Impact of CYP2C19 Genotype Status on Clinical Outcomes in Patients with Symptomatic Coronary Artery Disease, Stroke, and Peripheral Arterial Disease: A Systematic Review and Meta-Analysis.
Clopidogrel is widely used for the secondary prevention of atherothrombotic events in patients with coronary artery disease (CAD), ischemic stroke, and peripheral arterial disease (PAD). CYP2C19 plays a pivotal role in the conversion of clopidogrel to its active metabolite. Clopidogrel-treated carriers of a CYP2C19 loss-of-function allele (LOF) may have a higher risk of new atherothrombotic events. Previous studies on genotype-guided treatment were mainly performed in CAD and showed mixed results.
To simultaneously investigate the impact of CYP2C19 genotype status on the rate of atherothrombotic events in the most common types of atherosclerotic disease (CAD, stroke, PAD).
A comprehensive search in Pubmed, EMBASE, and MEDLINE from their inception to July 23rd 2023 was performed. Randomized controlled trials (RCTs) comparing genotype-guided and standard antithrombotic treatment, and cohort studies and post hoc analyses of RCTs concerning the association between CYP2C19 genotype status and clinical outcomes in clopidogrel-treated patients were included. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the safety end point major bleeding. Secondary endpoints were myocardial infarction, stent thrombosis, and ischemic stroke.
Forty-four studies were identified: 11 studies on CAD, 29 studies on stroke, and 4 studies on PAD. In CAD, genotype-guided therapy significantly reduced the risk of MACE [risk ratio (RR) 0.60, 95% confidence interval (CI) 0.43-0.83], myocardial infarction (RR 0.53, 95% CI 0.42-0.68), and stent thrombosis (RR 0.64, 95% CI 0.43-0.94), compared with standard antithrombotic treatment. The rate of major bleeding did not differ significantly (RR 0.93, 95% CI 0.70-1.23). Most RCTs were performed in patients after percutaneous coronary intervention (9/11). In stroke, LOF carriers had a significantly higher risk of MACE (RR 1.61, 95% CI 1.25-2.08) and recurrent ischemic stroke (RR 1.89, 95% CI 1.48-2.40) compared with non-carriers. No significant differences were found in major bleeding (RR 0.90, 95% CI 0.43-1.89). In the 6955 patients with symptomatic PAD treated with clopidogrel in the EUCLID trial, no differences in MACE or major bleeding were found between LOF carriers and non-carriers. In three smaller studies on patients with PAD treated with clopidogrel after endovascular therapy, CYP2C19 genotype status was significantly associated with atherothrombotic events.
Genotype-guided treatment significantly decreased the rate of atherothrombotic events in patients with CAD, especially after PCI. In patients with history of stroke, LOF carriers treated with clopidogrel had a higher risk of MACE and recurrent stroke. The available evidence in PAD with regard to major adverse limb events is too limited to draw meaningful conclusions.
PROSPERO identifier no. CRD42020220284.
Maas DPMSM
，Willems LH
，Kranendonk J
，Kramers C
，Warlé MC
... -
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Falls prevention interventions for community-dwelling older adults: systematic review and meta-analysis of benefits, harms, and patient values and preferences.
About 20-30% of older adults (≥ 65 years old) experience one or more falls each year, and falls are associated with substantial burden to the health care system, individuals, and families from resulting injuries, fractures, and reduced functioning and quality of life. Many interventions for preventing falls have been studied, and their effectiveness, factors relevant to their implementation, and patient preferences may determine which interventions to use in primary care. The aim of this set of reviews was to inform recommendations by the Canadian Task Force on Preventive Health Care (task force) on fall prevention interventions. We undertook three systematic reviews to address questions about the following: (i) the benefits and harms of interventions, (ii) how patients weigh the potential outcomes (outcome valuation), and (iii) patient preferences for different types of interventions, and their attributes, shown to offer benefit (intervention preferences).
