Tag: Patients

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These CT findings increase risk of thromboembolic events for patients with COVID pneumonia

These CT findings increase risk of thromboembolic events for patients with COVID pneumonia

New research highlights key CT findings that radiologists should be aware of when interpreting the exams of patients with COVID pneumonia. 

The paper details an analysis of 276 COVID patients and how their image findings correlated to their experiences with thromboembolic events. Corresponding author of the paper Mohd Ghadeeb, MD, from the Radiology Department at King Fahad Hospital in Saudi Arabia, and colleagues explained the importance and challenges involved in understanding COVID patients’ risks of clotting complications recently in Cureus: 

“Thromboembolic manifestations have a wide spectrum and vary significantly among different patients. These include venous thromboembolic events, arterial events, and microvascular thrombosis,” the researchers wrote. “The diagnosis of venous thromboembolic events, including deep venous thrombosis and pulmonary embolism, can be challenging due to overlapping clinical and laboratory features.” 

Ghadeeb and colleagues looked at the chest CT scans of patients admitted to their hospital with COVID pneumonia while also reviewing the patients’ electronic health records to single out anyone who had experienced a thromboembolic event. Out of these 276 admitted patients, 64 experienced thromboembolic events, 51 of whom were diagnosed with pulmonary embolism and 16 with deep vein thrombosis.  

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Impact of chronic hepatitis on cardiovascular events among type 2 diabetes patients in Taiwan pay-for-performance program – Scientific Reports

Research subjects

Patients with T2DM who joined the P4P from 2008 to 2010 were enrolled. Patients with a confirmed diagnosis of T2DM were defined as those who were hospitalized at least once or came in for outpatient visits at least three times within 1 year and had a primary or secondary diagnosis International Classification of Diseases (ICD) code “250,” “250.00,” or “250.02”38,39. Among them, patients with type 1 DM “250.x1” * or “250.x3;” gestational DM “648.0” or “648.8;” neonatal DM “775.1;” abnormal glucose tolerance test “790.2;” age < 20 years or > 100 years; and those who died within 1 year of joining P4P were excluded. Finally, 283,793 patients were included (Fig. 1). Based on the status of comorbid chronic hepatitis at enrollment, the patients were divided into four groups: no comorbid chronic hepatitis, named as “No chronic hepatitis”; comorbid liver B, named as “Hepatitis B” group; comorbid liver, named as “Hepatitis C” group; patients without viral hepatitis and with comorbid fatty liver were named as the “Fatty liver disease” group and were followed-up until the end of 2017. The “no comorbid chronic hepatitis” group was used as the reference group to analyze the correlation between different types of chronic hepatitis and the risk of cardiovascular disease.

Figure 1
figure 1

Flowchart for study subject selection. DM diabetes mellitus, P4P pay-for-performance, HBV hepatitis B virus, HCV hepatitis C virus.

Ethics statements

The National Health Insurance Research Database (NHIRD) is derived from Taiwan’s mandatory National Health Insurance program was established by the National Health Insurance Administration Ministry of Health and Welfare and maintained by the National Health Research Institute (NHRI). The patient identifications in the National Health Insurance Research Database have been scrambled and de-identified by the Taiwan government, and the database is commonly used for different types of research such as in medical, and public health fields. Thus, informed consent was waived by the Research Ethics Committee of the China Medical University, and the study protocol was approved by the research ethics committee of China Medical University and Hospital (IRB number: CMUH106-REC3-153) and was conducted in accordance with the principles of the Declaration of Helsinki.

Data sources

This retrospective cohort study analyzed data from the National Health Insurance Research Database of the “Applied Health Research Data Integration Service from National Health Insurance Administration”. The data included outpatient prescriptions and treatments, outpatient prescriptions and medical orders, inpatient medical expense lists, inpatient medical expense and medical order lists, insurance details of persons, major injury and illness, medical institution master files, diagnosis, and P4P education records.

Definitions of variables

Hepatitis B: Those with ICD-9 070.2, 070.20, 070.21, 070.22, 070.23, 070.3070.31, 070.32, or 070.33 or ICD-10 B16, B17.0, B18.0, B18.1, or B19.1 as the primary and secondary diagnosis during two outpatient visits or one hospitalization within 365 days of study enrollment.

Hepatitis C: Those with ICD-9 070.41, 070.44, 070.51, or V02.62 or ICD-10 B17.10, B17.11, B18.2, B19.20, B19.21, or Z22.52 as the primary and secondary diagnosis during two outpatient visits or one hospitalization within 365 days of study enrollment.

NAFLD: Those with ICD-9 571.8, 571.9, or ICD-10 K74.4, K74.5, K74.60, K74.69, K76.0, K76.9, etc. as the primary and secondary diagnosis during two outpatient visits or one hospitalization within 365 days of study enrollment, and without the occurrence of a hepatitis B or C code, for whom the first hospital visit within 365 days was defined as the date of diagnosis. Patients with concurrent viral hepatitis and NAFLD were classified as having viral hepatitis.

Age-based categorization included 20–39, 40–54, 55–64, 65–74, and ≥ 75 years age groups. Monthly salary was divided into five grades, namely ≤ NTD 17,280, NTD 17,281–22,800, NTD 22,801–36,300, NTD 36,301–45,800, and ≥ NTD 45,801. Charlson comorbidity index was divided into 0, 1, 2, and ≥ 3 after excluding scores correlated with independent or dependent variables40.

