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The American Journal of Psychiatry Feb 2016Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder follows a flat response curve... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder.
METHOD
The authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder.
RESULTS
Forty studies involving 10,039 participants were included. Longitudinal modeling (dose-by-time interaction=0.0007, 95% CI=0.0001-0.0013) and endpoint analysis (meta-regression: β=0.00053, 95% CI=0.00018-0.00088, z=2.98) demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects (meta-regression: β=0.00207, 95% CI=0.00071-0.00342, z=2.98) and decreased likelihood of all-cause dropout (meta-regression: β=-0.00093, 95% CI=-0.00165 to -0.00021, z=-2.54).
CONCLUSIONS
Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents (50 mg of fluoxetine). The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.
Topics: Citalopram; Depressive Disorder, Major; Dose-Response Relationship, Drug; Fluoxetine; Fluvoxamine; Humans; Paroxetine; Selective Serotonin Reuptake Inhibitors; Sertraline; Treatment Outcome
PubMed: 26552940
DOI: 10.1176/appi.ajp.2015.15030331 -
Clinical Microbiology and Infection :... May 2023The efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of acute COVID-19 is still under investigation, with conflicting results reported from... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of acute COVID-19 is still under investigation, with conflicting results reported from randomized controlled trials (RCTs). Different dosing regimens may have contributed to the contradictory findings.
OBJECTIVES
To evaluate the efficacy and safety of SSRIs and the effect of different dosing regimens on the treatment of acute COVID-19.
DATA SOURCES
Seven databases were searched from January 2020 to December 2022. Trial registries, previous reviews, and preprint servers were hand-searched.
STUDY ELIGIBILITY CRITERIA
RCTs and observational studies with no language restrictions.
PARTICIPANTS
COVID-19 inpatients/outpatients.
INTERVENTIONS
SSRIs prescribed after diagnosis were compared against a placebo or standard of care.
ASSESSMENT OF RISK OF BIAS
Risk of bias was rated using the revised Cochrane Risk of Bias Tool for Randomized Trials version 2.0 and Risk of Bias in Non-Randomized Studies of Interventions.
METHODS OF DATA SYNTHESIS
Outcomes were mortality, hospitalization, composite of hospitalization/emergency room visits, hypoxemia, requirement for supplemental oxygen, ventilator support, and serious adverse events. RCT data were pooled in random-effects meta-analyses. Observational findings were narratively described. Subgroup analyses were performed on the basis of SSRI dose, and sensitivity analyses were performed excluding studies with a high risk of bias. The Grading of Recommendations, Assessment, Development and Evaluations framework was used to assess the quality of evidence.
RESULTS
Six RCTs (N = 4197) and five observational studies (N = 1156) were included. Meta-analyses associated fluvoxamine with reduced mortality (risk ratio, 0.72; 95% CI, 0.63-0.82) and hospitalization (risk ratio, 0.79; 95% CI, 0.64-0.99) on the basis of moderate quality of evidence. Medium-dose fluvoxamine (100 mg twice a day) was associated with reduced mortality, hospitalization, and composite of hospitalization/emergency room visits, but low-dose fluvoxamine (50 mg twice a day) was not. Fluvoxamine was not associated with increased serious adverse events. Observational studies support the use of fluvoxamine and highlight fluoxetine as a possible alternative to SSRIs for the treatment of COVID-19.
DISCUSSION
Fluvoxamine remains a candidate pharmacotherapy for treating COVID-19 in outpatients. Medium-dose fluvoxamine may be preferable over low-dose fluvoxamine.
Topics: Humans; Selective Serotonin Reuptake Inhibitors; COVID-19; Fluoxetine; Fluvoxamine
PubMed: 36657488
DOI: 10.1016/j.cmi.2023.01.010 -
JAMA Network Open Apr 2022Widely available and affordable options for the outpatient management of COVID-19 are needed, particularly for therapies that prevent hospitalization. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Widely available and affordable options for the outpatient management of COVID-19 are needed, particularly for therapies that prevent hospitalization.
