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Immune checkpoint inhibitor therapy linked to higher incidence of cardiovascular events

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September 07, 2022

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Laenens reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

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Immune checkpoint inhibitor therapy appeared associated with an increased risk for major adverse cardiovascular events among patients with cancer and a prior history of cardiovascular disease, according to results of a retrospective study.

The findings, published in Journal of Clinical Oncology, suggest routine thorough cardiovascular history, electrocardiography and echocardiography might identify patients who need regular cardiovascular follow-up during and after immune checkpoint inhibitor treatment, researchers noted.

Among patients with cancer who received immune checkpoint inhibitors
Data derived from Laenens D, et al. J Clin Oncol. 2022;doi:10.1200/JCO.21.01808.


Immune checkpoint inhibitors (ICIs) have been known to cause immune-mediated myocarditis in some patients. However, incidence of other major adverse cardiovascular events after ICI therapy remains unknown, according to study background.

“The current literature on cardiovascular toxicity of ICIs consists mainly of case series,” Dorien Laenens, MD, cardiologist in the department of cardiology at University Hospitals Leuven in Belgium, and colleagues wrote. “Another limitation of the currently available data is that randomized clinical trials of ICIs focus on survival, response and disease control, usually [during] short follow-up periods.”

To address the lack of knowledge, researchers collected data from digital patient files of University Hospitals to identify incidence of and risk factors for major adverse cardiovascular events among 672 patients (median age, 65 years; 64.7% men) with cancer treated with ICIs, and compared incidence rates with patients with cancer not treated with ICIs and population controls after matching according to age, sex, cardiovascular history and cancer type.

Major adverse cardiovascular events — a composite of acute coronary syndrome, heart failure, stroke and transient ischemic attack — served as the primary endpoint. Acute coronary syndrome and heart failure served as secondary outcomes.

Median follow-up was 13 months (interquartile range, 6-22).


Overall, 572 patients received only one line of ICI therapy, 90 patients received two lines of therapy, eight patients received three lines and two patients received four lines. More than half of patients (54.9%) died — with 1.9% deemed cardiovascular deaths.

Researchers reported a 10.3% incidence of major cardiovascular events, with a median time to event of 5 months.

Results of multivariable analysis showed having a history of heart failure (HR = 2.27; 95% CI, 1.03-5.04) and valvular heart disease (HR = 3.01; 95% CI, 1.05-8.66) remained significantly associated with major adverse cardiovascular events.

“Cumulative incidence rates were significantly higher in the ICI group compared with the cancer cohort not exposed to ICI and the population controls, mainly driven by a higher risk of heart failure events,” the researchers wrote.


The findings reinforce the clinical relevance of a cardiovascular workup of patients with cancer before exposure to ICI treatment, particularly in those with preexisting cardiovascular disease, the researchers wrote.

“Prospective or retrospective all-comer studies with bigger cohorts are essential for capturing true incidence of major cardiac events in daily practice,” they continued.

“Concomitant cardiovascular disease is often an exclusion criterion in clinical trials. This might be one of the reasons why this type of toxicity is underreported in phase 3 trials. In addition, toxicity is often not part of the follow-up when treatment within the context of the study is ceased. Cohort studies like ours can compensate for these shortcomings.”

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Severe COVID-19 increases risk of future cardiovascular events

Study: COVID-19 severity and risk of subsequent cardiovascular events. Image Credit: Yurchanka Siarhei /

To date, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the virus responsible for the coronavirus disease 2019 (COVID-19), has infected over 603 million individuals and claimed more than 6.4 million lives worldwide.

About 30% of COVID-19 survivors continue to experience a wide range of persistent symptoms for several weeks since their initial diagnosis. This condition is commonly referred to as post-acute sequelae of SARS-CoV-2 infection (PASC) or “long COVID.”

Study: COVID-19 severity and risk of subsequent cardiovascular events. Image Credit: Yurchanka Siarhei /

Study: COVID-19 severity and risk of subsequent cardiovascular events. Image Credit: Yurchanka Siarhei /


Even though multisystem inflammatory syndrome is the most common PASC syndrome in adults and children, a wide range of other symptoms, including sleep difficulties, persistent fatigue, type 1 diabetes, and neurological disorders, have been reported. The incidence of these symptoms varies from one person to another based on their demographic and clinical characteristics.