The diabetes complications severity index (DCSI) was scored as 0, 1, and ≥ 2 points. The DCSI was calculated based on the classification and scoring method proposed by Young et al. If the patient had no complication, the score would be 0; for each complication, 1 point would be added; if the complication was serious, 2 points would be added. Based on this calculation method, the maximum score was 13 points41.

Cardiovascular disease: Those with ICD-9 398.91, 402.xx, 404.xx, 410.xx–414.xx, 422.xx, 425.xx or 428.xx, or ICD-10 I09.81, I11, I13, I20–I22, I24, I25, I40–I43, I50, R09.89, etc. as the primary and secondary diagnosis during two outpatient visits or one hospitalization within 365 days of study enrollment42.

Calculation of the coefficient of variation (CV% = standard deviation/mean) of HbA1c and fasting blood glucose: All measurements in the first year were used, and if the measurements were taken less than four times in the first year, measurements taken up to the second year were included. If measurements were taken less than four times in the 2 years, the patient would be excluded.

Adjusted CV = CV/√ (n/n − 1): When the examination data were limited, the examination times would affect the result of the CV. In this case, a relatively correct result of the CV with a reduced effect of the examination times could be obtained by correcting the examination times.

Analytical methods

Descriptive and inferential statistics were carried out according to the research objectives and framework. All research tests were based on a significance level of α = 0.05, and all statistical analyses were conducted using SAS software for Windows, version 9.4 (SAS Institute Inc., Cary, NC, USA). Descriptive statistics such as frequency, percentage, average, and standard deviation were used to describe the dependent and independent variables to be investigated in this study. This study adopted descriptive statistics to present the demographic characteristics, status of comorbidities, blood biochemical indicators, health status, economic factors, and medical care provider characteristics of patients with diabetes. The incidence of cardiovascular disease in patients with T2DM with chronic hepatitis per 1000 person-years was tested using univariate Poisson regression. The relative risks of cardiovascular disease in the four groups were calculated using a Cox proportional hazards model.

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The Patients’ Library and Children’s Library July events: – The Loop

Story time is presented weekdays at 10:30 on Channel 114 and on OneView Child Life and Children’s Library.

Special events, themes and presenters are announced below:

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July 2: Libraries closed

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July 3: Libraries closed

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July 4: Libraries closed

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Friday July 1 at 10:30 a.m.: Spiritual Services reads for story time on Channel 114 and on OneView Hospital channels Child Life and Children’s Library

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Wednesday July 6 at 10:30 a.m.: Barns and Cows Story Time and Activity on Channel 114 and on OneView Hospital channels Child Life and Children’s Library

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Wednesday July 6 at 1:45 p.m.: Activities Therapy presents Bingo on Channel 117 and on OneView Hospital channels Patients’ Library and Activities

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Friday July 8 at 10:30 a.m.: Spiritual Services reads for story time on Channel 114 and on OneView Hospital channels Child Life and Children’s Library

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Wednesday July 13 at 10:30 a.m.: National Ice Cream Day Story Time and Activity on Channel 114 and on OneView Hospital channels Child Life and Children’s Library

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Friday July 15 at 10:30 a.m.: Spiritual Services reads for story time on Channel 114 and on OneView Hospital channels Child Life and Children’s Library

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Wednesday July 20 at 10:30 a.m.: Space Exploration Day Story time and Activity on Channel 114 and on OneView Hospital channels Child Life and Children’s Library

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Wednesday July 20 at 1:45 p.m.: Activities Therapy presents Bingo on Channel 117 and on OneView Hospital channels Patients’ Library and Activities

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Friday July 22 at 10:30 a.m.: Spiritual Services reads for story time on Channel 114 and on OneView Hospital channels Child Life and Children’s Library

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Wednesday July 27 at 10:30 a.m.: International Tiger Day Story time and Activity on Channel 114 and on OneView Hospital channels Child Life and Children’s Library

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Wednesday June 29 at 1:30 p.m.: June TV Trivia on Channel 117 and on OneView Hospital Channel 117 Patients’ Library and Activities

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Friday July 29 at 10:30 a.m.: Spiritual Services reads for story time on Channel 114 and on OneView Hospital channels Child Life and Children’s Library

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DAA use decreases risk for cardiovascular events in patients with advanced fibrosis, HCV

Healio Logo - Gastroenterology

Source:

Lam L, et al. Abstract OS006. Presented at: International Liver Congress; June 22-26, 2022; London (hybrid meeting).

Disclosures:
Healio was unable to confirm relevant financial disclosures at the time of publication.


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LONDON — Direct-acting antiviral treatment correlated with a decreased risk for cardiovascular outcomes among patients with hepatitis C virus and advanced fibrosis but an increased risk for arrhythmias and conduction disorders.

“Several studies have revealed that hepatitis C virus can induce chronic inflammation and immune dysregulation, and this immune dysregulation and chronic inflammation explained the development of extrahepatic manifestations in chronic hepatitis C patients, including cardiovascular disease,” Laurent Lam, MD, a physician and doctoral researcher at the Pierre Louis Institute of Epidemiology and Public Health at Sorbonne University in Paris, told attendees at the International Liver Congress. “Few data are available regarding the long-term impact of DAAs on the occurrence of non-liver events.”

Using the prospective ANRS CO22 HEPATHER cohort, which derived individual data from the French National Health Insurance Database, Lam and colleagues analyzed 8,148 patients with chronic HCV between August 2012 and December 2015 for cardiovascular events and cancer incidence. The primary outcome was the association between DAA use and extrahepatic events.

