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HANOVER, N.H. – Aug. 31, 2020 – On March 28, the Food and Drug Administration (FDA) exercised its Emergency Use Authorization (EUA) authority to allow the use of hydroxychloroquine for the treatment of COVID-19. On June 15, after a number of studies failed to find positive effects, the agency revoked this authorization. This chain of events raises questions about the speed, rigor and potential politicization of the authorization process. These actions also may have hurt the FDA’s credibility and the public’s trust in the agency, which could decrease the public’s confidence in and adoption of eventual COVID-19 vaccines. In a Viewpoint piece published in JAMA: The Journal of the American Medical Association, a research team proposes reforms that the FDA could implement to improve the emergency use authorization process and drug approvals during public health crises, which could increase the FDA’s credibility and the public’s trust in it.

The recommendations are especially timely given that FDA Commissioner Stephen Hahn has stated that the agency will consider using the EUA process to authorize a COVID-19 vaccine, as well as the potential for full approval of COVID-19 vaccines in late 2020.

The FDA is “responsible for protecting public health,” which includes ensuring that drugs are safe and effective. “The FDA entered highly unchartered territory when it came to the approval and revocation of hydroxychloroquine for COVID-19, as emergency use authorizations have typically been used for diagnostics and only rarely for therapeutics,” explained co-author Herschel Nachlis, a research assistant professor of government and policy fellow in the Nelson A. Rockefeller Center for Public Policy and the Social Sciences at Dartmouth. “Through this piece in JAMA, we provide recommendations to help the agency make the authorization process more robust, rigorous and transparent in this pandemic environment,” he added.

 To improve the accountability and transparency of drug authorizations and approvals, the researchers propose four reforms:

The FDA could clarify evidentiary standards for EUAs and could create higher standards for widely used products like vaccines.

The FDA could consult with the external experts on its Advisory Committees before issuing EUAs. The committee meetings could be live-streamed and more opportunities for public input could be established.

Once COVID-19 vaccines are granted marketing authorization, the FDA could establish extensive adverse event reporting systems, facilitate phase 4 trials to monitor post-approval safety and efficacy, and engage the National Vaccine Injury Compensation Program.

As part of the FDA’s ongoing efforts to enhance public communication about COVID-19 diagnostics, therapeutics and vaccines, the FDA could launch public education campaigns and utilize communication tools like drug facts boxes to help explain regulatory decisions.

“The FDA’s regulatory processes are often considered the gold standard for the approval of drugs, and are fundamental to American and global public health,” said Nachlis. “Our entire pharmaceutical and healthcare system depends on this standard. Maintaining credibility and public trust is integral to the FDA’s ability to fulfill its mission. Now is the time for the FDA to consider ways to enhance its public support, as our nation and the world waits for effective vaccines to be quickly and safely developed, approved and deployed,” he added. 

DALLAS, August 31, 2020 -- People enrolled in a pharmacist-led telemonitoring program to control high blood pressure were about half as likely to have a heart attack or stroke compared to those who received routine primary care, according to new research published today in Hypertension, an American Heart Association journal.

Researchers, led by study author Karen L. Margolis, M.D., M.P.H., executive director of research at HealthPartners Institute in Minneapolis, Minn., found that a heart attack, stroke, stent placement or heart failure hospitalization occurred in 5.3% of the telemonitoring group vs. 10.4% of the routine primary care group.

"Home blood pressure monitoring linked with treatment actions from the health care team delivered remotely (telehealth support) in between office visits has been shown to lower blood pressure more than routine care, and patients really like it," said Margolis. "In addition, by avoiding serious cardiovascular events over 5 years, our results indicate significant cost savings." Patients reported that they liked having support from a trusted professional, rapid feedback and adjustments to their treatment, and having someone to be accountable to.

Margolis reports that over 5 years, the savings from reduced cardiovascular disease events exceeded the telemonitoring intervention costs by $1,900 per patient.

"The findings were just short of statistical significance," said Margolis, "meaning they could have been due to chance. However, we were surprised that the figures on serious cardiovascular events pointed so strongly to a benefit of the telemonitoring intervention," she said.

Uncontrolled high blood pressure is the largest modifiable risk factor contributing to death from all causes. Nearly half of U.S. adults have high blood pressure, defined as equal to or greater than 130 mm Hg systolic (top number), or 80 mm Hg diastolic (bottom number). However, most adults with high blood pressure don't have their numbers under control.

450 participants with uncontrolled high blood pressure were enrolled in the study, conducted at 16 primary care clinics within the HealthPartners system in Minnesota. Participants were blinded and randomized to two groups: 222 patients were in the routine primary care group, and 228 in the telemonitoring group that also received one year of remote care managed by a pharmacist. In the telemonitoring group, patients were able to measure their blood pressure at home and send it electronically to the pharmacist, who then worked with them to make medication and lifestyle changes in their treatment.

In clinic visits for all participants, researchers monitored blood pressure at enrollment, 6 months, 12 months, 18 months and 5 years; kept track of any heart attacks, strokes, coronary stents, heart failure hospitalizations and heart-related deaths that occurred; and counted all the costs of their blood pressure-related care and cardiovascular event care.

