Association between antihypertensive treatment and adverse events

Objective To examine the association between antihypertensive treatment and specific adverse events.

Design Systematic review and meta-analysis.

Eligibility criteria Randomised controlled trials of adults receiving antihypertensives compared with placebo or no treatment, more antihypertensive drugs compared with fewer antihypertensive drugs, or higher blood pressure targets compared with lower targets. To avoid small early phase trials, studies were required to have at least 650 patient years of follow-up.

Information sources Searches were conducted in Embase, Medline, CENTRAL, and the Science Citation Index databases from inception until 14 April 2020.

Main outcome measures The primary outcome was falls during trial follow-up. Secondary outcomes were acute kidney injury, fractures, gout, hyperkalaemia, hypokalaemia, hypotension, and syncope. Additional outcomes related to death and major cardiovascular events were extracted. Risk of bias was assessed using the Cochrane risk of bias tool, and random effects meta-analysis was used to pool rate ratios, odds ratios, and hazard ratios across studies, allowing for between study heterogeneity (τ²).

Results Of 15 023 articles screened for inclusion, 58 randomised controlled trials were identified, including 280 638 participants followed up for a median of 3 (interquartile range 2-4) years. Most of the trials (n=40, 69%) had a low risk of bias. Among seven trials reporting data for falls, no evidence was found of an association with antihypertensive treatment (summary risk ratio 1.05, 95% confidence interval 0.89 to 1.24, τ²=0.009). Antihypertensives were associated with an increased risk of acute kidney injury (1.18, 95% confidence interval 1.01 to 1.39, τ²=0.037, n=15), hyperkalaemia (1.89, 1.56 to 2.30, τ²=0.122, n=26), hypotension (1.97, 1.67 to 2.32, τ²=0.132, n=35), and syncope (1.28, 1.03 to 1.59, τ²=0.050, n=16). The heterogeneity between studies assessing acute kidney injury and hyperkalaemia events was reduced when focusing on drugs that affect the renin angiotensin-aldosterone system. Results were robust to sensitivity analyses focusing on adverse events leading to withdrawal from each trial. Antihypertensive treatment was associated with a reduced risk of all cause mortality, cardiovascular death, and stroke, but not of myocardial infarction.

Conclusions This meta-analysis found no evidence to suggest that antihypertensive treatment is associated with falls but found evidence of an association with mild (hyperkalaemia, hypotension) and severe adverse events (acute kidney injury, syncope). These data could be used to inform shared decision making between doctors and patients about initiation and continuation of antihypertensive treatment, especially in patients at high risk of harm because of previous adverse events or poor renal function.

Registration PROSPERO CRD42018116860.

Reference: BMJ 2021;372:n189

Efficacy and safety of antidepressants for the treatment of back pain and osteoarthritis

Objective To investigate the efficacy and safety of antidepressants for back and osteoarthritis pain compared with placebo.

Design Systematic review and meta-analysis.

Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, CINAHL, International Pharmaceutical Abstracts, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform from inception to 15 November and updated on 12 May 2020.

Eligibility criteria for study selection Randomised controlled trials comparing the efficacy or safety, or both of any antidepressant drug with placebo (active or inert) in participants with low back or neck pain, sciatica, or hip or knee osteoarthritis.

Data extraction and synthesis Two independent reviewers extracted data. Pain and disability were primary outcomes. Pain and disability scores were converted to a scale of 0 (no pain or disability) to 100 (worst pain or disability). A random effects model was used to calculate weighted mean differences and 95% confidence intervals. Safety (any adverse event, serious adverse events, and proportion of participants who withdrew from trials owing to adverse events) was a secondary outcome. Risk of bias was assessed with the Cochrane Collaboration’s tool and certainty of evidence with the grading of recommendations assessment, development and evaluation (GRADE) framework.