Among 22,326 and 12,905 person-years of DAA and no DAA exposure, analysis showed DAA exposure correlated with a reduced risk for peripheral arterial disease (HR = 0.54; 95% CI, 0.33-0.89), an overall beneficial effect on cardiovascular among patients with HCV/advanced fibrosis (adjusted HR = 0.58; 95% CI, 0.42-0.79) and an increased risk for arrhythmias and conduction disorders (HR = 1.46; 95% CI, 1.04-2.04).

Lam and colleagues observed no association between DAA use and extrahepatic cancer (HR = 1.23; 95% CI, 0.5-3.03).

“Direct-acting antiviral exposure reduced the risk for peripheral arterial disease, overall cardiovascular events and increased risk for arrhythmias and conduction disorders,” Lam concluded. “Direct acting antivirals are not associated with extrahepatic cancer development or reduction in our study.”


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International Liver Congress

International Liver Congress

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1 in 4 neurosurgery patients experience adverse events, at times linked to human error

Operating room during surgery

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One in four neurosurgery patients experience adverse events, of which 25% are attributable to human error, according to a study published in Brain and Spine.

“Adverse events in surgery are a relevant cause of economic costs, disability and death,” Hanno S. Meyer, of the department of neurosurgery at Technical University of Munich School of Medicine, and colleagues wrote. “In neurosurgery, there is ample potential for [adverse events] that are cost-intensive and cause severe patient harm, such as unplanned returns to the operating room or postoperative long-term neurologic deficits.”


Operating room during surgery

Source: Adobe Stock.

As little is known regarding the frequency of adverse events and contribution of human error in neurosurgery, Meyer and colleagues sought to investigate the incidence, nature and severity of both.

They conducted a prospective, observational study, which included 4,176 patients who underwent neurosurgery (2,258 cranial neurosurgery cases and 1,918 spinal neurosurgery cases) at a tertiary care academic hospital between September 2019 and September 2020. Adverse events, which were classified in line with the American College of Surgeons National Surgical Quality Improvement Program 30-day outcome complication definition (ACS-NSQUIP) and graded on a scale of 1 to 6 according to the Spine Adverse Events Severity System (SAVES-V2), were recorded daily and evaluated weekly by the department’s senior neurosurgeons. Incidence of human error was categorized as preoperative, intraoperative or postoperative.

Results showed that 25% of patients experienced at least one adverse event, and 25.9% of those events were associated with human error, particularly in execution (18.3%) or planning (5.6%) deficiencies. Researchers also found that 48.8% of cases had severe adverse events that were graded at least 3 on the SAVES-V2 scale, and patients with multiple adverse events (8.6%) experienced more severe events (67.6%). In addition, adverse events were more severe in cranial neurosurgery (57.6%) compared with spinal neurosurgery (39.4%).

“Prospective data on the incidence of all types of [adverse events] in neurosurgery bears significance not only for the education of our patients but also for the discussion of quality-based accreditation and reimbursement systems in upcoming health reforms,” Meyer and colleagues wrote.


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Fatigue in patients with advanced NASH may increase risk for adverse events

HGI0522Younossi_Graphic_01


Disclosures:
The study was funded by the Center for Outcomes Research in Liver Diseases and Gilead Sciences.


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Worse fatigue at baseline among patients with nonalcohol steatohepatitis-related advanced fibrosis and cirrhosis correlated with a higher risk adverse clinical events, according to published results.

“Although generally considered asymptomatic, almost half of patients with NASH have clinically significant fatigue which, in turn, has a profound negative impact on the overall patient experience,” Zobair M. Younossi, MD, president of Inova Medicine Services and professor and chairman of the department of medicine at Inova Fairfax Medical Campus in Virginia, and colleagues wrote in Clinical Gastroenterology and Hepatology. “In this context, ongoing clinical trials aim at finding a drug-based therapy for NASH that may reverse fibrosis and could also potentially improve fatigue. Given that, patient-reported outcome instruments are now commonly included in these trials in order to provide a comprehensive assessment of the impact of the investigational drugs on patients and their experience.”


HGI0522Younossi_Graphic_01



For 2 years, Younossi and colleagues followed 1,679 patients with biopsyconfirmed NASH, 802 had bridging fibrosis (F3) and 877 compensated cirrhosis (F4). Fatigue was quantified at baseline with the Chronic Liver Disease Questionnaire (CLDQ)- NASH fatigue domain. Time to liver-related clinical eventssuch as progression to histologic cirrhosis or hepatic decompensation in F3F4 was assessed with Cox proportional hazard model.

median follow-up of 16 months, 15% (n=123) of NASH F3 patients experienced liver-related events and 3.5% (n=31) of NASH F4 patients experienced hepatic decompensation. Among F3 patients, the mean baseline CLDQ-NASH fatigue score was 4.77hose who experienced liver-related events lower baseline scores 4.47 4.83. Among patients withF4, the mean fatigue score was 4.56 who decompensated3.74 4.59.

fter for confounders, correlation between lower fatigue scores and risk liver-related or decompensation events adjusted HR 0.85, per 1 point in fatigue score in F3; aHR = 0.62 in F4.

“This suggests that, in addition to commonly used clinical parameters, presence of clinically significant fatigue can identify NASH patients at risk for adverse events,” the authors wrote. “Since fatigue also negatively impacts patients [health-related quality of life] and work productivity, it adds to the disease burden related to NASH. Given the critical importance of fatigue in NASH, clinical trials of regimens for NASH should not only show improvement of surrogates of clinical endpoints, such as the stage of fibrosis or resolution of NASH, but also improvement in patient-reported endpoints, such as fatigue.”