OBJECTIVE
To perform a meta-analysis of the available randomized clinical trial evidence for fluvoxamine in the outpatient management of COVID-19.
DATA SOURCES
World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov.
STUDY SELECTION
Studies with completed outpatient trials with available results that compared fluvoxamine with placebo were included.
DATA EXTRACTION AND SYNTHESIS
The PRISMA 2020 guidelines were followed and study details in terms of inclusion criteria, trial demographics, and the prespecified outcome of all-cause hospitalization were extracted. Risk of bias was assessed by the Cochrane Risk of Bias 2 tool and a bayesian random effects meta-analysis with different estimates of prior probability was conducted: a weakly neutral prior (50% chance of efficacy with 95% CI for risk ratio [RR] between 0.5 and 2.0) and a moderately optimistic prior (85% chance of efficacy). A frequentist random-effects meta-analysis was conducted as a senstivity analysis, and the results were contextualized by estimating the probability of any association (RR ≤ 1) and moderate association (RR ≤ 0.9) with reduced hospitalization.
MAIN OUTCOMES AND MEASURES
All-cause hospitalization.
RESULTS
This systematic review and meta-analysis of 3 randomized clinical trials and included 2196 participants. The RRs for hospitalization were 0.78 (95% CI, 0.58-1.08) for the bayesian weakly neutral prior, 0.73 (95% CI, 0.53-1.01) for the bayesian moderately optimistic prior, and 0.75 (95% CI, 0.58-0.97) for the frequentist analysis. Depending on the scenario, the probability of any association with reduced hospitalization ranged from 94.1% to 98.6%, and the probability of moderate association ranged from 81.6% to 91.8%.
CONCLUSIONS AND RELEVANCE
In this systematic review and meta-analysis of data from 3 trials, under a variety of assumptions, fluvoxamine showed a high probability of being associated with reduced hospitalization in outpatients with COVID-19. Ongoing randomized trials are important to evaluate alternative doses, explore the effectiveness in vaccinated patients, and provide further refinement to these estimates. Meanwhile, fluvoxamine could be recommended as a management option, particularly in resource-limited settings or for individuals without access to SARS-CoV-2 monoclonal antibody therapy or direct antivirals.
Topics: Bayes Theorem; Fluvoxamine; Hospitalization; Humans; Outpatients; Randomized Controlled Trials as Topic; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35385087
DOI: 10.1001/jamanetworkopen.2022.6269 -
The Journal of Infection Dec 2022
Meta-Analysis
Topics: Humans; Fluvoxamine; COVID-19 Drug Treatment
PubMed: 36244547
DOI: 10.1016/j.jinf.2022.10.012 -
Scientific Reports Jun 2024There have been 774,075,242 cases of COVID-19 and 7,012,986 deaths worldwide as of January 2024. In the early stages of the pandemic, there was an urgent need to reduce... (Meta-Analysis)
Meta-Analysis
A systematic review and meta-analysis, investigating dose and time of fluvoxamine treatment efficacy for COVID-19 clinical deterioration, death, and Long-COVID complications.
