title stringlengths 1 1.19k | keywords stringlengths 0 668 | concept stringlengths 0 909 | paragraph stringlengths 0 61.8k | PMID stringlengths 10 11 |
|---|---|---|---|---|
Study protocol | A copy of the protocol for this study was submitted as an additional file to the journal. | PMC10731830 | ||
Authors’ contributions | Conceptualization: NE, Experimental work: NE, and YO, Interpretation of data: NE and MA writing original draft: NE. prepared tables: YO Review and editing: NE and MA All authors have read and reviewed the manuscript. | PMC10731830 | ||
Funding | This study was funded by the Deanship of Academic Research at the University of Jordan, Amman, Jordan. | PMC10731830 | ||
Availability of data and materials | This article has all the data that were collected or analyzed during this study. | PMC10731830 | ||
Declarations | PMC10731830 | |||
Ethics approval and consent to participate | dry dentures, denture | The study was conducted in accordance with the World Medical Declaration of Helsinki.The protocol of this study was reviewed and approved by the Deanship of Academic Research at the University of Jordan Hospital (IRB number: 42–2022).All participants involved in this study signed the consent form provided before the beginning of the study.Participants in this study were given instructions for using and cleaning the denture adhesives. Participants in group C were instructed to apply the adhesive on clean and dry dentures, once a day, away from the edges as shown in the diagram on the adhesive package, rinse mouth before use, press dentures in place firmly and bite down for few seconds to secure hold. For adhesive removal, participants were instructed to remove the adhesive using warm water and soft brush and use COREGA Cleanser (GlaxoSmithKline Brazil Ltda., Rio de Janeiro, Brazil) for more thorough cleaning. Participants in group O were given similar instructions, according to the leaflet provided with the adhesive and were instructed to clean mouth and dentures properly if adhesive residues remain using a clean paper towel. Participants in group S were instructed to place dry Sea.Bond seals, white side up, onto clean dry dentures, trim any overlap with scissors, lightly moisten and gently tap seal with fingertips, put denture in mouth and bite down evenly for 5 seconds. Participants were instructed to remove the seal at the end of the day by lifting the corner and peeling it away and to change seals daily. | PMC10731830 | |
Consent for publication | Not applicable. | PMC10731830 | ||
Competing interests | The authors declare no competing interests. | PMC10731830 | ||
References | PMC10731830 | |||
Significance: | toxicity, tumor, DLTs | TUMOR, PROLIFERATION, SOLID TUMORS, ADVERSE EVENT, TUMOR ANGIOGENESIS | Methionine aminopeptidase 2 (MetAP2) is essential to endothelial cell growth and proliferation during tumor angiogenesis. M8891 is a novel orally bioavailable, potent, selective, reversible MetAP2 inhibitor with antiangiogenic and antitumor activity in preclinical studies. The safety, tolerability, pharmacokinetics, and pharmacodynamics of M8891 monotherapy were assessed in a phase I, first-in-human, multicenter, open-label, single-arm, dose-escalation study (NCT03138538). Patients with advanced solid tumors received 7–80 mg M8891 once daily in 21-day cycles. The primary endpoint was dose-limiting toxicity (DLT) during cycle 1, with the aim to determine the maximum tolerated dose (MTD). Twenty-seven patients were enrolled across six dose levels. Two DLTs (platelet count decrease) were reported, one each at 60 and 80 mg/once daily M8891, resolving after treatment discontinuation. MTD was not determined. The most common treatment-emergent adverse event was platelet count decrease. M8891 plasma concentration showed dose-linear increase up to 35 mg and low-to-moderate variability; dose-dependent tumor accumulation of methionylated elongation factor 1α, a MetAP2 substrate, was observed, demonstrating MetAP2 inhibition. Pharmacokinetic/pharmacodynamic response data showed that preclinically defined target levels required for M8891 represents a novel class of reversible MetAP2 inhibitors and has demonstrated preclinical antitumor activity. This dose-escalation study assessed M8891 treatment for patients with advanced solid tumors. M8891 demonstrated favorable pharmacokinetics, tumoral target engagement, and a manageable safety profile, and thus represents a novel antitumor strategy warranting further clinical studies. | PMC10448909 |
Introduction | tumor | PROLIFERATION, TUMOR, SOLID TUMORS, TUMOR ANGIOGENESIS | Methionine aminopeptidase 2 (MetAP2) is one of two cytoplasmic methionine aminopeptidases ubiquitously expressed in mammalian cells. MetAPs catalyze N-terminal methionine excision from newly formed proteins, an essential step in cotranslational protein maturation ensuring protein stability and functionality. MetAP2 has been shown to play an essential role in the growth and proliferation of endothelial cells during tumor angiogenesis and tumor cell proliferation (Thus, MetAP2 could be a promising target in oncology (M8891 represents a novel class of orally bioavailable, potent, selective, and reversible MetAP2 inhibitors (We conducted this phase I study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of M8891 monotherapy in patients with advanced solid tumors. | PMC10448909 |
Materials and Methods | PMC10448909 | |||
Study Design | REGRESSION, SOLID TUMORS | This was a first-in-human (FIH), phase I, open-label, multicenter, single-arm, dose-escalation study designed to determine the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of M8891 in patients with advanced solid tumors (NCT03138538). An adaptive study design was applied, using a Bayesian two-parameter logistic regression model (BLRM). This study was designed to have two phases. Part 1, the monotherapy, dose-escalation phase, was completed according to protocol and is reported here. Part 2 of the study (combination of M8891 with cabozantinib) was not initiated; this was not due to safety concerns. Twenty-seven patients were enrolled from five sites in the United States between August 2017 (first patient visit) and September 2020 (last patient visit).This study was conducted in accordance with the protocol and consensus ethical principles derived from international guidelines including the Declaration of Helsinki, applicable International Conference on Harmonization Good Clinical Practice Guidelines, and other applicable laws and regulations. The protocol and all required associated documents were approved by the responsible Institutional Review Board or Independent Ethics Committee. All patients were required to provide written informed consent prior to enrollment. | PMC10448909 | |
Patient Eligibility | cancer, tumor | ONCOLOGY, CANCER, TUMOR, SOLID TUMORS | Eligible patients were ≥18 years of age and provided written informed consent; had histologically confirmed advanced solid tumors, refractory to or intolerant of existing cancer therapies, with no surgical, radiation, or systemic anticancer therapies available after at least one prior systemic anticancer therapy; had accessible tumor biopsies; and agreed to use a highly effective form of contraception.Key exclusion criteria included: an Eastern Cooperative Oncology Group (ECOG) performance status ≥2; severe bone marrow (hemoglobin <9.0 g/dL, neutrophil count <1.5 × 10 | PMC10448909 |
Treatment | toxicity, overdose | Patients received oral M8891 in 21-day cycles at doses of 7–80 mg once daily. The starting dose of 7 mg once daily was based on the dog highest non-severely toxic dose of 0.75 mg/kg/day divided by a safety factor of 6, which equated to a human dose of 7.5 mg (rounded to 7 mg) for a participant of 60 kg bodyweight. Safety Monitoring Committee (SMC) decisions on subsequent dose levels were supported by a BLRM with overdose control. In addition, the SMC could decide to switch from a once daily to twice daily dosing schedule if data suggested insufficient exposure (pharmacokinetics) and target engagement (pharmacodynamics) after completion of the dose-limiting toxicity (DLT) period of the third once daily dosing cohort (or at a later time) or if evidence suggested that | PMC10448909 | |
Assessments and Endpoints | nausea or vomiting, death, DLTs, bleeding, neutropenia, fever, fatigue, toxicity, Tumor, thrombocytopenia, TEAEs, SD, rash, treatment-emergent adverse events, hypertension | BLEEDING, NEUTROPENIA, TUMOR, ADVERSE EVENTS, BLOOD, THROMBOCYTOPENIA, DISEASE, EVENTS, HYPERTENSION, HEPATOCELLULAR INJURY | The primary endpoint was DLTs during the first 21-day treatment cycle of M8891, based on a predefined set of treatment-emergent adverse events (TEAE) with the aim to determine the MTD of M8891. At each dose level, the first patient was observed for DLTs for ≥7 days before the dosing of 2 subsequent patients was commenced. DLTs were defined as any of the following adverse events observed during the first 21-day treatment cycle and judged to be M8891-related or clinically relevant: death; events of clinical significance that would expose patients to unacceptable risk if dose escalation continued; treatment-related hepatocellular injury, for example, ALT/AST >3 × ULN with elevation of serum total bilirubin to >2 × ULN, without findings of clinical causality; grade 4 liver enzyme elevation; Grade 4 neutropenia or thrombocytopenia lasting >5 days; grade 3 neutropenia with fever; grade ≥3 thrombocytopenia with bleeding; treatment interruption of >7 days or >30% of total dose due to adverse events not related to the underlying disease or concomitant medication; grade ≥3 non-hematologic toxicity (excluding grade 3 nausea or vomiting lasting <48 hours and resolving to grade ≤1 spontaneously or with conventional medical intervention; grade 3 fatigue or rash of <5 days duration; grade 3 hypertension in the absence of maximal medical therapy; and grade 3 electrolyte abnormality that lasted <72 hours, was not clinically complicated, and resolved spontaneously or responded to conventional medical intervention). In addition, the SMC could define as a DLT any TEAE that impaired daily function, or any abnormality that occurred in patients treated with M8891 at any time in cycle 1 during the dose-escalation part of the trial.Secondary objectives included evaluating the safety, tolerability, pharmacokinetics, antitumor activity, and determining the RP2D of M8891. Safety evaluations included incidence and severity of TEAEs. All TEAEs were coded according to the Medical Dictionary for Regulatory Activities v23.0 (Efficacy endpoints included best overall response [BOR: complete response (CR), partial response (PR), stable disease (SD), or progressive disease] according to the RECIST v1.1. criteria (Blood samples for M8891 pharmacokinetic analysis were collected on cycle 1, day 1 at 0 hour (predose within 60 minutes prior to treatment administration) and at 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose; on cycle 1, day 8 at 0 hour (predose within 60 minutes prior to treatment administration); on cycle 1, day 15 at 0 hour (predose within 60 minutes prior to treatment administration) and at 1, 2, 3, 4, 6, 8, and 12 hours postdose; and on cycle 1, day 16 at 24 hours postdose (±60 minutes). From cycle 2 onward, blood samples for pharmacokinetic analysis were collected on day 1 at 0 hour (predose within 60 minutes prior to treatment administration). Validated LC/MS-MS bioanalytical methods were used to quantify concentrations of M8891 in plasma samples obtained from these blood samples. Pharmacokinetic parameters evaluated included observed maximum plasma concentration (Exploratory objectives included measuring the levels of the pharmacodynamic biomarker, methionylated elongation factor 1α (Met-EF1α), before and during M8891 treatment. Tumor biopsies were collected during the screening period and on cycle 2, day 1. White blood cell (WBC) samples were collected during the screening period, predose on days 1, 2, 8, and 15 of cycle 1 and postdose on days 1 and 15 of cycle 1. In addition, WBC samples were collected predose on days 1 and 15 of cycle 2. | PMC10448909 |
