Body

Oncotarget published "Phase 1 study of Z-Endoxifen in patients with advanced gynecologic, desmoid, and hormone receptor-positive solid tumors" which reported that Z-endoxifen administration was anticipated to bypass these variations, increasing active drug levels, and potentially benefiting patients responding sub-optimally to tamoxifen.

Patients with treatment-refractory gynecologic malignancies, desmoid tumors, or hormone receptor-positive solid tumors took oral Z-endoxifen daily with a 3 3 phase 1 dose escalation format over 8 dose levels.

Three patients had partial responses and 8 had prolonged stable disease; 44.4% of patients at dose levels 6–8 achieved one of these outcomes.

Six patients who progressed after tamoxifen therapy experienced partial response or stable disease for ≥ 6 cycles with Z-endoxifen; one with desmoid tumor remains on study after 62 cycles.

The Oncotarget article provides evidence that antitumor activity and prolonged stable disease are achieved with Z-endoxifen despite prior tamoxifen therapy, supporting further study of Z-endoxifen, particularly in patients with desmoid tumors.

The Oncotarget article provides evidence that antitumor activity and prolonged stable disease are achieved with Z-endoxifen despite prior tamoxifen therapy.

Dr. Alice P. Chen from The Division of Cancer Treatment and Diagnosis at The National Cancer Institute in Bethesda Maryland said, "Tamoxifen is a member of the selective estrogen receptor modulator (SERM) drug family and is approved by the FDA for the treatment of patients with estrogen receptor-positive (ER+) metastatic breast cancer, for adjuvant therapy of high-risk ER+/progesterone receptor-positive (PR+) breast cancer, and for chemoprevention in women at high risk of developing breast cancer."

However, only about 50% of women with metastatic ER breast cancer who receive treatment with tamoxifen derive benefit, and trials have yielded mixed results regarding the clinical benefit of tamoxifen based on dose or serum concentration.

Endoxifen and 4-hydroxy-tamoxifen have similar binding affinities for ERα and ERβ, which are approximately 100-fold higher than those of tamoxifen or NDM-tamoxifen, but endoxifen plasma concentrations following tamoxifen administration are 5- to 20-fold higher than 4-hydroxy-tamoxifen.

Multiple other factors, including age, body mass index, gender, and polypharmacy contribute to how patients metabolize tamoxifen into endoxifen.

Among patients who receive tamoxifen, levels of endoxifen are lower in poor metabolizers, a finding that appears to correlate with significantly reduced time to tumor recurrence in these patients compared to those with greater CYP2D6 metabolism following treatment with adjuvant tamoxifen.

The Chen Research Team concluded in their Oncotarget Research Output that additional preclinical and clinical data demonstrate that Z-endoxifen can elicit major responses in ER breast cancer that has progressed on tamoxifen.

Despite these data in breast cancer, the optimal dose or concentration of Z-endoxifen in other tumors is unknown; however, our observation that high dose Z-endoxifen elicits antitumor activity in patients with non-breast malignancies would be in keeping with the data already observed demonstrating Z-endoxifen antitumor activity in breast cancers that have progressed on tamoxifen.

Furthermore, the overall safety profile, achievable plasma concentrations of Z-endoxifen, and clinical efficacy seen in this trial indicate that this agent may particularly benefit patients who have progressed on tamoxifen treatment and suggest that further studies of Z-endoxifen should be considered in patients with non-breast malignancies.

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DOI - https://doi.org/10.18632/oncotarget.27887

Full text - https://www.oncotarget.com/article/27887/text/

Correspondence to - Alice P. Chen - chenali@mail.nih.gov

Keywords -
Z-endoxifen,
phase 1,
tamoxifen,
pharmacokinetics

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Journal

Oncotarget

DOI

10.18632/oncotarget.27887

A rare syndrome has been observed in people following vaccination against Covid-19. This involves thrombosis at unusual sites in the body, associated with a low thrombocyte (blood platelet) count and a clotting disorder. In medical jargon, this syndrome is referred to as VITT (vaccine-induced thrombotic thrombocytopenia). Doctors at the Department of Medicine I of MedUni Vienna and Vienna General Hospital (Division of Hematology and Hemastaseology) have now successfully treated an acute instance of this syndrome.

VITT is most probably caused by a defective immune response, whereby thrombocyte-activating antibodies are produced resulting in thrombocytopenia (low platelet count) and thrombosis. The mortality rate in VITT is high (40-50 %) and the syndrome requires immediate and appropriate treatment. However, the current recommendations are only empirical and are based on in-vitro data.

A team of doctors at the Department of Medicine I of MedUni Vienna and Vienna General Hospital, led by coagulation specialist Paul Knöbl, has now successfully treated a patient suffering from vaccine-induced prothrombotic immune thrombocytopenia (VIPIT). The female patient was admitted to the Department with a low platelet count and low fibrinogen levels. Fibrinogen is a protein that plays a major role in blood clotting. Knöbl reports: "Apart from that, her D-dimer values, which indicate thrombosis, were very high and an ELISA assay produced a clear positive result for heparin-PF4 antibodies - all signs of incipient thrombosis."

The doctors acted quickly, and the patient responded immediately to treatment with a high dose of intravenous immunoglobulin concentrates, cortisone and specific anticoagulants, so that thrombosis was prevented. Immunoglobulin concentrates contain antibodies that can block the misdirected immune response. The usual heparin preparations must not be used to prevent clotting, since they can trigger thrombosis, or aggravate it.

"In this case we were able to describe, for the first time, the efficacy of a potentially life-saving treatment strategy for vaccine-induced thrombosis," says Knöbl. These new findings have been published in the Journal of Thrombosis and Haemostasis. On the one hand, the findings support the current treatment recommendations, but they also show that prompt diagnosis and immediate initiation of treatment are necessary in order to prevent a life-threatening thrombosis. "This experience could be of great help in treating other patients with similar conditions."

Patients with both diabetes and heart failure who were treated with sotagliflozin, a novel investigational drug for diabetes, for a median of nine to 16 months experienced reductions of 22% to 43% in the risk of death or worsening heart failure compared with similar patients who were treated with a placebo. The drug was effective in patients with all forms of heart failure, including those whose heart muscle is abnormally stiff (preserved ejection fraction) and for whom there is currently no effective treatment, according to research presented at the American College of Cardiology's 70th Annual Scientific Session.

"Treatment with sotagliflozin robustly and significantly reduced cardiovascular adverse events across the full spectrum of patients with heart failure, including patients who have heart failure with preserved ejection fraction (HFpEF), for which no effective treatment is currently available," said Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women's Hospital Heart & Vascular Center, professor of medicine at Harvard Medical School, and principal investigator for the study. "The benefit for patients with HFpEF is striking--this is the first trial to find a significant benefit in this population. We believe that these results merit a recommendation that patients who have both diabetes and HFpEF should be treated with sotagliflozin or another medication in its class."

Ejection fraction is a measure of how much blood the heart pumps out each time it contracts. With a normal ejection fraction, 50% to 70% of the blood in the heart is pumped out with each heartbeat. In heart failure with reduced ejection fraction--a better known, more treatable form of the disease--weakness of the heart muscle means that only 40% or less of the blood in the heart is pumped out with each heartbeat.

By contrast, an HFpEF patient's ejection fraction is normal or near normal, but the heart must work harder to adequately fill with blood given abnormal stiffness of the heart muscle. HFpEF occurs in both men and women but is a particularly common problem among older women, Bhatt said.

