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Immune checkpoint inhibitor therapy linked to higher incidence of cardiovascular events

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September 07, 2022

2 min read

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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Timely intervention critical for major cardiac events after immune checkpoint therapy

Key study takeaways


Naqash AR, et al. Abstract 2508. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.

NIH funded this study. Naqash reports no relevant disclosures. Please see the abstract for all other researchers’ relevant financial disclosures.

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CHICAGO — Patients and prescribers should be more aware of the potential for major adverse cardiac events after immune checkpoint inhibitor-based therapy, according to retrospective study results presented at ASCO Annual Meeting.

The association between immune major adverse cardiac events (MACE) and noncardiac immune-related adverse events highlights the importance of a multidisciplinary management approach, researchers emphasized.

Key study takeaways

Data derived from Naqash AR, et al. Abstract 2508. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.

“To the best of our knowledge, this is the first-ever pooled analysis of immune checkpoint inhibitor clinical trials evaluating major adverse cardiac events,” Abdul Rafeh Naqash, MD, assistant professor in the early phase division of Stephenson Cancer Center at University of Oklahoma, said during a presentation. “These findings have important management implications, as more and more patients are being treated with anti-pD-1/PD-l1 combinations.”

Background and methods

Although rare, MACE can manifest in various ways among patients treated with immune checkpoint inhibitors. These events can result in considerable morbidity or death.

More work is needed to better define presentation of these events and their potential relationship with noncardiac immune-related adverse events among patients treated with immune checkpoint inhibitors, according to study background.

Abdul Rafeh Naqash, MD

Abdul Rafeh Naqash

Naqash and colleagues performed a retrospective pooled analysis of MACE captured in the NCI-Cancer Therapy Evaluation Program’s serious adverse events reporting database.

The analysis included patients treated with anti-PD-1/-PD-L1 therapy alone or in combination with other anticancer therapies as part of NCI-sponsored investigational clinical trials in the United States and Canada between June 2015 and December 2019.

The analysis included 6,925 patients. Slightly less than half (48%) received single-agent anti-PD-1/PD-L1 therapy. The remainder received those agents as part of combination therapy.


Forty patients (0.6%; median age, 68.5 years; 60% men) developed immune checkpoint inhibitor-related MACE.

The most common malignancies in this group included melanoma (37.5%), genitourinary cancer (16%), gastrointestinal cancer (12.5%), gynecologic cancer (7.5%), lymphoma (5%) and lung cancer (5%).

Median time to MACE from initial immune checkpoint inhibitor administration was approximately 28 days.

Researchers characterized the majority (77.5%) of MACE as grade 3 or higher (grade 3, 50%; grade 4, 20%; grade 5, 7.5%).

Myocarditis accounted for nearly half (45%; n = 18) of MACE, occurring a median two doses after immune checkpoint inhibitor administration. The majority (78%) of cases were grade 3 or higher.

Seventy-two percent of patients with myocarditis had been treated with anti-PD-1/PD-L1-based combination regimens, the most common of which included an anti-CTLA-4 inhibitor (92%).

Researchers reported four myocarditis-related deaths. All four of these individuals had concurrent myositis and three had concurrent transaminitis.

Nonmyocarditis MACE included dysrhythmias, cardiomyopathy, pericardial disorders, acute coronary syndrome and cardiac arrest.

More than half (65%) of patients who developed MACE experienced multisystem organ involvement with other noncardiac immune-related adverse events, the two most common being myositis (27.5%) and transaminitis (25%).

Nearly all patients (92.5%) with MACE required hospitalization and 30% required ICU admission.

Most patients (83%) with myocarditis experienced at least one noncardiac immune-related adverse event, and 50% of those with non-myocarditis MACE developed noncardiac immune-related adverse events.

Forty percent of those who developed MACE received single-agent PD-1/PD-L1 agent therapy, and 60% had received anti-PD-1/PD-L1 in combination with other therapies.

MACE occurred more frequently among patients treated with anti-PD-1/PD-L1 plus targeted therapies (2.1%) than anti-PD-1/PD-L1 plus anti-CTLA-4 therapies (0.9%), anti-PD-1/PD-L1 plus chemotherapy (0.83%) or single-agent anti-PD-1/PD-L1 (0.47%).

Next steps

Immune checkpoint inhibitor-related MACE has heterogeneous presentation and often is associated with poor prognosis, Naqash said.

“This makes timely identification and intervention critical,” Naqash said. “We also saw complex noncardiac immune-related adverse events present concurrently, which makes incorporation of a multidisciplinary approach consisting of cardiologists, oncologists, internists and other subspecialists essential in the management of these patients. In addition, the type of combination therapy may influence MACE risk and incidence, which suggests better characterization of MACE with anti-PD-1/PD-L1-based combination therapies is required.”