Statistical Analyses | toxicity, tumor, DLTs, overdose | EVENTS, TUMOR | No formal significance level was defined for this study and all analyses were considered descriptive. Five analysis sets were defined: the dose-escalation set included all patients treated in the dose-escalation cohorts who did not miss >4 cumulative days of planned M8891 doses in the first cycle unless they experienced a DLT; the safety analysis set included all patients who received at least one dose of M8891; the pharmacokinetic analysis set included all patients in the safety analysis set without major protocol deviations/violations or events that would affect pharmacokinetics; the pharmacodynamics in WBCs set included all patients who received at least one dose of M8891 and provided a predose and at least one postdose WBC assessment; and the pharmacodynamics in tumor tissue set included all patients who received at least one dose of M8891 and provided tumor tissue at baseline and at the postdose tumor assessment.To assist the SMC in making recommendations on the next dose level and the MTD, the posterior probabilities (2.5%, 25%, 50%, 75%, and 97.5% quantiles) of toxicity were estimated by a BLRM with overdose control. The model was updated with the number of evaluable patients and DLTs observed after completion of the DLT period for each cohort. The target toxicity for the suggested MTD by the BLRM was 30%.For the efficacy analysis, objective response and clinical benefit were summarized and 95% exact Clopper–Pearson confidence intervals (CI) were estimated (Dose proportionality was assessed using the “power model”; the pharmacokinetic endpoints, AUC, and | PMC10448909 |
Data Availability | For all new products or new indications approved in both the European Union and the United States after January 1, 2014, the healthcare business of Merck KGaA, Darmstadt, Germany will share patient-level and study-level data after deidentification as well as redacted study protocols and clinical study reports from clinical trials in patients. These data will be shared with qualified scientific and medical researchers, upon the researcher's request, as necessary for conducting legitimate research. Such requests must be submitted in writing to the company's data sharing portal. More information can be found at | PMC10448909 | ||
Results | PMC10448909 | |||
Patient Demographics and Disposition | ONCOLOGY, DISEASE | Baseline and disease history characteristics of all 27 patients enrolled are presented in Patient demographics and dispositionAbbreviations: ECOG, Eastern Cooperative Oncology Group; Max, maximum; Min, minimum; StD, standard deviation.
Thirteen of 27 patients (48.1%, | PMC10448909 | |
Safety | bleeding, DLTs, thrombocytopenia, TEAEs, decreased appetite | DISEASE PROGRESSION, BLEEDING, DEEP VEIN THROMBOSIS, THROMBOCYTOPENIA, ADVERSE EVENT, EVENTS | Overall, most patients (96.3%, 26/27) experienced a TEAE, with 21 (77.8%) reporting at least one TEAE considered related to M8891 by investigators (Overview of TEAEs for M8891Abbreviations: TEAE, treatment-emergent adverse event; QD, once daily.
TEAEs occurring in ≥15% patients are presented by dose level and overall, in TEAEs occurring in ≥15% of patients overall by dose levelAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; QD, once daily; TEAE, treatment-emergent adverse event.
In 4 patients, platelet count decrease or thrombocytopenia led to M8891 dose interruption [1 patient each in the 20 mg (thrombocytopenia) and 80 mg once daily (platelet count decrease) dose group] or study treatment discontinuation [1 patient each in the 35 mg and 60 mg once daily dose groups (both platelet count decrease)], with 3 patients subsequently recovering during the study period. Eight patients continued treatment with M8891 without dose interruption or reduction in response to platelet count decrease. One of these patients recovered while on treatment, 3 patients recovered after the last dose of M8891, and 4 patients had not recovered by the end of the study. In 1 patient in the 60 mg once daily dose group, platelet count decrease was detected 1 day after the last dose was administered; the patient subsequently recovered. The mean relative reduction in platelet count from baseline was greater with increasing dose levels (Mean relative change in platelet count from baseline per dose level in cycle 1 (%). C, cycle; D, day.Other common TEAEs were decreased appetite (Thirteen of 27 patients discontinued treatment due to disease progression (48.1%, all groups), 7 (25.9%) patients withdrew consent due to TEAEs, and another 7 (25.9%) patients experienced TEAEs that led to treatment discontinuation. Both, TEAEs leading to M8891 treatment discontinuation and M8891-related grade ≥3 TEAEs generally occurred more frequently at higher doses of M8891 (>20 mg once daily) than at lower doses (≤20 mg once daily). Six patients experienced TEAEs leading to study discontinuation that were considered M8891-related: deep vein thrombosis (Two DLTs of grade 4 platelet count decrease were reported in the study, one each in the 60 and 80 mg groups. Both patients were initially reported as having grade 1 platelet count decrease after 7 and 14 days of treatment, respectively, and subsequently developed grade 4 platelet count decrease. The DLTs were manageable, not complicated by bleeding events, and their severity decreased within 1 week after discontinuation of M8891.No clinically meaningful changes were observed in vital signs or ECG values from baseline to any postdose values. Most postdose laboratory tests values were rated grade 0 or 1 in severity. Three patients had shifts in baseline ECOG performance status to values ≥2.Taking into consideration the less than dose-proportional increase in exposure combined with safety observations at doses of 60 to 80 mg, the SMC recommended to de-escalate from 80 to 35 mg to further explore this dose as a potential RPD2. As a result, the DLT probability estimation by the BLRM did not reach sufficient precision due to the limited number of DLTs and sample size, and the MTD was not determined. | PMC10448909 |
Pharmacokinetics | The pharmacokinetic parameters for M8891 for cycle 1, days 1 and 15 are presented with summary statistics in Pharmacokinetic parameters of M8891 in plasma by treatment after single (cycle 1, day 1) and multiple dosing (cycle 1, day 15)Abbreviations: AUC
Except for a few subjects (Peak and total exposures (Plasma concentration–time profiles of M8891 (mean ± SD) at cycle 1, day 1 (From day 1 to day 15 of cycle 1, M8891 showed slight accumulation across all doses. The accumulation ratio for AUC ranged from 1.99 to 2.90, in line with a terminal half-life of approximately 30 hours and once daily dosing, and the accumulation ratio for Pharmacokinetic parameters after repeated dosing generally exhibited low to moderate interpatient variability, ranging from 7.7% to 51.7%. Starting with 20 mg, steady-state C | PMC10448909 | ||
Pharmacodynamics | tumor, tumors | TUMOR, TUMORS | Met-EF1α accumulation in tumors was observed at 7 mg once daily and tended to increase up to 35 mg once daily in a dose-dependent manner in line with the observed increase of exposure (Met-EF1α/protein levels in tumor on cycle 2, day 1 (individual patient dot plot). Open symbols show the pretreatment Met-EF1α levels, and the corresponding closed symbols show cycle 2, day 1 Met-EF1α levels for individual patients for the doses of 7, 12, 20, 35, 60, and 80 mg. The dashed line shows the target Met-EF1α level of 125 μg/mg protein expected to be correlated with efficacy. Met-EF1α, methionylated elongation factor 1α.At 12 mg once daily and higher, a low and variable pharmacodynamic response was detected in WBCs from cycle 1, day 15 onward; no obvious dose correlation was observed.On the basis of the observed safety, pharmacokinetic, and pharmacodynamic data, the SMC suggested a dose of 35 mg once daily as the RP2D for M8891 monotherapy. | PMC10448909 |
Efficacy | BOR of SD | DISEASE | Although no objective responses were observed in this heavily pretreated study population, 7 (25.9%) patients had a BOR of SD (Percentage change from baseline of the sum of longest target lesion diameters. The dashed lines show thresholds for progressive disease and PR. Dose levels are represented by different colors and symbols; the different curves at each dose level represent different patients. | PMC10448909 |
Discussion | bleeding, DLTs, tumor, neurotoxicity, tumors | BLEEDING, TUMOR, SOLID TUMORS, DRUG EFFECT, EVENTS, TUMOR GROWTH, TUMORS | In this phase I study, orally administered M8891 was clinically manageable in patients with advanced solid tumors. Among the 27 patients enrolled into the study, only two DLTs were observed, and, after enrolling a confirmatory cohort, the RP2D was determined as 35 mg once daily based on the absence of DLTs at doses ≤35 mg and a dose-proportional increase in M8891 exposure and Met-EF1α pharmacodynamic biomarker levels in tumors up to 35 mg once daily.TEAEs were generally grade 1–2 in severity and most were unrelated to M8891. Platelet count decrease was the most common TEAE, but these events were generally manageable clinically, and no associated bleeding events were observed. These results compare favorably with the safety profile of irreversible MetAP2 inhibitors, such as TNP-470, which showed considerable neurotoxicity in phase I studies (Exposure to M8891 increased by dose level and showed low-to-moderate interpatient variability following multiple doses based on pharmacokinetic parameters. The multiple-dose pharmacokinetics of M8891 compared favorably with high pharmacokinetic variability found in phase I studies with TNP-470 (M8891 treatment resulted in the accumulation of Met-EF1α in tumors in a dose-dependent manner, demonstrating inhibition of MetAP2 by M8891, consistent with preclinical studies (Although M8891 had shown significant tumor growth inhibition in preclinical models (As this was a phase I dose-escalation study, limitations include the open-label design and small sample size. The heterogeneity of tumor types enrolled in the study made it challenging to assign the efficacy or pharmacodynamic data to specific patient populations that may benefit more than others.In conclusion, M8891 is the first orally available, reversible MetAP2 inhibitor that has entered clinical development. This FIH study allowed determination of an RP2D based on relevant pharmacokinetics, pharmacodynamics, and safety observations; M8891 demonstrated a manageable safety profile with TEAEs in line with the patient population, drug effect, dose-proportional exposure up to 35 mg, Met-EF1α accumulation, and low-to-moderate interpatient variability of plasma concentration and corresponding parameters of pharmacokinetics. In addition, the observed exposure and target engagement anticipated to be required for | PMC10448909 |