Sotagliflozin belongs to a class of drugs known as SGLT1/2 inhibitors and is the first drug in this class shown to help control blood sugar levels in two ways: by modulating the rise in blood sugar levels after meals and by helping the body to eliminate more sugar in urine. Recent studies have shown that sotagliflozin also reduces heart attacks and strokes.

For this analysis, Bhatt and his colleagues combined, or "pooled," patient data from two large, randomized trials, known as SCORED and SOLOIST-WHF, which were each previously published in the New England Journal of Medicine.

The SCORED trial evaluated whether sotagliflozin prevented cardiovascular events, including deaths due to a heart attack or stroke and hospitalizations or urgent visits for heart failure, in patients who had both diabetes and chronic kidney disease. A total of 10,584 patients were randomly assigned to treatment with either sotagliflozin or a placebo. After a median follow-up period of 16 months, treatment with sotagliflozin reduced cardiovascular events by 26% compared with placebo.

The SOLOIST-WHF trial evaluated whether sotagliflozin prevented cardiovascular deaths and hospitalizations or urgent visits for heart failure in patients who had diabetes and worsening heart failure. In this trial, 1,222 patients were randomly assigned to treatment with either sotagliflozin or a placebo. After a median of nine months of follow-up, treatment with sotagliflozin reduced cardiovascular deaths and hospitalizations or urgent visits for heart failure by 33% compared with placebo.

For the current pooled analysis, the researchers examined the effectiveness of sotagliflozin treatment according to differences in patients' ejection fraction at study entry, which was available for all but 22 patients in the original trials. They performed analyses for both the entire pooled cohort of 11,784 patients and for a subgroup of 4,500 patients who had a history of heart failure (HF group). Among both groups, they found significant reductions in the risk of death due to cardiovascular causes and hospitalization or an urgent visit for heart failure, irrespective of ejection fraction at study entry. Among patients with an ejection fraction of 40% or less, sotagliflozin treatment reduced risk by 22% in both the entire cohort and in the HF group. For patients with an ejection fraction of 40% to 50%, sotagliflozin reduced risk in the entire cohort by 39% and in the HF group by 43%. For patients with HFpEF, the medication reduced risk by 30% in the entire cohort and by 33% in the HF group. All results were statistically significant and were similar for men and women, Bhatt said.

"We saw a significant reduction in the primary endpoint irrespective of patients' ejection fraction at study entry," Bhatt said. "The magnitude of the benefit in patients with HFpEF was surprising. Sotagliflozin offers a meaningful, incremental advance in improving outcomes for this challenging group of patients."

A limitation of the study is that the results apply only to patients with heart failure who also have diabetes, Bhatt said. The researchers had intended to also analyze the effect of sotagliflozin in patients with heart failure who did not have diabetes; however, this analysis was not performed because both the SCORED and SOLOIST-WHF trials were terminated early due to loss of funding at the onset of the COVID-19 pandemic.

A program designed to improve hospital care for patients with heart failure, the leading cause of hospitalization among adults over age 65, did not bring additional benefits beyond existing hospital quality improvement programs in a randomized controlled trial presented at the American College of Cardiology's 70th Annual Scientific Session.

Heart failure is a condition in which the heart becomes too weak or too stiff to pump blood effectively to the rest of the body. It causes symptoms such as swelling and fluid retention, shortness of breath and coughing.

In the CONNECT-HF study, one group of hospitals received additional auditing and feedback on performance and their quality of care for heart failure patients from an external group--in addition to their own existing quality improvement program. However, the group of hospitals showed no significant differences compared with hospitals that did not receive the intervention in terms of heart failure rehospitalization or death and a composite score for heart failure care quality.

"We were disappointed to find no difference," said Adam DeVore, MD, a cardiologist at Duke University Medical Center and the study's lead author. "These principles of audit and feedback don't seem to improve upon what already exists in terms of quality improvement for heart failure. This strategy doesn't work above what we are already doing; we need to find other ones that do, and we have a lot of work ahead of us."

Over the course of three years, the study enrolled 5,647 patients treated for heart failure with reduced ejection fraction at 161 participating hospitals. All hospitals already had an on-site quality improvement program designed to ensure compliance with guideline-based practices for heart failure treatment and reduce negative outcomes such as rehospitalization and death. For those randomized to receive the quality improvement intervention, researchers worked with each hospital's in-house quality improvement team to review and improve existing programs to reinforce evidence-based practices. For example, if a hospital found that many heart failure patients were not taking prescribed medicines reliably, the quality improvement team might work with in-house pharmacists to ensure patients start taking their medications before being discharged. The researchers independently tracked hospital discharges and post-discharge follow-up care and provided feedback to hospital care teams on performance metrics, a strategy of audits and feedback that had worked for other quality improvement initiatives in previous studies.

The first co-primary endpoint, heart failure rehospitalization or death from any cause, occurred in about 39% of patients in both study groups. There was no significant difference between groups in terms of this endpoint or the second co-primary endpoint, a composite score for heart failure care quality at the time of last follow-up.

DeVore said that there remains a need to improve the quality of care for people with heart failure and suggested that future interventions could employ digital and patient-facing tools or focus on care delivery outside of the hospital, such as at heart failure clinics.

"Patients with heart failure aren't getting the medical care they need to stay out of the hospital and live a good quality life without symptoms of heart failure, but it's not clear that the hospital should be the place to fix this problem," DeVore said. "Based on our findings, I don't think we're going to move the needle if we continue focusing our attention on the hospital if there is already a quality improvement program there."

The trial is unique in its use of a randomized study design for a quality improvement initiative. DeVore said that a patient panel helped inform the trial design, which researchers saw as a strength of the study. The trial was stopped early as a result of the COVID-19 pandemic and did not enroll as many patients as planned but was still adequately powered to reveal any differences between study groups, DeVore said.

The study was funded by Novartis Pharmaceuticals Corporation through an investigator-initiated trial program.

DeVore will be available to the media in a virtual press conference on Monday, May 17, at 9:30 a.m. ET / 13:30 UTC.

DeVore will present the study, "Care Optimization through Patient and Hospital Engagement Clinical Trial for Heart Failure: Primary Results of the Connect-HF Randomized Clinical Trial," on Monday, May 17, at 8 a.m. ET / 12:00 UTC, virtually.

As Covid-19 spread around the world, stock markets in individual countries took a major hit - yet stock markets in China where the disease first struck avoided significant falls - researchers at Lero, the Science Foundation Ireland Research Centre for Software found.

A research paper Immune or at-risk? Stock markets and the significance of the COVID-19 pandemic by a Lero team based at University of Limerick confirmed that the growth in COVID-19 cases largely explained changes in stock prices, but surprisingly did not have the same impact in China or on the global index (MSCI World).

The results of the study, to be published in the Journal of Behavioral and Experimental Finance in June, suggest that the implied volatility of the respective markets, often used as a proxy for investor sentiment, played a greater role in explaining market prices than COVID-19 growth.

Lead author Niall O'Donnell said the current pandemic provides us with a unique opportunity to identify the effect that pandemics have on financial markets.

"Our findings indicate that investors began to act before any realised financial damage was observed, highlighting again the significance of investor sentiment and the expectation of returns, rather than real revisions in financial returns. We additionally find that changes in the Chinese SSE 180 index and the MSCI World index prices were not significantly explained by COVID-19 growth.

