Colhoun HM, Du Y, Hanotin C, Donahue S. Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial. Atherosclerosis. 2016;244:138-146. doi: 10.1016/j.atherosclerosis.2015.11.010
25. Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, Brockmeyer M, Kandzari DE, Kubica JM, D'Agostino RB , Kubica J, Volpe M, Agewall S, Kereiakes DJ, Kelm M. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med. 2015;163:40-51. doi: 10.7326/M14-2957
26. FDA Advises of Adverse Effects from New Cholesterol Drugs. Sanofi, Regeneron Advised of 'Neurocognitive Adverse Events' in New Drug. Wall Street J. Reported March 7, 2014. Http://Www.Wsj.Com/News/ Articles/Sb10001424052702304732804579425612487904436?Keyword s=Fda+Advises+of+Adverse+Effects+from+New+Cholesterol+Drugs&Mg=Reno64-WsjandUrl=Http%3a%2f%2fonline.Wsj.Com%2farticle%2f sb10001424052702304732804579425612487904436.Html%3fkeywords %3dfda%2badvises%2bof%2badverse%2beffects%2bfrom%2bnew%2bc holesterol%2bdrugs. Accessed July 9, 2016. 2014
27. Briel M, Vale N, Schwartz GG, de Lemos JA, Colivicchi F, den Hartog FR, Ostadal P, Macin SM, Liem A, Mills E, Bhatnagar N, Bucher HC, Nordmann AJ. Updated evidence on early statin therapy for acute coronary syndromes: meta-analysis of 18 randomized trials involving over 14,000 patients. Int J Cardiol. 2012;158:93-100. doi: 10.1016/j. ijcard.2011.01.033
28. Vecka M, Tvrzická E, Stanková B, Novák F, Nováková O, Zák A. Hypolipidemic drugs can change the composition of rat brain lipids. Tohoku J Exp Med. 2004;204:299-308
29. Ott BR, Daiello LA, Dahabreh IJ, Springate BA, Bixby K, Murali M, Trikalinos TA. Do statins impair cognition? A systematic review and metaanalysis of randomized controlled trials. J Gen Intern Med. 2015;30:348-358. doi: 10.1007/s11606-014-3115-3
30. Richardson K. Improving access to care through unrestricted NP practice. Am J Nurs. 2013;113:11. doi: 10.1097/01.NAJ.0000431244.85062.23
31. McGuinness B, Craig D, Bullock R, Malouf R, Passmore P. Statins for the treatment of dementia. Cochrane Database Syst Rev. 2014:CD007514
32. Tuccori M, Montagnani S, Mantarro S, Capogrosso-Sansone A, Ruggiero E, Saporiti A, Antonioli L, Fornai M, Blandizzi C. Neuropsychiatric adverse events associated with statins: epidemiology, pathophysiology, prevention and management. CNS Drugs. 2014;28:249-272. doi: 10.1007/ s40263-013-0135-1
33. Kelley BJ, Glasser S. Cognitive effects of statin medications. CNS Drugs. 2014;28:411-419. doi: 10.1007/s40263-014-0147-5
34. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700
35. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring Inconsistency in Meta-Analyses. BMJ (Clinical research ed.). 2003;327:557-560
36. Egger M, Davey Smith G, Schneider M, Minder C. Bias in Meta-Analysis Detected by a Simple, Graphical Test. BMJ (Clinical research ed.). 1997;315:629-634
37. Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56:455-463
38. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928
39. Krempf M, Simpson RJ Jr, Ramey DR, Brudi P, Giezek H, Tomassini JE, Lee R, Farnier M. Patient and physician factors influence decision-making in hypercholesterolemia: a questionnaire-based survey. Lipids Health Dis. 2015;14:45. doi: 10.1186/s12944-015-0037-y
40. Schwartz GG, Bessac L, Berdan LG, Bhatt DL, Bittner V, Diaz R, Goodman SG, Hanotin C, Harrington RA, Jukema JW, Mahaffey KW, Moryusef A, Pordy R, Roe MT, Rorick T, Sasiela WJ, Shirodaria C, Szarek M, Tamby JF, Tricoci P, White H, Zeiher A, Steg PG. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J. 2014;168:682-689. doi: 10.1016/j.ahj.2014.07.028
41. Odyssey Outcomes: Evaluation of Cardiovascular Outcomes after an Acute Coronary Syndrome During Treatment with Alirocumab. https:// clinicaltrials.gov/ct2/show/NCT01663402?term=odyssey+outcomesandra nk=1. Accessed December 11, 2015
42. Further Cardiovascular Outcomes Research with Pcsk9 Inhibition in Subjects with Elevated Risk (Fourier). https://clinicaltrials.gov/ct2/show/ NCT01764633. Accessed December 11, 2015