They found:

In the telemonitoring group, there were 15 serious cardiovascular events (5 non-fatal heart attacks, 4 non-fatal strokes, 5 heart failure hospitalizations, 1 CV death) among 10 patients. This group also had 2 stent placements, making the total event rate 5.3%.

In the routine primary care group, there were 26 serious cardiovascular events (11 non-fatal heart attacks, 12 non-fatal strokes, 3 heart failure hospitalizations) among 19 patients. They also had 10 stent placements, making the total event rate 10.4%.

Based on these findings, "widespread adoption of the telemonitoring model might help U.S. adults with uncontrolled high blood pressure avoid serious cardiovascular events and reduce health care costs," according to Margolis and colleagues. They recommend future studies to figure out how to increase the number of patients engaged in home blood pressure monitoring over many years, and to measure cardiovascular risk factors and cardiovascular events over that extended period.

The study's limitations are its relatively small size, and it was at a single medical group's urban and suburban primary care clinics, which may not represent the diversity of patients who receive care in other settings across the country.

The European Society for Blood and Marrow Transplantation (EBMT), Europe's collaborative peer network of professionals working in the field of stem cell transplantation and cellular therapy, announced today the results of the phase III RACE trial during EBMTs virtual 46th Annual Meeting. Preliminary data show that adding Eltrombopag to standard immunosuppressive treatment is safe and increases response rates in patients with Severe Aplastic Anaemia (SAA).

SAA is a condition in which the bone marrow does not produce enough new blood cells. It is a rare, yet potentially fatal disease which can be treated with bone marrow transplantation or, for patients who are not eligible to receive a transplantation, with immunosuppressive treatment. The most commonly used immunosuppressive regimen includes horse ATG (hATG) in combination with Cyclosporine A (CsA). However, about 35% of patients do not respond to treatment or eventually relapse.

Eltrombopag is a thrombopoietin receptor agonist that was developed to stimulate thrombopoiesis (production of platelets), but it was subsequently shown to restore trilineage haematopoiesis. A previous single-arm study showed that adding Eltrombopag to standard immunosuppressive treatment appeared to improve the response rate as compared to the use of hATG plus CsA alone. The first results of the randomised controlled RACE trial now confirm that adding Eltrombopag to standard immunosuppression leads to significantly higher response rates compared to standard immunosuppressive treatment alone.

The RACE trial is sponsored by the EBMT with the financial support of Novartis and Pfizer. Professors. Régis Peffault de Latour (Head of the French Reference Center for Aplastic Anemia and PNH, Saint-Louis Hospital, and University of Paris) and Antonio M. Risitano (Federico II University, Naples, and Head of Hematology and the BMT Unit, Ospedale Moscati, Avellino, Italy) served as Principal Investigators of the study, and they designed the study together with Professor Carlo Dufour (Head of the Hemato Oncology and Stem Cell Transplantation Department. G.Gaslini Childrens' Research Hospital, Genova, Italy). Under the energetic and efficient coordination of Sofie Terwel, the trial was successfully conducted by the RACE study team at the EBMT Clinical Trial Office. The study was presented by Prof. Peffault de Latour at the presidential symposium of EBMT's virtual Annual Meeting and was granted the Van Bekkum Award, the most prestigious EBMT award for the best abstract submitted to the physician's programme.

The international, investigator-driven, open-label, phase III, randomised trial evaluated 197 patients with SAA. Patients were aged 15 years or older, had acquired SAA, and had not received prior immunosuppressive treatment. Patients were randomised to receive either standard immunosuppression (hATG 40 mg/kg x4d and CsA 5 mg/kg/d) or standard immunosuppression + Eltrombopag at the dose of 150 mg/d from day +14 until 6 months (or 3 months, in case of early complete response). The primary endpoint of the study is complete response (CR) at 3 months, with CR being defined as haemoglobin 100 g/L, neutrophils 1.0 g/L and platelets 100g/L, according to standard international criteria.

It was shown that three months after treatment start, patients who received the combination of hATG, CsA plus Eltrombopag had a significantly higher complete response rate compared to patients treated with hATG and CsA alone. These higher response rates were sustained at 6 months. Moreover, Eltrombopag was generally well-tolerated, with a comparable occurrence of adverse events in the two treatment arms. This trial also shows that in this rare disease, large randomised trials can successfully be run in collaboration with many expert centres in Europe.

"Eltrombopag is registered in Europe for second line treatment of aplastic anaemia, so it is only available to patients who cannot receive bone marrow transplantation and have failed immunosuppressive treatment" explains Prof. Peffault de Latour. Prof. Risitano states: "The RACE trial data shows that eltrombopag increased response rates for naïve SAA patients who are not eligible for hematopoietic stem cell transplantation. The RACE study team is continuing to follow up the trial participants up to two years and furthermore aims to set up a long-term follow-up study to monitor the effectiveness and safety of Eltrombopag up to ten years.". "The EBMT Clinical Trial Office is already actively working on this new project, which likely will provide the final evidence about the benefit of using triple therapy as initial treatment for Severe Aplastic Anemia." concludes Prof. Dufour.