"Instead, these indices were largely influenced by conventional market drivers linked to economic growth such as crude oil, bond yield spreads and implied volatility. We theorise based on these results, that among these factors, early interventions by China may have played a role in index price fluctuations also," added Mr O'Donnell.

The research team point out that global stock market losses of $16 trillion were observed in less than a month as the pandemic took hold and as fears rose of a worldwide recession.

Lero's Dr Barry Sheehan, a co-author on the study and course director of the MSc in Machine Learning for Finance programme at UL's Kemmy Business School, said: "Our analysis into the determinants of global stock market indices as COVID-19 spread provides valuable insights into the evolving market dynamics and price drivers during times of crisis and uncertainty."

Dr Darren Shannon, also of Lero and UL, said the work carried out by the team found that markets in Spain, Italy, the UK, and the USA were found to be negatively and significantly related to the total number of COVID-19 cases. This occurred despite controlling for other market drivers.

"However, COVID-19 cases did not significantly influence the sharp fall and subsequent rise of the Chinese SSE 180 index. Instead, fluctuations in market prices were explained by trading volumes, Brent crude oil price, implied market volatility, among other factors. Similarly, COVID-19 cases did not significantly influence the MSCI World index," he added.

Top experts from Brigham and Women's Hospital presented outcomes from some of the most-anticipated clinical trials in cardiology at the virtual American College of Cardiology's 70th Annual Scientific Session. In four Late-Breaking Clinical Trial presentations, Brigham cardiologists shared their latest findings on strategies to prevent future cardiovascular events in at-risk patient populations, results of a randomized clinical trial of a statin drug among patients critically ill with COVID-19, and more.

May 17, 2021, 1:30 PM - 1:40 PM

IL-6 Inhibitor Reduced Biomarkers of Inflammation in Patients at High Risk for Heart Attacks, Strokes

In work that builds upon and extends the potential clinical reach of the inflammatory hypothesis of heart disease, Paul M. Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention at the Brigham and the Eugene Braunwald Professor of Medicine, presented data on the IL-6 inhibitor Ziltivekimab. Ziltivekimab is a human monoclonal antibody targeting the IL-6 ligand that is being developed specifically for atherosclerosis. Ridker led RESCUE, a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the effects of ziltivekimab on multiple biomarkers of inflammation and thrombosis. The trial evaluated patients at high cardiovascular risk with chronic kidney disease (CKD) and elevated hsCRP.

In a late-breaking clinical trial presentation and in simultaneous publication in The Lancet, Ridker reported that ziltivekimab markedly reduced multiple biomarkers of systemic inflammation and thrombosis, including hsCRP, fibrinogen, SAA, sPLA2, and Lp(a). Investigators found minimal evidence of bone marrow suppression, infectious risk, hepatic toxicity, or change in atherogenic lipid levels.

"These phase II data suggest that ziltivekimab may be unique among currently available IL-6 inhibitors and strongly supports its use in future cardiovascular outcome trials," said Ridker.

Based on the safety and efficacy results of RESCUE, a new cardiovascular outcomes trial known as ZEUS is set to launch later this year.

In a separate presentation at ACC.21 (May 16 at 10 a.m.), Brigham cardiologist Muthiah Vaduganathan, MD, MPH, and colleagues presented data showing that people with heart failure and kidney disease face very high risks of adverse events and death yet are infrequently treated with guideline-recommended medical therapies. Their presentation underscored the unmet clinical need for patients with CKD.

May 17, 2021, 8:00 AM - 8:10 AM

SGLT 1/2 Inhibitor Shows Benefit in Men and Women with Heart Failure with Preserved Ejection Fraction

Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESC, executive director of Interventional Cardiovascular Programs at the Brigham's Heart & Vascular Center, presented evidence on the benefits of sotagliflozin across the spectrum of ejection fraction, including heart failure with preserved ejection fraction. Sotagliflozin inhibits both SGLT1 and SGLT2. Two clinical trials, SOLOIST-WHF and SCORED, demonstrated its protective effects for patients with diabetes and worsening heart failure as well as patients with diabetes and chronic kidney disease, respectively.

Bhatt presented data showing that sotagliflozin robustly and significantly reduced the composite of total cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure across the full range of ejection fraction, including in patients with heart failure with preserved ejection fraction. In on-treatment analyses, sotagliflozin demonstrated a significant reduction in cardiovascular death.

"These are the first randomized data from a prespecified analysis of clinical trials to show a significant effect of a therapy on heart failure with preserved ejection fraction," said Bhatt. "Additionally, sotagliflozin demonstrated a consistent and significant benefit in women."

May 16, 2021, 3:00 PM - 3:10 PM

Statin Drug Did Not Improve Outcomes for Patients Critically Ill with COVID-19

Behnood Bikdeli, MD, MS, a physician-investigator in the Brigham's Cardiovascular Medicine Division, presented results from the INSPIRATION-statin trial in a late-breaking clinical trials session. INSPIRATION-S is a randomized controlled clinical trial of hospitalized critically ill patients with COVID-19. Patients were randomized to receive atorvastatin 20mg daily or a matching placebo. The study's primary endpoint included a composite of adjudicated acute arterial thrombosis, venous thromboembolism (VTE), use of extracorporeal membrane oxygenation, or all-cause death within 30 days from enrollment. Bikdeli reported no statistically significant difference between the statin intervention and placebo.

"The body's exuberant inflammatory response is known to play a role in the acute respiratory distress syndrome (ARDS) which is seen in some cases of COVID-19," said Bikdeli. "We hypothesized that statins, which can have anti-inflammatory and antithrombotic effects, might be beneficial in patients with severe COVID-19. While we found no statistical difference between atorvastatin and placebo, we did see intriguing hints among patients who presented within the first seven days, and are interested in understanding these observations further."

May 15, 2021, 9:00 AM - 9:10 AM

Sacubitril/Valsartan Did Not Outperform an ACE Inhibitor

A late-breaking clinical trial highlighting the results of PARADISE-MI extends the Brigham's decades-long work in the area of angiotensin converting enzyme (ACE) inhibitors, which are used during acute myocardial infarction to save lives and reduce incidence of heart failure. Marc Pfeffer, MD, PhD, Distinguished Dzau Professor of Medicine at Harvard Medical School and cardiologist at the Brigham, presented the results of PARADISE-MI. The clinical trial compared the effectiveness of the heart failure drug sacubitril/valsartan to ramipril, a proven effective ACE inhibitor, at preventing cardiovascular death, heart failure hospitalization, and outpatient development of heart failure among patients who had survived a heart attack and had left ventricular systolic dysfunction and/or pulmonary congestion. There was a high use of guideline-based therapies and procedures prior to randomization.

Pfeffer reported that sacubitril/valsartan did not significantly lower rate of CV death, heart failure hospitalization or outpatient heart failure requiring treatment. However, pre-specified observations of reductions in both investigator reports of the primary composite as well as in the total (recurrent) adjudicated events support incremental clinical benefits of sacubitril/valsartan. The safety and tolerability of sacubitril/valsartan in this patient population was comparable to that of the ACE inhibitor.

"We found sacubitril/valsartan was as safe and well-tolerated as one of the best proven ACE inhibitors, even in an acutely ill population," said Pfeffer. "This trial is not likely going to change guidelines, but it should make physicians even more comfortable using sacubitril/valsartan in their patients with heart failure."