 


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Corticosteroid exposure associated with hospitalization for severe pain event among patients with sickle cell disease

Corticosteroid exposure associated with hospitalization for severe pain event among patients with sickle cell disease

People with sickle cell disease (SCD) who were recently prescribed a corticosteroid – a medicine frequently used to treat asthma or inflammation – were found to be significantly more likely to be hospitalized for a severe pain event, according to a paper published today in the journal Blood. The research also found that older adults, women, and people who were not taking the drug hydroxyurea to manage their underlying SCD symptoms were the most likely to be hospitalized.

SCD is the most common inherited red blood cell disorder in the United States, affecting an estimated 100,000 people. According to the Centers for Disease Control and Prevention (CDC), SCD affects one out of every 365 Black or African American births and one out of every 16,300 Hispanic American births. Pain events, also known as vaso-occlusive episodes (VOE), are the most common complications of SCD and can result in intense pain and potentially irreversible organ damage.

Apart from case reports, researchers say this is the first study to systematically evaluate the association between corticosteroid exposure and hospitalization for VOE.

Individuals living with SCD often suffer crippling episodes of pain, which can greatly impair their quality of life. Based on our data, corticosteroids are commonly prescribed for conditions unrelated to their underlying SCD. Vaso-occlusive events and related hospitalization appear to follow corticosteroid prescription fairly quickly. This evidence suggests corticosteroids may be contributing to the events and should be avoided as much as possible in these patients.”


Ondine Walter, MD, Study Author, Toulouse University Hospital in France

Notably, the median time between filling a prescription for a corticosteroid and hospitalization was just five days. Also striking was the fact that nearly half (46%) of patients with SCD had been prescribed at least one systemic corticosteroid during the study period. Dr. Walter said the results underscore the need for widespread education of clinicians and patients alike about the potential risks of using corticosteroids, especially when there isn’t a clear indication to use them.

“Corticosteroids are mostly easy to avoid, and in circumstances when they are necessary, it’s important to start them in collaboration with an SCD expert and to take all appropriate precautionary measures to administer them safely,” said Dr. Walter.

The study used data from a total of 5,151 patients with SCD drawn from the French National Health Insurance Database between 2010 and 2018. Patients had to have at least one hospitalization for VOE to be included, and corticosteroid exposure was identified using outpatient prescribing records.

The study found that those who had exposure to a corticosteroid – defined in the month leading up to the event – were significantly more likely to be hospitalized for VOE. People who were also taking hydroxyurea seem to have less risk of hospitalization compared with those not taking the drug, which may signal a potential protective effect of hydroxyurea on the occurrence of VOE, Dr. Walter explained. Hydroxyurea is often prescribed to reduce the number of pain events caused by SCD as well as the need for blood transfusions. The risk of admission was also lower in men compared to women and in children compared to adults.

“Some factors such as hydroxyurea use, male gender, and younger age were associated with a lower risk of hospitalization for VOE after corticosteroid exposure in our study. Still, based on these results, we still need to think twice about using corticosteroids when treating patients with SCD,” said Dr. Walter.

This study is limited in that it can only show an association between corticosteroids and VOE-related hospitalizations and not prove causation. Because corticosteroid exposure was based on dispensing data, it is also not possible to confirm that patients took the medicine, only that the prescription was filled.

With future research, investigators aim to understand how corticosteroids may prompt VOE. Studies have shown that the cessation of corticosteroids, in particular, has been associated with rebound pain. ASH’s Clinical Practice Guidelines on SCD recommend against using corticosteroids for acute pain management in patients with SCD. This study adds important data about the association of corticosteroid use with subsequent VOE to a growing body of evidence that suggests corticosteroids should be used only when needed, and under the guidance of an SCD expert.

Source:

American Society of Hematology

Journal reference:

Walter, O., et al. (2022) Risk of vaso-occlusive episode after exposure to corticosteroids in patients with sickle cell disease. Blood. doi.org/10.1182/blood.2021014473.

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Potential Link Found Between Thrombotic Events, Mortality in Patients With PV, ET

Potential Link Found Between Thrombotic Events, Mortality in Patients With PV, ET

Patients with polycythemia vera (PV) or essential thrombocythemia (ET) had a higher risk of thrombotic events than the general population, which was associated with mortality in a recent study.

Patients with polycythemia vera (PV) or essential thrombocythemia (ET) have a greater thrombotic risk vs the general population, and a recent study published in Leukemia Research found that among patients with PV or ET who had thrombotic events (TEs), mortality risk was higher and survival was shorter compared with those who did not have TEs in the study period.

PV and ET are characterized by the overproduction of erythrocytes and platelets, respectively, and both are rare. Symptoms can include fatigue, night sweats, concentration issues, bone pain, and various clinical features that can make it difficult to accurately diagnose. Shorter overall survival and increased TE risk compared with the general population also affect patients with PV or ET.

Based on Surveillance, Epidemiology, and End Results (SEER) registry data, estimated median overall survival is 12 years and 5-year mortality is 19% for both conditions. High rates of arterial and venous TEs are a known cause of morbidity and mortality in these patients, although study authors note that few contemporary studies have assessed the effect that TEs have on mortality in patients with PV and ET.

The current study aimed to assess mortality risk in patients with high-risk PV and intermediate- to high-risk ET who experienced a TE vs those who did not experience a TE during the study period.