Sophia Antipolis, France - 31 Aug 2020: There is no evidence that blood pressure lowering drugs increase the risk of cancer, according to the most extensive study conducted on the topic. The late breaking research is presented today at ESC Congress 2020.1

"Our results should reassure the public about the safety of antihypertensive drugs with respect to cancer, which is of paramount importance given their proven benefit for protecting against heart attacks and strokes," said study author Ms. Emma Copland, an epidemiologist at the University of Oxford, UK.

A potential link between blood pressure drugs and cancer has been debated for more than 40 years. The evidence for an increased or decreased risk of cancer with the use of antihypertensive medication has been inconsistent and conflicting.

This was the largest study on cancer outcomes in participants of randomised trials investigating antihypertensive medication - around 260,000 people in 31 trials. Investigators of all trials were asked for information on which participants developed cancer. Much of this information has not been published before, making the current analysis the most detailed yet.

Five antihypertensive drug classes were investigated separately: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, calcium channel blockers (CCBs), and diuretics.

The investigators estimated the effect of each drug class on the risk of developing any type of cancer, of dying from cancer, and of developing breast, colorectal, lung, prostate and skin cancers. They also examined whether there were any differences according to age, gender, body size, smoking status and previous antihypertensive medication use before taking part in the trial.

During an average of four years, there were around 15,000 new diagnoses of cancer. The researchers found no evidence that the use of any antihypertensive drug class increased the risk of cancer. This finding was consistent regardless of age, gender, body size, smoking status and previous antihypertensive medication use.

Each drug class was compared against all other control groups, including placebo, standard treatment and other drug classes.

There was no important effect of any individual drug class on overall cancer risk. The hazard ratio (HR) for any cancer was 0.99 (95% confidence interval [CI]) 0.94-1.04) with ACE inhibitors, 0.97 (95% CI 0.93-1.02) with ARBs, 0.98 (95% CI 0.89-1.08) with beta blockers, 1.06 (95% CI 1.01-1.11) with CCBs and 1.01 (95% CI 0.95-1.07) with diuretics. In statistical terms, these effect sizes were not significantly different from each other, so there was no evidence of an increased risk of cancer with any of the drug classes.

Similarly, there was no evidence that any type of antihypertensive medication had an effect on the probability of developing breast, colorectal, lung, prostate or skin cancer.

When participants were followed throughout the course of each trial, there was no indication that the risk of cancer increased with longer duration of use of these treatments.

Ms. Copland said: "Our study has addressed an ongoing controversy about whether antihypertensive medication increases the risk of developing cancer. We used the largest individual-level randomised evidence on antihypertensive medication to date and provide evidence for the safety of blood pressure lowering drugs in relation to cancer."

Sophia Antipolis, France - 31 Aug 2020: Losing weight could prevent or even reverse diabetes, according to late breaking research presented today at ESC Congress 2020.1

In 2019, approximately 463 million people worldwide had diabetes, of which the vast majority (around 90%) was type 2 diabetes.2 Diabetes doubles the risk of coronary heart disease, stroke, and death from cardiovascular disease.3 Obesity is the main modifiable cause of type 2 diabetes, while genetic make-up may also identify individuals with a greater likelihood of developing the condition.4

"Because we are born with our genes, it might be possible to pinpoint early in life who has a high chance of developing diabetes during their lifetime," said principal investigator Professor Brian Ference of the University of Cambridge, UK, and University of Milan, Italy. "We conducted this study to find out if combining inherited risk with current body mass index (BMI) could identify people at the highest risk of developing diabetes. Prevention efforts could then concentrate on these individuals."

The study included 445,765 participants of the UK Biobank. The average age was 57.2 years and 54% were women. Inherited risk of diabetes was assessed using 6.9 million genes. Height and weight were measured at enrolment to calculate BMI in kg/m2. Participants were divided into five groups according to genetic risk of diabetes. They were also divided into five groups according to BMI.

Participants were followed-up until an average age of 65.2 years. During that period, 31,298 developed type 2 diabetes.

Those in the highest BMI group (average 34.5 kg/m2) had an 11-fold increased risk of diabetes compared to participants in the lowest BMI group (average 21.7 kg/m2). The highest BMI group had a greater likelihood of developing diabetes than all other BMI groups, regardless of genetic risk.

"The findings indicate that BMI is a much more powerful risk factor for diabetes that genetic predisposition," said Professor Ference.

The investigators then used statistical methods to estimate whether the likelihood of diabetes in people with a high BMI would be even greater if they were overweight for a long period of time. They found that the duration of elevated BMI did not have an impact on the risk of diabetes.

Professor Ference said: "This suggests that when people cross a certain BMI threshold, their chances of diabetes go up and stay at that same high-risk level regardless of how long they are overweight."

He noted that the threshold is likely different for each person and would be the BMI at which they start to develop abnormal blood sugar levels. Professor Ference said: "The findings indicate that most cases of diabetes could be avoided by keeping BMI below the cut-off which triggers abnormal blood sugar. This means that to prevent diabetes, both BMI and blood sugar should be assessed regularly. Efforts to lose weight are critical when a person starts to develop blood sugar problems."

"It may also be possible to reverse diabetes by losing weight in the early stages before permanent damage occurs," said Professor Ference.