The research teams at the University of Hong Kong led by Professor Xuechen LI from the Research Division for Chemistry and Department of Chemistry, and Professor Yu WANG from the Department of Pharmacology and Pharmacy, reported a synthetic biotherapeutics with promising anti-tumour, insulin sensitising and hepatoprotective activities in the Journal of the American Chemical Society.

Obesity is a global pandemic associated with a significantly reduced life expectancy, it also increases the risk of type 2 diabetes, hypertension, coronary heart disease, stroke, chronic kidney disease and cancer. Adiponectin, as a protein hormone and adipokine, regulates glucose levels and improve lipid metabolism, and is a major player in the pathogenesis of obesity, insulin resistance and metabolic syndrome. Obese patients have low adiponectin levels, a condition known as hypoadiponectinemia, which contributes to increase risks of cardiovascular, metabolic diseases as well as aggressive development of malignancies with poor prognoses. Adiponectin supplementation is a long-sought-after strategy for the prevention and treatment of cancer and metabolic diseases, especially in obese patients. However, the adiponectin application in therapy has been hampered by the difficult production of human adiponectin.

The teams have been working on the development of synthetic compounds which can mimic the bioactivity of adiponectin over the past seven years. Finally, they developed an efficient synthetic approach to produce the adiponectin-derived glycopeptides that exhibit potent anti-tumour, insulin-sensitising and metabolic activities in various mouse models. The products hold greater potentials for clinical application in obesity and related medical complications, such as type 2 diabetes, hypertension, coronary heart disease, stroke, chronic kidney disease and cancer.

Professor Li and Professor Wang believe that this finding opens the door to explore the opportunity of using the synthetic glycopeptide as a potential adiponectin downsized mimic supplementary in clinical treatment. The apparent advantage of these synthetic glycopeptides is that they can be readily produced by chemical process. The two teams are continuing to apply for research grants which can support them to further evaluate the potential of these agents in preclinical studies for drug development.

Two months after undergoing renal denervation (RDN), patients with high blood pressure who did not respond to treatment with multiple medications had a greater reduction in daytime systolic blood pressure than patients who did not receive RDN, with no difference in major adverse effects, according to research presented at the American College of Cardiology's 70th Annual Scientific Session.

Patients who received RDN--a procedure that delivers energy to overactive nerves in the kidneys to decrease their activity--saw a median reduction of 8 mmHg in their daytime ambulatory systolic blood pressure compared with their level prior to treatment. They also had a 4.5 mmHg greater drop in median blood pressure compared with those who received the sham procedure, despite both groups receiving the same three guideline-recommended antihypertensive medications as background therapy. The benefit of RDN was consistent regardless of sex, ethnicity, age, waist size or blood pressure level at study entry.

"This study has shown for the first time that RDN can effectively lower blood pressure in patients in whom it is uncontrolled despite standardized treatment with three guideline-recommended medications," said Ajay Kirtane, MD, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons and an interventional cardiologist at New York-Presbyterian/Columbia University Irving Medical Center. Kirtane is a co-principal investigator of the trial.

High blood pressure, or hypertension, is a leading cause of heart attacks, strokes and death. According to the Centers for Disease Control and Prevention, nearly half of U.S. adults have high blood pressure. High blood pressure remains a major public health problem despite the availability of a wide range of medications to treat it, with as many as 40% of patients continuing to have uncontrolled high blood pressure despite treatment with medications, Kirtane said.

"RDN offers an additional tool that we could use to help these patients, hopefully achieving better overall control of hypertension, especially if longer-term data support the durability and safety of the procedure," he said.

Overactivity of the sympathetic nerves in the kidneys can contribute to high blood pressure. RDN works by delivering energy that decreases the overactivity of these nerves. Other studies in patients with less-severe hypertension have shown that, compared with a sham procedure, RDN reduces blood pressure. The procedure is performed in a hospital catheterization lab under local anesthesia and with X-ray imaging guidance. A catheter is directed from the femoral artery in the thigh to the arteries that supply blood to the kidneys. There, the catheter delivers ultrasound-based energy to the nerves in the arteries. Patients may be discharged the same day or may spend one night in the hospital after the procedure.

The international study, known as the RADIANCE-HTN TRIO trial, enrolled 989 patients in the U.S., the United Kingdom and five European countries. Patients' average age was 53 years and 80% were men. At study entry, patients were taking an average of four antihypertensive medications. Despite this, patients' average blood pressure at study entry was 163/104 mmHg. (According to the 2017 ACC/American Heart Association Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults, blood pressure of 130/80 mmHg or more is considered high.) Patients' median body mass index (BMI) was about 32.7 (a BMI of 30 or higher falls within the obesity range). Roughly a quarter of patients also had Type 2 diabetes.

Upon enrollment in the study, all patients were switched from their existing medications to a regimen consisting of three blood pressure-lowering medications combined into a single pill taken once daily. The use of such once-daily combination pills has been shown to improve patient adherence to blood pressure-reducing medication.

After four weeks on this once-daily, three-drug regimen, patients whose blood pressure was still 135/85 mmHg or higher as assessed by ambulatory blood pressure monitoring underwent non-invasive imaging to ensure that their renal arteries were suitable for RDN. A total of 136 patients were then randomly assigned to receive either ultrasound-based RDN or a sham procedure. A sham procedure is used in non-pharmacological studies; a control group receives an imitation procedure instead of the actual medical intervention that is being studied.

Neither the patients nor the doctors they saw for follow-up visits knew who had received RDN and who had received the sham procedure. All patients continued to take the once-a-day combination pill during the two-month follow-up period. Patients' urine was tested to evaluate how well they followed their treatment with the three-medication pill during the study.

The primary efficacy endpoint was the change in daytime ambulatory systolic blood pressure (the top number) from study entry to two months. The investigators also monitored major adverse events occurring within 30 days of the procedure, including death from any cause, kidney failure, a blood clot, any complications involving the veins or arteries serving the kidneys that required treatment, or a severe increase in blood pressure.

Compared with the sham procedure, daytime ambulatory systolic blood pressure, 24-hour ambulatory systolic blood pressure, nighttime ambulatory systolic blood pressure and systolic blood pressure measured in the doctor's office were all significantly lower with RDN. No differences in major adverse events were observed between the treatment arms.

Kirtane said that he and his colleagues will continue to follow the patients in the study for three years to assess the durability, safety and ongoing benefit of the RDN procedure.

This study was funded by ReCor Medical Inc., the manufacturer of the Paradise renal denervation system. Kirtane reports institutional funding to Columbia University and the Cardiovascular Research Foundation from ReCor Medical.

This study was simultaneously published online in The Lancet at the time of presentation.

Kirtane will be available to the media in a virtual press conference on Sunday, May 16, at 12:15 p.m. ET / 16:15 UTC.

Kirtane will present the study, "Endovascular Ultrasound Renal Denervation To Treat Hypertension Resistant To A Fixed Dose Triple Medication Pill: The Randomized Sham-controlled RADIANCE-HTN TRIO Trial," on Sunday, March 16, at 10:45 a.m. ET / 14:45 UTC, virtually.

ACC.21 will take place May 15-17 virtually, bringing together cardiologists and cardiovascular specialists from around the world to share the newest discoveries in treatment and prevention. Follow @ACCinTouch, @ACCMediaCenter and #ACC21 for the latest news from the meeting.

