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BACKGROUND AND OBJECTIVES: Cholinesterase inhibitors (ChEIs) have cardiovascular effects in addition to their neurological activity and might alter mortality. We wanted to know if treatment with ChEIs modifies mortality in patients with dementia.
METHODS: We searched PubMed, EMBASE, Cochrane CENTRAL, ClinicalTrials.gov and ICRTP, from their inception to November 2021, and screened bibliographies of reviews, guidelines and included studies. We included randomized controlled trials (RCTs) and non-randomized controlled studies at lower risk of bias comparing ChEI treatment with placebo or usual treatment, for 6 months or longer, in patients with dementia of any type. Two investigators independently assessed studies for inclusion, assessed their risk of bias and extracted data, using predefined forms. Any discordance between investigators was solved by discussion and consensus. Data on all-cause and cardiovascular mortality, measured as either crude death rates or multivariate adjusted hazard ratios (HR), was pooled using a random-effect model. Information size achieved was assessed using trial sequential analysis (TSA). We followed PRISMA guidelines.
RESULTS: 24 studies (12 RCTs, 12 cohorts, mean follow-up 6 to 120 months), cumulating 79 153 patients with Alzheimer's (13 studies), Parkinson's (1), vascular (1) or any type (9) dementia, fulfilled inclusion criteria. Pooled all-cause mortality in control patients was 15.1 per 100 person-years. Treatment with ChEIs was associated with lower all-cause mortality (unadjusted RR 0.74, 95%CI 0.66 - 0.84; adjusted HR 0.77, 95%CI 0.70 - 0.84, moderate to high quality evidence). This result was consistent between randomized and non-randomized studies and in several sensitivity analyses. No difference appeared between subgroups by type of dementia, age, individual drug or dementia severity. Less data was available for cardiovascular mortality (3 RCTs, 2 cohorts, 9 182 patients, low to moderate quality evidence), which was also lower in patients treated with ChEIs (unadjusted RR 0.61, 95%CI 0.40 - 0.93, adjusted HR 0.47, 95%CI 0.32 - 0.68). In TSA analysis, results for all-cause mortality were conclusive, but not those for cardiovascular mortality.
DISCUSSION: There is moderate to high quality evidence of a consistent association between long-term treatment with ChEIs and a reduction in all-cause mortality in patients with dementia. These findings may influence decisions to prescribe ChEIs in those patients.
TRIAL REGISTRATION INFORMATION: This systematic review was registered in the PROSPERO international prospective register of systematic reviews with the number CRD42021254458 (11/06/2021).
|Family Medicine (FM)/General Practice (GP)|
As a family physician, I found these results interesting. The reduction risk in mortality with ChEIs seems clear, despite the funnel plot showing a possible publication bias, which means that some unpublished studies may show different results. The big problem is the main outcome, because mortality is probably not the main concern of people with dementia and their families, but quality of life is. With these results, I will keep using ChEIs as second-line therapy in selected patients.
A game-changer in how we think about cholinesterase inhibitors.
As a geriatrician, I prescribe these drugs much less frequently in very frail patients and those with significant cardiovascular disease, particularly if they are on drugs that slow heart rate. I am also hesitant to prescribe them in patients with falls. I am concerned that the attempts to correct for bias might not be as successful as we would hope.
I think this has a time-related bias, such as immortal time bias. The same problem happened in the study of metformin and cancer mortality (PMC3507580 => PMC9131745). For example, the largest observational study in this MA (PMID:16089241) clipped two years of data from 1998-2000 (I couldn't read the original text for this one). The mean follow-up period in this MA was the same, so I think they did their analysis without considering the start period of donepezil.
The start date of donepezil seems to have existed in the data, so maybe the original study did a sensitivity analysis.. I'm not sure.
Is mortality the outcome of interest in patients with dementia? Shouldn't it rather be quality-of-life?