There have been 774,075,242 cases of COVID-19 and 7,012,986 deaths worldwide as of January 2024. In the early stages of the pandemic, there was an urgent need to reduce the severity of the disease and prevent the need for hospitalization to avoid stress on healthcare systems worldwide. The repurposing of drugs to prevent clinical deterioration of COVID-19 patients was trialed in many studies using many different drugs. Fluvoxamine (an SSRI and sigma-1 receptor agonist) was initially identified to potentially provide beneficial effects in COVID-19-infected patients, preventing clinical deterioration and the need for hospitalization. Fourteen clinical studies have been carried out to date, with seven of those being randomized placebo-controlled studies. This systematic review and meta-analysis covers the literature from the outbreak of SARS-CoV-2 in late 2019 until January 2024. Search terms related to fluvoxamine, such as its trade names and chemical names, along with words related to COVID-19, such as SARS-CoV-2 and coronavirus, were used in literature databases including PubMed, Google Scholar, Scopus, and the ClinicalTrials.gov database from NIH, to identify the trials used in the subsequent analysis. Clinical deterioration and death data were extracted from these studies where available and used in the meta-analysis. A total of 7153 patients were studied across 14 studies (both open-label and double-blind placebo-controlled). 681 out of 3553 (19.17%) in the standard care group and 255 out of 3600 (7.08%) in the fluvoxamine-treated group experienced clinical deterioration. The estimated average log odds ratio was 1.087 (95% CI 0.200 to 1.973), which differed significantly from zero (z = 2.402, p = 0.016). The seven placebo-controlled studies resulted in a log odds ratio of 0.359 (95% CI 0.1111 to 0.5294), which differed significantly from zero (z = 3.103, p = 0.002). The results of this study identified fluvoxamine as effective in preventing clinical deterioration, and subgrouping analysis suggests that earlier treatment with a dose of 200 mg or above provides the best outcomes. We hope the outcomes of this study can help design future studies into respiratory viral infections and potentially improve clinical outcomes.
Topics: Fluvoxamine; Humans; COVID-19 Drug Treatment; COVID-19; SARS-CoV-2; Treatment Outcome; Clinical Deterioration; Selective Serotonin Reuptake Inhibitors
PubMed: 38862591
DOI: 10.1038/s41598-024-64260-9 -
PloS One 2024Recently, several randomized controlled trials (RCTs) of fluvoxamine have been successfully conducted for the treatment of patients with coronavirus disease 2019... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Recently, several randomized controlled trials (RCTs) of fluvoxamine have been successfully conducted for the treatment of patients with coronavirus disease 2019 (COVID-19). This systematic review and meta-analysis was to evaluate the efficacy and safety of fluvoxamine in patients with COVID-19.
METHODS
MEDLINE, EMBASE, Cochrane Library and clinicaltrials.gov were searched for RCTs which were performed to evaluate fluvoxamine and placebo up to January 31, 2024. Review Manager 5.3 was used to perform meta-analysis. The risk ratio (RR) and mean difference (MD) was analyzed and calculated with a random effect model.
RESULTS
We pooled 4,711 participants from six RCTs (2,382 in the fluvoxamine group and 2,329 in the placebo group). Compared to the placebo group, the fluvoxamine group had a significantly lower rate of clinical deterioration (RR, 0.73; P = 0.004; 95% CI, 0.59 to 0.90; I2 = 0%) and hospitalization (RR, 0.76; P = 0.04; 95% CI, 0.59 to 0.99; I2 = 0%). In the meantime, compared with the placebo group, fluvoxamine group did not show any higher risk of AEs (P = 0.13 and 0.91, respectively) in safety outcomes analysis. The subgroup analysis showed that fluvoxamine treatment performed more than 200 mg daily appears to be more effective than those performed less than 200 mg daily in reducing clinical deterioration and hospitalization risks, while not exhibiting higher AE and SAE risks than placebo group.
CONCLUSION
Fluvoxamine for patients with COVID-19, especially those who take 200 mg or more daily, is superior to the placebo group in reducing clinical deterioration and hospitalization, and did not show any higher risk of AEs and SAEs in safety concerns, which might be a promising intervention for COVID-19.