Acknowledgments | The authors would like to thank the patients, investigators, co-investigators, and the study teams at each of the participating centers and the healthcare business of Merck KGaA, Darmstadt, Germany. The trial was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945). Medical writing assistance was provided by Daniel Smalley, Bioscript Stirling Ltd and funded by the healthcare business of Merck KGaA, Darmstadt, Germany.Marie-Christine Bissery, PhD and Stephan Braun, MD PhD, both employees of CureTeq AG, reviewed the article for scientific and medical accuracy. The authors are fully responsible for the content of this article, and the views and opinions described in the publication reflect solely those of the authors. | PMC10448909 | ||
Authors’ Disclosures | P. | ONCOLOGY, EMD | M.A. Carducci reports personal fees from Pfizer, Sanofi Genzyme, and AstraZeneca outside the submitted work. C. Habermehl reports personal fees from Merck KGaA outside the submitted work. F. Rohdich reports other. O. Karpenko reports personal fees from Merck healthcare KGaA, during the conduct of the study; personal fees from Sanofi, AstraZeneca, Daiichi Sankyo, and Sierra Oncology outside the submitted work. C. Gimmi reports a patent to P20-114-IN-PCT pending; and C. Gimmi was an employee of Merck KgAa at the time of the study conduct. P. LoRusso reports other from AbbVie, Agios, Five Prime, GenMab, Halozyme, Roche-Genentech, Genentech, CytomX, Takeda, SOTIO, Cybrexa, Agenus, Tyme, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, Glaxo-Smith Kline, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, MacroGenics, Kyowa Kirin, Kineta, Zentalis, Molecular Templates, ABL Bio, SK Life Sciences, STCube, Bayer, I-Mab, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanist, Mersana, BAKX Therapeutics, Scenic Biotech, Qualigen, Roivant, Neurotrials, and Actuate Therapeutics outside the submitted work. F. Rohdich and L. Pudelko are employees of the healthcare business of Merck KGaA, Darmstadt, Germany. No disclosures were reported by the other authors. | PMC10448909 |
Authors’ Contributions | PMC10448909 | |||
References | PMC10448909 | |||
ABSTRACT. | malaria, parasitemia, infections | MALARIA, PARASITEMIA, INFECTIONS, FETAL GROWTH RESTRICTION | Financial support: This work was funded by grants from the Academy of Finland (79787 and 207010), the Foundation for Pediatric Research in Finland, and the Medical Research Fund of Tampere University Hospital.Disclosures: The azithromycin and its placebo used in the study were provided free of charge by Pfizer Inc (New York, NY), which had no role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript.Authors’ addresses: Lotta Hallamaa, Mari Luntamo, Ulla Ashorn, Teija Kulmala, and Yue-Mei Fan, Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland, E:mails: Maternal malaria and infections during pregnancy are risk factors for fetal growth restriction. We assessed the impact of preventive treatment in pregnancy on maternal malaria and fetal growth. Between 2003 and 2006, we enrolled 1,320 pregnant Malawian women, 14–26 gestation weeks, in a randomized trial and treated them with two doses of sulfadoxine-pyrimethamine (SP, control) at enrollment and between 28–34 gestation weeks; with monthly SP from enrollment until 37 gestation weeks; or with monthly SP and azithromycin twice, at enrollment and between 28 and 34 gestation weeks (AZI-SP). Participants were seen at 4-week intervals until 36 completed gestation weeks and weekly thereafter. At each visit, we collected dried blood spots for real-time polymerase chain reaction diagnosing of malaria parasitemia and, in a random subgroup of 341 women, we measured fetal biparietal diameter and femur length with ultrasound. For the monthly SP versus the control group, the odds ratios (OR) (95% CI) of malaria parasitemia during the second, third, and both trimesters combined were 0.79 (0.46–1.37), 0.58 (0.37–0.92), and 0.64 (0.42–0.98), respectively. The corresponding ORs for the AZI-SP versus control group were 0.47 (0.26–0.84), 0.51 (0.32–0.81), and 0.50 (0.32–0.76), respectively. Differences between the AZI-SP and the monthly SP groups were not statistically significant. The interventions did not affect fetal biparietal diameter and femur length growth velocity. The results suggest that preventive maternal treatment with monthly SP reduced malaria parasitemia during pregnancy in Malawi and that the addition of azithromycin did not provide much additional antimalarial effect. | PMC10077022 |
INTRODUCTION | LBW, malaria, microscopy-diagnosed, parasitemia, infections | MALARIA, PARASITEMIA, INFECTIONS | Low birth weight (LBW) is an important risk factor of childhood mortality, morbidity, and lower intellectual ability later in life.Typical interventions aimed to reduce LBW incidence focus on improving maternal nutrition, managing maternal infections, encouraging a healthy life style, and providing health services to pregnant women.In the current study, we aimed to determine the relative impact of the two interventions, compared with a two-dose SP IPTp regimen, on maternal malaria parasitemia in the second and third trimesters of pregnancy. Additionally, we assessed the impact of the two IPTp interventions on fetal growth velocity. We have earlier shown that monthly SP regimen with and without azithromycin reduced the prevalence of microscopy-diagnosed malaria at 32 weeks of gestation and polymerase chain reaction (PCR)-diagnosed malaria at delivery, without major differences between monthly SP and AZI-SP groups. | PMC10077022 |
METHODS | PMC10077022 | |||
Background/study design. | PCR-diagnosed malaria parasitemia | PRETERM DELIVERY, SECONDARY | This study is a secondary analysis of maternal PCR-diagnosed malaria parasitemia throughout pregnancy and ultrasound-assessed fetal growth as part of Lungwena Antenatal Intervention Study. The trial was a single-center, randomized, partially placebo-controlled, outcome assessor–blinded, three-arm clinical trial in rural Malawi. The original study hypothesis was that preterm delivery (i.e., the primary outcome of the study) and other adverse pregnancy outcomes could be reduced by IPTp with monthly SP alone or in combination with two doses of azithromycin. | PMC10077022 |
Participants and follow-up. | Details of the inclusion and exclusion criteria and randomization are available in the original trial publication.All participants were seen at the health center at 4-week intervals until 36 completed gestation weeks and weekly thereafter. At each visit, the mothers underwent an interview, a routine antenatal investigation, and blood sampling. From the blood samples taken at the clinic, 100 μL (two spots, each 50 μL) was applied to Whatman FTA filter paper (Whatman plc, Maidstone, UK), air-dried, and placed in individually sealed plastic bags with a desiccant. The sample bags were stored in dry conditions at room temperature prior to transport to the Tampere University, Finland. The gathered dried blood spot (DBS) samples were analyzed by first extracting the DNAPelvic ultrasound to assess fetal biparietal diameter and femur length was performed for all study participants at the first antenatal visit and for a random subgroup of 341 women at each subsequent visit. Pelvic ultrasound was done with a portable analyzer by a research nurse (Aloka SSD-500; Aloka Co. Ltd., Tokyo, Japan, or Hitachi EUB 310; Hitachi, Ltd., Tokyo, Japan). Hadlock tables were used to calculate fetal age at the first visit. | PMC10077022 | ||
Outcomes. | parasitemia, PCR-diagnosed malaria parasitemia, PCR-diagnosed | MALARIA, PARASITEMIA | To identify maternal malaria parasitemia status, all DBS samples were run on an ABI 7900 Real-Time System (Applied Biosystems, Foster City, CA). Samples were considered positive if both cycle threshold values were below 45. We aimed at high sensitivity and specificity and therefore analyzed all samples in duplicate. Reactions with only one amplification curve reaching the threshold line were repeated. Analyses of PCR-diagnosed malaria parasitemia included participants who had at least one DBS sample collected after enrollment and who had all the background information available that we used as covariates in the analyses. We have previously reported the prevalence of maternal PCR-diagnosed peripheral blood malaria parasitemia at delivery, but we excluded these samples from our main analyses because the samples had been analyzed with a different laboratory protocol.Biparietal diameter and femur length were measured in duplicate as millimeters. An average of the two measurements was used and rounded down. We excluded twin pregnancies because we could not confirm which fetus was measured. Of the 341 participants with repeated biparietal diameter and femur length measurements, the analysis included the results of 337 participants who had all background information available that was used as covariates in the analyses. We graphically compared the biparietal diameter and femur length in our sample to the 5th, 50th, and 95th percentile in the INTERGROWTH-21st standards. | PMC10077022 |
