Validity, significance, strengths, limitations, and evidentiary value of real-world clinical data for combination therapy in Alzheimer's disease: comparison of efficacy and effectiveness studies.
BACKGROUND
Randomized controlled efficacy trials (RCTs), the scientific gold standard, are required for regulatory approval of Alzheimer's disease (AD) interventions, yet provide limited information regarding real-world therapeutic effectiveness.


OBJECTIVE
To compare the nature of evidence regarding the combination of approved AD treatments from RCTs versus long-term observational controlled studies (LTOCs).


METHODS
Comparisons of strengths, limitations, and evidence level for monotherapy [cholinesterase inhibitor (ChEI) or memantine] and combination therapy (ChEI + memantine) in RCTs versus LTOCs.


RESULTS
RCTs examined highly selected populations over months. LTOCs collected data across multiple AD stages in large populations over many years. RCTs and LTOCs show similar patterns favoring combination over monotherapy over placebo/no treatment. Long-term combination therapy compared to monotherapy reduced cognitive and functional decline and delayed time to nursing home admission. Persistent treatment was associated with slower decline. While LTOCs used control groups, adjusted for multiple covariates, had higher external validity, and favorable ethical, practical and cost considerations, their limitations included potential selection bias due to lack of placebo comparisons and randomization.


CONCLUSIONS
Naturalistic LTOCs provide complementary long-term level II evidence to complement level I evidence from short-term RCTs regarding therapeutic effectiveness in AD that may otherwise be unobtainable. A coordinated strategy/consortium to pool LTOC data from multiple centers to estimate long-term comparative effectiveness, risks/benefits, and costs of AD treatments is needed.
Department of Neurology, Massachusetts General Hospital, Boston, Mass 02114, USA. atri@nmr.mgh.harvard.edu
Alireza
A
Atri
Susan D
SD
Rountree
Oscar L
OL
Lopez
Rachelle S
RS
Doody
D000544:Alzheimer Disease / Q000188:drug therapy*; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D015331:Cohort Studies; D016206:Databases, Bibliographic / Q000706:statistics & numerical data; D004359:Drug Therapy, Combination / Q000009:adverse effects / Q000379:methods*; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D006801:Humans; D008559:Memantine / Q000627:therapeutic use*; D008609:Mental Status Schedule; D015201:Meta-Analysis as Topic; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results; D013997:Time Factors; D016896:Treatment Outcome
D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D008559:Memantine