Several studies have indicated the manifestation of multiple cardiovascular complications, such as arrhythmia, hypertension, acute myocardial infarction, thromboembolism, and cerebrovascular accidents, in individuals who have recovered from COVID-19. However, a limited number of studies have confirmed that severe COVID-19 leads to a high risk of cardiovascular diseases.

A recent Clinical Infectious Diseases journal study determines the relationship between COVID-19 severity and risk of subsequent cardiovascular events (CVEs) in a large cohort.

Study findings

A retrospective cohort study was performed using nationwide health insurance claims data of adults from the United States Health Verity Real-Time Insights and Evidence database. Increased COVID-19 severity was found to enhance the risk of developing subsequent CVEs among individuals without a cardiac history in previous years. 

As compared to COVID-19 patients who required outpatient care, those who required hospital admission were more likely to experience CVEs. Among COVID-19 hospitalized patients, those admitted to the intensive care unit (ICU) were almost 80% more likely to develop CVEs than non-ICU hospitalized patients.

In fact, non-ICU hospitalized patients exhibited only a 28% possibility of experiencing CVEs thirty days after initial COVID-19 symptoms. Additionally, as compared to COVID-19 outpatients, hospitalized patients were more likely to be admitted for a CVE after recovering from COVID-19.

In younger adults, the incidence of cardiovascular sequelae was lower as compared to older adults. Aside from CVEs, other severe outcomes, such as thrombotic events and cerebrovascular accidents, were observed in patients who recovered from severe COVID-19. However, such observations were less likely in COVID-19 patients who required only outpatient care.

The study findings emphasize the importance of vaccination, as demonstrated by its ability to reduce severe disease. Similarly, prompt antiviral treatment of acute COVID-19 has been recommended, which would help reduce the possibility of transition to severe illness.

Both COVID-19 vaccination and timely therapeutic interventions would alleviate the risk of severe COVID-19 and subsequently decrease the possibility of experiencing CVEs.

The findings of the present study are consistent with previous research that has reported a higher incidence of myocarditis and pericarditis in patients who recovered from severe SARS-CoV-2 infection. Nevertheless, it was observed that elevated cardiovascular risk after acute infection may not be exclusive to COVID-19.

In fact, some other diseases that have been associated with an increased risk of long-term CVEs are influenza and pneumonia bacteremia. Additionally, 22-65% of sepsis survivors are at an increased risk of CVEs.

The underlying mechanism responsible for the increased risk of CVEs following SARS-CoV-2 infection has not been determined. SARS-CoV-2 infects cardiac myocytes through their interaction with the angiotensin-converting enzyme 2 (ACE-2) receptor, which might remain persistent; therefore, this interaction induces chronic inflammatory responses and subsequent tissue damage or fibrosis.

Another mechanism related to the development of CVEs following recovery from COVID-19 is an autoimmune response to cardiac antigens that causes delayed damage to cardiac tissues. Anti-heart antibodies also correlated with cardiovascular manifestation and COVID-19.

Viral toxicity is another possible mechanism that might cause long-term cardiac damage or thrombosis in vasculitis. However, in the future, more research is needed to confirm the mechanisms related to cardiac damage after SARS-CoV-2 infection.


Due to the lack of a COVID-19-negative control group, the authors failed to quantify the elevated risk of CVEs in COVID-19 patients. The unwanted inclusion of patients with a history of CVEs could have overestimated the result as well. The impact of vaccination status on the incidence of CVE was not studied.

Despite these limitations, the present study strongly emphasized that patients who recovered from severe COVID-19 were at a greater risk of developing CVEs. As compared to COVID-19 patients who required outpatient care, those who were admitted to the ICU were at a higher risk of experiencing CVEs.

The importance of COVID-19 vaccination in preventing severe infection was strongly emphasized in this study.