Statistical analysis. | peripheral blood malaria parasitemia, parasitemia | MALARIA, PARASITEMIA, REGRESSIONS, SECONDARY, REGRESSION, PRETERM DELIVERY | The sample size of 440 pregnant women per group was planned to give 80% power at a 5% level of significance to detect a 40% reduction in the rate of preterm delivery, which was the trial’s main hypothesis.Treatment allocation for the study was broken for the analysis of the trial’s main hypothesis. The statistician for this secondary analysis was different from the one doing the analyses for the main hypothesis. For this analysis the statistician (L.H.) merged the treatment allocation codes with maternal malaria parasitemia and fetal ultrasound data only after data were cleaned, the analysis plan was written, and the syntax for the analysis was done with a mock code. The analysis was based on the principle of intention-to-treat. We conducted statistical analyses with Stata 16.1 (StataCorp, College Station, TX).For maternal malaria parasitemia during pregnancy, we calculated the proportion of positive malaria parasitemia DBS samples by intervention group during the entire follow-up period and for the second trimester (from 14 weeks + 0 days to 26 weeks + 6 days of gestation) and third trimester (from 27 weeks + 0 days of gestation to the end) of pregnancy. We estimated the odds ratios (ORs) between the three groups with mixed-effects logistic regressions with random intercepts by participant. Because of different timing of enrollment in terms of gestational weeks, the timing and number of the 4-weekly assessments per pregnancy varied. There were also missed visits during the follow-up. We used a mixed effects model that allows uneven timing and in which the random effect captures individual intercepts despite the variation in number of observations per participant. We estimated two different models: one for the entire follow-up period and one estimating the OR for the second and third trimesters separately. The model estimating the OR for the second and third trimesters separately allowed the estimates of treatment effect to differ between trimesters. Based on the OR, we estimated marginal risk ratios between the intervention groups from the model for the entire follow-up period.We modeled biparietal diameter (mm) and femur length (mm) in relation to gestational weeks and intervention groups during the second and third trimesters of pregnancy by mixed-effects linear regression. Because fetal growth was not linear throughout pregnancy, we used two separate models to estimate the slopes for the second and third trimesters. The duration of pregnancy was centered to 14 weeks, which was the shortest duration of pregnancy at enrollment in the data. The model included random intercepts and random slopes by participants and allowed variation in the timing and number of ultrasound measurements per pregnancy. The random effects were allowed to be correlated. We estimated the change in biparietal diameter and femur length in relation to gestational weeks, with an interaction term between intervention groups and weeks of gestation, and the slope was multiplied by 4 to obtain the change per 4 gestational weeks. We calculated the differences in the rates of change between the three groups.The proportion of women with none or one previous pregnancy and with microscopic peripheral blood malaria parasitemia at enrollment was higher in the control group than in the intervention groups.The null hypothesis of no difference between groups was rejected if As an exploratory analysis, we performed tests for interaction between interventions and number of previous pregnancies (as a continuous variable), maternal HIV status, and bed net use at enrollment by using the likelihood ratio test and considered | PMC10077022 |
Ethics committee approval. | Both the original trial and the follow-up were performed according to Good Clinical Practice and the ethical standards of the Declaration of Helsinki. The protocol was approved by the College of Medicine Research and Ethics Committee, Malawi, and the Ethical Committee of Pirkanmaa Hospital District, Finland. This trial has been registered at | PMC10077022 | ||
RESULTS | PMC10077022 | |||
Enrollment and background. | parasitemia | MALARIA, PARASITEMIA | Between December 1, 2003, and October 11, 2006, 1,320 women were enrolled in the study and randomized to control (436), monthly SP (441), and AZI-SP groups (443). At enrollment the intervention groups were similar except for small differences in the prevalence of microscopic malaria parasitemia and mean number of previous pregnancies (Baseline characteristics of the participating women at enrollment, by study groupAZI = azithromycin; BMI = body mass index; Hb = hemoglobin; PCR = polymerase chain reaction; SP = sulfadoxine-pyrimethamine.Value missing for one participant.The mean (SD) number of scheduled SP treatments received, among those included in these analyses, was 2.0 (0.2) in the control group, 4.0 (0.9) in the monthly SP group, and 4.0 (0.8) in the AZI-SP group. Women in the AZI-SP group received a mean (SD) of 2.0 (0.2) azithromycin doses. A DBS sample at enrollment and at least once thereafter with all covariate data was available from 97.5% of the participants. Excluding DBS sample at enrollment, the mean (SD) number of DBS samples included in the analyses during the second and third trimesters were 1.4 (0.5) and 2.5 (0.8) samples per participant, respectively, with no difference between groups. Each participant in the monthly ultrasound follow-up group had at least one ultrasound measurement after enrollment (Enrollment, randomization, and follow-up. AZI-SP = intervention group with monthly sulfadoxine-pyrimethamine (SP) and two doses of azithromycin; PCR = polymerase chain reaction. | PMC10077022 |
Maternal malaria parasitemia. | malaria, parasitemia | MALARIA, REGRESSION, PARASITEMIA | The overall proportion (Proportion of malaria parasitemia positive samples, using the locally weighted scatterplot smoothing technique with bandwidth (0.2). AZI-SP = intervention group with monthly sulfadoxine-pyrimethamine (SP) and two doses of azithromycin.Proportion of maternal malaria parasitemia by intervention group during the whole pregnancy and the second and third trimesters of pregnancy separatelyAZI = azithromycin; OR = odds ratio; SP = sulfadoxine-pyrimethamine.Unadjusted proportions.Estimated with mixed-effects logistic regression, adjusted for polymerase chain reaction test result at enrollment, number of previous pregnancies, and duration of pregnancy at the time of malaria test.Second trimester from 14 weeks + 0 days of gestation to 26 weeks + 6 days of gestation; third trimester from 27 weeks + 0 days of gestation to the end of pregnancy.There was no statistically significant interaction on the proportion of malaria parasitemia between the intervention group and number of previous pregnancies (Proportion of maternal malaria parasitemia by intervention group throughout pregnancy, stratified by number of previous pregnancies, HIV status, and use of bed net during previous night before enrollmentAZI = azithromycin; OR = odds ratio; SP = sulfadoxine-pyrimethamine.Unadjusted proportions.Estimated with mixed-effects logistic regression, adjusted for malaria parasitemia status (polymerase chain reaction) at enrollment, number of previous pregnancies (except when stratified by number of previous pregnancies), and duration of pregnancy at the time of malaria test. | PMC10077022 |
Fetal growth. | SE, parasitemia | REGRESSION, PARASITEMIA, MALARIA | The mean (SD) biparietal diameter of the fetuses was 41.8 mm (7.4) at enrollment, 77.1 mm (4.6) at 28–32 weeks of pregnancy, and 90.7 mm (4.3) at 37–38 weeks of pregnancy. Corresponding values for femur length were 22.5 mm (6.1), 52.0 mm (4.0), and 63.3 mm (4.3), respectively. The mean biparietal diameter was close to the 95th percentile of INTERGROWTH-21st standards at the beginning of the second trimester of pregnancy but fell below the 50th percentile toward the end of pregnancy. The mean femur length was close to the 50th percentile of INTERGROWTH-21st standard at the beginning of the second trimester but fell to the 5th percentile toward the end of pregnancy (Mean fetal biparietal diameter (mm) and femur length (mm) compared with INTERGROWTH-21st standards, using the locally weighted scatterplot smoothing technique with bandwidth (0.2). LAIS = Lungwena Antenatal Intervention Study.The estimated mean (standard error [SE]) change in biparietal diameter per 4 weeks during the second trimester of pregnancy was 12.4 mm (0.3), 12.0 mm (0.3), and 11.9 mm (0.3) in the control, monthly SP, and AZI-SP groups, respectively. Corresponding changes in biparietal diameter during the third trimester of pregnancy were 7.1 mm (0.3), 7.0 mm (0.2), and 6.9 mm (0.2). There were no statistically significant differences between the intervention groups during either of the trimesters (each Change in fetal biparietal diameter (mm) and femur length (mm) per 4 weeks by intervention group during the second and third trimesters of pregnancyAZI = azithromycin; OR = odds ratio; SP = sulfadoxine-pyrimethamine; SE = standard error.Second trimester from 14 weeks + 0 days of gestation to 26 weeks + 6 days of gestation; third trimester from 27 weeks + 0 days of gestation to the end of pregnancy.Estimated with mixed-effects linear regression, adjusted for ultrasound measurement at enrollment, number of previous pregnancies, malaria parasitemia status (polymerasce chain reaction) at enrollment, maternal body mass index at enrollment, and duration of pregnancy at time of ultrasound measurement.Estimated mean (SE) change in femur length per 4 weeks during the second trimester was 9.4 mm (0.4), 9.9 mm (0.3), and 9.1 mm (0.3) mm in the control, monthly SP, and AZI-SP groups, respectively. Corresponding changes in femur length during the third trimester of pregnancy were 6.7 mm (0.3), 6.0 mm (0.2), and 6.1 mm (0.2). There were no statistically significant differences between the intervention groups during either of the trimesters (each A sensitivity analysis excluding biparietal diameter and femur length values measured at or after 38 weeks of gestation did not change the results ( | PMC10077022 |