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Ocala CEP highlights tiny horses helping Ocala residents that experienced traumatic events

Ocala CEP highlights tiny horses helping Ocala residents that experienced traumatic events

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OCALA, Fla. (WCJB) – Residents of Ocala, who have experienced traumatic events, are getting a little help.

Our friends from the CEP share with us how tiny horses are bringing therapy to those in need.

RELATED STORY: Ocala CEP highlights HCA Florida’s Comprehensive Stroke Center’s acceptance of patients

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Common Adverse Events with Single-Agent or Combination Therapy

Common Adverse Events with Single-Agent or Combination Therapy

Metastatic Renal Cell Carcinoma: Safety and Efficacy of Available Treatment Options and Considerations for Patient Management – Episode 18

Mehmet Asim Bilen, MD, provides an overview of commonly observed adverse events in patients with metastatic RCC receiving single-agent or combination therapy.

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Reduced kidney function caused by antithrombotic therapy can influence bleeding events

Reduced kidney function caused by antithrombotic therapy can influence bleeding events

Antithrombotic therapy is prescribed to prevent thrombotic (blood clotting inside a blood vessel) events but the treatment also increases the likelihood of experiencing a bleeding event, which can be extremely serious if it occurs in a vital organ. Aging societies tend to have an increased number of patients undergoing antithrombotic therapy, and the drugs used in this treatment can affect kidney function. In particular, reduced kidney function caused by antithrombotic medications can significantly influence bleeding events. It is highly recommended that patients, especially those with decreased kidney function, have a detailed discussion with their doctor about the possible risks and benefits of proceeding with antithrombotic therapy.

Patients with heart arrythmia (atrial fibrillation) have a high risk for thrombotic events in blood vessels that could lead to permanent organ damage-;such as cerebral infarction-;and are prescribed antithrombotic therapy to lower their risk of developing blood clots. However, the risk of bleeding events simultaneously increases due to the nature of these medications. The severity of these bleeding events is highly variable, ranging from epistaxis (nosebleeds) to fatal brain hemorrhage.

While kidney function is known to be related to bleeding event risk, researchers at Kumamoto, Miyazaki, and Tohoku Universities in Japan conducted a post-hoc subgroup analysis of the Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial to determine the impact of kidney function on the risk of recurrent bleeding events during antithrombotic therapy. Their analysis revealed that the effect of kidney function on recurrent bleeding risk events was quite large for patients undergoing this treatment. They also found that the bleeding risk decreased with time for patients with healthy kidney function but remained high for patients with decreased kidney function. Clearly, the decision to use such a therapy should be balanced between the expected antithrombotic effects and bleeding risks.

In most cases, it is considered better to continue antithrombotic therapies even after bleeding events as long as the event was not severe. However, it is not surprising that both patients and physicians hesitate to continue the therapy after any bleeding event. To assess for drug safety and efficacy, these drugs are usually measured by the numbers of bleeding and thrombotic events. Unfortunately, in the assessment of antithrombotic therapy, most studies only consider the first event in their analyses even though patients could experience multiple events throughout their lifetime. This study revealed that the impact of kidney function on bleeding risk during antithrombotic therapy is larger than estimated in previous studies. Furthermore, patients with healthy kidney function appear to have a decreased risk of experiencing a bleeding event over time, but the risk for patients with reduced kidney function remains high as time continues.

A detailed discussion between patients and physicians based on all current scientific evidence about the risks and benefits of antithrombotic therapy is highly recommended. Our analysis should be quite useful in facilitating this type of discussion.”

Dr. Kunihiko Matsui, Study Leader, Kumamoto University Hospital’s Department of General Medicine and Primary Care


Journal reference:

Matsui, K., et al. (2022) The impact of kidney function in patients on antithrombotic therapy: a post hoc subgroup analysis focusing on recurrent bleeding events from the AFIRE trial. BMC Medicine.

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World events, time change and anger piling on pandemic pressures

World events, time change and anger piling on pandemic pressures

Chuck Norris

Chuck Norris

Don’t care much for the constant mid-March ritual of moving our clocks ahead one hour? According to Beth Ann Malow, a professor of neurology and pediatrics at Vanderbilt University, 63% of Americans would like to see it eliminated.

The thing is, daylight saving time represents much more than a disruption to daily routines. Given the stresses heaped upon us in our world of uncertainties, it could be the proverbial straw that broke the camel’s back.

“Beyond simple inconvenience,” writes Malow on, “Researchers are discovering that ‘springing ahead’ each March is connected with serious negative health effects.”

“In a 2020 commentary for the journal JAMA Neurology, my co-authors and I reviewed the evidence linking the annual transition to daylight saving time to increased strokes, heart attacks and teen sleep deprivation,” she says.