Results 33 trials (5318 participants) were included. Moderate certainty evidence showed that serotonin-noradrenaline reuptake inhibitors (SNRIs) reduced back pain (mean difference −5.30, 95% confidence interval −7.31 to −3.30) at 3-13 weeks and low certainty evidence that SNRIs reduced osteoarthritis pain (−9.72, −12.75 to −6.69) at 3-13 weeks. Very low certainty evidence showed that SNRIs reduced sciatica at two weeks or less (−18.60, −31.87 to −5.33) but not at 3-13 weeks (−17.50, −42.90 to 7.89). Low to very low certainty evidence showed that tricyclic antidepressants (TCAs) did not reduce sciatica at two weeks or less (−7.55, −18.25 to 3.15) but did at 3-13 weeks (−15.95, −31.52 to −0.39) and 3-12 months (−27.0, −36.11 to −17.89). Moderate certainty evidence showed that SNRIs reduced disability from back pain at 3-13 weeks (−3.55, −5.22 to −1.88) and disability due to osteoarthritis at two weeks or less (−5.10, −7.31 to −2.89), with low certainty evidence at 3-13 weeks (−6.07, −8.13 to −4.02). TCAs and other antidepressants did not reduce pain or disability from back pain.

Conclusion Moderate certainty evidence shows that the effect of SNRIs on pain and disability scores is small and not clinically important for back pain, but a clinically important effect cannot be excluded for osteoarthritis. TCAs and SNRIs might be effective for sciatica, but the certainty of evidence ranged from low to very low.

Systematic review registration PROSPERO CRD42020158521.

Reference: BMJ 2021;372:m4825

Treatment interventions to maintain abstinence from alcohol in primary care

Objective To determine the most effective interventions in recently detoxified, alcohol dependent patients for implementation in primary care.

Design Systematic review and network meta-analysis.

Data sources Medline, Embase, PsycINFO, Cochrane CENTRAL, ClinicalTrials.gov, and the World Health Organization’s International Clinical Trials Registry Platform.

Study selection Randomised controlled trials comparing two or more interventions that could be used in primary care. The population was patients with alcohol dependency diagnosed by standardised clinical tools and who became detoxified within four weeks.

Data extraction Outcomes of interest were continuous abstinence from alcohol (effectiveness) and all cause dropouts (as a proxy for acceptability) at least 12 weeks after start of intervention.

Results 64 trials (43 interventions) were included. The median probability of abstinence across placebo arms was 25%. Compared with placebo, the only intervention associated with increased probability of abstinence and moderate certainty evidence was acamprosate (odds ratio 1.86, 95% confidence interval 1.49 to 2.33, corresponding to an absolute probability of 38%). Of the 62 included trials that reported all cause dropouts, interventions associated with a reduced number of dropouts compared with placebo (probability 50%) and moderate certainty of evidence were acamprosate (0.73, 0.62 to 0.86; 42%), naltrexone (0.70, 0.50 to 0.98; 41%), and acamprosate-naltrexone (0.30, 0.13 to 0.67; 17%). Acamprosate was the only intervention associated with moderate confidence in the evidence of effectiveness and acceptability up to 12 months. It is uncertain whether other interventions can help maintain abstinence and reduce dropouts because of low confidence in the evidence.

Conclusions Evidence is lacking for benefit from interventions that could be implemented in primary care settings for alcohol abstinence, other than for acamprosate. More evidence from high quality randomised controlled trials is needed, as are strategies using combined interventions (combinations of drug interventions or drug and psychosocial interventions) to improve treatment of alcohol dependency in primary care.

Systematic review registration PROSPERO CRD42016049779.

Reference: BMJ 2020;371:m3934

Efficacy and safety of lowering LDL cholesterol in older patients

Background

The clinical benefit of LDL cholesterol lowering treatment in older patients remains debated. We aimed to summarise the evidence of LDL cholesterol lowering therapies in older patients.

Methods

In this systematic review and meta-analysis, we searched MEDLINE and Embase for articles published between March 1, 2015, and Aug 14, 2020, without any language restrictions. We included randomised controlled trials of cardiovascular outcomes of an LDL cholesterol-lowering drug recommended by the 2018 American College of Cardiology and American Heart Association guidelines, with a median follow-up of at least 2 years and data on older patients (aged ≥75 years). We excluded trials that exclusively enrolled participants with heart failure or on dialysis because guidelines do not recommend lipid-lowering therapy in such patients who do not have another indication. We extracted data for older patients using a standardised data form for aggregated study-level data. We meta-analysed the risk ratio (RR) for major vascular events (a composite of cardiovascular death, myocardial infarction or other acute coronary syndrome, stroke, or coronary revascularisation) per 1 mmol/L reduction in LDL cholesterol.

