ABSTRACT
BACKGROUND: The efficacy of daily co-trimoxazole, an antifolate used for malaria chemoprevention in pregnant women living with HIV, is threatened by cross-resistance of Plasmodium falciparum to the antifolate sulfadoxine-pyrimethamine. We assessed whether addition of monthly dihydroartemisinin-piperaquine to daily co-trimoxazole is more effective at preventing malaria infection than monthly placebo plus daily co-trimoxazole in pregnant women living with HIV. METHODS: We did an individually randomised, two-arm, placebo-controlled trial in areas with high-grade sulfadoxine-pyrimethamine resistance in Kenya and Malawi. Pregnant women living with HIV on dolutegravir-based combination antiretroviral therapy (cART) who had singleton pregnancies between 16 weeks' and 28 weeks' gestation were randomly assigned (1:1) by computer-generated block randomisation, stratified by site and HIV status (known positive vs newly diagnosed), to daily co-trimoxazole plus monthly dihydroartemisinin-piperaquine (three tablets of 40 mg dihydroartemisinin and 320 mg piperaquine given daily for 3 days) or daily co-trimoxazole plus monthly placebo. Daily co-trimoxazole consisted of one tablet of 160 mg sulfamethoxazole and 800 mg trimethoprim. The primary endpoint was the incidence of Plasmodium infection detected in the peripheral (maternal) or placental (maternal) blood or tissue by PCR, microscopy, rapid diagnostic test, or placental histology (active infection) from 2 weeks after the first dose of dihydroartemisinin-piperaquine or placebo to delivery. Log-binomial regression was used for binary outcomes, and Poisson regression for count outcomes. The primary analysis was by modified intention to treat, consisting of all randomised eligible participants with primary endpoint data. The safety analysis included all women who received at least one dose of study drug. All investigators, laboratory staff, data analysts, and participants were masked to treatment assignment. This trial is registered with ClinicalTrials.gov, NCT04158713. FINDINGS: From Nov 11, 2019, to Aug 3, 2021, 904 women were enrolled and randomly assigned to co-trimoxazole plus dihydroartemisinin-piperaquine (n=448) or co-trimoxazole plus placebo (n=456), of whom 895 (99%) contributed to the primary analysis (co-trimoxazole plus dihydroartemisinin-piperaquine, n=443; co-trimoxazole plus placebo, n=452). The cumulative risk of any malaria infection during pregnancy or delivery was lower in the co-trimoxazole plus dihydroartemisinin-piperaquine group than in the co-trimoxazole plus placebo group (31 [7%] of 443 women vs 70 [15%] of 452 women, risk ratio 0·45, 95% CI 0·30-0·67; p=0·0001). The incidence of any malaria infection during pregnancy or delivery was 25·4 per 100 person-years in the co-trimoxazole plus dihydroartemisinin-piperaquine group versus 77·3 per 100 person-years in the co-trimoxazole plus placebo group (incidence rate ratio 0·32, 95% CI 0·22-0·47, p<0·0001). The number needed to treat to avert one malaria infection per pregnancy was 7 (95% CI 5-10). The incidence of serious adverse events was similar between groups in mothers (17·7 per 100 person-years in the co-trimoxazole plus dihydroartemisinin-piperaquine group [23 events] vs 17·8 per 100 person-years in the co-trimoxazole group [25 events]) and infants (45·4 per 100 person-years [23 events] vs 40·2 per 100 person-years [21 events]). Nausea within the first 4 days after the start of treatment was reported by 29 (7%) of 446 women in the co-trimoxazole plus dihydroartemisinin-piperaquine group versus 12 (3%) of 445 women in the co-trimoxazole plus placebo group. The risk of adverse pregnancy outcomes did not differ between groups. INTERPRETATION: Addition of monthly intermittent preventive treatment with dihydroartemisinin-piperaquine to the standard of care with daily unsupervised co-trimoxazole in areas of high antifolate resistance substantially improves malaria chemoprevention in pregnant women living with HIV on dolutegravir-based cART and should be considered for policy. FUNDING: European and Developing Countries Clinical Trials Partnership 2; UK Joint Global Health Trials Scheme (UK Foreign, Commonwealth and Development Office; Medical Research Council; National Institute for Health Research; Wellcome); and Swedish International Development Cooperation Agency.
Subject(s)
Antimalarials , Artemisinins , Folic Acid Antagonists , HIV Infections , Malaria , Piperazines , Quinolines , Female , Humans , Infant , Pregnancy , Antimalarials/adverse effects , Chemoprevention , Folic Acid Antagonists/therapeutic use , HIV Infections/epidemiology , HIV Infections/prevention & control , HIV Infections/drug therapy , Kenya/epidemiology , Malaria/epidemiology , Malaria/prevention & control , Malawi/epidemiology , Placenta , Pregnancy Outcome , Pregnant Women , Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use , Double-Blind MethodABSTRACT
BACKGROUND: Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known. METHODS: In this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin. RESULTS: A total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was -0.40 log10 colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log10 CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%). CONCLUSIONS: Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.).