Topics: Fluvoxamine; Humans; COVID-19 Drug Treatment; Randomized Controlled Trials as Topic; SARS-CoV-2; COVID-19; Treatment Outcome; Hospitalization
PubMed: 38753761
DOI: 10.1371/journal.pone.0300512 -
Journal of Comparative Effectiveness... Dec 2019To conduct a systematic literature review of high-risk resectable cutaneous melanoma adjuvant therapeutics and compare safety and efficacy. The systematic literature... (Comparative Study)
Comparative Study Meta-Analysis
To conduct a systematic literature review of high-risk resectable cutaneous melanoma adjuvant therapeutics and compare safety and efficacy. The systematic literature review included randomized controlled trials investigating: dabrafenib plus trametinib (DAB + TRAM), nivolumab, pembrolizumab, ipilimumab, vemurafenib, chemotherapy and interferons. Outcomes included overall survival (OS), relapse-free survival, distant metastasis-free survival and safety. All outcomes were synthesized using Bayesian network meta-analysis. Across relapse-free survival, distant metastasis-free survival and OS, DAB + TRAM had the lowest estimated hazards of respective events relative to all other treatments (exception relative to nivolumab in OS). Differences were significant relative to placebo, chemotherapy, interferons and ipilimumab. DAB + TRAM has improved efficacy over historical treatment options (ipilimumab, interferons and chemotherapy) and comparable efficacy with other targeted and immune checkpoint inhibitors.
Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Imidazoles; Interferons; Ipilimumab; Male; Melanoma; Middle Aged; Neoplasm Recurrence, Local; Network Meta-Analysis; Nivolumab; Oximes; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Skin Neoplasms; Treatment Outcome; Vemurafenib
PubMed: 31778073
DOI: 10.2217/cer-2019-0061 -
PloS One 2022Clinical Depression and the subsequent low immunity is a comorbidity that can act as a risk factor for the severity of COVID-19 cases. Antidepressants such as Selective... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Clinical Depression and the subsequent low immunity is a comorbidity that can act as a risk factor for the severity of COVID-19 cases. Antidepressants such as Selective serotonin reuptake inhibitor and Serotonin-norepinephrine reuptake inhibitors are associated with immune-modulatory effects, which dismiss inflammatory responses and reduce lung tissue damage. The current systematic review and meta-analysis aims to evaluate the effect of antidepressant drugs on the prognosis and severity of COVID-19 in hospitalized patients.
METHODS
A systematic search was carried out in PubMed/Medline, EMBASE, and Scopus up to June 14, 2022. The following keywords were used: "COVID-19", "SARS-CoV-2", "2019-nCoV", "SSRI", "SNRI", "TCA", "MAOI", and "Antidepressant". A fixed or random-effect model assessed the pooled risk ratio (RR) with 95% CI. We considered P < 0.05 as statistically significant for publication bias. Data were analyzed by Comprehensive Meta-Analysis software, Version 2.0 (Biostat, Englewood, NJ).
RESULTS
Fourteen studies were included in our systematic review. Five of them were experimental with 2350, and nine of them were observational with 290,950 participants. Eight out of fourteen articles revealed the effect of antidepressants on reducing the severity of COVID-19. Selective serotonin reuptake inhibitors drugs, including Fluvoxamine, Escitalopram, Fluoxetine, and Paroxetine, and among the Serotonin-norepinephrine inhibitors medications Venlafaxine, are reasonably associated with reduced risk of intubation or death. Five studies showed no significant effect, and only one high risk of bias article showed the negative effect of antidepressants on the prognosis of Covid-19. The meta-analysis of clinical trials showed that fluvoxamine could significantly decrease the severity outcomes of COVID-19 (RR: 0.763; 95% CI: 0.602-0.966, I2: 0.0).
FINDINGS
Most evidence supports that the use of antidepressant medications, mainly Fluvoxamine, may decrease the severity and improve the outcome in hospitalized patients with SARS-CoV-2. Some studies showed contradictory findings regarding the effects of antidepressants on the severity of COVID-19. Further clinical trials should be conducted to clarify the effects of antidepressants on the severity of COVID-19.