Findings

Data from six articles were included in the systematic review and meta-analysis, which included 24 trials from the Cholesterol Treatment Trialists’ Collaboration meta-analysis plus five individual trials. Among 244 090 patients from 29 trials, 21 492 (8·8%) were aged at least 75 years, of whom 11 750 (54·7%) were from statin trials, 6209 (28·9%) from ezetimibe trials, and 3533 (16·4%) from PCSK9 inhibitor trials. Median follow-up ranged from 2·2 years to 6·0 years. LDL cholesterol lowering significantly reduced the risk of major vascular events (n=3519) in older patients by 26% per 1 mmol/L reduction in LDL cholesterol (RR 0·74 [95% CI 0·61–0·89]; p=0·0019), with no statistically significant difference with the risk reduction in patients younger than 75 years (0·85 [0·78–0·92]; p _interaction=0·37). Among older patients, RRs were not statistically different for statin (0·82 [0·73–0·91]) and non-statin treatment (0·67 [0·47–0·95]; p _interaction=0·64). The benefit of LDL cholesterol lowering in older patients was observed for each component of the composite, including cardiovascular death (0·85 [0·74–0·98]), myocardial infarction (0·80 [0·71–0·90]), stroke (0·73 [0·61–0·87]), and coronary revascularisation (0·80 [0·66–0·96]).

Interpretation

In patients aged 75 years and older, lipid lowering was as effective in reducing cardiovascular events as it was in patients younger than 75 years. These results should strengthen guideline recommendations for the use of lipid-lowering therapies, including non-statin treatment, in older patients.

Funding

None.

Reference: TheLancet, VOLUME 396, ISSUE 10263, P1637-1643, NOVEMBER 21, 2020

Central fatness and risk of all cause mortality: systematic review and dose-response meta-analysis of 72 prospective cohort studies

Objective To quantify the association of indices of central obesity, including waist circumference, hip circumference, thigh circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index, with the risk of all cause mortality in the general population, and to clarify the shape of the dose-response relations.

Design Systematic review and meta-analysis.

Data sources PubMed and Scopus from inception to July 2019, and the reference lists of all related articles and reviews.

Eligibility criteria for selecting studies Prospective cohort studies reporting the risk estimates of all cause mortality across at least three categories of indices of central fatness. Studies that reported continuous estimation of the associations were also included.

Data synthesis A random effects dose-response meta-analysis was conducted to assess linear trend estimations. A one stage linear mixed effects meta-analysis was used for estimating dose-response curves.

Results Of 98 745 studies screened, 1950 full texts were fully reviewed for eligibility. The final analyses consisted of 72 prospective cohort studies with 2 528 297 participants. The summary hazard ratios were as follows: waist circumference (10 cm, 3.94 inch increase): 1.11 (95% confidence interval 1.08 to 1.13, I²=88%, n=50); hip circumference (10 cm, 3.94 inch increase): 0.90 (0.81 to 0.99, I²=95%, n=9); thigh circumference (5 cm, 1.97 inch increase): 0.82 (0.75 to 0.89, I²=54%, n=3); waist-to-hip ratio (0.1 unit increase): 1.20 (1.15 to 1.25, I²=90%, n=31); waist-to-height ratio (0.1 unit increase): 1.24 (1.12 to 1.36, I²=94%, n=11); waist-to-thigh ratio (0.1 unit increase): 1.21 (1.03 to 1.39, I²=97%, n=2); body adiposity index (10% increase): 1.17 (1.00 to 1.33, I²=75%, n=4); and A body shape index (0.005 unit increase): 1.15 (1.10 to 1.20, I²=87%, n=9). Positive associations persisted after accounting for body mass index. A nearly J shaped association was found between waist circumference and waist-to-height ratio and the risk of all cause mortality in men and women. A positive monotonic association was observed for waist-to-hip ratio and A body shape index. The association was U shaped for body adiposity index.

Conclusions Indices of central fatness including waist circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index, independent of overall adiposity, were positively and significantly associated with a higher all cause mortality risk. Larger hip circumference and thigh circumference were associated with a lower risk. The results suggest that measures of central adiposity could be used with body mass index as a supplementary approach to determine the risk of premature death.

Reference: BMJ 2020;370:m3324

Association between high blood pressure and long term cardiovascular events in young adults: systematic review and meta-analysis

Objective To evaluate and quantify the future risk of cardiovascular events in young adults with high blood pressure.