Subject(s)
AIDS-Related Opportunistic Infections/drug therapy , Amphotericin B/administration & dosage , Antifungal Agents/administration & dosage , Fluconazole/administration & dosage , Flucytosine/administration & dosage , Meningitis, Cryptococcal/drug therapy , AIDS-Related Opportunistic Infections/mortality , Administration, Oral , Africa South of the Sahara , Amphotericin B/adverse effects , Antifungal Agents/adverse effects , Drug Administration Schedule , Drug Therapy, Combination , Fluconazole/adverse effects , Flucytosine/adverse effects , HIV Infections/complications , Meningitis, Cryptococcal/mortalityABSTRACT
BACKGROUND: Intermittent preventive treatment in pregnancy (IPTp) with dihydroartemisinin-piperaquine is more effective than IPTp with sulfadoxine-pyrimethamine at reducing malaria infection during pregnancy in areas with high-grade resistance to sulfadoxine-pyrimethamine by Plasmodium falciparum in east Africa. We aimed to assess whether IPTp with dihydroartemisinin-piperaquine, alone or combined with azithromycin, can reduce adverse pregnancy outcomes compared with IPTp with sulfadoxine-pyrimethamine. METHODS: We did an individually randomised, double-blind, three-arm, partly placebo-controlled trial in areas of high sulfadoxine-pyrimethamine resistance in Kenya, Malawi, and Tanzania. HIV-negative women with a viable singleton pregnancy were randomly assigned (1:1:1) by computer-generated block randomisation, stratified by site and gravidity, to receive monthly IPTp with sulfadoxine-pyrimethamine (500 mg of sulfadoxine and 25 mg of pyrimethamine for 1 day), monthly IPTp with dihydroartemisinin-piperaquine (dosed by weight; three to five tablets containing 40 mg of dihydroartemisinin and 320 mg of piperaquine once daily for 3 consecutive days) plus a single treatment course of placebo, or monthly IPTp with dihydroartemisinin-piperaquine plus a single treatment course of azithromycin (two tablets containing 500 mg once daily for 2 consecutive days). Outcome assessors in the delivery units were masked to treatment group. The composite primary endpoint was adverse pregnancy outcome, defined as fetal loss, adverse newborn baby outcomes (small for gestational age, low birthweight, or preterm), or neonatal death. The primary analysis was by modified intention to treat, consisting of all randomised participants with primary endpoint data. Women who received at least one dose of study drug were included in the safety analyses. This trial is registered with ClinicalTrials.gov, NCT03208179. FINDINGS: From March-29, 2018, to July 5, 2019, 4680 women (mean age 25·0 years [SD 6·0]) were enrolled and randomly assigned: 1561 (33%; mean age 24·9 years [SD 6·1]) to the sulfadoxine-pyrimethamine group, 1561 (33%; mean age 25·1 years [6·1]) to the dihydroartemisinin-piperaquine group, and 1558 (33%; mean age 24·9 years [6.0]) to the dihydroartemisinin-piperaquine plus azithromycin group. Compared with 335 (23·3%) of 1435 women in the sulfadoxine-pyrimethamine group, the primary composite endpoint of adverse pregnancy outcomes was reported more frequently in the dihydroartemisinin-piperaquine group (403 [27·9%] of 1442; risk ratio 1·20, 95% CI 1·06-1·36; p=0·0040) and in the dihydroartemisinin-piperaquine plus azithromycin group (396 [27·6%] of 1433; 1·16, 1·03-1·32; p=0·017). The incidence of serious adverse events was similar in mothers (sulfadoxine-pyrimethamine group 17·7 per 100 person-years, dihydroartemisinin-piperaquine group 14·8 per 100 person-years, and dihydroartemisinin-piperaquine plus azithromycin group 16·9 per 100 person-years) and infants (sulfadoxine-pyrimethamine group 49·2 per 100 person-years, dihydroartemisinin-piperaquine group 42·4 per 100 person-years, and dihydroartemisinin-piperaquine plus azithromycin group 47·8 per 100 person-years) across treatment groups. 12 (0·2%) of 6685 sulfadoxine-pyrimethamine, 19 (0·3%) of 7014 dihydroartemisinin-piperaquine, and 23 (0·3%) of 6849 dihydroartemisinin-piperaquine plus azithromycin treatment courses were vomited within 30 min. INTERPRETATION: Monthly IPTp with dihydroartemisinin-piperaquine did not improve pregnancy outcomes, and the addition of a single course of azithromycin did not enhance the effect of monthly IPTp with dihydroartemisinin-piperaquine. Trials that combine sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine for IPTp should be considered. FUNDING: European & Developing Countries Clinical Trials Partnership 2, supported by the EU, and the UK Joint-Global-Health-Trials-Scheme of the Foreign, Commonwealth and Development Office, Medical Research Council, Department of Health and Social Care, Wellcome, and the Bill-&-Melinda-Gates-Foundation.
