Domink Glinz1, Viktoria L Gloy1, Andreas U Monsch2, Reto W Kressig3, Chandni Patel1, Kimberly Alba McCord1, Zanfina Ademi4, Yuki Tomonaga5, Matthias Schwenkglenks6, Heiner C Bucher1, Heike Raatz7. 1. Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel and University of Basel, Switzerland. 2. Memory Clinic, University Centre for Medicine of Aging, Felix Platter Hospital and University of Basel, Switzerland. 3. University Centre for Medicine of Ageing, Felix Platter Hospital, and University of Basel, Switzerland. 4. Institute of Pharmaceutical Medicine, University of Basel, Switzerland / School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia. 5. Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Switzerland. 6. School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia, / Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Switzerland. 7. Institute of Pharmaceutical Medicine, University of Basel, Switzerland / Kleijnen Systematic Reviews Ltd., Escrick, York, United Kingdom.
Abstract
BACKGROUND: The clinical efficacy and safety of combination therapy with acetylcholinesterase inhibitor (AChEI) and memantine compared to AChEI or memantine alone in patients with Alzheimer’s disease is inconclusive. AIMS OF THE STUDY: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing the clinical efficacy and safety of combination therapy of AChEI and memantine to monotherapy with either substance in patients with moderate to severe Alzheimer's disease (Mini-Mental State Examination score is <20). METHODS: We systematically searched EMBASE, Medline and CENTRAL until February 2018 for eligible RCTs. We pooled the outcome data using inverse variance weighting models assuming random effects, and assessed the quality of evidence (QoE) according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We included nine RCTs (2604 patients). At short-term follow-up (closest to 6 months), combination therapy compared to AChEI monotherapy had a significantly greater effect on cognition than AChEI monotherapy (standardised mean difference [SMD] 0.20, 95% confidence interval [CI] 0.05 to 0.35, 7 RCTs, low QoE) and clinical global impression (SMD −0.15, 95% CI −0.28 to −0.01, 4 RCTs, moderate QoE), but not on activities of daily living (SMD 0.09, 95% CI −0.01 to 0.18, 5 RCTs, moderate QoE) or behavioural and psychological symptoms of dementia (mean difference −3.07, 95% CI −6.53 to 0.38, 6 RCT, low QoE). There was no significant difference in adverse events (relative risk ratio 1.05, 95% CI 0.98 to 1.12, 4 RCTs, low QoE). Evidence for long-term follow-up (≥ 9 months) or nursing home placement was sparse. Only two studies compared combination therapy with memantine monotherapy. CONCLUSIONS: Combination therapy had statistically significant effects on cognition and clinical global impression. The clinical relevance of these effects is uncertain. The overall QoE was very low. With the current evidence, it remains unclear whether combination therapy adds any benefit. Large pragmatic RCTs with long-term follow-up and focus on functional outcomes, delay in nursing home placement and adverse events are needed.  .
BACKGROUND: The clinical efficacy and safety of combination therapy with acetylcholinesterase inhibitor (AChEI) and memantine compared to AChEI or memantine alone in patients with Alzheimer&rsquo;s disease is inconclusive. AIMS OF THE STUDY: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing the clinical efficacy and safety of combination therapy of AChEI and memantine to monotherapy with either substance in patients with moderate to severe Alzheimer&#39;s disease (Mini-Mental State Examination score is &lt;20). METHODS: We systematically searched EMBASE, Medline and CENTRAL until February 2018 for eligible RCTs. We pooled the outcome data using inverse variance weighting models assuming random effects, and assessed the quality of evidence (QoE) according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We included nine RCTs (2604 patients). At short-term follow-up (closest to 6 months), combination therapy compared to AChEI monotherapy had a significantly greater effect on cognition than AChEI monotherapy (standardised mean difference [SMD] 0.20, 95% confidence interval [CI] 0.05 to 0.35, 7 RCTs, low QoE) and clinical global impression (SMD &minus;0.15, 95% CI &minus;0.28 to &minus;0.01, 4 RCTs, moderate QoE), but not on activities of daily living (SMD 0.09, 95% CI &minus;0.01 to 0.18, 5 RCTs, moderate QoE) or behavioural and psychological symptoms of dementia (mean difference &minus;3.07, 95% CI &minus;6.53 to 0.38, 6 RCT, low QoE). There was no significant difference in adverse events (relative risk ratio 1.05, 95% CI 0.98 to 1.12, 4 RCTs, low QoE). Evidence for long-term follow-up (&ge; 9 months) or nursing home placement was sparse. Only two studies compared combination therapy with memantine monotherapy. CONCLUSIONS: Combination therapy had statistically significant effects on cognition and clinical global impression. The clinical relevance of these effects is uncertain. The overall QoE was very low. With the current evidence, it remains unclear whether combination therapy adds any benefit. Large pragmatic RCTs with long-term follow-up and focus on functional outcomes, delay in nursing home placement and adverse events are needed. &nbsp.