This retrospective, observational study included 50,405 Medicare fee-for-service (FFS) beneficiaries with PV and 124,569 with ET. All data were based on the Medicare FFS claims database, and eligible patients had either a PV or ET diagnosis and at least 1 inpatient or at least 2 outpatient claims between January 1, 2010, and December 31, 2017.

The median patient age was 73 years in the PV group and 76 in the ET cohort. A total of 6268 patients (12.4%) in the PV cohort had a history of TEs before PV diagnosis. Median follow-ups were 34.5 months for the PV cohort and 25.5 months in the ET cohort.

In the ET cohort, 23,908 patients (19.2%) had a history of TEs pre diagnosis. During follow-up, 6023 (12.0%) patients with PV and 14,156 (11.4%) with ET received hydroxyurea. In the PV cohort, 14,571 patients with PV (28.9%) underwent at least 1 phlebotomy.

Although past studies have shown that TEs are common among those with PV or ET, this study showed a particularly high occurrence of TEs despite shorter follow-up times vs previous analyses.

“Notably, most of these prior analyses included substantial proportions of low-risk patients,” the study authors wrote. “Patients included in the current analyses were generally older than previous cohort studies and had high rates of comorbidities, likely due to the age thresholds applied for eligibility for the analysis (≥ 65 years), which may have contributed to increased frequency of vascular complications.”

Of the patients with PV, 14,334 (28.4%) experienced a TE in the follow-up period, with the most common being ischemic stroke (46.0%), transient ischemic attack (TIA; 30.7%), and acute myocardial infarction (AMI; 29.9%). In the ET group, 30,478 patients (24.5%) experienced a postdiagnosis TE. Ischemic stroke (42.5%), AMI (25.9%), and TIA (24.8%) were the most common TEs in this cohort.

After adjusting for other patient characteristics, those in the PV group who experienced a postdiagnosis TE were at an increased risk of mortality than those who did not (adjusted HR [aHR], 18.6; 95% CI, 16.1-21.6; P < 0.001). Patients who experienced pre-index TEs were at an even higher risk (aHR, 34.4; 95% CI, 24.0-49.4; P < 0.001).

In the ET cohort, patients who experienced a TE post diagnosis were also at an increased risk compared with those who did not (aHR, 25.2; 95% CI, 23.1-27.5; P < 0.001). Similar to findings in the PV cohort, patients with ET who had a prediagnosis TE were at a greater risk of mortality than those who did not have a prediagnosis TE (aHR, 37.5; 95% CI, 31.7-44.3).

In both cohorts, hyperlipidemia was a common comorbidity and the authors noted it might also be associated with TE prevalence. Despite the study’s limitations, including reliance on claims data and the lack of treatment data analysis for the overall cohort, the findings suggest that mortality risk was significantly higher in patients who experienced TEs in tandem with PV or ET, they added.

“Thrombosis risk mitigation remains an important management goal in patients with PV and ET, particularly among those with a history of thrombotic events,” the authors wrote, adding, “More studies are needed to better define and understand ET and PV thrombotic event rates in various high-risk populations in a real-world setting.”

Reference

Pemmaraju N, Gerds AT, Yu J, et al. Thrombotic events and mortality risk in patients with newly diagnosed polycythemia vera or essential thrombocythemia. Leuk Res. Published online February 16, 2022. doi:10.1016/j.leukres.2022.106809

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Female Patients More Likely Than Males to Experience Severe Adverse Events During Cancer Treatment, Study Finds

Female Patients More Likely Than Males to Experience Severe Adverse Events During Cancer Treatment, Study Finds

Women are known to experience more adverse events with chemotherapy, but a recent study found an increased risk across therapy types, especially immunotherapy.

Women receiving chemotherapy are likely to have more adverse events (AEs) than men undergoing the treatment, but very little research has assessed the differences between men and women’s experiences with immunotherapy or targeted therapy. A recent study explored the role of patient sex in symptomatic and objective AEs with cytotoxic, immune, and targeted therapies for cancer.

The study, published in the Journal of Clinical Oncology, used SWOG Cancer Research Network phase 2 and 3 clinical trial data from trials between 1980 and 2019. Sex-specific cancers were excluded from the analysis.

In total, 13 symptomatic AEs and 14 objective and measurable AEs were analyzed. Symptomatic AEs included those in the Patient-Reported Outcome Common Terminology Criteria for Adverse Events given past evidence that clinician reports may under-report symptomatic AEs. Objective AEs were laboratory-based or measurable and were also categorized as either hematologic or nonhematologic.

Overall, 23,296 patients including 8838 women (37.9%) from 202 trials were included in the study. Of the patients included, 17,417 received chemotherapy, 2319 received immunotherapy, and 3560 received targeted therapy. Collectively, patients experienced 274,688 AEs, with 15,051 (64.6%) experiencing AEs of grade 3 or higher. Chemotherapy was especially prevalent in trials between 1989 and 1999. Immunotherapy and targeted therapies were more common from 2010 to 2019.

“It has been understood that women have more toxicity from chemotherapy than men, but almost no research has aimed to understand whether that pattern held for novel treatments like immunotherapy or targeted therapies,” study author Joseph Unger, PhD, associate professor, biostatistician, and health sciences researcher at Fred Hutchinson Cancer Center, said in a statement. “We found similar large differences, especially for immune treatments.”