The American College of Cardiology envisions a world where innovation and knowledge optimize cardiovascular care and outcomes. As the professional home for the entire cardiovascular care team, the mission of the College and its 54,000 members is to transform cardiovascular care and to improve heart health. The ACC bestows credentials upon cardiovascular professionals who meet stringent qualifications and leads in the formation of health policy, standards and guidelines. The College also provides professional medical education, disseminates cardiovascular research through its world-renowned JACC Journals, operates national registries to measure and improve care, and offers cardiovascular accreditation to hospitals and institutions. For more, visit ACC.org.

Clopidogrel outperformed aspirin in what is believed to be the first and largest randomized trial to compare the effectiveness of the two antiplatelet drugs as long-term maintenance therapy for patients who had no adverse events after one year of dual antiplatelet therapy (DAPT) following the insertion of a coronary stent. After two years of follow-up, chronic maintenance therapy with clopidogrel resulted in a 30% reduction in deaths, heart attacks, strokes or major bleeding events, according to research presented at the American College of Cardiology's 70th Annual Scientific Session.

"These data confirm our working hypothesis that long-term maintenance antiplatelet monotherapy with clopidogrel produces better outcomes than aspirin in patients who are adverse event-free at one year after coronary stenting," said Hyo-Soo Kim, MD, PhD, professor of internal medicine at Seoul National University Hospital in South Korea and lead author of the study.

The trial met its primary endpoint, a composite of death from any cause, heart attack, stroke or a major bleeding event within two years of study entry, which occurred in 5.7% of patients assigned to clopidogrel and 7.7% of those assigned to aspirin.

Ischemic heart disease is an umbrella term for problems caused by insufficient blood flow to the heart, such as heart attacks and unstable angina. Stenting, also known as coronary angioplasty or percutaneous coronary intervention, is a minimally invasive procedure in which a flexible tube (catheter) is threaded through an artery under local anesthesia. At the site of an arterial blockage, a tiny balloon at the tip of the catheter is inflated to unblock the artery, and a stent--a tiny mesh tube coated with medication--is inserted to prop the coronary artery open and restore blood flow to the heart.

Blood cells known as platelets help the blood to clot, and both clopidogrel and aspirin stop platelets from clotting. Current treatment guidelines recommend a DAPT regimen of two antiplatelet drugs for six to 12 months after the insertion of a coronary stent to prevent blood clots.

"However, the optimal single antiplatelet agent for long-term maintenance therapy beyond the duration of DAPT has been unclear," Kim said. He added that in clinical practice, physicians may maintain patients on DAPT for as long as 18 months, depending on the patients' level of risk for clotting.

This trial, known as HOST-EXAM (EXtended Antiplatelet Monotherapy), enrolled 5,436 patients who had received a coronary stent. Patients' average age was 63 years; 75% were men, 34% had diabetes and 13% had chronic kidney disease. After completing between six and 18 months of DAPT without experiencing any adverse events, patients were randomly assigned to receive single-agent maintenance therapy with either clopidogrel or aspirin.

In addition to the primary endpoint, researchers also separated out blood-clotting events (death, heart attack, hospital readmission due to acute coronary syndrome, or a blood clot in the stent) from all bleeding events and analyzed them as secondary endpoints. They found that blood-clotting events occurred in 3.8% of the patients who took clopidogrel compared with 5.6% of those who took aspirin; bleeding events were seen in 2.3% of patients in the clopidogrel group versus 3.3% of those in the aspirin group. All of the differences between the groups were statistically significant.

"These results confirm that clopidogrel is superior to aspirin at reducing the incidence of blood-clotting events," Kim said. "What is interesting is that clopidogrel also performed better than aspirin at reducing bleeding events. Such findings that one antiplatelet agent is better than the other in reducing both clotting and bleeding events have been observed in other studies comparing different antiplatelet regimens, suggesting that thrombotic and bleeding events are tightly associated with each other. For example, when patients experience bleeding, they stop the antiplatelet agents leading [them to experience] thrombotic events."

Kim said that the results apply only to patients who had completed between six and 18 months of DAPT without any adverse events.

"It may be difficult to directly extrapolate our results to patients who received DAPT for a shorter period, such as one or three months," he said. "However, our results may be useful in helping physicians to select antiplatelet monotherapy for patients who are in the chronic stable phase after coronary stenting."

The two years of patient follow-up in the HOST-EXAM trial is longer than that of many previous trials comparing antiplatelet drug regimens in patients who have received a coronary stent, Kim said. He and his colleagues plan to continue their follow-up for a total of five years to gain further insights into the long-term benefits and trade-offs of clopidogrel compared with aspirin. Because the daily cost of clopidogrel is higher than that of aspirin, Kim said, he and his team are also planning a follow-up study that will examine the cost-effectiveness of the two medications.

Another limitation is that the trial was not blinded, meaning that both patients and their doctors knew which drug patients were receiving. Also, the total number of reported adverse events in both groups was lower than the investigators had expected when they designed the trial, which suggests that adverse events could have been under-reported. However, Kim said he believes the main reason for the lower-than-expected rate of adverse events was not under-reporting but the quality of care that evolved over the seven-year study period.

Among patients who had a cardiac stent inserted after a heart attack, switching to less-potent dual antiplatelet therapy (DAPT) after 30 days was safer and more effective in preventing adverse events a year later than continuing on a high-potency DAPT regimen, according to data presented at the American College of Cardiology's 70th Annual Scientific Session.

"We have shown that, in patients who have had a heart attack and who've been treated with newer-generation stents and guideline-recommended medical therapy, de-escalation of DAPT by switching from ticagrelor to clopidogrel is completely safe and more effective than continuing to treat patients with ticagrelor," said Kiyuk Chang, MD, professor of Cardiology, Division of Internal Medicine at the Catholic University of Korea in Seoul and lead author of the study.

The study's primary endpoint, a composite of death due to a heart attack or stroke, a nonfatal heart attack or stroke, or bleeding requiring medical intervention at any time from one to 12 months after the stenting procedure, was met.

Stenting, also known as coronary angioplasty or percutaneous coronary intervention (PCI), is a minimally invasive procedure in which a flexible tube (catheter) is threaded through an artery under local anesthesia. At the site of an arterial blockage, a tiny balloon at the tip of the catheter is inflated to unblock the artery, and a stent--a tiny mesh tube coated with medication--is inserted to prop it open.

Current treatment guidelines recommend that after the insertion of a cardiac stent, patients should receive DAPT, which includes aspirin and a P2Y12 inhibitor like clopidogrel or ticagrelor, for six to 12 months. P2Y12 is a receptor on the surface of platelets--blood cells that help the blood to clot. P2Y12 inhibitors reduce clotting by partially blocking the action of the P2Y12 receptors. Ticagrelor is a newer agent that, compared with clopidogrel, is more potent, faster acting and has a more predictable antiplatelet effect, but also poses a higher risk of bleeding. Switching between P2Y12-inhibiting medications can increase (escalate) or decrease (de-escalate) the level of P2Y12 receptor inhibition.

Previous studies have shown that patients are at the highest risk for another heart attack during the first 30 days after stent insertion. Bleeding risk, by contrast, remains high during the maintenance phase of treatment (after the first 30 days). This trial, known as TALOS-AMI, is the largest study to date to test the safety and efficacy of a DAPT de-escalation strategy in minimizing the risk of both another heart attack and a bleeding episode, Chang said.