Subject(s)
Antimalarials , Pregnancy Complications, Parasitic , Quinolines , Infant, Newborn , Pregnancy , Female , Humans , Adult , Young Adult , Pyrimethamine/adverse effects , Sulfadoxine/adverse effects , Pregnancy Outcome , Antimalarials/adverse effects , Azithromycin/adverse effects , Pregnancy Complications, Parasitic/drug therapy , Pregnancy Complications, Parasitic/prevention & control , Pregnancy Complications, Parasitic/epidemiology , Drug Combinations , Kenya , TanzaniaABSTRACT
BACKGROUND: In sub-Saharan Africa, health-care provision for chronic conditions is fragmented. The aim of this study was to determine whether integrated management of HIV, diabetes, and hypertension led to improved rates of retention in care for people with diabetes or hypertension without adversely affecting rates of HIV viral suppression among people with HIV when compared to standard vertical care in medium and large health facilities in Uganda and Tanzania. METHODS: In INTE-AFRICA, a pragmatic cluster-randomised, controlled trial, we randomly allocated primary health-care facilities in Uganda and Tanzania to provide either integrated care or standard care for HIV, diabetes, and hypertension. Random allocation (1:1) was stratified by location, infrastructure level, and by country, with a permuted block randomisation method. In the integrated care group, participants with HIV, diabetes, or hypertension were managed by the same health-care workers, used the same pharmacy, had similarly designed medical records, shared the same registration and waiting areas, and had an integrated laboratory service. In the standard care group, these services were delivered vertically for each condition. Patients were eligible to join the trial if they were living with confirmed HIV, diabetes, or hypertension, were aged 18 years or older, were living within the catchment population area of the health facility, and were likely to remain in the catchment population for 6 months. The coprimary outcomes, retention in care (attending a clinic within the last 6 months of study follow-up) for participants with either diabetes or hypertension (tested for superiority) and plasma viral load suppression for those with HIV (>1000 copies per mL; tested for non-inferiority, 10% margin), were analysed using generalised estimating equations in the intention-to-treat population. This trial is registered with ISCRTN 43896688. FINDINGS: Between June 30, 2020, and April 1, 2021 we randomly allocated 32 health facilities (17 in Uganda and 15 in Tanzania) with 7028 eligible participants to the integrated care or the standard care groups. Among participants with diabetes, hypertension, or both, 2298 (75·8%) of 3032 were female and 734 (24·2%) of 3032 were male. Of participants with HIV alone, 2365 (70·3%) of 3365 were female and 1000 (29·7%) of 3365 were male. Follow-up lasted for 12 months. Among participants with diabetes, hypertension, or both, the proportion alive and retained in care at study end was 1254 (89·0%) of 1409 in integrated care and 1457 (89·8%) of 1623 in standard care. The risk differences were -0·65% (95% CI -5·76 to 4·46; p=0·80) unadjusted and -0·60% (-5·46 to 4·26; p=0·81) adjusted. Among participants with HIV, the proportion who had a plasma viral load of less than 1000 copies per mL was 1412 (97·0%) of 1456 in integrated care and 1451 (97·3%) of 1491 in standard care. The differences were -0·37% (one-sided 95% CI -1·99 to 1·26; pnon-inferiority<0·0001 unadjusted) and -0·36% (-1·99 to 1·28; pnon-inferiority<0·0001 adjusted). INTERPRETATION: In sub-Saharan Africa, integrated chronic care services could achieve a high standard of care for people with diabetes or hypertension without adversely affecting outcomes for people with HIV. FUNDING: European Union Horizon 2020 and Global Alliance for Chronic Diseases.
Subject(s)
Anti-HIV Agents , Diabetes Mellitus , HIV Infections , Hypertension , Female , Humans , Male , Anti-HIV Agents/therapeutic use , Diabetes Mellitus/therapy , Diabetes Mellitus/drug therapy , HIV Infections/complications , HIV Infections/epidemiology , HIV Infections/therapy , Hypertension/therapy , Hypertension/drug therapy , Tanzania/epidemiologyABSTRACT
BACKGROUND: We investigated the impact of Drug-Drug Interactions (DDIs) on virologic control among HIV-positive pregnant women initiating antiretroviral therapy while identifying drivers for Traditional Medicine (TM) use and exploring the nature and extent of TM-related DDIs. METHODS: Employing a three-pronged approach, we examined DDIs arising from comedication, including TM, in ART. The DolPHIN-2 trial (NCT03249181) randomized 268 HIV-positive pregnant women in Uganda and South Africa to dolutegravir (DTG)-based (135) or efavirenz-based (133) regimens while systematically recording comedications and screening for DDIs. We used Cox regression models to compare time-to-virologic control between participants with and without DDIs. We conducted in-depth interviews and focus group discussions among 37 and 67 women with and without HIV, respectively, to explore reasons for TM use during pregnancy. Additionally, in-vitro and in-vivo studies evaluated the composition and impact of clay-based TM, mumbwa, on DTG plasma exposure. RESULTS: The baseline prevalence of DDIs was 67.2%, with TM use prevalent in 34% of participants, with mumbwa being the most frequent (76%, 69/91). There was no difference in virologic response between participants with and without DDIs. Fetal health and cultural norms were among the reasons cited for TM use. Analysis of mumbwa rods confirmed significant amounts of aluminium (8.4%-13.9%) and iron (4%-6%). In Balb-C mice, coadministration of mumbwa led to a reduction in DTG exposure observed in the AUC0-24 (-21%; Pâ=â0.0271) and C24 (-53%; Pâ=â0.0028). CONCLUSIONS: The widespread use of clay-based TM may compromise HIV treatment, necessitating medication screening and counselling to manage DDIs in pregnant women.
ABSTRACT
AIM: To examine the associations of tea consumption (both frequency and type) with (1) prediabetes and diabetes and (2) urinary glucose and sodium excretion in Chinese community-dwelling adults. MATERIALS AND METHODS: In 1923 participants (457 with diabetes, 720 with prediabetes, and 746 with normoglycaemia), the frequency (occasional, frequent, daily, or nil) and type (green, black, dark, or other) of tea consumption were assessed using a standardized questionnaire. Morning spot urinary glucose and urine glucose-to-creatinine ratios (UGCRs) were assessed as markers of urinary glucose excretion. Tanaka's equation was used to estimate 24-h urinary sodium excretion. Logistic and multivariate linear regression analyses were performed. RESULTS: Compared with non-tea drinkers, the corresponding multivariable-adjusted odds ratios (ORs) for prediabetes and diabetes were 0.63 (95% confidence interval [CI] 0.48, 0.83) and 0.58 (95% CI 0.41, 0.82) in participants drinking tea daily. However, only drinking dark tea was associated with reduced ORs for prediabetes (0.49, 95% CI 0.36, 0.66) and diabetes (0.41, 95% CI 0.28, 0.62). Dark tea consumption was associated with increased morning spot urinary glucose (0.22 mmol/L, 95% CI 0.11, 0.34 mmol/L), UGCR (0.15 mmol/mmol, 95% CI 0.05, 0.25 mmol/L) and estimated 24-h urinary sodium (7.78 mEq/day, 95% CI 2.27, 13.28 mEq/day). CONCLUSIONS: Regular tea consumption, especially dark tea, is associated with a reduced risk of dysglycaemia and increased urinary glucose and sodium excretion in Chinese community-dwelling adults.