While 64.6% of all patients experienced 1 or more severe AE, women had a 34% greater risk of severe toxicity than men (odds ratio [OR], 1.34; 95% CI, 1.27 to 1.42; P < .001). Women were at an increased risk across treatment types, especially immunotherapy (OR, 1.49; 95% CI, 1.24 to 1.78; P < .001).

Women were at a 33.3% greater risk of experiencing symptomatic AEs (OR, 1.33; 95% CI, 1.26 to 1.41; P < .001) compared with men (27.9%). They also had an increased risk of hematologic AEs compared with men (45.2% vs. 39.1%) and objective nonhematologic AEs (30.9% vs 29.0%). Women treated with immunotherapy were at an especially higher risk of severe symptomatic and hematologic AEs than men who received immunotherapy (33.7% vs 25.4%). Severe objective, nonhematologic AEs occurred at similar rates in men and women across treatment types.

These findings suggest that, in addition to the typical patient and tumor characteristics considered in cancer treatment decisions, patient sex may be a key factor in maximizing treatment efficacy while limiting toxicity. This is especially relevant with immunotherapy, during which women were at the greatest risk for severe AEs in this study.

The authors presented several possible explanations for the sex-related differences in AEs. They could be related to body size differences and relative dosing, differences in medication adherence for oral therapies, bias in the interpretation and reporting of AEs, or different reporting habits in men and women. However, the authors noted that objective hematologic AEs were also more common in women in these trials.

One study limitation is the population, which is limited to clinical trials and therefore likely includes younger, healthier patients than the general patient population, study authors said. The study also only included the worst toxicity grade in each category, so there was no observation of toxicity patterns over time.

Despite limitations, these findings suggest that sex could be an important factor in individualizing cancer treatment and maximizing efficacy.

“If confirmed, our findings suggest that underlying mechanisms may result in generalized worse toxicity outcomes for women, with or without corresponding survival improvements or detriments,” the authors wrote. “Therefore, more awareness of symptom differences or reporting differences in women versus men is needed.”

Reference

Unger JM, Vaidya R, Albain KS, et al. Sex differences in risk of severe adverse events in patients receiving immunotherapy, targeted therapy, or chemotherapy in cancer clinical trials. J Clin Oncol. Published online February 4, 2022. doi:10.1200/JCO.21.02377

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Angiotensinogen and Risk of Stroke Events in Patients with Type 2 Diab | DMSO

Angiotensinogen and Risk of Stroke Events in Patients with Type 2 Diab | DMSO

Introduction

Type 2 diabetes has been considered a vital risk factor for promoting the occurrence and/or development of cardiovascular disease (CVD), such as stroke and coronary heart disease (CHD), and CVD mortality.1–3 Previous studies have shown that individuals with type 2 diabetes may have different severities of the disease, which depends on the presence of comorbidities or other risk factors.4 Well-understood risk heterogeneity and identifying individuals at long-term risk could help improve and personalize cardiovascular risk management for these individuals with type 2 diabetes.

Activation of the renin-angiotensin system (RAS) is a vital pathophysiological mechanism of CVD and renal insufficiency in diabetic patients.5 Many previous observational studies have demonstrated that inhibiting the RAS, which is currently the front-line treatment for diabetic nephropathy,5 could delay worsening renal function and reduce the risk of CVD morbidity and mortality in patients with diabetes.6–8 Importantly, although RAS inhibition has shown many beneficial effects, not all patients showed significant improvements in the prognosis of CVD complications. Hence, accurately estimating the active state of the intrarenal RAS might provide a good opportunity to help identify whether diabetic patients are at high risk of poor prognosis. The kidney has all parts of the RAS pathway that can produce angiotensinogen, which further promotes the production of angiotensin II (angII).9 AngII, produced by the kidney, has been reported to pose a key role in renal function and hemodynamics, affecting the development of cardiovascular pathology.10

Recently, several cross-sectional studies have reported that urinary angiotensinogen may be considered a potential biomarker of renal dysfunction in hypertensive patients.11,12 However, whether urinary and/or serum levels of angiotensinogen can be considered potential biomarkers for predicting stroke risk is still unclear. In this study, we measured urinary and serum levels of angiotensinogen in patients with type 2 diabetes. We aimed to assess whether angiotensinogen levels are associated with stroke prognosis.

Methods

Study Sample

We studied 488 hospitalized patients with type 2 diabetes from Tianjin Nankai Hospital in China between January 2009 and December 2015. None of the included patients had other serious chronic diseases, such as cancers, liver diseases, or respiratory diseases, before admission. After discharge, the patients with type 2 disease were contacted by telephone. A total of 21 patients with type 2 diabetes were excluded from this cohort study due to the diagnosis of serious chronic diseases within three months before admission, including neoplastic diseases (N=10), liver diseases (N=7) and other serious diseases (N=4). The diagnostic criteria for type 2 diabetes were determined by 3 endocrinologists.13 For the purposes of this study, during a mean follow-up of 5 years, ischemic or hemorrhagic stroke requiring hospitalization was defined as an endpoint event. The endpoint event was diagnosed by two neurologists. The Ethics Committee of Tianjin Nankai Hospital approved this study. This was a retrospective study, so this study applied for patients informed exemption according to the Declaration of Helsinki guidelines.

Follow-Up

The included diabetic patients were followed up by telephone and/or reviewing, until the occurrence of endpoint events. The endpoint events of this study were defined as ischemic stroke requiring rehospitalization, hemorrhagic stroke requiring rehospitalization and death caused by stroke. During the 5-year follow-up period, 7 patients with diabetes were lost to follow-up.