Differences in the shape and texture of men and women's hearts could potentially explain why their risk of heart disease differs, according to research funded by the British Heart Foundation (BHF). The findings are being presented at the European Society of Cardiology (ESC) Congress.

Researchers at Queen Mary University of London, in collaboration with the University of Barcelona and University of Southampton, used new ways to look at the heart structure of 667 healthy people - 309 men and 358 women - from the UK Biobank Imaging study.

The team looked at cardiac magnetic resonance (CMR) scans, a type of heart scan used to diagnose and give information on various heart conditions. They have developed a new heart-specific image analysis 'toolkit', called CMR radiomics, to obtain more detailed information about the heart. The 'toolkit' was applied to scans of the left ventricle - the part of the heart responsible for pumping blood around the body.

When researchers compared numerous measures of heart texture and shape, they found that in men, the heart muscle was dominated by more coarse textures. Whereas women's hearts had finer grained textures.

They also found significant differences in the overall shape of male and female hearts, including that men had a larger surface area of heart muscle compared to women, even after accounting for body size.

The heart shape and texture were found to change with age. Participants were categorised into three different age groups: 45-54 years, 55-64 years, and 65-74 years of age.

Differences in heart shape between men and women decreased with age, whilst texture differences remained across all age groups and dominated in older age.

Researchers will now apply this technique to the CMR scans of people with heart and circulatory diseases - including those with diabetes, high blood pressure, high cholesterol, and coronary heart disease. This will hopefully reveal how the more intricate details of the heart structure differs between cardiovascular health and disease.

Dr Zahra Raisi-Estabragh, BHF Clinical Research Training Fellow at Queen Mary University of London and lead researcher, said:

"The current image analysis tools available in hospitals do not fully encompass the complexity of the heart's architecture. We need to be able to see the heart in much greater detail to be able to truly understand how it changes between men and women, with ageing, and during the development of heart disease. Our technology has great potential to do just that.

"This work is part of a wider research strategy to develop CMR radiomics as a tool to improve patient care. Our ultimate goal is to use our imaging 'toolkit' to allow faster and more accurate diagnosis of heart disease, improve our estimations of future risk of heart conditions, and better understand the processes underlying cardiovascular disease."

Dr Sonya Babu-Narayan, Associate Medical Director of the British Heart Foundation, said:

"CMR scans give us a wealth of information about the heart, meaning that we can understand it to greater depths than ever before. But the researchers have dug even deeper to find buried treasure within this routine data, revealing subtler differences that vary more between men and women and by age than what we normally see.

"Next we need to find out if this technology can prove useful to assess cardiovascular risk in both women and men."

Professor Steffen Petersen, Professor of Cardiology at Queen Mary University of London who supervised the project said:

"This innovative work demonstrates the potential of UK Biobank as a powerful research resource and the immense value of cross-disciplinary and international collaborations in advancing knowledge of the heart."

Sophia Antipolis, France - 30 Aug 2020: The POPular TAVI trial has challenged current guideline recommendations on antiplatelet treatment after transcatheter aortic valve implantation (TAVI) in patients not taking oral anticoagulation. The findings are presented in a Hot Line session today at ESC Congress 2020.1

"Aspirin alone as compared to aspirin with clopidogrel reduced the bleeding rate significantly, with an absolute reduction of more than 10%," said coordinating investigator Dr. Jorn Brouwer of St. Antonius Hospital, Nieuwegein, the Netherlands. "At the same time, aspirin alone compared to aspirin with clopidogrel did not result in an increase in thromboembolic events as captured in the secondary outcomes."

Aortic stenosis (narrowing of the aortic valve) is the most prevalent heart valve problem in Europe. TAVI is an established treatment for patients with severe symptomatic aortic stenosis. It is estimated that the annual number of procedures in Europe could reach 177,000.

Risks of bleeding and ischaemic complications after TAVI are relatively high and are associated with increased mortality. Guidelines recommend adding clopidogrel to aspirin therapy for three to six months after the procedure to reduce thromboembolic events.2,3 However, explorative studies have indicated that the temporary addition of clopidogrel is linked with a higher rate of major bleeding without a decrease in thromboembolic complications.

The POPular TAVI trial investigated the optimal antithrombotic therapy in two cohorts: patients not on oral anticoagulants (cohort A) and patients on chronic oral anticoagulation (cohort B). The results of cohort B have been published.4 Both cohorts were powered separately for the study outcomes.

The current study (cohort A) excluded patients who had undergone coronary artery stenting using a drug-eluting stent within three months or bare metal stent within one month prior to TAVI. A total of 665 patients without an indication for oral anticoagulation were randomly allocated to aspirin alone (331 patients) or aspirin with three months of clopidogrel (334 patients).

The study tested the hypothesis that aspirin alone compared to aspirin with clopidogrel for three months would reduce the rate of bleeding at one year. The co-primary outcomes were: 1) all bleeding (procedural and non-procedural) and 2) non-procedural bleeding.