ABSTRACT
BACKGROUND: Given the substantial prevalence of cardiovascular disease (CVD) in low-income and middle-income countries (LMICs), evaluation of behavioral counseling for prevention of CVD is important. METHODS: We pooled nationally representative cross-sectional surveys from 36 LMICs between 2013 and 2020. The population was divided into three groups according to CVD risk: the potential risk group, the risk group and the CVD group. We estimated the prevalence of six types of behavioral counseling among the three groups separately: smoking, salt reduction, fruit and vegetable intake, dietary fat reduction, physical activity and body weight. RESULTS: There were 16,057 (25.4%) in the potential risk group, 43,113 (49.9%) in the risk group, and 7796 (8.6%) in the CVD group. The prevalence of receiving at least four types of counseling in the three groups was 15.6% (95% CI 13.9 to 17.5), 14.9% (95% CI 14.0 to 15.9), and 19.8% (95% CI 17.7 to 22.2), respectively. The lowest prevalence was for tobacco use counseling: 24.5% (95% CI 22.5 to 26.4), 23.2% (95% CI 22.1 to 24.3), and 32.1% (95% CI 29.5 to 34.8), respectively. The prevalence of counseling was higher in upper-middle-income countries than in lower-middle-income countries. Women, older people, those with more education, and those living in urban areas were more likely to receive counseling. CONCLUSION: The prevalence of behavioral counseling for CVD is low in LMICs, especially among potentially at-risk populations and in low-income countries. These findings highlight the current urgent need to improve CVD prevention and management systems to enhance behavioral counseling and intervention.
Subject(s)
Cardiovascular Diseases , Counseling , Developing Countries , Humans , Cardiovascular Diseases/prevention & control , Cardiovascular Diseases/epidemiology , Female , Male , Cross-Sectional Studies , Middle Aged , Adult , Prevalence , Poverty , Exercise , Aged , Health Behavior , Smoking/epidemiology , Risk FactorsABSTRACT
BACKGROUND: Percutaneous coronary intervention (PCI) with primary stenting, which stands for stent implantation regardless of obtaining satisfactory results with balloon angioplasty, has superseded conventional plain old balloon angioplasty with provisional stenting. With drug-coated balloon (DCB), primary DCB angioplasty with provisional stenting has shown non-inferiority to primary stenting for de novo coronary small vessel disease. However, the long-term efficacy and safety of such a strategy to the primary stenting on clinical endpoints in de novo lesions without vessel diameter restrictions remain uncertain. STUDY DESIGN: The REC-CAGEFREE I is an investigator-initiated, multicenter, randomized, open-label trial aimed to enroll 2270 patients with acute or chronic coronary syndrome from 43 interventional cardiology centers in China to evaluate the non-inferiority of primary paclitaxel-coated balloons angioplasty to primary stenting for the treatment of de novo, non-complex lesions without vessel diameter restrictions. Patients who fulfill all the inclusion and exclusion criteria and have achieved a successful lesion pre-dilatation will be randomly assigned to the two arms in a 1:1 ratio. Protocol-guided DCB angioplasty and bailout stenting after unsatisfactory angioplasty are mandatory in the primary DCB angioplasty group. The second-generation sirolimus-eluting stent will be used as a bailout stent in the primary DCB angioplasty group and the treatment device in the primary stenting group. The primary endpoint is the incidence of Device-oriented Composite Endpoint (DoCE) within 24 months after randomization, including cardiac death, target vessel myocardial infarction, and clinically and physiologically indicated target lesion revascularization. DISCUSSION: The ongoing REC-CAGEFREE I trial is the first randomized trial with a clinical endpoint to assess the efficacy and safety of primary DCB angioplasty for the treatment of de novo, non-complex lesions without vessel diameter restrictions. If non-inferiority is shown, PCI with primary DCB angioplasty could be an alternative treatment option to primary stenting. TRIAL REGISTRATION: Registered on clinicaltrial.gov (NCT04561739).
Subject(s)
Angioplasty, Balloon, Coronary , Cardiac Catheters , Cardiovascular Agents , Coated Materials, Biocompatible , Coronary Artery Disease , Paclitaxel , Humans , Angioplasty, Balloon, Coronary/instrumentation , Angioplasty, Balloon, Coronary/adverse effects , Angioplasty, Balloon, Coronary/mortality , Treatment Outcome , Cardiovascular Agents/administration & dosage , Cardiovascular Agents/adverse effects , China , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Coronary Artery Disease/therapy , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/mortality , Time Factors , Female , Male , Middle Aged , Multicenter Studies as Topic , Stents , Aged , Drug-Eluting Stents , Equivalence Trials as Topic , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: Patients treated with drug-coated balloons (DCB) have the theoretical advantage of adopting a low-intensity antiplatelet regimen due to the absence of struts and polymers. Nevertheless, the optimal antiplatelet strategy for patients undergoing DCB-only treatment remains a topic of debate and has not been investigated in randomized trials. METHODS: The REC-CAGEFREE II is an investigator-initiated, prospective, open-label, multi-center, randomized, non-inferiority trial aimed to enroll 1908 patients from ≥ 40 interventional cardiology centers in China to evaluate the non-inferiority of an antiplatelet regimen consisting of Aspirin plus Ticagrelor for one month, followed by five months Ticagrelor monotherapy, and then Aspirin monotherapy for six months (Experimental group) compared to the conventional treatment of Aspirin plus Ticagrelor for 12 months (Reference group) in patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) using paclitaxel-coated balloons (DCB) exclusively. Participants will be randomly assigned to the Experimental or Reference group in a 1:1 ratio. The randomization will be stratified based on the center and the type of lesion being treated (De novo or in-stent restenosis). The primary endpoint is net adverse clinical events (NACE) within 12 months of PCI, which includes the composite of all-cause death, any stroke, any myocardial infarction, any revascularization and Bleeding Academic Research Consortium (BARC) defined type 3 or 5 bleeding. The secondary endpoint, any ischemic and bleeding event, which includes all-cause death, any stroke, MI, BARC-defined type 3 bleeding, any revascularization, and BARC-defined type 2 bleeding events, will be treated as having hierarchical clinical importance in the above order and analyzed using the win ratio method. DISCUSSION: The ongoing REC-CAGEFREE II trial aims to assess the efficacy and safety of a low-intensity antiplatelet approach among ACS patients with DCB. If non-inferiority is shown, the novel antiplatelet approach could provide an alternative treatment for ACS patients with DCB. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04971356.