Measurement of Serum and Urinary Angiotensinogen Levels

Fasting venous blood samples were obtained from the diabetic patients in the first morning after inclusion. The concentrations of angiotensinogen in urine and serum samples were measured by using enzyme-linked immunosorbent assays (ELISA) at baseline.14 Angiotensinogen concentrations were tested three times in each patient, and the average value of the three results was used for statistical analysis. The interassay and intra-assay coefficients of variability for the serum and urine angiotensinogen assays were 6.5% and 4.5%, respectively.

The blood samples were also measured for serum albumin (ABL), glycosylated hemoglobin (HbA1c), hemoglobin (Hb), low density lipoprotein (LDL), high sensitivity C-reactive protein (hs-CRP) and high density lipoprotein (HDL) levels and were tested at the same time by using immunoassay on an ELECSYS2010 instrument (Roche Diagnostics, Germany). Serum levels of the estimated glomerular filtration rate (eGFR) were calculated by using the Chronic Kidney Disease (CKD) Epidemiology Collaboration equation.15 For research purposes, an eGFR<60 mL/min/1.73 m2 was considered renal insufficiency.

Statistical Analysis

All of the data were analyzed by using SPSS 22.0, and a P ≤ 0.05 was considered to be statistically significant. The Kolmogorov–Smirnov test was used to analyze the normality of the data. t-tests or chi-square tests were performed to compare the two groups (eGFR≥60 mL/min/1.73 m2 and eGFR<60 mL/min/1.73 m2). In the multivariate analysis, Cox regression analysis was performed to identify the independent values of serum and urinary angiotensinogen levels at baseline on predicting the risk of stroke events in patients with type 2 diabetes. To further evaluate the independent association, we further excluded the effect of “duration of diabetes” by sensitivity analysis. Moreover, we also analyzed the association between serum and urinary angiotensinogen levels at baseline and the risk of stroke events during the follow-up period using stratified analysis by adding “taking RAS inhibitors” and “an eGFR≥60 mL/min/1.73 m2”. Additionally, an endpoint (stroke event)-free curve was constructed by the Kaplan–Meier method, and the Log rank test was performed.

Results

Clinical Characteristics of the 467 Patients with Type 2 Diabetes at Baseline

The clinical characteristics of the patients with type 2 diabetes at baseline are presented in Table 1. According to the median value of the eGFR (57 mL/min/1.73 m2), all the patients were divided into two groups. The patients with low eGFRs (<57 mL/min/1.73 m2) tended to have longer durations of diabetes, higher systolic and diastolic blood pressures, and higher rates of ever being a smoker, ever being a drinker, taking RAS inhibitors and having a CVD history, compared with patients with high eGFRs (≥57 mL/min/1.73 m2, all P<0.05). For laboratory measurements, the patients with low eGFRs had higher levels of urinary angiotensinogen, LDL, HbA1c and Hs-CRP and lower levels of ALB and Hb than those with high eGFRs (all P<0.05). Interestingly, serum angiotensinogen was not significantly different between the two groups (P>0.05).

Table 1 Clinical Characteristics in 467 Patients with Type 2 Diabetes at Baseline

Cox Proportional Hazard Analysis for the Associations Between Serum and Urinary Angiotensinogen Levels and Stroke Events in Patients with Type 2 Diabetes

All included patients were prospectively followed up for a median period of 5 years, and 47 patients had stroke events (including ischemic and hemorrhagic stroke). Kaplan–Meier analysis showed that patients with low eGFRs (<57 mL/min/1.73 m2) had a significantly higher rate of stroke events than those with high eGFRs (Figure 1, P=0.040). To further investigate the potential risk for stroke events, a multivariate Cox proportional hazard regression model was used. Urinary angiotensinogen levels (HR=2.78, 95% CI 1.54–5.94, P=<0.001) were associated with an increased risk of stroke events when adjustments for age, sex, BMI, ever smoking and ever drinking were made, which was similar to serum angiotensinogen levels (HR=1.54, 95% CI 1.10–3.27, P=0.037) in Model 1 (Table 2). The significant associations changed slightly after adding systolic and diastolic blood pressures and CVD history in Model 1. After continuing to add the laboratory measurements into Model 2, our results suggested that urinary angiotensinogen levels (HR=2.74, 95% CI 1.50–5.88, P=<0.001, Model 3) were an independent predictor for the risk of stroke events in patients with type 2 diabetes, but not serum angiotensinogen levels (HR=1.42, 95% CI 0.95–2.65, P=0.071, Model 3).

Table 2 Cox Proportional Hazard Analysis for the Association Between Urinary and Serum Angiotensinogen Levels and Stroke Events in Patients with Type 2 Diabetes

Figure 1 Kaplan–Meier analysis of the endpoint-free curve stratified into 2 groups by median level of the eGFR.

We performed an additional sensitivity analysis to evaluate the associations of urinary and serum angiotensinogen levels with the risk of stroke events in patients with type 2 diabetes by adding “duration of diabetes” as a covariate (Table 3). Similarly, the results also suggested that higher urinary angiotensinogen levels still contributed to an increased risk of stroke events (HR=2.71, 95% CI 1.48–5.82, P<0.001, Model 3), but not serum angiotensinogen levels (HR=1.37, 95% CI 0.89–2.21, P=0.104, Model 3), after adjusting for the confounding factors.