Topics: Antidepressive Agents; Fluoxetine; Fluvoxamine; Humans; Norepinephrine; Paroxetine; SARS-CoV-2; Serotonin; Selective Serotonin Reuptake Inhibitors; Venlafaxine Hydrochloride; COVID-19 Drug Treatment
PubMed: 36201406
DOI: 10.1371/journal.pone.0267423 -
The Cochrane Database of Systematic... Apr 2017Uterine fibroids are smooth muscle tumours arising from the uterus. These tumours, although benign, are commonly associated with abnormal uterine bleeding, bulk symptoms... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Uterine fibroids are smooth muscle tumours arising from the uterus. These tumours, although benign, are commonly associated with abnormal uterine bleeding, bulk symptoms and reproductive dysfunction. The importance of progesterone in fibroid pathogenesis supports selective progesterone receptor modulators (SPRMs) as effective treatment. Both biochemical and clinical evidence suggests that SPRMs may reduce fibroid growth and ameliorate symptoms. SPRMs can cause unique histological changes to the endometrium that are not related to cancer, are not precancerous and have been found to be benign and reversible. This review summarises randomised trials conducted to evaluate the effectiveness of SPRMs as a class of medication for treatment of individuals with fibroids.
OBJECTIVES
To evaluate the effectiveness and safety of SPRMs for treatment of premenopausal women with uterine fibroids.
SEARCH METHODS
We searched the Specialised Register of the Cochrane Gynaecology and Fertility Group, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and clinical trials registries from database inception to May 2016. We handsearched the reference lists of relevant articles and contacted experts in the field to request additional data.
SELECTION CRITERIA
Included studies were randomised controlled trials (RCTs) of premenopausal women with fibroids who were treated for at least three months with a SPRM.
DATA COLLECTION AND ANALYSIS
Two review authors independently reviewed all eligible studies identified by the search. We extracted data and assessed risk of bias independently using standard forms. We analysed data using mean differences (MDs) or standardised mean differences (SMDs) for continuous data and odds ratios (ORs) for dichotomous data. We performed meta-analyses using the random-effects model. Our primary outcome was change in fibroid-related symptoms.
MAIN RESULTS
We included in the review 14 RCTs with a total of 1215 study participants. We could not extract complete data from three studies. We included in the meta-analysis 11 studies involving 1021 study participants: 685 received SPRMs and 336 were given a control intervention (placebo or leuprolide). Investigators evaluated three SPRMs: mifepristone (five studies), ulipristal acetate (four studies) and asoprisnil (two studies). The primary outcome was change in fibroid-related symptoms (symptom severity, health-related quality of life, abnormal uterine bleeding, pelvic pain). Adverse event reporting in the included studies was limited to SPRM-associated endometrial changes. More than half (8/14) of these studies were at low risk of bias in all domains. The most common limitation of the other studies was poor reporting of methods. The main limitation for the overall quality of evidence was potential publication bias. SPRM versus placebo SPRM treatment resulted in improvements in fibroid symptom severity (MD -20.04 points, 95% confidence interval (CI) -26.63 to -13.46; four RCTs, 171 women, I = 0%; moderate-quality evidence) and health-related quality of life (MD 22.52 points, 95% CI 12.87 to 32.17; four RCTs, 200 women, I = 63%; moderate-quality evidence) on the Uterine Fibroid Symptom Quality of Life Scale (UFS-QoL, scale 0 to 100). Women treated with an SPRM showed reduced menstrual blood loss on patient-reported bleeding scales, although this effect was small (SMD -1.11, 95% CI -1.38 to -0.83; three RCTs, 310 women, I = 0%; moderate-quality evidence), along with higher rates of amenorrhoea (29 per 1000 in the placebo group vs 237 to 961 per 1000 in the SPRM group; OR 82.50, 95% CI 37.01 to 183.90; seven RCTs, 590 women, I = 0%; moderate-quality evidence), compared with those given placebo. We could draw no conclusions regarding changes in pelvic pain owing to variability in the estimates. With respect to adverse effects, SPRM-associated endometrial changes were more common after SPRM therapy than after placebo (OR 15.12, 