Subject(s)
Acute Coronary Syndrome , Percutaneous Coronary Intervention , Stroke , Humans , Acute Coronary Syndrome/therapy , Acute Coronary Syndrome/drug therapy , Aspirin , Drug Therapy, Combination , Hemorrhage/chemically induced , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/methods , Platelet Aggregation Inhibitors/therapeutic use , Prospective Studies , Stroke/etiology , Ticagrelor/therapeutic use , Treatment Outcome , Randomized Controlled Trials as Topic , Multicenter Studies as Topic , Equivalence Trials as TopicABSTRACT
BACKGROUND: Abnormal blood potassium levels are associated with an increased risk of cardiometabolic diseases and mortality in the general population; however, evidence regarding the association between dyskalemia and mortality among patients with cardiovascular disease (CVD) remains inconclusive. This study aimed to evaluate the association of potassium levels with all-cause and cardiovascular mortality among patients with CVD. METHODS: PubMed, Embase, Web of Science, and Cochrane Library databases were searched up to August 2023 to identify relevant cohort studies among patients with CVD, such as myocardial infarction, stroke, and heart failure. Abnormal potassium levels were considered as hypokalemia or hyperkalemia. The primary outcomes were all-cause mortality based on follow-up length (including in-hospital, short-term and long-term mortality) and cardiovascular mortality. The methodological quality of included studies was assessed by using the Newcastle-Ottawa Scale. The pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models. Restricted cubic splines were applied to explore the dose-response relationship. RESULTS: Thirty-one cohort studies involving 227,645 participants with an average age of 68.3 years were included in the meta-analysis, all of which achieved moderate to high quality. Hyperkalemia was significantly associated with an approximately 3.0-fold increased risk of all-cause in-hospital mortality (RR:2.78,95CI%:1.92,4.03), 1.8-fold of all-cause short-term mortality (RR:1.80, 95CI%:1.44,2.27), 1.3-fold of all-cause long-term mortality (RR:1.33, 95CI%:1.19,1.48) and 1.2-fold of cardiovascular mortality (RR:1.19, 95CI%:1.04,1.36). Similar positive associations were also observed between hypokalemia and risk of all-cause mortality and cardiovascular mortality. The RRs of all-cause in-hospital, short-term, long-term mortality and cardiovascular mortality with hyperkalemia were attenuated to 2.21 (95CI%:1.60,3.06), 1.46(95CI%:1.25,1.71), 1.23 (95CI%:1.09,1.39) and 1.13 (95CI%:1.00,1.27) when treating hypokalemia together with normokalemia as the reference group. A U-shaped association was observed between potassium levels and mortality, with the lowest risk at around 4.2 mmol/L. CONCLUSIONS: Both hypokalemia and hyperkalemia were positively associated with the risk of mortality in patients with CVD. Our results support the importance of potassium homeostasis for improving the CVD management. REGISTRATION: PROSPERO, CRD42022324337.
Subject(s)
Cardiovascular Diseases , Hyperkalemia , Hypokalemia , Humans , Aged , Cohort Studies , PotassiumABSTRACT
The diagnosis of inflammatory bowel disease (IBD) in children and the need to distinguish between subtypes (Crohn's disease (CD) and ulcerative colitis (UC)) requires lengthy investigative and invasive procedures. Non-invasive, rapid, and cost-effective tests to support these diagnoses are needed. Faecal volatile organic compounds (VOCs) are distinctive in IBD. VOC profiles can be rapidly determined using a gas chromatography-sensor device (OdoReader©). In an inception-cohort of children presenting with suspected IBD, we directly compared the diagnostic fidelity of faecal calprotectin (FCP, a non-specific protein marker of intestinal inflammation) with OdoReader© VOC profiles of children subsequently diagnosed with IBD with matched controls diagnosed with other gastrointestinal conditions. The OdoReader© was 82% (95% confidence interval 75-89%) sensitive and 71% (61-80%) specific but did not outperform FCP (sensitivity 93% (77-99%) and specificity 86% (67-96%); 250 µg/g FCP cut off) in the diagnosis of IBD from other gastrointestinal conditions when validated in a separate sample from the same cohort. However, unlike FCP and better than other similar technologies, the OdoReader© could distinguish paediatric CD from UC (up to 88% (82-93%) sensitivity and 80% (71-89%) specificity in the validation set) and justifies further validation in larger studies. A non-invasive test based on VOCs could help streamline and limit invasive investigations in children.