In addition, the study tested the hypothesis that aspirin alone would be non-inferior to aspirin with clopidogrel with respect to two secondary outcomes at one year. The first examined bleeding and thromboembolic events and was a composite of cardiovascular mortality, non-procedural bleeding, all-cause stroke, or myocardial infarction. The second examined only thromboembolic events and was a combination of cardiovascular mortality, ischaemic stroke, or myocardial infarction.

Regarding the co-primary outcomes, aspirin alone resulted in a significantly lower incidence of bleeding compared to aspirin with clopidogrel at one year. All bleeding occurred in 50 patients (15.1%) receiving aspirin alone versus 89 (26.6%) patients receiving aspirin with clopidogrel (risk ratio [RR] 0.57; 95% confidence interval [CI] 0.42-0.77; p=0.001). Non-procedural bleeding occurred in 50 patients (15.1%) and 83 (24.9%), respectively (RR 0.61; 95% CI 0.44-0.83; p=0.005).

For the secondary outcome on bleeding and thromboembolic events, aspirin alone was superior compared to combined therapy. The outcome occurred in 76 patients (23.0%) receiving aspirin alone compared to 104 patients (31.1%) receiving aspirin with clopidogrel (difference -8.2 percentage points; 95% CI for noninferiority -14.9 to -1.5; p

The secondary outcome on thromboembolic events occurred in 32 patients (9.7%) receiving aspirin alone compared to 33 patients (9.9%) receiving aspirin with clopidogrel (difference -0.2 percentage points; 95% CI for noninferiority -4.7 to 4.3; p=0.004).

Dr. Brouwer said: "The trial shows that aspirin alone should be used in patients undergoing TAVI who are not on oral anticoagulation and have not recently undergone coronary stenting."

Sophia Antipolis, France - 29 Aug 2020: Patients with newly diagnosed atrial fibrillation benefit from early rhythm control therapy, according to results of the EAST-AFNET 4 trial presented in a Hot Line session today at ESC Congress 2020.1

Rhythm control therapy is typically delayed unless patients have persistent symptoms on otherwise effective rate control. The EAST-AFNET 4 trial investigated whether rhythm control therapy - with antiarrhythmic drugs or ablation - delivered soon after diagnosis improves outcomes.2,3

"The risk of severe cardiovascular complications and death in patients with atrial fibrillation is highest in the first year after diagnosis, suggesting that early therapy could be most beneficial," said principal investigator Professor Paulus Kirchhof of the University Heart and Vascular Centre UKE Hamburg, Germany and University of Birmingham, UK. "Furthermore, atrial fibrillation causes atrial damage within a few weeks of disease onset. Early rhythm control therapy could reduce or prevent this damage, making it more effective."

A total of 2,789 patients in the first year of atrial fibrillation diagnosis and with at least two cardiovascular conditions were enrolled from 135 sites in 11 countries during 2011 to 2016. Patients were randomised 1:1 to early rhythm control therapy or usual care, stratified by sites. Patients in both groups received treatment for cardiovascular conditions, anticoagulation, and rate control according to guidelines.

Patients in the early rhythm control group received antiarrhythmic drugs or catheter ablation (chosen by the local study teams). Rhythm control therapy was escalated when recurrent atrial fibrillation was documented clinically or by ECG, including monitoring with patient-operated ECG devices.

Patients in the usual care group were initially managed with rate control. Rhythm control therapy was only used to mitigate severe atrial fibrillation-related symptoms despite optimal rate control, following current guidelines.

The first primary outcome was a composite of cardiovascular death, stroke, worsening heart failure, and acute coronary syndrome. The second primary outcome was nights spent in hospital per year. The primary safety outcome was a composite of stroke, all-cause death, and serious adverse events caused by rhythm control therapy.

During a median follow-up of 5.1 years, the first primary outcome occurred in 249 patients on early therapy and in 316 patients receiving usual care. Adjusting for the group-sequential design of the trial, it occurred less often in patients on early rhythm control (hazard ratio [HR] 0.79; confidence interval [CI] 0.67-0.94; p=0.005). The absolute risk reduction with early rhythm control was 1.1% per year.

The clinical benefit of early rhythm control was consistent across subgroups, including asymptomatic patients and patients without heart failure. All components of the primary outcome occurred numerically less often in patients randomised to early therapy, and cardiovascular death and stroke were significantly reduced compared to usual care.

Regarding the second primary outcome, there was no difference in nights spent in hospital between groups (early therapy 5.8±21.9 days/year; usual care 5.1±15.5 days/year; p=0.226).

The primary safety outcome did not differ between groups (early therapy 231 events; usual care 223 events). Complications of rhythm control therapy were more common in patients on early therapy, but occurred infrequently, in line with other recent rhythm control trials.

Professor Kirchhof said: "Rhythm control therapy initiated soon after diagnosis of atrial fibrillation reduces cardiovascular complications without increasing time spent in hospital and without safety concerns. These results have the potential to completely change clinical practice towards rhythm control therapy early after the diagnosis of atrial fibrillation."

Sophia Antipolis, France - 29 Aug 2020: Mavacamten improves heart function and symptoms in patients with obstructive hypertrophic cardiomyopathy, according to results of the EXPLORER-HCM trial presented in a Hot Line session today at ESC Congress 2020.1

"The results of this pivotal trial support a role for disease-specific therapy for obstructive hypertrophic cardiomyopathy (HCM) which treats the cause instead of just managing symptoms," said principal investigator Professor Iacopo Olivotto of Careggi University Hospital, Florence, Italy.