DISCUSSION | LBW, stunting, malaria, parasitemia, weight gain, PCR-diagnosed malaria parasitemia | MALARIA, PRETERM BIRTH, PARASITEMIA | The aim of this study was to determine the impact of antenatal monthly SP with or without two doses of azithromycin on maternal PCR-diagnosed malaria parasitemia and fetal biparietal diameter and femur length growth velocity in the second and third trimesters of pregnancy compared with two doses of SP. In a sample of 1,320 rural Malawian women, the odds of malaria parasitemia during the second and third trimesters separately or combined were up to 50% lower among participants treated with monthly SP or AZI-SP compared with those in the control group. There were no statistically significant interactions between malaria parasitemia and maternal HIV status, parity, or bed net use. However, the odds of malaria parasitemia were 50–76% lower among HIV-positive and primiparous women in the monthly SP and AZI-SP groups compared with those in the control group, with statistically significant differences among primiparous women in both intervention groups compared with the control. There were no differences between the groups in the growth velocity of biparietal diameter or femur length.The strengths of this trial include random group allocation, broad inclusion criteria, a large sample size, comprehensive follow-up, and blinding of the outcome assessors. Internal validity could have been compromised by variation in the timing of DBS collection in terms of 1) gestational weeks and ultrasound measurements during pregnancy, 2) the small baseline differences in the prevalence of maternal malaria parasitemia and number of previous pregnancies between the intervention groups, and 3) that the study was not powered to detect small differences between the monthly SP and the AZI-SP groups or find interactions for the outcomes. However, we used all available malaria parasitemia and ultrasound measurements as outcomes, regardless of the timing, using mixed effect models that allowed this. All the models adjusted for variables with imbalance at baseline. Thus, we believe these factors did not bias our conclusions, and we consider the findings indicative of a causal association between the antenatal monthly SP and AZI-SP interventions and reduced maternal malaria parasitemia prevalence during pregnancy. The impact may have been larger among primiparous or HIV-positive women than among multiparous or HIV-negative women, but the study was not sufficiently powered to make firm conclusions from the subgroup analyses. In contrast, the findings do not provide support for a hypothesis that either of the interventions would affect biparietal diameter or femur length growth velocity.Our results are in line with other studies that have shown a positive impact of monthly SP on maternal malaria during pregnancy compared with the two-dose SP regimen.Although maternal malaria has been shown to have a negative impact on fetal and newborn head size and length,Because we did not measure fetal abdominal circumference in this study, we could not use ultrasound assessment to calculate fetal weight gain during pregnancy in the way we assessed gains in length. However, we have previously reported that infants born to mothers in the AZI-SP group had about 40% lower incidence of LBW and 140 g higher mean birth weight than infants born to mothers in the control group.Earlier results from this trial have shown that antenatal AZI-SP treatment reduced the incidence of preterm birth, LBW, and incidence of stunting during the first 5 years of a child’s life compared with two doses of SP.After the implementation of our study 15–20 years ago, the recommendation for IPTp has changed from two doses to monthly dosing with SP.In conclusion, results from this study support the hypothesis that monthly SP with or without two doses of azithromycin reduced maternal malaria parasitemia during pregnancy in Malawi. In contrast, the study findings did not provide evidence that the same interventions would affect growth velocity of fetal biparietal diameter and femur length. When combined with earlier results on birth size, the findings suggest that the AZI-SP intervention increased mean infant length at 1 month of age mainly by extending the duration of pregnancy and increased birth weight also by increasing the speed of fetal weight gain. The addition of azithromycin to monthly SP did not greatly improve the antimalarial effect of the IPTp regimen but further improved birth outcomes through other mechanisms, probably through antibacterial and anti-inflammatory pathways. | PMC10077022 |
ACKNOWLEDGMENTS | We thank the study participants, the people of Lungwena, the staff at the Lungwena Training Health Centre and the Malindi and Mangochi Hospitals, and our research nurses and assistants. | PMC10077022 | ||
REFERENCES | PMC10077022 | |||
Background | This study updated 3-year analyses to further characterize the impact of docetaxel, cisplatin, and fluorouracil (TPF) chemotherapy followed by surgery. | PMC10761379 | ||
Methods | cancer | PRIMARY TUMOR, CANCER, OESOPHAGEAL SQUAMOUS CELL CARCINOMA | This study was a single-center phase 2 clinical trial. Patients with a diagnosis of borderline resectable esophageal squamous cell carcinoma (BR-ESCC) because of the primary tumor or bulky lymph node that potentially invaded adjacent organs were eligible. The treatment started with TPF chemotherapy followed by surgery if the cancer was resectable, or by concurrent chemoradiation if it was unresectable. This updated report presents the 3-year overall survival (OS) and progression-free survival (PFS) rates. | PMC10761379 |
Results | Surgery was performed for 27 patients (57.4%), and R0 resection was confirmed in 25 patients (53.2%). Pathologic complete response was confirmed in four patients (8.5%). The median follow-up time for the surviving patients was 44.8 months (range, 3.4–74.6 months). The median OS for all the patients was 41.9 months (95% confidence interval [CI], 18.6–65.3 months), with a median PFS of 38.7 months (95% CI, 23.5–53.9 months). The 3-year survival rate for all the patients was 54.4%. The 3-year survival rate for the R0 patients was 65.4%. | PMC10761379 | ||
Patients and Methods | Cancer | CANCER | The study was approved by the ethics committee of Sun Yat-sen University Cancer Center. All patients included in the study provided written informed consent before enrollment. The study was registered at ClinicalTrials.gov (NCT02976909). | PMC10761379 |
Patients | As previously reported, | PMC10761379 | ||
Study Design and End Points | The NEOCRTEC-1601 study was a single-center phase 2 clinical trial. The details of the borderline resectable criteria and clinical staging were described in our previous report. | PMC10761379 | ||
Treatment Procedure | tumor, tumors | TUMOR, POSTOPERATIVE COMPLICATIONS, TUMOR PROGRESSION, PRIMARY TUMOR, TUMORS | The protocol therapy started with two or three cycles of TPF-induction chemotherapy (intravenous [IV] paclitaxel 135 mg/mAfterward, if curative resection was considered possible on multidisciplinary consultation reassessment, the patient was scheduled for conversion surgery 3–4 weeks after induction therapy. McKeown esophagectomy combined with two-field lymphadenectomy was performed. The grade of postoperative complications was defined according to the Clavien-Dindo classification. In addition, chemoradiotherapy was recommended for patients receiving R1/R2 resection.Concurrent chemoradiotherapy was administered as the main treatment for the patients who had tumors still considered unresectable after reassessment. If no tumor progression occurred during induction chemotherapy, the paclitaxel plus cisplatin (TP) regimen was recommended.The gross tumor volume (GTV) encompassed the primary tumor and enlarged regional lymph nodes, as determined by imaging and endoscopy examinations. The clinical target volume (CTV) was determined by a GTV plus a 0.8- to 1.0-cm lateral margin and a 3.0- to 5.0-cm craniocaudal margin that included subclinical involvement. The planning target volume was defined as a CTV plus a 0.5- to 0.8-cm margin. The total planned dose for the planning target volume was 56–60 Gy in 2-Gy fractions per day 5 days a week. All the patients were irradiated by external beam radiation using 6 to 8-MV photon energies of the intensity-modulated radiation technique. | PMC10761379 |
Pathologic Analysis | TRG, tumor, Cancer | TUMOR, DEGENERATION, RESIDUAL TUMOR, REGRESSION, CANCER | Evaluations of residual tumor (R) were classified as follows: R0 resection (no microscopic and macroscopic residual tumor), R1 resection (only microscopic residual tumor), and R2 resection (macroscopic residual tumor). A condition without grossly and microscopically viable tumor in the entire surgical specimen, including the primary site and any resected lymph nodes, was defined as a pathologic complete response (pCR).The American Joint Committee on Cancer (AJCC)/College of American Pathologists (CAP) tumor regression grade (TRG) was classified as follows: TRG 0 (pCR: no residual tumor cells), TRG 1 (near complete response: single or small groups of residual tumor cells), TRG 2 (partial response: residual tumors with degeneration of tumor cells and desmoplastic response), TRG 3 (poor or no response: a large number of tumor cells observed with little or no response to treatment). | PMC10761379 |
Statistical Analysis | According to the retrospective data from our center, the R0 resection rate for BR-ESCC with surgery alone was approximately 20% (3/12) and expected to increase to 40%. With a one-sided alpha significance level of 0.05 and a statistical power of 80%, the inclusion of 40 patients was required for evaluation of the R0 resection rate. In addition, assuming a dropout rate of 15%, at least 46 cases needed to be enrolled. The 95% CI for the R0 resection rate was calculated based on the binomial distribution.Both OS and DFS were estimated using the Kaplan-Meier method, and a log-rank test was used for comparisons between the groups. In addition to comparing survival between the surgery and non-surgery patients, we divided the patients into two groups based on whether they underwent R0 resection. The patients in the R0 group included those who underwent R0 operation. The patients in non-R0 group comprised two types of patients: those who did not undergo surgery (The chi-square test or Fisher’s exact test and Student’s | PMC10761379 | ||
Results | PMC10761379 | |||
Survival | The median follow-up time for the surviving patients was 44.8 months (range, 3.4–74.6 months). The median OS for all the patients was 41.9 months (95% CI, 18.6–65.3 months), and the median PFS for all the patients was 38.7 months (95% CI, 23.5–53.9 months). The 3-year survival rate was 54.4% (95% CI, 40.2–69.5 %), and the 3-year PFS rate was 52.3% (95% CI, 36.3–65.7%) (Fig. Overall survival and progression-free survival. As mentioned in our previous report, the patients were divided into two groups according to whether they underwent surgery. The non-surgery group comprised two types of patients: the patients who received DCRT without surgery and those who received neither DRCT nor surgery. The median OS was significantly more favorable in the surgery group than in the non-surgery group (not reached vs 26.5 months; HR, 0.43; 95% CI, 0.19–0.97); Furthermore, in accordance with whether they underwent R0 resection, the patients were divided into the R0 group (The OS for the R0 group was significantly longer than for the non-R0 group (not reached vs 26.5 months; HR, 0.38; 95% CI, 0.17–0.85; | PMC10761379 | ||
Acknowledgment | This study was supported by the National Natural Science Foundation of China (grant nos. 81972614 and 82273032) and the Natural Science Foundation of Guangdong Province, China (grant no.2022A1515012217). | PMC10761379 | ||
Funding | National Natural Science Foundation of China, 81972614, 82273032, Natural Science Foundation of Guangdong Province, No.2022A1515012217. | PMC10761379 | ||
Disclosures | There are no conflicts of interest. | PMC10761379 | ||
References | PMC10761379 | |||