Subject(s)
Colitis, Ulcerative , Crohn Disease , Feces , Volatile Organic Compounds , Humans , Colitis, Ulcerative/diagnosis , Child , Crohn Disease/diagnosis , Volatile Organic Compounds/analysis , Male , Female , Feces/chemistry , Adolescent , Chromatography, Gas/methods , Child, Preschool , Inflammatory Bowel Diseases/diagnosis , Diagnosis, Differential , Leukocyte L1 Antigen Complex/analysis , Biomarkers/analysis , Biosensing Techniques/methods , Biosensing Techniques/instrumentationABSTRACT
AIMS/HYPOTHESIS: In sub-Saharan Africa (SSA), 5% of adults are living with type 2 diabetes and this is rising sharply, with a greater increase among people with HIV. Evidence on the efficacy of prevention strategies in this cohort is scarce. We conducted a Phase II double-blind placebo-controlled trial that aimed to determine the impact of metformin on blood glucose levels among people with prediabetes (defined as impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT]) and HIV in SSA. METHODS: Adults (≥18 years old) who were stable in HIV care and found to have prediabetes (IFG and/or IGT) and who were attending hospitals in Dar es Salaam, Tanzania, were randomised to receive sustained-release metformin, 2000 mg daily, or matching placebo between 4 November 2019 and 21 July 2020. Randomisation used permuted blocks. Allocation was concealed in the trial database and made visible only to the Chief Pharmacist after consent was taken. All participants, research and clinical staff remained blinded to the allocation. Participants were provided with information on diet and lifestyle and had access to various health information following the start of the coronavirus disease 2019 (COVID-19) pandemic. Participants were followed up for 12 months. The primary outcome measure was capillary blood glucose measured 2 h following a 75 g glucose load. Analyses were by intention-to-treat. RESULTS: In total, 364 participants (182 in each arm) were randomised to the metformin or placebo group. At enrolment, in the metformin and placebo arms, mean fasting glucose was 6.37 mmol/l (95% CI 6.23, 6.50) and 6.26 mmol/l (95% CI 6.15, 6.36), respectively, and mean 2 h glucose levels following a 75 g oral glucose load were 8.39 mmol/l (95% CI 8.22, 8.56) and 8.24 mmol/l (95% CI 8.07, 8.41), respectively. At the final assessment at 12 months, 145/182 (79.7%) individuals randomised to metformin compared with 158/182 (86.8%) randomised to placebo indicated that they had taken >95% of their medicines in the previous 28 days (p=0.068). At this visit, in the metformin and placebo arms, mean fasting glucose levels were 6.17 mmol/l (95% CI 6.03, 6.30) and 6.30 mmol/l (95% CI 6.18, 6.42), respectively, and mean 2 h glucose levels following a 75 g oral glucose load were 7.88 mmol/l (95% CI 7.65, 8.12) and 7.71 mmol/l (95% CI 7.49, 7.94), respectively. Using a linear mixed model controlling for respective baseline values, the mean difference between the metformin and placebo group (metformin-placebo) was -0.08 mmol/l (95% CI -0.37, 0.20) for fasting glucose and 0.20 mmol/l (95% CI -0.17, 0.58) for glucose levels 2 h post a 75 g glucose load. Weight was significantly lower in the metformin arm than in the placebo arm: using the linear mixed model adjusting for baseline values, the mean difference in weight was -1.47 kg (95% CI -2.58, -0.35). In total, 16/182 (8.8%) individuals had a serious adverse event (Grade 3 or Grade 4 in the Division of Acquired Immunodeficiency Syndrome [DAIDS] adverse event grading table) or died in the metformin arm compared with 18/182 (9.9%) in the placebo arm; these events were either unrelated to or unlikely to be related to the study drugs. CONCLUSIONS/INTERPRETATION: Blood glucose decreased over time in both the metformin and placebo arms during the trial but did not differ significantly between the arms at 12 months of follow up. Metformin therapy was found to be safe for use in individuals with HIV and prediabetes. A larger trial with longer follow up is needed to establish if metformin can be safely used for the prevention of diabetes in people who have HIV. TRIAL REGISTRATION: The trial is registered on the International Standard Randomised Controlled Trial Number (ISRCTN) registry ( www.isrctn.com/ ), registration number: ISCRTN76157257. FUNDING: This research was funded by the National Institute for Health Research using UK aid from the UK Government to support global health research.
Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Glucose Intolerance , HIV Infections , Metformin , Prediabetic State , Adult , Humans , Adolescent , Prediabetic State/drug therapy , Glucose Intolerance/drug therapy , Blood Glucose/analysis , Tanzania , Glucose , Fasting , Double-Blind Method , HIV Infections/drug therapyABSTRACT
BACKGROUND: Children who have been hospitalized with severe anemia in areas of Africa in which malaria is endemic have a high risk of readmission and death within 6 months after discharge. No prevention strategy specifically addresses this period. METHODS: We conducted a multicenter, two-group, randomized, placebo-controlled trial in nine hospitals in Kenya and Uganda to determine whether 3 months of malaria chemoprevention could reduce morbidity and mortality after hospital discharge in children younger than 5 years of age who had been admitted with severe anemia. All children received standard in-hospital care for severe anemia and a 3-day course of artemether-lumefantrine at discharge. Two weeks after discharge, children were randomly assigned to receive dihydroartemisinin-piperaquine (chemoprevention group) or placebo, administered as 3-day courses at 2, 6, and 10 weeks after discharge. Children were followed for 26 weeks after discharge. The primary outcome was one or more hospital readmissions for any reason or death from the time of randomization to 6 months after discharge. Conditional risk-set modeling for recurrent events was used to calculate hazard ratios with the use of the Prentice-Williams-Peterson total-time approach. RESULTS: From May 2016 through May 2018, a total of 1049 children underwent randomization; 524 were assigned to the chemoprevention group and 525 to the placebo group. From week 3 through week 26, a total of 184 events of readmission or death occurred in the chemoprevention group and 316 occurred in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.54 to 0.78; P<0.001). The lower incidence of readmission or death in the chemoprevention group than in the placebo group was restricted to the intervention period (week 3 through week 14) (hazard ratio, 0.30; 95% CI, 0.22 to 0.42) and was not sustained after that time (week 15 through week 26) (hazard ratio, 1.13; 95% CI, 0.87 to 1.47). No serious adverse events were attributed to dihydroartemisinin-piperaquine. CONCLUSIONS: In areas with intense malaria transmission, 3 months of postdischarge malaria chemoprevention with monthly dihydroartemisinin-piperaquine in children who had recently received treatment for severe anemia prevented more deaths or readmissions for any reason after discharge than placebo. (Funded by the Research Council of Norway and the Centers for Disease Control and Prevention; ClinicalTrials.gov number, NCT02671175.).