A separate post on co-authored by Deepa Burman, co-director of the Pediatric Sleep Evaluation Center at UPMC Children’s Hospital of Pittsburgh, and Hiren Muzumdar, director of the Pediatric Sleep Evaluation Center, notes that sleep deprivation can result in increases of workplace injuries and automobile accidents. One individual’s sleep deprivation can affect an entire family.

People are also reading…

“You may notice more frequent meltdowns, irritability and loss of attention and focus,” they say.

I wonder, could uncontrolled anger be far behind?

Now, watching a devastating war unfold on social media is also hammering away at our collective mental health. We’re all being heightened by graphic and disturbing images that fill our feeds, writes Time magazine reporter Jamie Ducharme.

“Tracking up-to-the-minute developments can come at a cost. … Footage and photos from Ukraine flooding social media and misinformation spreading rampantly (has) implications for public health,” she reports.

It has long been the responsibility of traditional media outlets for editors to decide which content is too graphic to show, or to label disturbing images with warnings. As pointed out by Roxane Cohen Silver, a professor of psychological science at the University of California, Irvine, today anyone “can take pictures and videos and immediately distribute that (on social media) without warning, potentially without thinking about it.”

Jason Steinhauer, founder of the History Communication Institute, says, “Russia has been waging a social media and misinformation war for the past 10 to 12 years.” This has only gotten worse since its invasion of Ukraine.

We should not be surprised at all that studies now suggest that news coverage of the pandemic has contributed to our mental distress. “Adding yet another difficult topic to the mix can worsen those feelings,” Cohen Silver says.

Yet the war is hardly the only attack on our senses. At a time when we are most vulnerable, the Federal Trade Commission reports that predatory fraudsters bilked consumers of an estimated $5.8 billion last year. According to the agency, it represents a 70% increase over 2020. “Almost 2.8 million people filed a fraud complaint, an annual record” and “the highest number on record dating back to 2001,” reports the FTC. “Imposter scams were most prevalent, but investment scams cost the typical victim the most money.”

“Those figures also don’t include reports of identity theft and other categories,” the report points out. “More than 1.4 million Americans also reported being a victim of identity theft in 2021; another 1.5 million filed complaints related to ‘other’ categories (including credit reporting companies failing to investigate disputed information, or debt collectors falsely representing the amount or status of debt).”

The mounting stresses placed upon us are now posing a threat to not just our mental and financial health but our physical well-being.

According to a working paper from researchers at the Naval Postgraduate School and the University of Pennsylvania, “In 2020, the risk of outdoor street crimes initially rose by more than 40% and was consistently between 10-15% higher than it had been in 2019 through the remainder of the year.” Researchers also believe that the finding “points to the potential for other crimes to surge the way homicides have as cities reopen and people return to the streets,” says the report.

Adds Megan McArdle commenting on the report in an op-ed for the Washington Post, “community trust in the police might have plummeted, possibly making people more likely to settle scores on their own. Or police might have reacted to public anger by pulling back from active policing, creating more opportunities for crime.”

Hans Steiner is a professor emeritus of Stanford’s Department of Psychiatry and Behavioral Sciences who has logged decades of work studying anger and aggression. In an interview posted on the Stanford University website, he says he believes that “the coronavirus pandemic, with its extreme disruption of normal daily life and uncertainty for the future, compounded by several other crises (economic distress, racial tension, social inequities, political and ideological conflicts) puts us all to the test: we find ourselves immersed in a pool of negative emotions: fear, sadness, contempt, and yes, anger. What do we do with this forceful emotion?”

“Anger signals that we are being threatened, injured, deprived, robbed of rewards and expectancies,” Steiner says. It should be “one of our adaptive tools to deal with the most difficult circumstances. Sometimes it becomes an obstacle to our struggles, especially when it derails into aggression and even violence.”

Anger problems are now spilling over into record accounts of hate crimes. It seems that today’s circumstances, with anger management and rule of law seemingly at an all-time low, have caused many individuals to become ticking time bombs. Reports CBS News, “the total number of hate crimes nationwide has increased every year but one since 2014, according to FBI data, which includes statistics through 2020.”

Steiner says that “maladaptive anger and aggression has the following characteristics: 1. It arises without any trigger, seemingly out of the blue; 2. it is disproportionate to its trigger in its frequency, intensity, duration and strength; 3. it does not subside after the offending person has apologized; 4. it occurs in a social context which does not sanction anger and aggression.”

Who among us has not seen or maybe even experienced some, maybe all, of these behavior characteristics?

“In such conflicts we need to remind ourselves that diatribes, lies and accusations will not move us forward; compassion, empathy and the reminder that we are all in this horrible situation together (needs to) inspire us,” Steiner advises.