We searched four databases for benefits and harms (MEDLINE, Embase, AgeLine, CENTRAL, to August 25, 2023) and three for outcome valuation and intervention preferences (MEDLINE, PsycINFO, CINAHL, to June 9, 2023). For benefits and harms, we relied heavily on a previous review for studies published until 2016. We also searched trial registries, references of included studies, and recent reviews. Two reviewers independently screened studies. The population of interest was community-dwelling adults ≥ 65 years old. We did not limit eligibility by participant fall history. The task force rated several outcomes, decided on their eligibility, and provided input on the effect thresholds to apply for each outcome (fallers, falls, injurious fallers, fractures, hip fractures, functional status, health-related quality of life, long-term care admissions, adverse effects, serious adverse effects). For benefits and harms, we included a broad range of non-pharmacological interventions relevant to primary care. Although usual care was the main comparator of interest, we included studies comparing interventions head-to-head and conducted a network meta-analysis (NMAs) for each outcome, enabling analysis of interventions lacking direct comparisons to usual care. For benefits and harms, we included randomized controlled trials with a minimum 3-month follow-up and reporting on one of our fall outcomes (fallers, falls, injurious fallers); for the other questions, we preferred quantitative data but considered qualitative findings to fill gaps in evidence. No date limits were applied for benefits and harms, whereas for outcome valuation and intervention preferences we included studies published in 2000 or later. All data were extracted by one trained reviewer and verified for accuracy and completeness. For benefits and harms, we relied on the previous review team's risk-of-bias assessments for benefit outcomes, but otherwise, two reviewers independently assessed the risk of bias (within and across study). For the other questions, one reviewer verified another's assessments. Consensus was used, with adjudication by a lead author when necessary. A coding framework, modified from the ProFANE taxonomy, classified interventions and their attributes (e.g., supervision, delivery format, duration/intensity). For benefit outcomes, we employed random-effects NMA using a frequentist approach and a consistency model. Transitivity and coherence were assessed using meta-regressions and global and local coherence tests, as well as through graphical display and descriptive data on the composition of the nodes with respect to major pre-planned effect modifiers. We assessed heterogeneity using prediction intervals. For intervention-related adverse effects, we pooled proportions except for vitamin D for which we considered data in the control groups and undertook random-effects pairwise meta-analysis using a relative risk (any adverse effects) or risk difference (serious adverse effects). For outcome valuation, we pooled disutilities (representing the impact of a negative event, e.g. fall, on one's usual quality of life, with 0 = no impact and 1 = death and ~ 0.05 indicating important disutility) from the EQ-5D utility measurement using the inverse variance method and a random-effects model and explored heterogeneity. When studies only reported other data, we compared the findings with our main analysis. For intervention preferences, we used a coding schema identifying whether there were strong, clear, no, or variable preferences within, and then across, studies. We assessed the certainty of evidence for each outcome using CINeMA for benefit outcomes and GRADE for all other outcomes.
A total of 290 studies were included across the reviews, with two studies included in multiple questions. For benefits and harms, we included 219 trials reporting on 167,864 participants and created 59 interventions (nodes). Transitivity and coherence were assessed as adequate. Across eight NMAs, the number of contributing trials ranged between 19 and 173, and the number of interventions ranged from 19 to 57. Approximately, half of the interventions in each network had at least low certainty for benefit. The fallers outcome had the highest number of interventions with moderate certainty for benefit (18/57). For the non-fall outcomes (fractures, hip fracture, long-term care [LTC] admission, functional status, health-related quality of life), many interventions had very low certainty evidence, often from lack of data. We prioritized findings from 21 interventions where there was moderate certainty for at least some benefit. Fourteen of these had a focus on exercise, the majority being supervised (for > 2 sessions) and of long duration (> 3 months), and with balance/resistance and group Tai Chi interventions generally having the most outcomes with at least low certainty for benefit. None of the interventions having moderate certainty evidence focused on walking. Whole-body vibration or home-hazard assessment (HHA) plus exercise provided to everyone showed moderate certainty for some benefit. No multifactorial intervention alone showed moderate certainty for any benefit. Six interventions only had very-low certainty evidence for the benefit outcomes. Two interventions had moderate certainty of harmful effects for at least one benefit outcome, though the populations across studies were at high risk for falls. Vitamin D and most single-component exercise interventions are probably associated with minimal adverse effects. Some uncertainty exists about possible adverse effects from other interventions. For outcome valuation, we included 44 studies of which 34 reported EQ-5D disutilities. Admission to long-term care had the highest disutility (1.0), but the evidence was rated as low certainty. Both fall-related hip (moderate certainty) and non-hip (low certainty) fracture may result in substantial disutility (0.53 and 0.57) in the first 3 months after injury. Disutility for both hip and non-hip fractures is probably lower 12 months after injury (0.16 and 0.19, with high and moderate certainty, respectively) compared to within the first 3 months. No study measured the disutility of an injurious fall. Fractures are probably more important than either falls (0.09 over 12 months) or functional status (0.12). Functional status may be somewhat more important than falls. For intervention preferences, 29 studies (9 qualitative) reported on 17 comparisons among single-component interventions showing benefit. Exercise interventions focusing on balance and/or resistance training appear to be clearly preferred over Tai Chi and other forms of exercise (e.g., yoga, aerobic). For exercise programs in general, there is probably variability among people in whether they prefer group or individual delivery, though there was high certainty that individual was preferred over group delivery of balance/resistance programs. Balance/resistance exercise may be preferred over education, though the evidence was low certainty. There was low certainty for a slight preference for education over cognitive-behavioral therapy, and group education may be preferred over individual education.
To prevent falls among community-dwelling older adults, evidence is most certain for benefit, at least over 1-2 years, from supervised, long-duration balance/resistance and group Tai Chi interventions, whole-body vibration, high-intensity/dose education or cognitive-behavioral therapy, and interventions of comprehensive multifactorial assessment with targeted treatment plus HHA, HHA plus exercise, or education provided to everyone. Adding other interventions to exercise does not appear to substantially increase benefits. Overall, effects appear most applicable to those with elevated fall risk. Choice among effective interventions that are available may best depend on individual patient preferences, though when implementing new balance/resistance programs delivering individual over group sessions when feasible may be most acceptable. Data on more patient-important outcomes including fall-related fractures and adverse effects would be beneficial, as would studies focusing on equity-deserving populations and on programs delivered virtually.
Not registered.
Pillay J
，Gaudet LA
，Saba S
，Vandermeer B
，Ashiq AR
，Wingert A
，Hartling L
... -
《Systematic Reviews》
ResearchGate
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