95% CI 6.45 to 35.47; five RCTs, 405 women, I = 0%; low-quality evidence). SPRM versus leuprolide acetate In comparing SPRM versus other treatments, two RCTs evaluated SPRM versus leuprolide acetate. One RCT reported primary outcomes. No evidence suggested a difference between SPRM and leuprolide groups for improvement in quality of life, as measured by UFS-QoL fibroid symptom severity scores (MD -3.70 points, 95% CI -9.85 to 2.45; one RCT, 281 women; moderate-quality evidence) and health-related quality of life scores (MD 1.06 points, 95% CI -5.73 to 7.85; one RCT, 281 women; moderate-quality evidence). It was unclear whether results showed a difference between SPRM and leuprolide groups for reduction in menstrual blood loss based on the pictorial blood loss assessment chart (PBAC), as confidence intervals were wide (MD 6 points, 95% CI -40.95 to 50.95; one RCT, 281 women; low-quality evidence), or for rates of amenorrhoea (804 per 1000 in the placebo group vs 732 to 933 per 1000 in the SPRM group; OR 1.14, 95% CI 0.60 to 2.16; one RCT, 280 women; moderate-quality evidence). No evidence revealed differences between groups in pelvic pain scores based on the McGill Pain Questionnaire (scale 0 to 45) (MD -0.01 points, 95% CI -2.14 to 2.12; 281 women; moderate-quality evidence). With respect to adverse effects, SPRM-associated endometrial changes were more common after SPRM therapy than after leuprolide treatment (OR 10.45, 95% CI 5.38 to 20.33; 301 women; moderate-quality evidence).
AUTHORS' CONCLUSIONS
Short-term use of SPRMs resulted in improved quality of life, reduced menstrual bleeding and higher rates of amenorrhoea than were seen with placebo. Thus, SPRMs may provide effective treatment for women with symptomatic fibroids. Evidence derived from one RCT showed no difference between leuprolide acetate and SPRM with respect to improved quality of life and bleeding symptoms. Evidence was insufficient to show whether effectiveness was different between SPRMs and leuprolide. Investigators more frequently observed SPRM-associated endometrial changes in women treated with SPRMs than in those treated with placebo or leuprolide acetate. As noted above, SPRM-associated endometrial changes are benign, are not related to cancer and are not precancerous. Reporting bias may impact the conclusion of this meta-analysis. Well-designed RCTs comparing SPRMs versus other treatments are needed.
Topics: Amenorrhea; Antineoplastic Agents, Hormonal; Estrenes; Female; Humans; Leiomyoma; Leuprolide; Menstruation; Mifepristone; Norpregnadienes; Oximes; Pelvic Pain; Quality of Life; Randomized Controlled Trials as Topic; Receptors, Progesterone; Uterine Neoplasms
PubMed: 28444736
DOI: 10.1002/14651858.CD010770.pub2 -
European Journal of Preventive... Mar 2017Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A (Lp-PLA), has not reduced risk of cardiovascular disease outcomes in recent randomized... (Review)
Review
Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A (Lp-PLA), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA enzyme activity is causally relevant to coronary heart disease. Methods In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7, the gene encoding Lp-PLA. We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA-lowering alleles. Results Lp-PLA activity was decreased by 64% ( p = 2.4 × 10) with carriage of any of the four loss-of-function variants, by 45% ( p < 10) for every allele inherited at Val279Phe, and by 2.7% ( p = 1.9 × 10) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA activity by 65% ( p < 10). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA activity were: 0.95 (0.88-1.03) with Val279Phe; 0.92 (0.74-1.16) with carriage of any loss-of-function variant; 1.01 (0.68-1.51) with Val379Ala; and 0.95 (0.89-1.02) with darapladib treatment. Conclusions In a large-scale human genetic study, none of a series of Lp-PLA-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA is unlikely to be a causal risk factor.
Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adult; Aged; Alleles; Benzaldehydes; Case-Control Studies; Coronary Disease; Female; Gene Expression Regulation; Genotype; Humans; Male; Middle Aged; Molecular Targeted Therapy; Oximes; Phospholipase A2 Inhibitors; Polymorphism, Single Nucleotide; Randomized Controlled Trials as Topic; Reference Values; Reproducibility of Results; Risk Assessment; Treatment Outcome
PubMed: 27940953
DOI: 10.1177/2047487316682186