BACKGROUND: | heart failure, death | HEART FAILURE, LEFT VENTRICULAR SYSTOLIC DYSFUNCTION | Percutaneous coronary intervention (PCI) is frequently undertaken in patients with ischemic left ventricular systolic dysfunction. The REVIVED (Revascularization for Ischemic Ventricular Dysfunction)-BCIS2 (British Cardiovascular Society-2) trial concluded that PCI did not reduce the incidence of all-cause death or heart failure hospitalization; however, patients assigned to PCI reported better initial health-related quality of life than those assigned to optimal medical therapy (OMT) alone. The aim of this study was to assess the cost-effectiveness of PCI+OMT compared with OMT alone. | PMC10782932 |
METHODS: | heart failure, left ventricular systolic dysfunction | HEART FAILURE, LEFT VENTRICULAR SYSTOLIC DYSFUNCTION, REGRESSION | REVIVED-BCIS2 was a prospective, multicenter UK trial, which randomized patients with severe ischemic left ventricular systolic dysfunction to either PCI+OMT or OMT alone. Health care resource use (including planned and unplanned revascularizations, medication, device implantation, and heart failure hospitalizations) and health outcomes data (EuroQol 5-dimension 5-level questionnaire) on each patient were collected at baseline and up to 8 years post-randomization. Resource use was costed using publicly available national unit costs. Within the trial, mean total costs and quality-adjusted life-years (QALYs) were estimated from the perspective of the UK health system. Cost-effectiveness was evaluated using estimated mean costs and QALYs in both groups. Regression analysis was used to adjust for clinically relevant predictors. | PMC10782932 |
RESULTS: | Between 2013 and 2020, 700 patients were recruited (mean age: PCI+OMT=70 years, OMT=68 years; male (%): PCI+OMT=87, OMT=88); median follow-up was 3.4 years. Over all follow-ups, patients undergoing PCI yielded similar health benefits at higher costs compared with OMT alone (PCI+OMT: 4.14 QALYs, £22 352; OMT alone: 4.16 QALYs, £15 569; difference: −0.015, £6782). For both groups, most health resource consumption occurred in the first 2 years post-randomization. Probabilistic results showed that the probability of PCI being cost-effective was 0. | PMC10782932 | ||
CONCLUSIONS: | left ventricular systolic dysfunction | LEFT VENTRICULAR SYSTOLIC DYSFUNCTION | A minimal difference in total QALYs was identified between arms, and PCI+OMT was not cost-effective compared with OMT, given its additional cost. A strategy of routine PCI to treat ischemic left ventricular systolic dysfunction does not seem to be a justifiable use of health care resources in the United Kingdom. | PMC10782932 |
REGISTRATION: | URL: | PMC10782932 | ||
WHAT IS KNOWN | heart failure, death, left ventricular systolic dysfunction | HEART FAILURE, LEFT VENTRICULAR SYSTOLIC DYSFUNCTION | Percutaneous coronary intervention (PCI) is frequently utilized in patients with ischemic left ventricular systolic dysfunction.The REVIVED (Revascularization for Ischemic Ventricular Dysfunction)-BCIS2 (British Cardiovascular Society-2)trial demonstrated that PCI did not decrease all-cause death or heart failure hospitalization rates although patients undergoing PCI initially reported an improved health-related quality of life compared with optimal medical therapy alone.The economic and health consequences of a PCI strategy for ischemic left ventricular systolic dysfunction remain unknown. | PMC10782932 |
WHAT THE STUDY ADDS | Heart failure, HF, coronary artery disease, left ventricular systolic dysfunction | HEART FAILURE, LEFT VENTRICULAR SYSTOLIC DYSFUNCTION, CORONARY ARTERY DISEASE | This study evaluates the economic implications associated with PCI in ischemic left ventricular systolic dysfunction patients, filling a crucial knowledge gap.Results indicate that although PCI provides similar health benefits, it comes at a higher cost when compared with optimal medical therapy alone.Most health resource utilization occurred in the first 6 months post-randomization, related to the PCI procedures.Study findings indicate that routine PCI as a treatment strategy for ischemic left ventricular systolic dysfunction is not cost-effective, which has implications for health care resource allocation.
Heart failure (HF) is an increasing worldwide health problem, with coronary artery disease being the most common cause.In the REVIVED trial, it was hypothesized that revascularization with PCI in addition to optimal MT (OMT) compared with OMT alone could improve event-free survival in patients with severe ischemic left ventricular systolic dysfunction (ILVD).The aim of our current analysis was to assess the cost-effectiveness of PCI for patients with severe stable ILVD by using patient-level resource use and patient-reported outcome data collected in the REVIVED trial. | PMC10782932 |
METHODS | PMC10782932 | |||
Trial Design and Patient Population | HEART | REVIVED was a prospective, multicenter, randomized, open-label trial involving 700 patients with ILVDThe patients enrolled had a median age of 69 years, 12% were female, the median British Cardiovascular Intervention Society jeopardy score was 10, the mean baseline LVEF was 27%±6.8%, and 26% had New York Heart Association class III or IV functional status ( | PMC10782932 | |
Economic Analysis | The analysis follows the preferred methods of the UK National Institute for Health and Care Excellence | PMC10782932 | ||
Estimation of Costs | coronary artery disease | CORONARY ARTERY DISEASE | Health care resources used by each participant in the trial were obtained from the trial case report forms completed by trial investigators. The case report form captured the health resource consumption at baseline, 6 months, 12 months, and then on a yearly basis, with only postrandomization consumption included for analysis. Relevant health resources included revascularization, prescribed medications, HF hospital admissions and related treatments, implantable cardiac device implantation or upgrade, outpatient visits, and clinical investigations (eg, echocardiogram) during the first 2 years following randomization. HF hospitalizations, unplanned revascularizations, and implantable device information were collected yearly for 2 to 8 years. Unit costs for the health resources were obtained from National NHS Reference Costs databasesHealth care resource use was combined with relevant unit costs and aggregated to produce a total cost for each trial participant. Six distinct cost categories were defined: planned and unplanned revascularization procedures, medications, hospitalization, implanted devices, and clinical investigations (including hemoglobin, creatinine, cholesterol, low density lipoprotein, high density lipoprotein, triglyceride, B-type natriuretic peptide, hemoglobin A1c, and echocardiogram). Within the intervention arm, planned revascularization procedures encompassed the costs associated with the initial planned percutaneous coronary procedures and their subsequent stages. Unplanned revascularization is related to any subsequent unplanned PCIs or CABG procedures throughout trial follow-up. Medication costs are related to cardiac medication at randomization, at hospital discharge, and relevant assessment points of follow-up in both arms of the trial. The cost of medication was estimated according to the dosage and duration of each drug consumed. HF hospitalization costs include costs related to inpatient stays, as well as any associated diagnostic tests, procedures, and medication required within that admission. Implantable device costs encompassed the device itself (cardiac resynchronization therapy, cardiac resynchronization therapy with defibrillator, or implantable cardioverter defibrillator only) and all costs associated with its implantation or upgrade. Finally, clinical investigation costs were related to the diagnosis and management of coronary artery disease and HF, including costs associated with tests such as blood tests and echocardiograms (prerandomization eligibility testing was not considered).By estimating the costs associated with each of these categories, we aimed to provide a comprehensive understanding of the cost burden associated with treating patients with ILVD. Costs were expressed as total per-participant costs over the follow-up period. | PMC10782932 |
Health-Related Quality of Life | In the REVIVED trial, health-related quality of life was assessed using the KCCQ and the EQ-5D-5L questionnaires. | PMC10782932 | ||
Multiple Imputation | Missing responses to the EuroQol 5-dimension (EQ-5D) instrument were imputed using multiple imputations by chained equations. | PMC10782932 | ||
Regression Analysis | REGRESSION | Generalized linear models were used to estimate independently predicted total costs and QALYs over the follow-up period. Adjustment for clinically relevant and validated covariates was performed, consistent with the primary outcome analysis.To consider the potential interdependence and correlation between costs and outcomes, a seemingly unrelated regression model was performed as a modeling alternative. | PMC10782932 | |
Cost-Effectiveness Analysis | SENSITIVITY | Incremental cost-effectiveness analysis was conducted based on differences in mean costs and QALYs between the 2 randomized groups. In the context of 1 group having higher mean costs and QALYs, incremental cost-effectiveness was estimated as the relevant intervention’s incremental cost per additional QALY. Judgments on the cost-effectiveness of interventions were performed by comparing the incremental cost-effectiveness ratio to the National Institute for Health and Care Excellence cost-effectiveness threshold range of £20 000 to £30 000 per QALY gained.Sensitivity analyses were performed to assess the robustness of the results. The analyses were conducted to evaluate the impact of key assumptions and uncertainties on the estimated incremental cost-effectiveness ratio and to test the validity of the findings. A probabilistic sensitivity analysis was considered to account for the joint uncertainty in all parameters simultaneously based on 1000 random samples from the parameter distributions, enabling the estimation of the probability of each intervention being cost-effective at a range of cost-effectiveness thresholds. A scenario analysis was also considered by varying the unit cost of implantable devices (CRT, CRT-D, and ICD only), covering values reported in 2 different sources ( | PMC10782932 | |
RESULTS | Between 2013 and 2020, 347 patients were randomized to PCI+OMT and 353 to OMT alone. A total of 225 patients (32%) died during the median trial follow-up of 41 months. The KCCQ overall summary score at 6 months increased by 6.5 points more in the PCI+OMT arm (+11.2 versus +4.7). However, by 24 months, the difference was not significant (70.6 versus 68.1, a difference of 2.6); the same trend was also seen in EQ-5D-5L. | PMC10782932 | ||