Journal reference:

  • Wiemken, L. T., McGrath, L. J., Andersen, K. M., et al. (2022). COVID-19 severity and risk of subsequent cardiovascular events. Clinical Infectious Diseases. doi:10.1093/cid/ciac661.
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Childhood Risk Factors and Adult Cardiovascular Events | NEJM

Childhood Risk Factors and Adult Cardiovascular Events | NEJM

To the Editor: Jacobs et al. (May 19 issue)1 explored the association of several childhood risk factors (body-mass index [BMI], systolic blood pressure, total cholesterol level, triglyceride level, and smoking status) with vascular events in adulthood. They found that there was an association between childhood risk factors and cardiovascular events in midlife. However, neither albuminuria nor the estimated glomerular filtration rate (eGFR) was assessed. Albuminuria and a decreased eGFR are key risk factors for cardiovascular events and, together with BMI, systolic blood pressure, lipid levels, and smoking, are used in adults to assess cardiovascular risk. An elevated eGFR may indicate . . .

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Gout flares associated with subsequent cardiovascular events

Gout flares associated with subsequent cardiovascular events

Experts at the University of Nottingham, in collaboration with experts at Keele University, have found that the risk of heart attacks and strokes temporarily increases in the four months after a gout flare.

The research showed that gout patients who suffered from a heart attack or stroke were twice as likely to have had a gout flare in the 60 days prior to the event, and one and a half times more likely to have a gout flare in the 61-120 days prior.

The results of the study, led by Professor Abhishek in the School of Medicine at the University of Nottingham, are published in the journal JAMA.

Gout is a common form of arthritis that affects one in 40 adults in the UK. It is caused by high levels of uric acid, a chemical produced by breakdown of tissues in the body and present in certain foods and drinks.

At high levels, uric acid is deposited in and around joints as needle shaped urate crystals. Once released from their deposits, these crystals cause severe inflammation manifesting as joint pain, swelling, redness, and tenderness that often lasts for 1-2 weeks. These episodes, called gout flares, often recur. Inflammation is also a risk factor for heart attack and stroke.

People with gout tend to have more cardiovascular risk factors, although there have been no previous studies about whether gout flares are linked with an increased risk of heart attack and stroke. In this study, the experts examined whether there was a temporary increase in risk of heart attack or stroke after a gout flare.

The team used anonymized data from 62,574 patients with gout treated in the National Health Service in the UK. Of these, 10,475 experienced heart attack or stroke after the diagnosis of gout, while others of similar age, sex, and duration of gout, did not experience such events. They evaluated the association between heart attacks or strokes and recent gout flares and adjusted these results for comorbidities, socioeconomic deprivation, lifestyle factors and prescribed medications among other things. They found that gout patients who suffered a heart attack or stroke were twice as likely to have had a gout flare in the 60 days prior to the event, and one and a half times more likely to have a gout flare in the preceding 61-120 days.

They found a similar high rate of heart attack or stroke in the 0-60 and 61-120 days after gout flares compared with other time periods, when they used information from only patients who consulted for a gout flare and also experienced either heart attack or stroke. This further strengthened the finding that gout flares are associated with a transient increase in cardiovascular events following flares. The increased odds and rates persisted when people with pre-existing heart disease or stroke before their gout diagnosis were excluded, and when shorter exposure periods such as 0-15 and 16-30 days prior to heart attack or stroke, were considered.

Gout patients who died from a heart attack or stroke had over four times the odds of experiencing a gout flare in the preceding 0-60 days and over twice the odds of gout flare in the preceding 61-120 days.

This is the first study of its kind to examine whether there is an association between recent gout flares and heart attacks and strokes.

The results show that among patients with gout, patients who experienced a heart attack or stroke had significantly increased odds of a gout flare during the preceding 120-days compared with patients who did not experience such events. These findings suggest that gout flares are associated with a transient increase in cardiovascular events following flares.

People with recurrent gout flares should be considered for long-term treatment with urate lowering treatments such as allopurinol. This is a reliable way of removing urate crystal deposits and providing freedom from gout flares. Patients should also be considered for concurrent treatment with anti-inflammatory medicines such as colchicine for the first few months because urate lowering treatments may trigger gout flares in the short term.

People with gout should be encouraged to adopt a healthy lifestyle with appropriate treatment of conditions such as high blood pressure, high cholesterol, obesity and diabetes to minimise their background risk of heart attack and stroke”

Professor Abhishek, lead author on the study


Journal reference:

Cipolletta, E., et al. (2022) Association Between Gout Flare and Subsequent Cardiovascular Events Among Patients With Gout. JAMA.