Subject(s)
Anemia/drug therapy , Antimalarials/therapeutic use , Artemisinins/therapeutic use , Malaria/prevention & control , Quinolines/therapeutic use , Aftercare , Child, Preschool , Drug Combinations , Endemic Diseases , Female , Humans , Infant , Kenya/epidemiology , Malaria/epidemiology , Male , Patient Readmission/statistics & numerical data , Uganda/epidemiologyABSTRACT
BACKGROUND: The effect of iron supplementation during pregnancy on birth outcomes may vary with maternal genetic background and needs more investigation. OBJECTIVES: This prospective study aimed to evaluate the interactions between maternal iron supplementation and iron metabolism-related genetic polymorphisms on birth outcomes. METHODS: This was a substudy from a community-based randomized control trial conducted in Northwest China, which included 860 women from the 2 micronutrient supplementation groups (folic acid [FA] and FA + iron group). Maternal peripheral blood, sociodemographic and health-related information, and neonatal birth outcomes were collected. Six single nucleotide polymorphisms in iron metabolism-related genes were genotyped. The alleles associated with decreased iron/hemoglobin status were used as the effect alleles. The genetic risk score (GRS) that reflected the genetic risk of low iron/hemoglobin status was estimated using the unweighted and weighted methods. Generalized estimating equations with small-sample corrections were applied to evaluate the interactions between iron supplementation and SNPs/GRS on birth outcomes. RESULTS: There were significant interactions between maternal iron supplementation and rs7385804 (P = 0.009), rs149411 (P = 0.035), rs4820268 (P = 0.031), the unweighted GRS (P = 0.018), and the weighted GRS (P = 0.009) on birth weight. Compared with FA supplementation only, FA + iron supplementation significantly increased birth weight among women with more effect alleles in rs7385804 (ß: 88.8 g, 95% CI: 9.2, 168.3) and the GRSs (the highest unweighted GRS, ß: 135.5 g, 95% CI: 7.7, 263.4; the highest weighted GRS, ß: 145.9 g, 95% CI: 43.4, 248.5); it had a trend of decreasing birth weight and increasing low birth weight risk among women with fewer effect alleles. CONCLUSIONS: In our population, maternal genetic background related to iron metabolism plays a significant role in determining the efficacy of iron supplementation. Routine iron supplementation could be more beneficial to fetal weight growth among mothers with higher genetic risk for low iron/hemoglobin status.
Subject(s)
Dietary Supplements , Iron , Pregnancy , Infant, Newborn , Female , Humans , Prospective Studies , Birth Weight , East Asian People , Micronutrients , Folic Acid , Hemoglobins , Polymorphism, GeneticABSTRACT
OBJECTIVE: Diabetes prevalence has risen rapidly in Sub-Saharan Africa, but rates of retention in diabetes care are poorly understood. We conducted a systematic review and meta-analysis to determine rates of retention in care of persons with type 2 diabetes. METHODS: We searched MEDLINE, Global Health and CINAHL online databases for cohort studies and randomised control trials (RCTs) published up to 12 October 2021, that reported retention in or attrition from care for patients with type 2 diabetes in Sub-Saharan Africa. Retention was defined as persons diagnosed with diabetes who were alive and in care or with a known outcome, while attrition was defined as loss from care. RESULTS: From 6559 articles identified, after title and abstract screening, 209 articles underwent full text review. Forty six papers met the inclusion criteria, comprising 22,610 participants. Twenty one articles were of RCTs of which 8 trials had 1 year or more of follow-up and 25 articles were of non-randomised studies of which 19 had 12 months or more of follow-up. A total of 11 studies (5 RCTs and 6 non-randomised) were assessed to be of good quality. Sixteen RCTs were done in secondary or tertiary care settings. Their pooled retention rate (95% CI) was 80% (77%, 84%) in the control arm. Four RCTs had been done in primary care settings and their pooled retention rate (95% CI) was 53% (45%, 62%) in the control arm. The setting of one trial was unclear. For non-randomised studies, retention rates (95% CI) were 68% (62%, 75%) among 19 studies done in secondary and tertiary care settings, and 40% (33%, 49%) among the 6 studies done in primary care settings. CONCLUSION: Rates of retention in care of people living with diabetes are poor in primary care research settings.
Subject(s)
Diabetes Mellitus, Type 2 , Retention in Care , Humans , Diabetes Mellitus, Type 2/therapy , Africa South of the Sahara/epidemiology , Cohort StudiesABSTRACT
Epidemiological evidence on the association between potassium and cardiometabolic outcomes remains controversial. This study aimed to examine associations of dietary intake and blood and urinary levels of potassium with risk of type 2 diabetes, cardiovascular disease (CVD), and mortality. Relevant prospective studies were retrieved through a comprehensive search of four electronic databases up to July 1, 2023. Random-effects models were used to pool the study-specific relative risks (RRs) and 95% confidence intervals (CIs). Fifty-six studies were included in this meta-analysis. A higher intake of potassium was significantly associated with a 16% lower risk of CVD (RR: 0.84, 95% CI: 0.78-0.90). Similar inverse associations were also observed between potassium intake and mortality. Each 1.0 g/d increment in potassium intake was associated with a decreased risk of CVD (RR: 0.85, 95% CI: 0.80-0.91) and all-cause mortality (RR: 0.93, 95% CI: 0.88-0.99). For blood and urinary potassium levels, higher level of blood potassium increased the risk of all-cause mortality by 23% (RR: 1.23, 95% CI: 1.11-1.36). The association of blood potassium levels with mortality was nonlinear (Pnon-linearit<0.001). However, urinary potassium levels were inversely associated with the risk of all-cause mortality (RR: 0.84, 95% CI: 0.76-0.93). Our findings support the benefits of moderate potassium consumption for primary prevention of chronic diseases and premature death.