DISCUSSION | left ventricle systolic dysfunction, Angioplasty, coronary artery disease | REGRESSION, DISEASE, CORONARY ARTERY DISEASE, STABLE ANGINA | In this prospective within-trial cost-effectiveness analysis of the REVIVED trial, no appreciable difference in total QALYs was identified between arms, but the PCI+OMT strategy was substantially more expensive than OMT alone, largely due to the upfront cost of PCI. Consequently, PCI+OMT was economically dominated and not cost-effective compared with OMT. When parameter uncertainty is allowed, there was no probability of PCI+OMT being cost-effective at a threshold of ≥£20 000 per QALY. The clinical results of REVIVED were neutral for the comparison of strategies, with no safety concerns raised with PCI, in contrast to the STICH trial where CABG was associated with a 3-fold to 4-fold excess in mortality within the first 2 years following randomization.No prior study has reported on the incremental costs of the PCI against relevant comparators for patients with ILVD. Our findings are in contrast to the economic analysis performed on the STICH trial data.Economic analyses of revascularization by PCI have also been performed for the COURAGE (Clinical Outcomes Utiliz- ing Revascularization and Aggressive Drug Evalu- ation) and ORBITA (Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina) trials in patients with stable coronary artery disease although these studies specifically excluded patients with severe left ventricle systolic dysfunction and multivessel disease. Notwithstanding the important differences in target populations, different settings (United States and United Kingdom), modeling assumptions (within trial and model based), and comparators (best MT and placebo), the results of the aforementioned analyses support the view of some disparity in the economic value of PCI.The clinical results of REVIVED were neutral for the comparison of strategies, with no safety concerns raised with PCI, in contrast to the STICH trial where CABG was associated with a 3-fold to 4-fold excess in mortality within the first 2 years following randomization.A strength of this economic analysis was the relatively long study follow-up period (up to 8 years; median, 3.4 years). This offers a good understanding of the medium- to long-term costs and benefits of the strategies being evaluated. While a lifetime analysis could have been conducted, the results of this 8-year analysis indicated that this was unnecessary. Given the clinical, cost-related, and health-related quality-of-life results that we have reported, there seems to be unlikely a scenario in which long-term costs and outcomes would make PCI a cost-effective treatment, and we think that it is reasonable to conclude that estimated cost-effectiveness over an 8-year time horizon is generalizable to the patient’s lifetime. For this reason, no modeling to extrapolate evidence from the trial to the long term was considered necessary.By using regression analyses in our study, we aimed to provide an unbiased estimate of the expected costs and health outcomes associated with each treatment, as should be the objectives of any cost-effectiveness analysis. By describing the relationship between the outcome of interest and treatment assignment, it helped us identify the expected costs and outcomes associated with the comparator treatment. The regression framework also enabled a characterization of the decision uncertainty from which an assessment of the need for any additional research could be made. A note that the uncertainty expressed in the cost-effectiveness estimates presented relate to second-order uncertainty (uncertainty around the mean for the average patient with severe ILVD) and is subject to structural uncertainty (uncertainty relating to the form of regression model implemented). On the latter, model specification may hinder an appropriate reflection of parameter uncertainty, which may be reflected in the relatively narrow CIs of the predicted total costs. With its advantages and disadvantages, alternative modeling has been implemented through a seemingly unrelated regression model.The study has some limitations. The resource uses collected within the REVIVED trial are believed to be comprehensive though the aim of our study was not to estimate the total cost burden of ILVD but to capture cost and QALY differences between therapies here under scrutiny. Nevertheless, and as with many trial analyses, there are practical limits to what has been collected. For example, the total number of clinical tests performed on trial patients is likely to exceed what was captured in the case report form as only mandated tests to inform the specified clinical outcomes were captured. The total cost of managing these patients is likely to be appreciably higher than we have estimated; however, these uncaptured costs are likely to be distributed evenly between groups. Another potential limitation of our work is that medication data were collected only for the initial 2 years of follow-up. These limitations apply to both study arms and are unlikely to impact the overall conclusions of the analysis. A sensitivity analysis using alternative unit costs from NHS Reference Costs 2020/2021Health-related quality of life collected via the EQ-5D-5L questionnaire contained a proportion of missing data. This was due to a small proportion of patients being lost to follow-up, being too unwell to complete the questionnaires, and limitations in face-to-face visits due to the COVID-19 pandemic. It was assumed that systematic differences between the missing and observed EQ-5D index scores existed, but these could be entirely explained by other observed variables. Thus, multiple imputation was used to address missingness, generate multiple imputed data sets, and achieve a similar time frame of analysis, providing a fuller understanding of the health-related quality-of-life data. This approach allowed us to account for any gaps or missing values in the per-patient QALY calculations and ensure a comprehensive evaluation of the health outcomes for both the OMT and PCI+OMT arms.Finally, our analysis is based specifically on costs relating to the UK NHS and cannot, therefore, be directly transferable to other health systems. The costs of PCI are relatively low in the publicly funded NHS by comparison with privately funded health care systems, such as the United States. If similar health resource consumption and health-related quality of life are assumed, a higher cost for PCI would augment overall costs further and further increase its negative economic impact.In summary, our results have identified that, for patients with severe ILVD in the United Kingdom, revascularization using PCI in addition to OMT is not considered to be cost-effective when compared with OMT alone, given its additional cost. These conclusions were robust to different modeling assumptions and unit costs. Routine use of PCI for the treatment of severe ILVD does not seem to be a justifiable use of the UK NHS resources. | PMC10782932 |
APPENDIX | Rocchiccioli, Donna Exley, Natalia, Claudia | HEART, MARION, WRIGHT, MOORE, EDWARDS, WELLS, CROSS, STUART, HORTON, FRASER, BROWN | REVIVED Sites and Investigators: Guy’s and St Thomas’ Hospital: Prof Divaka Perera (principal investigator); Prof Amedeo Chiribiri, Prof Gerry Carr-White, Dr Antonis Pavlidis, Prof Simon Redwood, Dr Brian Clapp, Prof Aldo Rinaldi, Dr Haseeb Rahman, Dr Natalia Briceno (coinvestigators); Sophie Arnold, Amy Raynsford, Karen Wilson, Lucy Clack (coordinators). Golden Jubilee National Hospital, Glasgow: Prof Mark Petrie (principal Investigator); Dr Margaret McEntegart, Dr Stuart Watkins, Dr Aadil Shaukat, Dr Paul Rocchiccioli (Coinvestigators); Marion McAdam, Elizabeth McPherson, Louise Cowan, Marie Wood (Coordinators). Barts Heart Centre, London: Dr Roshan Weerackody (principal investigator); Dr Ceri Davies, Dr Elliot Smith, Dr Bhavik Modi (coinvestigators); Bindu Mathew, Oliver Mitchelmore, Rita Adrego, Mervyn Andiapen (coordinators). Royal Bournemouth Hospital: Dr Peter O’Kane (principal investigator); Dr Jehangir Din (coinvestigator); Sarah Kennard, Sarah Orr, Cathie Purnell (coordinators). Leeds General Infirmary: Prof John Greenwood (principal investigator); Dr Jonathan Blaxill, Dr Abdul Mozid (coinvestigators); Michelle Anderson, Kathryn Somers (coordinators). Royal Victoria Hospital, Belfast: Dr Lana Dixon (principal investigator); Dr Simon Walsh, Dr Mark Spence (coinvestigators); Patricia Glover, Caroline Brown (coordinators). King’s College Hospital, London: Dr George Amin-Youssef (principal investigator); Prof Ajay Shah, Prof Theresa McDonagh, Dr Jonathan Byrne, Dr Nilesh Pareek (coinvestigators); Jonathan Breeze, Catherine Antao (coordinators). Bristol Royal Infirmary: Dr Kalpa De Silva (principal investigator); Dr Julian Strange, Dr Tom Johnson, Dr Angus Nightingale (coinvestigators); Laura Gallego, Cristina Medina (coordinators). Glenfield Hospital, Leicester: Prof Anthony Gershlick (principal investigator); Prof Gerald McCann, Dr Andrew Ladwiniec, Prof Iain Squire (coinvestigators); Joanna Davison, Kris Kenmuir-Hogg (coordinators). St George’s Hospital, London: Prof James Spratt (principal investigator); Dr Claudia Cosgrove, Dr Rupert Williams, Dr Sam Firoozi, Dr Pitt Lim (coinvestigators); Giovanna Bonato, Vennessa Sookhoo (coordinators). Pinderfields Hospital, Wakefield: Dr Dwayne Conway (principal investigator); Dr Paul Brooksby (coinvestigator); Judith Wright, Donna Exley (coordinators). New Cross Hospital, Wolverhampton: Dr James Cotton (principal investigator); Dr Richard Horton (coinvestigator); Stella Metherell, Andrew Smallwood (coordinators). Kettering General Hospital: Dr Kai Hogrefe (principal investigator); Dr Adrian Cheng (coinvestigator); Charmaine Beirnes, Sian Sidgwick (coordinators). Royal Free Hospital, London: Dr Tim Lockie (principal investigator); Dr Niket Patel, Dr Roby Rakhit (coinvestigators); Nina Davies, Angelique Smit (coordinators). Manchester Royal Infirmary: Dr Fozia Ahmed (principal investigator); Dr Cara Hendry, Dr Farzin Fath-Odoubadi, Dr Douglas Fraser, Dr Mamas Mamas (coinvestigators); Anu Oommen, Thabitha Charles (coordinators). Royal Infirmary of Edinburgh: Dr Miles Behan (principal investigator); Dr Alan Japp (coinvestigator); Belinda Rif (coordinator). Sunderland Royal Hospital: Dr Nicholas Jenkins (principal investigator); Dr Sam McClure (coinvestigator); Pauline Oates, Karen Martin (coordinators). Wythenshawe Hospital: Dr Eltigani Abdelaal (principal investigator); Dr Jaydeep Sarma, Dr Sanjay Shastri, Dr Jo Riley (coinvestigators); Sarra Giannopoulou, Sophie Quinn (coordinators). Liverpool Heart and Chest Hospital: Dr Pradeep Magapu (principal investigator); Prof Rod Stables, Dr David Wright (coinvestigators); Janet Barton, Nichola Clarkson (coordinators). Southampton General Hospital: Dr Michael Mahmoudi (principal investigator); Dr Andrew Flett, Prof Nick Curzen (coinvestigators); Judith Radmore, Sam Gough (coordinators). Royal Devon & Exeter Hospital: Dr Andrew Ludman (principal investigator); Dr Hibba Kurdi (coinvestigator); Samantha Keenan (coordinator). University Hospitals Coventry and Warwickshire: Prof Prithwish Banerjee (principal