Design Systematic review and meta-analysis.

Data sources Medline, Embase, and Web of Science were searched from inception to 6 March 2020. Relative risks were pooled using a random effects model and expressed with 95% confidence intervals. Absolute risk difference was calculated. Dose-response relations between blood pressure and individual outcomes were assessed by a restricted cubic spline model.

Eligibility criteria for selecting studies Studies were selected that investigated the adverse outcomes of adults aged 18-45 with raised blood pressure. The primary study outcome was a composite of total cardiovascular events. Coronary heart disease, stroke, and all cause mortality were examined as secondary outcomes.

Results Seventeen observational cohorts consisting of approximately 4.5 million young adults were included in the analysis. The average follow-up was 14.7 years. Young adults with normal blood pressure had increased risk of cardiovascular events compared with those with optimal blood pressure (relative risk 1.19, 95% confidence interval 1.08 to 1.31; risk difference 0.37, 95% confidence interval 0.16 to 0.61 per 1000 person years). A graded, progressive association was found between blood pressure categories and increased risk of cardiovascular events (high normal blood pressure: relative risk 1.35, 95% confidence interval 1.22 to 1.49; risk difference 0.69, 95% confidence interval 0.43 to 0.97 per 1000 person years; grade 1 hypertension: 1.92, 1.68 to 2.19; 1.81, 1.34 to 2.34; grade 2 hypertension: 3.15, 2.31 to 4.29; 4.24, 2.58 to 6.48). Similar results were observed for coronary heart disease and stroke. Generally, the population attributable fraction for cardiovascular events associated with raised blood pressure was 23.8% (95% confidence interval 17.9% to 28.8%). The number needed to treat for one year to prevent one cardiovascular event was estimated at 2672 (95% confidence interval 1639 to 6250) for participants with normal blood pressure, 1450 (1031 to 2326) for those with high normal blood pressure, 552 (427 to 746) for those with grade 1 hypertension, and 236 (154 to 388) for those with grade 2 hypertension.

Conclusions Young adults with raised blood pressure might have a slightly increased risk of cardiovascular events in later life. Because the evidence for blood pressure lowering is limited, active interventions should be cautious and warrant further investigation.

Reference:  BMJ 2020;370:m3222

Update to living systematic review on drug treatments for covid-19

This living systematic review by Siemieniuk and colleagues (BMJ 2020;370:m2980) has been updated. For the latest update, visit doi:10.1136/bmj.m2980.

Reference: BMJ 2020;370:m3536

Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis

Objective To determine the clinical manifestations, risk factors, and maternal and perinatal outcomes in pregnant and recently pregnant women with suspected or confirmed coronavirus disease 2019 (covid-19).

Design Living systematic review and meta-analysis.

Data sources Medline, Embase, Cochrane database, WHO COVID-19 database, China National Knowledge Infrastructure (CNKI), and Wanfang databases from 1 December 2019 to 26 June 2020, along with preprint servers, social media, and reference lists.

Study selection Cohort studies reporting the rates, clinical manifestations (symptoms, laboratory and radiological findings), risk factors, and maternal and perinatal outcomes in pregnant and recently pregnant women with suspected or confirmed covid-19.

Data extraction At least two researchers independently extracted the data and assessed study quality. Random effects meta-analysis was performed, with estimates pooled as odds ratios and proportions with 95% confidence intervals. All analyses will be updated regularly.