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

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

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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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Primary hyperparathyroidism associated with an increased risk of fractures and cardiovascular events | 2 Minute Medicine

Primary hyperparathyroidism associated with an increased risk of fractures and cardiovascular events | 2 Minute Medicine

1. In this cohort study, among 16 374 Swedish adult patients with primary hyperparathyroidism, the risk hip fracture was increased by 51%, and risk of cardiovascular events increased by 45% compared to matched healthy participants.

2. Parathyroidectomy was associated with a reduced risk of any fracture, hip fracture, cardiovascular events and death.

Evidence Rating Level: 2 (Good)

Study Rundown: Primary hyperparathyroidism (pHPT) is an endocrine disorder in which individuals have an elevated serum calcium combined with a normal or high blood level of parathyroid hormone. Known concerns of pHPT include increased bone loss and an elevated risk of fractures at sites including the spine, wrist, ribs and pelvis. As such, this retrospective cohort study investigated whether untreated pHPT was associated with an increased risk of fractures and cardiovascular events (CVEs) in comparison with the risk of a sex, age and country-matched control group and whether parathyroidectomy was associated with a reduction in these outcomes. The study included patients who were diagnosed with pHPT at hospitals in Sweden between 2006 to 2017. The primary outcomes were fractures, CVEs, and death. A total of 16 374 patients with pHPT were identified with a mean age of 67.5 years. Compared with the control group, the pHPT group was found to have a higher risk of any fracture by 39%, hip fracture by 51%, CVEs 45% and death 72%. Parathyroidectomy was associated with a reduced risk of any fracture by 17% and death by 59%. A major strength of this study was that in terms of the number of patients with untreated pHPT and multiple observed outcomes, it is the largest analysis performed thus far. As a result of the observational design however, a limitation to this study is that it could not establish causality, although the time-dependent analysis suggested an association between parathyroidectomy and reduced risk of fractures, CVEs and death.

Click to read the study in JAMA Network Open

Relevant Reading: Survival after the diagnosis of primary hyperparathyroidism: a population-based study

In-Depth [retrospective cohort]: This study investigated whether primary hyperparathyroidism (pHPT) was associated with an increased risk of fractures, CVEs and mortality, compared to the risk of a sex, age and country-matched control group. Data was collected from patients diagnosed with pHPT at hospitals in Sweden between July 1, 2006 to December 31, 2017. Each patient was matched with 10 control individuals from the general population. A total of 16 374 patients with pHPT were identified (mean SD age, 67.5 [12.9] years; 12806 women [78.2%]), with 163 740 control individuals. The median follow-up time for the pHPT group was 1.15 (.040-4.06) years and for the control it was 4.62 (2.08-7.51) years. Patients with pHPT had significantly higher risks of any fracture (unadjusted HR, 1.39; 95% CI, 1.31-1.48), major osteoporotic fracture (unadjusted HR, 1.43; 95% CI, 1.33-1.54), hip fracture (unadjusted HR, 1.51; 95% CI, 1.35-1.70), and injurious fall (unadjusted HR, 1.51; 95% CI, 1.42-1.60) compared with those in the control group. The risk of fractures was significantly increased at the following sites: wrist (unadjusted HR, 1.34; 95 CI, 1.18-1.52), upper arm (unadjusted HR, 1.46; 95% CI, 1.25-1.71) and lower leg (unadjusted HR, 1.31; 95% CI, 1.12-1.54). The risk of any CVE for patients with pHPT was increased (unadjusted HR, 1.45; 95% CI, 1.34-1.57), as well as the risk for acute myocardial infarction (unadjusted HR, 1.39; 95% CI, 1.24-1.56) and ischemic stroke (unadjusted HR, 1.51; 95%CI, 1.36-1.68). The risk of death (unadjusted HR, 1.72; 95% CI, 1.65-1.80) was also increased in higher in patients with pHPT compared to the control group. There was a substantial increase in the risk of kidney stones, almost 4 times higher in patients with pHPT (unadjusted HR, 3.65; 95% CI, 3.27-4.08) than in control individuals. Of the 16 374 patients with pHPT, 6934 (42.3%) underwent a parathyroidectomy. While using the Poisson regression model to study the pHPT group separately, parathyroidectomy was found to be associated with a reduced risk of hip fracture (HR, 0.78; 95% CI, 0.61-0.98), any fracture (HR, 0.83; 95% CI, 0.75-0.93), injurious fall (HR, 0.83; 95% CI, 0.74-0.92), CVE (HR, 0.84; 95% CI, 0.73-0.97), and death (HR, 0.59; 95% CI, 0.53-0.65).