investigator); Dr Luke Tapp (coinvestigator); Nigel Edwards, Catherine Gibson (coordinators). Lister Hospital, Stevenage: Dr Neville Kukreja (principal investigator); Dr Mary Lynch (coinvestigator); Claire Barratt (coordinator). The James Cook University Hospital, Middlesbrough: Dr Mark de Belder (principal investigator); Dr Jeet Thambyrajah, Dr Neil Swanson (coinvestigators); Cath Richardson, Bev Atkinson (coordinators). Derriford Hospital, Plymouth: Dr Girish Viswanathan (principal investigator); Darren Waugh (coordinator). Worcestershire Acute Hospitals: Dr Helen Routledge (principal investigator); Dr Jasper Trevelyan (coinvestigator); Angela Doughty (coordinator). Worthing Hospital: Dr Nick Pegge (principal investigator); Dr Sukhbir Dhamrait (coinvestigator); Sally Moore (coordinator). Blackpool Victoria Hospital: Dr Gavin Galasko (principal investigator); Dr Christopher Cassidy (coinvestigator); Natalia Waddington (coordinator). Dorset County Hospital: Dr Tim Edwards (principal investigator); Dr Javed Iqbal, Dr Fraser Witherow (coinvestigators); Jenny Birch, Melanie Munro (coordinators). Salisbury District Hospital: Dr Tim Wells (principal investigator); Dr Manas Sinha (coinvestigator); Linda Frost (coordinator). Birmingham Heartlands Hospital: Dr Kaeng Lee (principal investigator); Dr James Beattie, Dr Mike Pitt (coinvestigators); Alan Chung (coordinator). Great Western Hospital, Swindon: Dr Steve Ramcharitar (principal investigator); Laura McCafferty (coordinator). Ninewells Hospital, Dundee: Dr Thomas Martin (principal investigator); Dr John Irving, Dr Zaid Iskandar (coinvestigators); Anita Hutcheon (coordinator). Northern General Hospital, Sheffield: Dr Julian Gunn (principal investigator); Dr Abdallah Al-Mohammad (coinvestigator); Michael Agyemang (coordinator). Queen Alexandra Hospital, Portsmouth: Dr Huw Griffiths (principal investigator); Prof Paul Kalra (coinvestigator); Serena Howe (coordinator). Royal Oldham Hospital: Dr Tim Gray (principal investigator); Dr Jolanta Sobolewska (coinvestigator); Louise Morby (coordinator). Basingstoke and North Hampshire Hospital: Dr Jason Glover (principal investigator); Dr James Beynon (coinvestigator); Janet Knight (coordinator). North Wales Cardiac Centre: Dr Paul Das (principal investigator); Dr Chris Bellamy (coinvestigator); Emily Harman (coordinator). The York Hospital: Mr Maurice Pye (principal investigator); Dr Simon Megarry (coinvestigator); Yvonne McGill, Heidi Redfearn (coordinators). | PMC10782932 |
ARTICLE INFORMATION | PMC10782932 | |||
Sources of Funding | arrhythmia | HEART, ARRHYTHMIA | This trial was sponsored by King’s College London and funded by the National Institute for Health and Care Research Health Technology Assessment Program (10/57/67). The arrhythmia analyses were supported by the British Heart Foundation (fellowship FS/CRTF/21/24190 and the King’s British Heart Foundation Center of Research Excellence grant RE/18/2/34213). | PMC10782932 |
Disclosures | None. | PMC10782932 | ||
Supplemental Material | Supplemental MethodsTables S1–S10References | PMC10782932 | ||
Supplementary Material | PMC10782932 | |||
Nonstandard Abbreviations and Acronyms | Cardiomyopathy | HEART FAILURE, CARDIOMYOPATHY, APPENDIX, HEART | coronary artery bypass graftingEuroQol 5-dimensionEuroQol 5 dimension 5 levelheart failureischemic left ventricular systolic dysfunctionKansas City Cardiomyopathy Questionnairemedical therapyoptimal medical therapypercutaneous coronary interventionquality-adjusted life-yearRevascularization for Ischemic Ventricular DysfunctionSurgical Treatment for Ischemic Heart FailureA list of all REVIVED Sites and Investigators is given in the Appendix.For Sources of Funding and Disclosures, see page 14.Supplemental Material is available at This work was presented as an abstract at the American Heart Association Scientific Sessions, November 11-13, 2023. | PMC10782932 |
REFERENCES | PMC10782932 | |||
Background | Pulse oximetry as a home or remote monitoring tool accelerated during the pandemic for patients with COVID-19, but evidence on its use is lacking. | PMC9926282 | ||
Aim | cardiovascular comorbidity | To assess the feasibility of home monitoring by pulse oximetry of patients aged ≥40 years with cardiovascular comorbidity and moderate-to-severe COVID-19. | PMC9926282 | |
Design and setting | A primary care-based, open, pilot randomised controlled trial, with nested process evaluation, was undertaken in the Netherlands. | PMC9926282 | ||
Method | From November 2020 to June 2021, eligible patients presenting to one of 14 participating Dutch general practices were randomly allocated to regular measurement of peripheral oxygen saturation (at least three SpO | PMC9926282 | ||
Results | Hypoxemia | All 41 participants (21 intervention, 20 usual care) completed the 45-day follow-up period. Overall, the intervention group performed 97.6% of protocolised measurements; the median daily measurement per participant was 2.7 (interquartile range 1–4). Hypoxemia (SpO | PMC9926282 | |
Conclusion | Home monitoring of patients with moderate-to-severe COVID-19 by pulse oximetry appeared feasible; adherence was high, patients reported a high feeling of safety, while the number of primary care consultations remained similar to usual care. | PMC9926282 | ||
INTRODUCTION | cardiovascular comorbidity, fits | A pulse oximeter is a small, easy-to-operate, non-invasive tool to measure the peripheral oxygen saturation (SpOTherefore, a primary care-based, open, pilot randomised controlled trial (RCT) was conducted. The aim was to assess the feasibility of a trial of home monitoring by pulse oximetry for patients aged ≥40 years with cardiovascular comorbidity and moderate-to-severe COVID-19 compared with usual care.How this fits in | PMC9926282 | |
METHOD | PMC9926282 | |||
Trial design | Between November 2020 and June 2021, an open-label, individually randomised (one-to-one) controlled pilot trial, with nested process evaluation, was conducted in Dutch primary care. | PMC9926282 | ||
Public and patient involvement | chronic or oncologic disease | Patients of the Patient and Family Advisory Council from the ZonMw institution in the Netherlands provided input in defining research questions, outcomes, and data collection at the design stage of the study. This group consisted of middle-aged patients with chronic or oncologic disease who received structured care via a transmural care programme, thus belonging to the COVID-19 risk group. The results will be shared with the patients involved. | PMC9926282 | |
Participants | cardiovascular comorbidity, anaemia, shortness of breath | RESPIRATORY TRACT INFECTION, ANAEMIA | Patients were aged ≥40 years with cardiovascular comorbidity who presented to the GP with moderate-to-severe COVID-19 symptoms. Moderate-to-severe symptoms were defined as at least 3 days with a body temperature ≥37.5°C and either a) new onset of symptoms of respiratory tract infection; b) a feeling of shortness of breath; and/or c) sudden exhaustion. They were patients for whom it was considered necessary to closely follow-up, according to the GP. The following patients were excluded: those requiring hospital admission; those with known severe anaemia (pulse oximetry can be inaccurate and SpOGPs from 14 participating general practices in the vicinity of Utrecht informed potentially eligible participants about the study verbally and via a patient information letter. Those who were interested, and tested positive for COVID-19, were asked for consent to share their contact details with the University Medical Center (UMC) Utrecht research team for eligibility screening. Eligible patients who expressed interest in trial participation were visited at home under safe circumstances with COVID-19 protection to obtain full-written informed consent. Next, the study physician accessed a trial randomisation website for concealed study treatment assignment via a computer-generated sequence list developed by an independent data manager, that is, home monitoring by pulse oximetry or usual care. The study physician informed the GP about the randomisation result. | PMC9926282 |
Intervention | All participants in the intervention group received an FDA-approved for medical use pulse oximeter (Nonin 3230); together with verbal, written, and visual instructions to measure their SpOBefore distribution, all pulse oximeters were registered, checked, and released by the Department of Medical Technology and Clinical Physics at the UMC Utrecht. | PMC9926282 | ||
Data collection | disability | At baseline, a short interviewer-administered questionnaire was completed, including demographic data and the 12-item WHODAS 2.0 (World Health Organization Disability Assessment Schedule 2.0), which is a generic assessment instrument developed by the WHO to measure health and disability (scale: 0 = no disability to 48 = high disability).Patients in the intervention group recorded their oxygen saturation in a paper diary three times a day for 14 days. After 14 days, participants reported their overall feeling of safety over the previous 2 weeks on a 0 (completely unsafe) to 100 (completely safe) visual analogue scale by phone.At the end of the 45-day follow-up period, participants completed the 12-item WHODAS 2.0 again and those in the control group were asked by phone if they had used a pulse oximeter at home after study enrolment. Healthcare utilisation was captured by retrieving patients’ primary care electronic health record data. | PMC9926282 | |
Outcomes | The primary outcome was feasibility of a trial of home monitoring by pulse oximetry defined as successful inclusion of approximately 50 participants within 6 months who were willing to a) be randomised; and b) adhere to study procedures.Secondary outcomes included quantitative data about the use of pulse oximetry in practice (see process evaluation below), patient-reported feeling of safety over the first 2 weeks, and disability-free survival after 45 days as determined by percentage change in 12-item WHODAS 2.0 sum score from baseline to 45 days: number of GP consultations, number of emergency department (ED) visits, hospital and/or intensive care unit (ICU) admissions, number of days alive at home, and all-cause mortality. | PMC9926282 | ||
Process evaluation | In a process evaluation alongside the trial, the study examined how the intervention was used in practice in terms of fidelity (intervention carried out as planned), dose (intervention was used as long and frequently as planned), adjustments (whether made to the intervention and why), and reach (whether the intended audience had been reached). | PMC9926282 | ||
Sample size considerations | A formal sample-size calculation was not performed for this feasibility pilot trial. It was initially aimed to randomise approximately 50 participants, a number deemed to be sufficient to assess the feasibility of the trial. | PMC9926282 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.