ABSTRACT
Mechanistic studies have suggested that antioxidants have beneficial effects on age-related macular degeneration (AMD). This study aimed to investigate the association between the types and sources of dietary vitamin and carotenoid intakes and AMD risk in China. A matched case-control study of 260 AMD cases and 260 matched controls was performed. The participants were interviewed for dietary information and potential confounders, and comprehensive ophthalmic examinations were performed. Conditional logistic models were used to estimate the odds ratio (OR) and 95 % confidence interval (CI) of specific vitamins and carotenoids and their main sources. When comparing the extreme quartiles, the ORs (95 % CI) were 0·30 (0·10, 0·88) for lutein and 0·28 (0·11, 0·74) for ß-cryptoxanthin. The associations for other dietary vitamin and carotenoid intakes were generally weaker and non-significant. Higher intakes of spinach and egg, which are important sources of lutein, were associated with a reduced odds of AMD. ORs (95% CIs) comparing extreme categories were 0·42 (0·20, 0·88) for spinach and 0·52 (95% CI: 0·27, 0·98) for egg. Participants who were in the highest category of both egg intake and spinach intake had a much greater reduced odds of having AMD (OR: 0·23; 95% CI: 0·08, 0·71) than those in the lowest category of egg intake and spinach intake. In conclusion, a higher intake of lutein and lutein-rich foods was associated with a significantly decreased odds of AMD. These findings provide further evidence of the benefits of lutein and lutein-rich foods in the prevention of AMD.
Subject(s)
Macular Degeneration , Vitamins , Humans , Carotenoids , Lutein , Case-Control Studies , Vitamin A , Macular Degeneration/epidemiology , Macular Degeneration/etiology , Macular Degeneration/prevention & control , Vitamin K , ZeaxanthinsABSTRACT
Many clinical trials include time-to-event or survival data as an outcome. To compare two survival distributions, the log-rank test is often used to produce a P-value for a statistical test of the null hypothesis that the two survival curves are identical. However, such a P-value does not provide the magnitude of the difference between the curves regarding the treatment effect. As a result, the P-value is often accompanied by an estimate of the hazard ratio from the proportional hazards model or Cox model as a measurement of treatment difference. However, one of the most important assumptions for Cox model is that the hazard functions for the two treatment groups are proportional. When the hazard curves cross, the Cox model could lead to misleading results and the log-rank test could also perform poorly. To address the problem of crossing curves in survival analysis, we propose the use of the win ratio method put forward by Pocock et al. as an estimand for analysing such data. The subjects in the test and control treatment groups are formed into all possible pairs. For each pair, the test treatment subject is labelled a winner or a loser if it is known who had the event of interest such as death. The win ratio is the total number of winners divided by the total number of losers and its standard error can be estimated using Bebu and Lachin method. Using real trial datasets and Monte Carlo simulations, this study investigates the power and type I error and compares the win ratio method with the log-rank test and Cox model under various scenarios of crossing survival curves with different censoring rates and distribution parameters. The results show that the win ratio method has similar power as the log-rank test and Cox model to detect the treatment difference when the assumption of proportional hazards holds true, and that the win ratio method outperforms log-rank test and Cox model in terms of power to detect the treatment difference when the survival curves cross.
Subject(s)
Proportional Hazards Models , Humans , Survival Analysis , Control Groups , Monte Carlo MethodABSTRACT
The win ratio method has been increasingly applied in the design and analysis of clinical trials. However, the win ratio method is a univariate approach that does not allow for adjusting for baseline imbalances in covariates, although a stratified win ratio can be calculated when the number of strata is small. This paper proposes an adjusted win ratio to control for such imbalances by inverse probability of treatment weighting (IPTW) method. We derive the adjusted win ratio with its variance and suggest three IPTW adjustments: IPTW-average treatment effect (IPTW-ATE), stabilized IPTW-ATE (SIPTW-ATE) and IPTW-average treatment effect in the treated (IPTW-ATT). The proposed adjusted methods are applied to analyse a composite outcome in the CHARM trial. The statistical properties of the methods are assessed through simulations. Results show that adjusted win ratio methods can correct the win ratio for covariate imbalances at baseline. Simulation results show that the three proposed adjusted win ratios have similar power to detect the treatment difference and have slightly lower power than the corresponding adjusted Cox models when the assumption of proportional hazards holds true but have consistently higher power than adjusted Cox models when the proportional hazard assumption is violated.
ABSTRACT
Generalized pairwise comparisons and win statistics (i.e., win ratio, win odds and net benefit) are advantageous in analyzing and interpreting a composite of multiple outcomes in clinical trials. An important limitation of these statistics is their inability to adjust for covariates other than by stratified analysis. Because the win ratio does not account for ties, the win odds, a modification that includes ties, has attracted attention. We review and combine information on the win odds to articulate the statistical inferences for the win odds. We also show alternative variance estimators based on the exact permutation and bootstrap as well as statistical inference via the probabilistic index. Finally, we extend multiple-covariate regression probabilistic index models to the win odds with a univariate outcome. As an illustration we apply the regression models to the data in the CHARM trial.