HCM affects approximately 1 in 500 people. It is defined by left ventricular hypertrophy that cannot be explained by another cardiac or systemic disease. The majority of HCM patients have obstructive HCM, where a combination of cardiac hypertrophy, excess contractility and abnormal movement of the mitral valve blocks or reduces blood flow from the left ventricle to the aorta - called left ventricular outflow tract (LVOT) obstruction.

Common symptoms include dyspnoea, atypical chest pain, palpitations, fatigue, and feeling lightheaded or fainting. Some people have few or no symptoms. But for others, HCM is a debilitating and life-changing disease resulting in physical limitations and lower quality of life. In some patients, the left ventricular remodelling progresses to refractory heart failure.

Currently available medical treatments focus on symptom relief and fail to address the underlying causes of obstructive HCM. These non-specific agents often have modest efficacy or substantial side effects. Surgical septal myectomy and alcohol septal ablation are efficacious but carry the risks inherent to invasive procedures and require specific expertise that is not always available. Therefore, an effective pharmacological therapy for obstructive HCM is an important unmet need.

Mavacamten is a first-in-class cardiac myosin inhibitor that directly targets the underlying pathophysiology of HCM and restores the heart's normal function. In early clinical trials, treatment with mavacamten led to significant improvements of symptoms, physical function, exercise capacity, and quality of life, and reduced LVOT obstruction in patients with obstructive HCM.

EXPLORER-HCM was a pivotal, global, phase 3, randomised, placebo-controlled clinical trial that tested the efficacy and safety of mavacamten in treating symptomatic obstructive HCM. A total of 251 patients received once daily mavacamten or placebo for 30 weeks. The endpoints were chosen to examine exercise capacity, symptoms, LVOT obstruction, functional status, and quality of life.

The primary endpoint assessed the treatment effect of mavacamten at week 30 relative to placebo on both symptoms and cardiac function. It was defined as achieving 1) ?1.5 mL/kg/min improvement in peak oxygen consumption (peak VO2) and ?1 New York Heart Association (NYHA) class reduction OR 2) ?3.0 mL/kg/min improvement in peak VO2 and no worsening of NYHA class.

Secondary endpoints included change from baseline to week 30 in post-exercise LVOT gradient and patient-reported outcomes such as the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and HCM Symptom Questionnaire-Shortness-of-Breath (HCMSQ-SoB) subscore.

At week 30, 45 (36.6%) patients on mavacamten met the primary composite endpoint versus 22 (17.2%) on placebo (p=0.0005). All secondary endpoints, including post-exercise LVOT gradient and patient-reported outcomes, also demonstrated statistically significant improvements for mavacamten as compared to placebo (all p

Safety and tolerability with mavacamten were similar to placebo. Some 11 serious adverse events were reported in 8.1% of patients on mavacamten versus 20 events in 8.6% of patients on placebo. Serious cardiac adverse events occurred in four patients treated with mavacamten (two atrial fibrillation, two stress cardiomyopathy), and four in the placebo group (three atrial fibrillation, one atrial fibrillation and congestive heart failure).

Professor Olivotto said: "The totality and consistency of the results showed benefit of mavacamten treatment compared to placebo in patients on background HCM therapy. Mavacamten improved functional capacity, LVOT gradient, symptoms, and key aspects of quality of life in patients with obstructive HCM and was generally well tolerated."

Sophia Antipolis, France - 29 Aug 2020: Empagliflozin reduces the risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure and a reduced ejection fraction. That's the finding of the EMPEROR-Reduced trial presented in a Hot Line session today at ESC Congress 2020.1

The EMPEROR-Reduced trial was designed to evaluate the effects of empagliflozin 10 mg once daily (as compared with placebo) in patients with heart failure and a reduced ejection fraction, with or without diabetes, who were already receiving all appropriate treatments for heart failure.2

The primary endpoint was the composite of cardiovascular death or hospitalisation for heart failure. Secondary endpoints included adverse renal outcomes, defined as chronic dialysis or renal transplant or sustained reduction of estimated glomerular filtration rate (eGFR).

By adjusting eligibility based on natriuretic peptide levels to the baseline ejection fraction, the trial preferentially enrolled higher-risk patients, who had not been well-represented in earlier studies.

The trial enrolled 3,730 patients with heart failure and a left ventricular ejection fraction of 40% or less, with or without diabetes. Patients were randomly assigned to empagliflozin 10 mg once daily or placebo.

During a median follow-up of 16 months, the primary endpoint occurred in 361 patients in the empagliflozin group and 462 patients in the placebo group (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.65-0.86; p

Adverse renal outcomes occurred in 30 patients in the empagliflozin group and 58 patients in the placebo group (HR 0.50; 95% CI 0.32-0.77; p

Uncomplicated genitourinary tract infections were more common in the empagliflozin group (1.3% vs. 0.4%), but the frequency of hypotension, volume depletion and hypoglycaemia were similar in the two groups.