Image: PD

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Analysis finds little proof that testosterone treatment increases the risk of cardiovascular events

Analysis finds little proof that testosterone treatment increases the risk of cardiovascular events

Testosterone replacement therapy appears safe in the short-to-medium term to treat a condition caused by deficiency of the male sex hormone, according to the most comprehensive analysis of the treatment to date, published in The Lancet Healthy Longevity journal.

The findings suggest that men given testosterone to treat hypogonadism are at no greater risk of heart attack, stroke, and other cardiovascular events in the short-to-medium term than men who do not receive testosterone treatment.

Testosterone replacement therapy is the standard treatment for hypogonadism, which can cause sexual dysfunction, weakening of bones and muscles, and reduced quality of life. Risk factors for the condition include aging (as testosterone levels decline with age), obesity (BMI of 30 kg/m2 or above), and diabetes.

Despite being widely used, the cardiovascular safety of testosterone treatment has until now remained unclear due to inconsistent findings. This is because most previous clinical studies have relied on aggregate data, rather than individual participant data and have not published details of individual adverse events.

Prescribing of testosterone for hypogonadism is increasing globally, but conflicting messages about its safety may have led to many patients not receiving the treatment. Ongoing studies should help to determine the longer-term safety of testosterone but, in the meantime, our results provide much-needed reassurance about its short-to-medium term safety. Our findings could have important implications for the treatment of men with hypogonadism worldwide.”

Jemma Hudson, Study Lead Author, University of Aberdeen

The authors conducted a systematic review identifying 35 eligible clinical trials published since 1992, of which 17 provided individual participant data. A blinded analysis by two independent clinicians enabled the classification of every cardiovascular event, allowing for a more robust analysis of the cardiovascular safety of testosterone treatment.

A meta-analysis using individual participant data from 17 studies and a further meta-analysis integrating these data with the aggregate data provided by the 18 trials that did not provide individual participant data were performed.

Among the 17 trials with individual patient data, 1,750 participants received testosterone and 1,681 were given a placebo. The average length of testosterone treatment was 9.5 months. The average age of participants was 65 years, and most were white and did not smoke. Participants’ average BMI was 30 kg/m2, which is considered obese.

A meta-analysis showed there were 120/1,601 (7.5%) cardiovascular events in the testosterone group and 110/1,519 (7.2%) in the placebo group across 13 trials that provided this information. Patient age, smoking or diabetes status did not affect cardiovascular risk. Similarly, there was no significant difference in mortality rate between the testosterone group (6/1,621 deaths, 0.4%) and the placebo group (12/1,537 deaths, 0.8%) across the 14 trials that provided individual patient data on mortality, but only limited data were available.

The researchers also found that testosterone significantly reduced serum total cholesterol, high-density lipoprotein (HDL), and triglycerides compared with placebo. However, there were no significant differences in serum low-density lipoprotein (LDL), blood pressure, glycaemic parameters, diabetes incidence, and prostate adverse outcomes between the testosterone and placebo groups.

The meta-analysis that integrated individual participant data with aggregate data showed similar results.

The authors acknowledge some limitations to their study. There was little available data evaluating the cardiovascular safety of testosterone treatment beyond 12 months, and the very small number of deaths recorded during testosterone trials hampered the authors’ ability to analyze why they occurred.

However, the longer-term safety of testosterone treatment is currently being investigated in another clinical trial. While the meta-analysis of aggregate data showed similar results to the one involving individual patient data only, it cannot be ruled out with certainty that a high number of unreported cardiovascular events in the trials that did not provide individual participant data could alter the current conclusions.


Journal reference:

Hudson, J., et al. (2022) Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis. The Lancet Healthy Longevity.