Results 77 studies were included. Overall, 10% (95% confidence interval 7% to14%; 28 studies, 11 432 women) of pregnant and recently pregnant women attending or admitted to hospital for any reason were diagnosed as having suspected or confirmed covid-19. The most common clinical manifestations of covid-19 in pregnancy were fever (40%) and cough (39%). Compared with non-pregnant women of reproductive age, pregnant and recently pregnant women with covid-19 were less likely to report symptoms of fever (odds ratio 0.43, 95% confidence interval 0.22 to 0.85; I²=74%; 5 studies; 80 521 women) and myalgia (0.48, 0.45 to 0.51; I²=0%; 3 studies; 80 409 women) and were more likely to need admission to an intensive care unit (1.62, 1.33 to 1.96; I²=0%) and invasive ventilation (1.88, 1.36 to 2.60; I²=0%; 4 studies, 91 606 women). 73 pregnant women (0.1%, 26 studies, 11 580 women) with confirmed covid-19 died from any cause. Increased maternal age (1.78, 1.25 to 2.55; I²=9%; 4 studies; 1058 women), high body mass index (2.38, 1.67 to 3.39; I²=0%; 3 studies; 877 women), chronic hypertension (2.0, 1.14 to 3.48; I²=0%; 2 studies; 858 women), and pre-existing diabetes (2.51, 1.31 to 4.80; I²=12%; 2 studies; 858 women) were associated with severe covid-19 in pregnancy. Pre-existing maternal comorbidity was a risk factor for admission to an intensive care unit (4.21, 1.06 to 16.72; I²=0%; 2 studies; 320 women) and invasive ventilation (4.48, 1.40 to 14.37; I²=0%; 2 studies; 313 women). Spontaneous preterm birth rate was 6% (95% confidence interval 3% to 9%; I²=55%; 10 studies; 870 women) in women with covid-19. The odds of any preterm birth (3.01, 95% confidence interval 1.16 to 7.85; I²=1%; 2 studies; 339 women) was high in pregnant women with covid-19 compared with those without the disease. A quarter of all neonates born to mothers with covid-19 were admitted to the neonatal unit (25%) and were at increased risk of admission (odds ratio 3.13, 95% confidence interval 2.05 to 4.78, I²=not estimable; 1 study, 1121 neonates) than those born to mothers without covid-19.

Conclusion Pregnant and recently pregnant women are less likely to manifest covid-19 related symptoms of fever and myalgia than non-pregnant women of reproductive age and are potentially more likely to need intensive care treatment for covid-19. Pre-existing comorbidities, high maternal age, and high body mass index seem to be risk factors for severe covid-19. Preterm birth rates are high in pregnant women with covid-19 than in pregnant women without the disease.

Systematic review registration PROSPERO CRD42020178076.

Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

Reference: BMJ 2020;370:m3320

Self-management interventions to reduce healthcare use and improve quality of life among patients with asthma: systematic review and network meta-analysis

Objective To compare the different self-management models (multidisciplinary case management, regularly supported self-management, and minimally supported self-management) and self-monitoring models against usual care and education to determine which are most effective at reducing healthcare use and improving quality of life in asthma.

Design Systematic review and network meta-analysis.

Data sources Medline, the Cochrane Library, CINAHL, EconLit, Embase, Health Economics Evaluations Database, NHS Economic Evaluation Database, PsycINFO, and ClinicalTrials.gov from January 2000 to April 2019.

Review methods Randomised controlled trials involving the different self-management models for asthma were included. The primary outcomes were healthcare use (hospital admission or emergency visit) and quality of life. Summary standardised mean differences (SMDs) and 95% credible intervals were estimated using bayesian network meta-analysis with random effects. Heterogeneity and publication bias were assessed.

Results From 1178 citations, 105 trials comprising 27 767 participants were included. In terms of healthcare use, both multidisciplinary case management (SMD –0.18, 95% credible interval −0.32 to −0.05) and regularly supported self-management (–0.30, −0.46 to −0.15) were significantly better than usual care. For quality of life, only regularly supported self-management (SMD 0.54, 0.11 to 0.96) showed a statistically significant benefit compared with usual care. For trials including adolescents/children (age 5-18 years), only regularly supported self-management showed statistically significant benefits (healthcare use: SMD –0.21, −0.40 to −0.03; quality of life: 0.23, 0.03 to 0.48). Multidisciplinary case management (SMD –0.32, −0.50 to −0.16) and regularly supported self-management (–0.32, −0.53 to −0.11) were most effective at reducing healthcare use in patients with symptoms of severe asthma at baseline.

Conclusions This network meta-analysis indicates that regularly supported self-management reduces the use of healthcare resources and improves quality of life across all levels of asthma severity. Future healthcare investments should provide support that offer reviews totalling at least two hours to establish self-management skills, reserving multidisciplinary case management for patients with complex disease.

Systematic review registration PROSPERO number CRD42019121350.

Reference: BMJ 2020;370:m2521

Update to living systematic review on prediction models for diagnosis and prognosis of covid-19

Reference: BMJ 2020;370:m2810