Principal investigator Dr. Milton Packer of Baylor University Medical Centre, Dallas, Texas said: "Empagliflozin reduced the risk of serious heart failure events by 30% and decreased the risk of serious adverse renal outcomes by 50%. This trial extends the benefits of SGLT2 inhibitors to higher-risk patients and shows a meaningful benefit on renal outcomes in patients with heart failure for the first time."

Dr. Packer said: "Based on the combined results of our trial (together with the earlier trial with dapagliflozin), we believe that SGLT2 inhibition with empagliflozin and dapagliflozin will now become a new standard of care for patients with heart failure and a reduced ejection fraction."

Two recent studies were unable to rule out that H1N1 ("swine flu") vaccination ("Pandemrix") and seasonal influenza vaccination given to pregnant women might be associated with autism-spectrum disorder in the offspring. Now, a large study by researchers at Karolinska Institutet in Sweden, published in the journal Annals of Internal Medicine, refutes any such association.

Autism spectrum disorder is a severe neurodevelopmental childhood disorder characterized by impaired communication, lack of social skills and repetitive behavior. The disease has its onset in childhood.

While some studies indicate that influenza vaccination during pregnancy protects against morbidity in both the woman and her offspring, the long-term risks of H1N1 vaccination during fetal life have not been examined in detail. However two recent studies were unable to rule out that offspring to women undergoing influenza or H1N1 influenza vaccination during pregnancy, and especially during the first trimester, were at increased risk of autism-spectrum disorder.

Researchers from Karolinska Institutet, linked vaccination data in pregnant women from seven Swedish healthcare regions in 2009-2010 to the Swedish Medical Birth Register and the Swedish National Patient Register to identify autism-spectrum disorder in the offspring.

The importance of vaccination research

Of the 39,726 vaccine-exposed children, 394 (cumulative incidence, 1.0%) had a diagnosis of autism-spectrum disorder during the six-year follow-up compared with 330 (1.1%) among 29,293 unexposed children. Adjusting for potential confounders, H1N1 vaccine exposure during fetal life was not associated with a later childhood diagnosis of autism-spectrum disorder (adjusted hazard ratio=0.95; 95%CI=0.81-1.12). Results were similar for vaccinations in the first pregnancy trimester.

"Our null findings are important since some people have suspected that vaccinations could cause autism, and the anti-vaccine movement seems to be growing in the Western world," says lead author, Professor Jonas F Ludvigsson, pediatrician at Örebro University Hospital and professor at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet. "H1N1 vaccination has previously been linked to an increased risk of narcolepsy in young people, but vaccinating pregnant women does not seem to influence the risk of autism-spectrum disorder in the offspring,"

He continues: "Vaccination research has never been more important. Anticipating a vaccine against COVID-19, millions of pregnant women are likely to be offered such a vaccination. While our research group did not study COVID-19 vaccine effects, our research on H1N1 vaccination adds to the current knowledge about vaccines, pregnancy and offspring disease in general."

Adjusted for other factors

The researchers adjusted their analyses for such confounders as maternal smoking, height-weight, maternal age and comorbidity in order to minimize the influence of other factors that might explain any association between vaccination and autism.

"Without taking such factors into consideration, so-called confounding may create spurious associations that do not reflect a true association," adds co-author, Ass. Prof. Bjorn Pasternak, Department of Medicine, Karolinska Institutet (Solna).

Data presented at one of the opening sessions at this year's European and International Congress on Obesity (ECOICO 2020) held online this year (1-4 September) will show the clear relationship between obesity and the severity of COVID-19 disease. The session is presented by François Pattou, Professor of Surgery at the Faculty of Medicine of the University of Lille, and head of the Department of General and Endocrine Surgery at Lille University Hospital, France.

In his presentation, Prof Pattou will discuss French data from the earlier part of the epidemic (some of it published in the journal Obesity) that rapidly revealed that patients with obesity were facing more serious disease and a higher mortality risk than patients without obesity. Furthermore, he will discuss how areas of France with higher prevalence of obesity appeared to take longer to release their lockdown restrictions (because the virus was still circulating more in those areas), by showing a map comparing the two situations.

At the beginning of April, both general and intensive care admissions for COVID-19 began to rise sharply in Lille University Hospital, and across France and other European countries. An analysis conducted by Pattou and colleagues included 124 intensive care unit (ICU) admissions with COVID-19, and compared them with 306 patients who had been in ICU for other reasons, without COVID-19.

The data showed that among ICU patients with COVID-19, around half had obesity (BMI above 30), with a quarter having severe obesity (BMI of 35 or above). Most of the remaining patients (around 40%) were overweight, with only around 10% of patients in the healthy weight range (BMI 25 or under). Among the non-COVID-19 ICU patients, the story was very different: a quarter had obesity or severe obesity; a further quarter were overweight, and around half fell into the healthy weight range.

A similar trend emerged regarding which ICU patients with COVID-19 had to be put on ventilators. Of the 89 requiring mechanical ventilation, more than half had obesity or severe obesity, while most of most of the other patients were overweight. Patients with a BMI in the healthy range of 25 and under made up less than 10% of patients needing a ventilator. Among the 35 patients in ICU who did not deteriorate to the point of needing mechanical ventilation, a much lower proportion had obesity or serious obesity (less than 25%), while around half fell into the overweight category, and the other quarter the normal weight range.