Table 3 Sensitivity Analysis for the Association Between Urinary and Serum Angiotensinogen Levels and Stroke Events in Patients with Type 2 Diabetes

Stratified Analysis of the Associations Between Urinary and Serum Angiotensinogen Levels and Stroke Events in Patients with Type 2 Diabetes by “Taking RAS Inhibitors” and “an eGFR≥60 mL/Min/1.73 M2”

Stratified analysis was performed by adding “taking RAS inhibitors” and “an eGFR≥60 mL/min/1.73 m2” as covariates. Our results still showed that the association between urinary angiotensinogen levels and the risk of stroke events in patients with type 2 diabetes was significant (HR=2.64, 95% CI 1.45–5.78, P<0.001, Model 3) and was not affected by “taking RAS inhibitors”, as shown in Table 4. Importantly, the significant association was affected by “an eGFR≥60 mL/min/1.73 m2”, as shown in Table 5. We found that a significant association existed only in patients with eGFRs<60 mL/min/1.73 m2 (HR=2.78, 95% CI 1.59–6.30, P<0.001, Model 3) and not in patients with eGFRs≥60 mL/min/1.73 m2 (HR=1.39, 95% CI 0.95–3.53, P=0.054, Model 3). In addition, serum angiotensinogen levels still had no association with the risk of stroke events in the stratified analysis.

Table 4 Stratified Analysis for the Association Between Urinary and Serum Angiotensinogen Levels and Stroke Events in Patients with Type 2 Diabetes by “Taking RAS Inhibitors”

Table 5 Stratified Analysis for the Association Between Urinary and Serum Angiotensinogen Levels and Stroke Events in Patients with Type 2 Diabetes by “Egfr≥60 mL/Min/1.73 M2”

Discussion

In the present study, our baseline data suggested that patients with higher urinary levels of angiotensinogen had lower eGFRs. However, serum levels of angiotensinogen were not associated with the eGFR. Moreover, Cox regression analysis suggested that diabetic patients with high levels of urinary angiotensinogen had a high rate of stroke events. Our results documented that increasing urinary angiotensinogen levels were associated with a higher risk for stroke events in diabetic patients. Furthermore, the significant relationship of urinary angiotensinogen levels with stroke risk can be affected by renal function.

Although previous studies have documented that angiotensinogen can be produced and secreted from both the liver and kidneys,10 serum and urinary levels of angiotensinogen originating from different sources pose different impacts on renal function.16,17 Existing evidence suggests that human angiotensinogen cannot be detected in urine obtained from hypertensive and nonhypertensive rats that were injected with human angiotensinogen, which may be explained by the limited glomerular permeability of circulating angiotensinogen and/or degrading angiotensinogen in tubules.18 Under normal renal structure and function, it has been reported that angiotensinogen is expressed in proximal tubular cells and released into the ureter.10 However, in the case of hyperglycemia, the expression of angiotensinogen is significantly increased in proximal tubular cells.19,20 Furthermore, some clinical investigations have reported that diabetic patients have higher urinary angiotensinogen levels,21 whereas there was no difference in serum angiotensinogen levels between diabetic patients and control individuals.21 This previous evidence may suggest that blood angiotensinogen is not a direct source of urinary angiotensinogen. Consistently, our results also suggested that urinary angiotensinogen originates locally from the kidney instead of serum.

Increased angiotensinogen expression in tubules can promote the activation of the intrarenal RAS. Consistent with our study, diabetic patients with low eGFRs had a greater increase in urinary angiotensinogen levels than serum angiotensinogen levels. One similar finding showed that CKD patients with low eGFRs documented higher urinary angiotensinogen levels, suggesting a negative relationship between urinary angiotensinogen levels and renal function.22 Studies have long confirmed the correlation between abnormal renal function and CVDs.23 Our multivariate correlational analysis reported that elevated levels of urinary angiotensinogen contributed to high stroke risk. Hence, the increased levels of urinary angiotensinogen might contribute to the pathological development of stroke, which may be explained by renal dysfunction and/or the incidence of CVD caused by diabetes mellitus.

Our results have several obvious strengths. On the one hand, in the first morning after admission, blood and urinary tests can better reflect the levels of serum and urinary angiotensinogen in diabetic patients. We are the first to find that urinary angiotensinogen can be considered a valuable predictor for endpoints (stroke events requiring rehospitalization) in diabetic patients. On the other hand, our study confirmed complete follow-up and standardized adjudication of the endpoint, so our results are very reliable. Certainly, this study also has several limitations, including a small sample size in a single center. First, although many various confounding factors, including renal function, were adjusted in our study, which may be the most important factor influencing urinary angiotensinogen levels, some other potential confounding factors were not eliminated due to other unknown determinants of urinary angiotensinogen levels. Second, because urinary levels of angiotensinogen were measured in the first morning after admission, the time-dependent variables after discharge were not assessed, which might cause survivorship biases. Third, using many covariates in our Cox regression analysis may have caused overfitting of the model, leading to bias in the results. Finally, we did not further investigate the mechanisms underlying the association of urinary angiotensinogen levels with stroke. Additionally, our study only included the Asian race and limits the generalizability of our results to other races, such as white and black races. In summary, these limitations should be considered in future studies to elaborate on this work.

Conclusions

Our results suggested that elevated urinary levels of angiotensinogen contributed to higher stroke risk in diabetic patients. Reducing urinary levels of angiotensinogen might be a new biomarker to reduce stroke risk.

Funding

There is no funding to report.

Disclosure

The authors report no conflicts of interest in this work.

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