Write to Chuck Norris at with questions about health and fitness.

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Hemophilia A Gene Therapy Reduced Bleeding Events, Need for Clotting Factors

Hemophilia A Gene Therapy Reduced Bleeding Events, Need for Clotting Factors

The phase 3 trial of valoctocogene roxaparvovec for severe hemophilia A showed it reduced bleeding events as well as the use of factor VIII concentrates.

A phase 3 trial of valoctocogene roxaparvovec, a gene therapy for severe hemophilia A, showed it reduced bleeding events as well as the use of factor VIII concentrates and increased endogenous production of clotting factors.

Severe hemophilia A, defined as a factor VIII level of 1 IU/dL or lower, carries the highest risk of spontaneous and traumatic bleeding, resulting in loss of limbs, chronic pain, decreased quality of life, and higher risk of mortality. About 1 in 5000 males is born with the rare disease, and about 60% have the most severe form, according to the National Organization for Rare Disorders.

Outcomes for individuals with hemophilia A, caused by a deficient F8 gene, have improved with factor VIII concentrates that are used prophylactically, but bleeding events are not eliminated.

If approved by the FDA, the adeno-associated virus (AAV) vector gene therapy would be sold as Roctavian by BioMarin, which funded the study. The FDA has granted valoctocogene roxaparvovec Regenerative Medicine Advanced Therapy and Breakthrough Therapy designations; according to press reports, it could be priced as high as $3 million, making it the most expensive therapy to date.

Writing in The New England Journal of Medicine, the authors said the gene therapy enables steady production of factor VIII without additional prophylactic measures. However, the authors also said, “The expression of the transferred gene appears to decline over time; further study is needed to address whether repeat treatment will be necessary or possible.”1

Participants in the trial (GENEr8-1) were 134 adult men 18 years or older who had previously been treated with clotting-factor prophylaxis for at least 1 year, 2 of whom were living with HIV. At baseline, 61.9% of the participants were receiving factor VIII prophylaxis with standard half-life products, 27.6% with extended half-life products, and 17.9% with plasma-derived products. None of the participants were receiving emicizumab (Helimbra), a humanized bispecific monoclonal antibody that joins both factor IXa and X, which are proteins necessary to activate the natural coagulation cascade and restore the blood clotting process.

Exclusion criteria for the open-label, single-group, multicenter, phase 3 study included those who had preexisting anti-AAV5 antibodies, factor VIII inhibitors, or significant liver disease.

Patients received a single infusion of valoctocogene roxaparvovec at a dose of 6×1013 vector genomes per kilogram of body weight, and investigators examined the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion.

Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates.

Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. The analysis included data from 132 HIV-negative participants, including 112 participants enrolled from a prospective noninterventional study.

Results showed:

  • A decline in annualized rates of factor VIII use of 98.6% and treated bleeding of 83.8% (P <.001 for both comparisons)
  • A median factor VIII activity level of 5 IU/dL or higher in 88.1% of participants

As for safety, all participants had at least 1 adverse event (AE); 22 of 134 (16.4%) reported serious AEs.

Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with glucocorticoids. The other most common AEs were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%).

There were no deaths in the trial or withdrawals due to AEs, and there was no thrombosis or development of factor VIII inhibitors.

The investigators wrote that “intra- and interindividual variability in factor VIII activity after gene transfer were notable.” Seven participants had a median factor VIII activity level of greater than 150 IU/dL; 12 participants had a median factor VIII activity level of less than 3 IU/dL, measured by chromogenic assay; and 2 participants, measured by a 1-stage assay, had a factor VIII activity level of less than 1 IU/dL.

The causes of the variability are not fully known; the authors said biologic variables and molecular events related to gene transfer and expression may impact endogenous factor VIII production.

There were a few limitations to the study. The 2 participants with HIV were excluded from the primary analysis, and so generalizing the results to that population may be constrained. In addition, direct comparisons to emicizumab cannot be made because the participants had previously been using factor VIII concentrates, but the authors said “the annualized rates of treated bleeding here were similar to those reported with long-term emicizumab prophylaxis.”

In an accompanying editorial, the author called valoctocogene roxaparvovec “a new choice for care that could be truly transformative and liberating for eligible men with hemophilia” and called on payers, policymakers, and others to get ready for its entrance.2


1. Ozelo MC, Mahlangu J, Pasi KJ, et al; GENEr8-1 Trial Group. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Engl J Med. 2022;386:1013-1025. doi:10.1056/NEJMoa2113708

2. Thornberg CD. Prepare the way for hemophilia A gene therapy. N Engl J Med. 2022;386:1081-1082. doi:10.1056/NEJMe2200878