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Higher Serum Urea Levels in CKD Predict Cardiovascular Events

Blood sample

Elevated serum urea levels in patients with nondialysis-dependent chronic kidney disease (CKD) predict cardiovascular events and death, according to study findings presented at the European Renal Association (ERA) 59th Congress held in Paris, France, and virtually.

Ziad Massy, MD, PhD, of Ambroise Paré University Hospital, Boulogne-Billancourt, France, and colleagues stratified 2507 patients from the CKD-REIN cohort by baseline serum urea level. Over a median of 3 years, 451 patients experienced their first atheromatous or nonatheromatous cardiovascular event. The overall incidence rate was 7.1 per 100 person-years.

In adjusted analyses, patients with serum urea levels in the top tertile (15.1 mmol/L or higher) had a significant 2.1-fold increased risk for cardiovascular events compared with those who had levels in the bottom tertile (less than 10.5 mmol/L), the investigators reported. The middle tertile of serum urea (10.5–15.1 mmol/L) was associated with a nonsignificant 1.3-fold increased risk of cardiovascular events. The cardiovascular events rate was 4.1, 6.3, and 11.6 per 100 person-years for the bottom, middle, and top tertile, respectively. Of the full cohort, 54% had a history of cardiovascular disease.

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Over a median 4.8 years, 407 patients died before initiating kidney replacement therapy at a rate of 4.0 per 100 person-years. Compared with the bottom tertile of serum urea, the risk for all-cause mortality was a nonsignificant 1.3-fold higher for the middle tertile and a significant 1.7-fold higher for the top tertile, the investigators reported.

“Beyond [cardiovascular] risk factors including eGFR, this hypothesis-generating study suggests that serum urea level is a predictor of cardiovascular outcomes in patients with moderate to advanced CKD,” Dr Massy’s team concluded in a study abstract. Further research is needed to confirm the findings and explore mechanisms, including whether urea is a direct or indirect uremic toxin, as some studies indicate.


Laville S, Couturier A, Lambert O, et al. Serum urea levels and cardiovascular disease in patients with chronic kidney disease. Presented at: ERA 59th Congress; May 19-22, 2022, Paris, France, and virtual. Abstract MO496.

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Erectile Dysfunction Ups Risk for Major Adverse Cardiovascular Events

Vascular system, illustration

Men with erectile dysfunction (ED) are at increased risk for major adverse cardiovascular events (MACE), especially those who live in rural areas, according to study findings presented at the 2022 American Urological Association annual meeting in New Orleans, Louisiana.

The study included 428,241 men, of whom 49,959 had ED (32,138 from urban areas and 17,821 from rural areas) and 378,282 did not (233,073 and 145,209 from urban and rural areas, respectively).

Overall, MACE occurred in 8.9% of men with ED compared with 4.6% of those without ED. The proportions of men who experienced MACE were 8.2% and 10.2% among men with ED from urban and rural areas, respectively, and 4.2% and 5.2%, respectively, for men without ED from urban and rural areas, respectively.

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Compared with men from urban areas who did not have ED, men with ED who lived in rural areas and those with ED from urban areas had a significant 54% and 26% higher risk for MACE, respectively, in weighted analyses, investigator Uday Mann, MD, of the University of Manitoba in Winnipeg, Canada, reported.

Among men with ED, those from rural areas had a significant 22% higher risk for MACE compared with those from an urban setting. Among men without ED, men from rural areas had a significant 14% increased risk for MACE compared with those from urban areas.

The median time to a MACE was 2721, 2620, 2520, and 2438 days in the ED urban, ED rural, no ED rural, and no ED urban groups, respectively.

The investigators adjusted for age, socioeconomic status, diabetes, hypertension, dyslipidemia, renal disease, and index year.

“It is imperative for health care professionals who manage patients with ED to discuss the risk of future cardiovascular disease and identify comorbid conditions to mitigate risk,” Dr Mann concluded.

The investigators considered men to have ED if they had at least 2 ED prescriptions (including oral, intraurethral, and/or injection therapies) filled within 1 year. They defined MACE as myocardial infarction, coronary revascularization procedures, ischemic stroke, or hospitalization for heart failure.


Mann U, Brar R, Patel P. Erectile dysfunction is an independent risk factor for major adverse cardiovascular events. Presented at AUA 2022, May 13-16, 2022, New Orleans, Louisiana. Abstract PD49-05.