The trial enrolled 2,697 patients from East Asia (80% male, median age 60 years) 30 days after they had undergone stenting following a heart attack. During the month after their procedure, all patients had received DAPT with ticagrelor plus aspirin and had experienced no serious adverse events such as another heart attack, stroke or major bleeding. Patients were randomly assigned either to continue taking ticagrelor plus aspirin daily for a year or to switch after 30 days to clopidogrel, a less-potent P2Y12 inhibitor, plus aspirin.

At one year, the adverse events defined in the primary endpoint (death due to a heart attack or stroke, a nonfatal heart attack or stroke, or bleeding requiring medical intervention) occurred in 59 patients in the clopidogrel group (4.6%) compared with 104 in the ticagrelor group (8.2%), a statistically significant difference. Three percent of patients in the clopidogrel group experienced bleeding that required medical intervention, compared with 5.6% in the ticagrelor group, also a statistically significant difference. Outcomes for arterial blockages (ischemia) were similar in the two groups.

"We found that the higher-potency DAPT regimen with ticagrelor was needed only during the first 30 days after a heart attack, when the risks of another heart attack or arterial blockage are highest, and that this regimen may be harmful once this early phase has passed," Chang said. "Many cardiologists are already using DAPT de-escalation in patient treatment, and the results of this study provide scientific evidence to justify this practice."

The study findings have limitations, Chang said. The trial was not blinded, meaning that both patients and their doctors knew who was receiving which drug. Secondly, the trial was conducted only in South Korea. A genetic variant that reduces the effectiveness of clopidogrel occurs significantly more frequently in people of East Asian ethnicity than in other ethnic groups, he said.

"However, we showed the clinical safety and efficacy of switching from ticagrelor to clopidogrel in an East Asian population, which suggests that this de-escalation strategy could be safely applied to clinically similar patients of other ethnicities," he said.

Another limitation is that the overall incidence of primary endpoint events in the trial was lower than the researchers had initially estimated, Chang said. In both groups, fewer patients than expected experienced arterial blockages during the study period. This finding may be explained in part by the fact that patients were randomly assigned to treatment 30 days after undergoing PCI, rather than at the time of PCI, and that all patients enrolled in the trial had received the most technologically advanced cardiac stents, which may pose a lower risk for adverse events than older devices. Additionally, a relatively large difference in the number of expected versus actual bleeding events was seen in the clopidogrel group, while in the ticagrelor group the gap between expected and observed bleeding events was smaller.

Chang and his colleagues are now planning to conduct a follow-up study that will examine differences in outcomes between patients similar to those enrolled in the TALOS-AMI trial who are or are not treated with the DAPT de-escalation strategy in the "real world" outside of a clinical trial setting.

Taking medications to protect the heart from damage associated with adjuvant breast cancer therapy--medications that are administered in addition to surgery to remove a tumor--did not significantly improve markers of heart health two years after breast cancer treatment, according to a study presented at the American College of Cardiology's 70th Annual Scientific Session.

The researchers reported no significant differences between patients who took an angiotensin receptor blocker (candesartan cilexetil) or a beta-blocker (metoprolol succinate) compared with placebos in terms of left ventricular ejection fraction (LVEF), a measure of the heart's ability to effectively pump blood and the trial's primary endpoint. The study, which included a broad population of patients who were undergoing treatment for breast cancer, suggests many patients face a low risk of heart damage from contemporary adjuvant therapy and do not benefit from routinely administered cardioprotective drugs during chemotherapy, according to the researchers.

"If patients don't have preexisting heart conditions or high cardiovascular risks from the start--for example, hypertension or diabetes--it seems to be relatively safe to administer adjuvant therapy," said Siri Lagethon Heck, MD, PhD, a cardiovascular radiologist at Akershus University Hospital, Lørenskog, Norway, and the study's lead author. "In this patient group, the therapy isn't as dangerous as previously thought, and in general, patients should not be afraid that their cancer therapy will harm their heart."

Previous studies have identified heart failure, which weakens the heart's ability to pump blood, as a potential side effect of anthracyclines and monoclonal antibodies like trastuzumab. About 30% of patients with breast cancer receive anthracycline-containing chemotherapy after surgery. However, it has been unclear whether cardioprotective drugs can help patients avoid treatment-related heart damage or which patients would be most likely to benefit from this preventive treatment.

For the trial, called Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA), the researchers enrolled 120 patients with early-stage breast cancer and randomly assigned the patients to take candesartan cilexetil (commonly used to treat high blood pressure and heart failure), metoprolol succinate (commonly used for the treatment of high blood pressure, after a heart attack or for heart failure), both drugs or only placebos during their breast cancer treatment. Neither the patients nor the doctors involved in the study were aware of which combination of drugs or placebos each patient received. At the start of the study and after a median of 23 months, patients underwent a cardiac MRI to assess their heart function. Overall, patients experienced only a slight reduction in LVEF--less than 2 percentage points in all groups--and there were no significant differences between groups.

Based on the findings, researchers said prescribing heart-protective medications during adjuvant therapy is likely not warranted in most cases for patients without preexisting cardiovascular risk factors.

"Cardioprotective treatment with these drugs may give the patients side effects and should not be given routinely when it's not needed," Heck said.

The researchers found no significant differences in the secondary outcome change in concentrations of troponin I and T, markers of injury to the heart muscle.

Researchers said patients who already have heart disease or related risk factors likely face the greatest risk of heart damage from adjuvant therapy. To advance efforts to prevent heart failure in these patients, the researchers are now conducting a separate, multicenter trial to test the heart failure medication sacubitril/valsartan in more high-risk patients. They are also further analyzing data from the PRADA trial to determine factors that may increase a person's risk for heart damage.

"We want to try to identify the patients who are at higher risk for heart problems and who might benefit more from cardioprotective drugs," Heck said. "With this information, we can really put the effort where the help is needed."

The study was conducted in a single medical center, saw less of a decline in ejection fraction than anticipated and may have lacked the statistical power to detect very minor differences in heart function; however, such small differences are unlikely to be clinically important. The testing of two drugs in one trial and the fact that patients were followed from before their cancer therapy until more than a year after discontinuation of adjuvant therapy and study drugs represent key strengths, Heck said.

Sophia Antipolis, 17 May 2021: Women with mildly elevated blood pressure in their early 40s have a two-fold risk of acute coronary syndromes in their 50s compared to their counterparts with normal blood pressure. That's the finding of a study published on World Hypertension Day in the European Journal of Preventive Cardiology, a journal of the European Society of Cardiology (ESC).1

"Even if they feel healthy, women should have their blood pressure measured by their primary care physician and repeated at regular intervals with the frequency dependent on the level," said study author Dr. Ester Kringeland of the University of Bergen, Norway. "Those with other risk factors for heart disease, such as obesity, diabetes, autoimmune disorders, pregnancy complications, or parents with high blood pressure need more intense monitoring."

Previous studies have suggested that high blood pressure is a stronger risk factor for heart disease in women than in men. In addition, young and middle-aged women have on average lower blood pressure than men, but despite this, the threshold for diagnosing high blood pressure is the same in both sexes. This study investigated whether mildly elevated blood pressure (130-139/80-89 mmHg) was a stronger risk factor for acute coronary syndromes in women than in men.

Blood pressure was measured in 6,381 women and 5,948 men participating in the community-based Hordaland Health Study at age 41 years. Heart attacks were recorded during 16 years of follow up.

The researchers found that in women, having mildly elevated blood pressure was associated with a doubled risk of acute coronary syndromes during midlife. This association was not found in men after adjusting for other cardiovascular disease risk factors.

Dr. Kringeland said: "Our analyses confirmed that mildly elevated blood pressure affects the risk of acute coronary syndromes in a sex-specific manner. The results add to emerging evidence indicating that high blood pressure has particularly unfavourable effects on women's hearts."

Dr. Kringeland noted that the findings probably reflect differences between women and men in how the small arteries respond to elevated blood pressure, but this needs to be further explored. She said: "Young women have on average lower blood pressure than men, but a steeper increase is observed in women starting in the third decade. Since the threshold for high blood pressure is the same in both sexes, young women have in fact had a relatively larger increase than men before being diagnosed with high blood pressure."

Dr. Kringeland concluded: "Women should know their blood pressure. To retain a normal blood pressure, it is recommended to maintain normal body weight, keep a healthy diet and exercise regularly. Furthermore, it is advisable to avoid smoking and excess consumption of alcohol and salt."

Professor Bryan Williams, ESC chairperson of the European hypertension guidelines2 and Chair of Medicine at University College London, UK said: "This is a very important finding with a strong message. It has often been assumed based on the way we are encouraged to estimate risk of heart disease, that the cardiovascular risk associated with elevated blood pressure in mid-life life is greater for men than women. Importantly, this study suggests that this is not the case and that even mild elevations in blood pressure in women in early and mid-life should not be ignored."

A unique commission that today issued major new recommendations aimed at fully understanding and reducing the global burden of heart disease in women was led by Roxana Mehran, MD, Professor of Medicine, and Population Health Science and Policy, and Director of Interventional Cardiovascular Research and Clinical Trials at the Icahn School of Medicine at Mount Sinai.

"The Lancet Women and Cardiovascular Disease Commission" developed specific, worldwide recommendations for heart disease prevention and treatment based on an unprecedented global review and analysis. The recommendations included expanding education and health programs, and research on women's heart disease. The commission's report was published on May 16 in The Lancet, and simultaneously presented at the American College of Cardiology's 70th Annual Scientific Session.

Cardiovascular disease is the leading cause of death for women around the world. There are roughly 275.2 million women diagnosed with heart disease worldwide, and 20.8 million in the United States, a majority of these cases are preventable.

The Lancet Women and Cardiovascular Disease Commission report was authored by 17 senior experts in the field from 11 countries. Their goals were to address current gaps in knowledge among physicians and patients, outline region-specific recommendations for reducing the burden of heart disease in women, and ultimately improve the outcomes of women with cardiovascular disease by 2030.

"For the first time ever, we are trying to gain a comprehensive understanding of what it may take to reduce heart disease among women worldwide. This problem has persisted unchanged for decades and this commission is a critical step toward finding solutions," says Dr. Mehran. "For example, physicians are aware that hypertension, smoking, hyperlipidemia, and diabetes are the most important evidence-based risk factors for heart disease. We now need to direct our study toward lesser-known risk factors that impact women's health. Specifically, stress, psychosocial, and economic deprivation play a pronounced but understudied role. The commission concludes that by studying these types of factors, we can better prevent, identify, and treat heart disease, reducing mortality rates and improving women's health on a global scale."

The commission's recommendations are based on an analysis of the 2019 Global Burden of Disease Study data coordinated by the Institute for Health Metrics and Evaluation - an independent global health research center at the University of Washington. Among other findings, the report highlights that women are disproportionately affected by certain risk factors for heart disease compared to men, including sex-specific factors such as preterm delivery, premature menopause, and domestic violence. Additionally, women in all stages of life are at risk of developing risk factors for heart disease, including those who had childhood obesity, and pre-eclampsia. The report points out socioeconomic factors such as education and access to care that play a significant role in the prevalence and impact of heart disease in women around the world. The review finds more attention should be directed to addressing the increasing rates of heart attack and heart disease among young women.

Based on these findings, the Commission outlined an ambitious list of ten recommendations for reducing the burden of cardiovascular disease in women over the next decade. They include educating health care providers and patients on early detection to prevent heart disease in young women; scaling up heart health programs in highly populated and underdeveloped regions; and prioritizing sex-specific research on heart disease in women and intervention strategies.

"Establishing these recommendations is an important step, but it's even more important how the ten these key messages are pragmatically implemented into concrete real-life settings. Furthermore, Mount Sinai research has also shown that in order to help reduce the global burden of women's heart disease, it's important to develop motivating heart disease prevention programs starting in early childhood and for women before and during pregnancy," says Valentin Fuster, MD, PhD, Director of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital.

"These recommendations are a roadmap for combating this No. 1 killer of women around the world. It is an undertaking of massive scale and scope and will require total commitment from governments, health organizations, technology sectors, and funding agencies to prioritize this urgent need for change. It is our hope that this roadmap will be the north star for the future of women's heart health," added Dr. Mehran.

The Lancet women and cardiovascular disease Commission outlines 10 ambitious recommendations to improve health outcomes for millions of women around the world and achieve the global targets set.

In the first-ever global report on cardiovascular disease (CVD) in women, researchers call for urgent action to improve care and prevention, fill knowledge gaps, and increase awareness to tackle the worldwide leading cause of death among women. The all female-led Commission report was published in The Lancet and presented during a plenary session at the American College of Cardiology's 70th Annual Scientific Session (ACC.21).

The Lancet women and cardiovascular disease Commission: reducing the global burden by 2030 is authored by 17 leading experts from 11 countries. The Commission aims to help reduce the global burden of cardiovascular conditions - including heart disease and stroke - that account for 35% of deaths in women worldwide by 2030. The Commission's calls to urgently address and reduce CVD in women align with the United Nations Sustainable Development Goals (SDGs) which aim to reduce premature deaths from non-communicable diseases, including CVD, by one-third by 2030. [1]

The authors have outlined 10 ambitious recommendations to tackle inequities in diagnosis, treatment, and prevention to reduce CVD in women, including educating health care providers and patients on early detection to prevent heart disease in women; scaling up heart health programs in highly populated and underdeveloped regions; and prioritizing sex-specific research on heart disease in women and intervention strategies.

Professor Roxana Mehran, from Mount Sinai Medical Center, USA, says: "Cardiovascular disease in women remains understudied, under-recognised, under-diagnosed, and under-treated globally. Achieving the important target set by the United Nations requires bold, distinct strategies to not only target factors contributing to CVD but also to identify sex-specific biological mechanisms in women. Making permanent improvements to the worldwide care of women with CVD requires coordinated efforts and partnerships involving policymakers, clinicians, researchers, and the wider community." [2]

The global burden of cardiovascular disease in women

The Commissioners report data from the 2019 Global Burden of Disease Study [3] for the first time to describe the extent of cardiovascular disease in women worldwide, including disease prevalence, mortality, and risk factors.

In 2019, there were approximately 275 million women around the world with CVD, with global age-standardised prevalence estimated at 6,402 cases per 100,000. The leading cause of death from CVD worldwide in 2019 was ischemic heart disease (47% of CVD deaths), followed by stroke (36% of CVD deaths). There are considerable geographical differences in CVD, with the highest age-standardised prevalence in Egypt, Iran, Iraq, Libya, Morocco, and United Arab Emirates, while the countries with lowest prevalence are Bolivia, Peru, Colombia, Ecuador, and Venezuela.

Although globally the prevalence of CVD in women has been declining, with an overall decrease of 4.3% since 1990, some of the world's most populous nations have seen an increase in CVD, including China (10% increase), Indonesia (7%), and India (3%). These increases indicate a need for initiatives to expand prevention, diagnosis, and treatment of CVD in women who live in highly populated and industrialising regions.

The highest CVD mortality rates are in Central Asia, Eastern Europe, North Africa, and the Middle East, Oceania and Central Sub-Saharan Africa, where age-standardised mortality exceeds 300 deaths per 100,000 women. High-income Asia Pacific, Australasia, Western Europe, Andean Latin America and High-income North America recorded the lowest rates, with fewer than 130 deaths per 100,000 women. Evidence of important regional trends highlight a need for improved data collection at local and regional levels to effectively prevent, recognise, and treat CVD in women.

CVD risk factors in women

High blood pressure is the greatest risk factor contributing to years of lost life from CVD in women, followed by high body mass index and high LDL cholesterol. While these well-established risk factors might affect women differently than men, there are sex-specific risk factors such as premature menopause and pregnancy related-disorders that must be more widely recognized and prioritized as part of treatment and prevention efforts worldwide.

The Commissioners highlight a number of under-recognised CVD risk factors that also require attention. These include social factors - such as unemployment - linked to anxiety and depression, and disparities based on socioeconomic and cultural status, race, and poverty. Among their recommendations are a greater focus on mental health in clinical practice, and targeted policy work to support low socioeconomic status populations in developed and emerging countries.

Professor Bairey Merz, of the Cedars-Sinai Medical Center, USA, says: "While some risk factors for CVD are similar for women and men, women are more likely to suffer from health disparities due to cultural, political or socioeconomic factors. For instance, some social or religious norms - such as restrictions on participation in sport and physical activities - can contribute to CVD in women, highlighting an urgent need for culturally appropriate initiatives that are tailored to different regions and populations."

The Commission also highlights the need to increase awareness of CVD risk in women among physicians, scientists, and health care providers, and that there is an unmet need for CVD prediction models that include sex-specific risk factors.

Tailored interventions are urgently needed

Interventions to reduce CVD should be tailored for the most vulnerable populations globally, including women from minority or indigenous populations and those whose roles in society are strongly defined by traditional or religious norms. However, it is also important to reach groups not typically viewed as being at high risk, such as young women - a group in which heart attacks and smoking rates are increasing. In the past decade, 53 (27%) of 195 countries and territories recorded significant decreases in the prevalence of smoking among men, while only 32 (16%) recorded significant reductions for women.

Despite a vital need for knowledge about sex-related differences in optimal treatment and improved outcomes in patients of both sexes, women have long been under-represented in CVD clinical trials. The Commissioners recommend a number of strategies to include more women, including addressing barriers to participation - such as family care issues - adopting more inclusive enrolment criteria, and educating recruitment staff on the importance of involving women in trials.

Professor Liesl Zuhlke, of Red Cross Children's and Groote Schuur Hospitals and the University of Cape Town, South Africa, says: "The momentum to strive for equity and equality more broadly for women socially and culturally translates to an extraordinary time to channel that same energy into improving women's health. Being the leading killer of women globally, CVD must take precedence for our attention and action. This Commission's work is both a starting point and a call to action to mobilise and energise health care professionals, policymakers - and women themselves - to work toward a healthier future." [2]

The Commissioners acknowledge some limitations to their report. As this was a report aiming to capture sex-related differences in cardiovascular disease, and not a systematic review, a bias towards highlighting evidence for sex-related disparities over neutral findings cannot be excluded. There was only limited assessment of the important distinction between sex and gender in the report, in part because the terms are often used interchangeably in the literature. The limited availability of quality data on transgender women also meant the Commission was unable to investigate cardiovascular health for this group. Overall evidence presented in the report may be dominated by data from white women and developed countries, reflecting the current availability of more robust data from these populations and regions. More research to explore all these factors is needed.

Writing in a Linked Comment, Dr Ana Olga Mocumbi of the Mozambique National Institute of Health, who was not involved in the Commission report, adds, "In the midst of the COVID-19 pandemic, values of human dignity, solidarity, altruism, and social justice should guide our communities to ensure equitable share of wealth and leveraging of efforts towards the reduction of cardiovascular disease burden in women worldwide. The Commission's recommendations on additional funding for women's cardiovascular health programmes, prioritisation of integrated care programmes, including combined cardiac and obstetric care, and strengthening of the health systems accords with efforts to bridge the gap for the world's worst off. Such a shift in women's cardiovascular care would be a major step towards equity, social justice, and sustainable development."

ATS 2021, New York, NY - By removing "race correction" from the interpretation of pulmonary function test (PFT) results, Black individuals were shown to have a significantly higher prevalence and severity of lung disease, according to research presented at the ATS 2021 International Conference.

Alexander Moffett, MD, clinical fellow, Division of Pulmonary, Allergy and Critical Care, University of Pennsylvania Perelman School of Medicine, and colleagues, sought to determine the real-world consequences of race correction for the interpretation of PFT results. Race correction, a standard practice in PFT interpretation that has no biological basis, results in a decrease in the predicted lower limit of "normal" for FEV1 (the maximum amount of air a person can forcibly exhale in one second) and FVC (forced vital capacity--maximum amount exhaled forcefully after breathing in deeply) for Black patients.

"The use of race correction in clinical algorithms may mask and, thus, reinforce the effects of structural racism, including known disparities in care processes and outcomes for Black patients with lung diseases," stated Dr. Moffett. "Black patients are both undiagnosed and underdiagnosed."

Dr. Moffett and colleagues used American Thoracic Society guidelines to interpret pulmonary function tests performed at the University of Pennsylvania Health System between 2010 and 2020 involving patients who self-identified as Black or African-American. These guidelines were applied using the reference values for spirometry (a commonly used type of pulmonary function test) developed by the Global Lung Function Initiative, both with and without race correction--14,080 test results in all.

The researchers compared the two sets of interpretations with respect to the diagnosis of obstructive, restrictive, and mixed pulmonary defects, along with the gradation of severity of these defects.

"Removal of race correction led to results indicating the presence of more serious pulmonary disease," stated Dr. Moffett. "The removal of race correction led to an increase in the percentage of patients with any pulmonary defect from 59.5 percent to 81.7 percent, a significant difference of 20.8 percent. This means that we may be missing a large number of patients, who may be undertreated or not treated at all."

Looking at specific pulmonary disease categories, the removal of Black race correction led to a diagnosis of obstruction for an additional 414 patients and an increase in the prevalence of obstructive lung disease in this group from 22.1 percent to 23.9 percent, a difference of 1.7 percent. Removal of race correction also led to the diagnosis of restricted breathing for an additional 665 patients, an increase in the prevalence of restrictive lung disease from 8.8 percent to 13.5 percent, a difference of 4.7 percent. Among patients with an obstructive, restrictive, or mixed defect, the percentage for whom correction removal led to an increase in the severity of disease was 48.6 percent.

"There are many ways one might remove race correction from pulmonary function test interpretation and further work is needed, involving the collaboration of patients and clinicians, to develop a broad consensus on this point," said Dr. Moffett. "The preliminary research reported here is intended to start a larger conversation concerning the current assumptions that inform pulmonary function test interpretation and the ways in which these assumptions may promote the unequal distribution of medical resources. Our hope is that in identifying the clinical implications of race correction, we can begin to convince other health professionals of the importance of this topic of conversation, developing the science of pulmonary function test interpretation on a stronger scientific foundation to promote more just medical care."