Looking specifically at the individual BMI groups, almost all patients COVID-19 ICU patients with severe obesity (87%) needed a ventilator, dropping to 75% for 'regular' obesity (BMI 30-35), 60% for patients in the overweight category, and 47% for those in the healthy BMI range.

Professor Pattou says: "Several months into the COVID-19 pandemic, the increased risk posed by this virus to people living with obesity could not be clearer. Our data show that the chances of increasing to more severe disease increases with BMI, to the point where almost all intensive care COVID-19 patients with severe obesity will end up on a ventilator."

Further analysis by Pattou and colleagues, that has been published in The Lancet Diabetes & Endocrinology, showed that, among the patients analysed at Lille University Hospital, ICU patients with COVID-19 were almost 3 times more likely to have obesity than ICU patients without COVID-19.

Finally in his presentation, Professor Pattou will discuss an ongoing multicentre trial including more than 1,500 patients taking place at two centres in the USA, 18 in Europe, and one in Israel, to gather more data on the how increasing BMI and having obesity relates to the increased risk of mechanical ventilation (ClinicalTrials.gov Identifier: NCT04391738).

NEW YORK, NY--A new study of the antibodies produced by people with gluten sensitivity may lead to a better way to detect the condition and treat it.

Until recently, many doctors often dismissed the complaints of people who claimed to be sensitive to foods containing gluten but did not have celiac disease, a well-documented autoimmune disease triggered by exposure to the dietary protein found in wheat, rye, and barley.

That view has changed in the past few years, based partly on studies by Armin Alaedini, PhD, assistant professor of medicine at Columbia University Vagelos College of Physicians and Surgeons, that have delved into the biological basis for non-celiac gluten sensitivity.

But many aspects of non-celiac gluten sensitivity -- including what causes it and how to diagnose it -- remain poorly understood.

The new study by Alaedini shows that people with non-celiac gluten sensitivity, like those with celiac disease, produce a high level of anti-gluten antibodies, but the two conditions differ in the types of antibodies produced and the inflammatory responses these antibodies can instigate.

Alaedini and his team analyzed blood samples from 40 patients with celiac disease, 80 patients with non-celiac gluten sensitivity, and 40 healthy controls, all of whom consumed an unrestricted, gluten-containing diet.

"We found that the B cells of celiac disease patients produced a subclass profile of IgG antibodies with a strong inflammatory potential that is linked to autoimmune activity and intestinal cell damage," says Alaedini. "In contrast, the patients with non-celiac gluten sensitivity produced IgG antibodies that are associated with a more restrained inflammatory response."

Those antibodies could be used in the future to help physicians more easily detect people with non-celiac gluten sensitivity, which is currently difficult to diagnose.

The antibody profiles also hint at potential new therapies for celiac disease, which is currently treated only with diet. "The data suggest that celiac patients generate a strong B-cell inflammatory response each time they consume gluten, whereas the immune system in people with non-celiac gluten sensitivity learns from its earlier encounters with gluten and generates less-inflammatory responses to the antigen in subsequent interactions."

"If we can drive specific immune cells of celiac patients toward their less inflammatory states, we may be able to prevent or reduce the severity of the immunologic reaction to gluten."

Sophia Antipolis, France - 29 Aug 2020: Dramatic reductions in the risk of heart attacks in patients with diabetes coincides with major increases in the use of preventive medications. That's the finding of late breaking research presented today at ESC Congress 2020.1

"Our results suggest that when patients are diagnosed with type 2 diabetes, starting medications to prevent cardiovascular disease has a substantial impact on the risk of heart attacks and premature death," said principal investigator Dr. Christine Gyldenkerne of Aarhus University Hospital, Denmark.

People with type 2 diabetes are twice as likely to have a heart attack or die from heart disease compared to people without diabetes.

Management of patients with type 2 diabetes has changed considerably over the last two decades, with increased focus on prevention of cardiovascular disease. This was the first study to examine how these changes may have affected the risk of heart attacks and premature death in patients with newly diagnosed type 2 diabetes and no previous cardiovascular disease.

The researchers identified all patients in Denmark initiating therapy for type 2 diabetes from 1996 to 2011 - a total of 211,278 patients. Each patient with diabetes was matched on age and sex with five people without diabetes from the general population. Those with previous cardiovascular disease were excluded.

All participants were followed for seven years. Using data from national health registries, the researchers recorded heart attacks and death during follow-up. They also noted the use of medications to prevent cardiovascular disease at the time of diabetes diagnosis.

The researchers found that patients with newly diagnosed type 2 diabetes and no previous cardiovascular disease experienced major reductions in the risk of heart attack and death. From 1996 to 2011, the relative risk was reduced by 61% for heart attack and by 41% for death. During the same period, the absolute risks of heart attack and death reduced by 4% and 12%, respectively.

When comparing patients with diabetes to the general population, the initially large differences in risk narrowed over time. By the end of the study, the risk of heart attack among patients with diabetes was only marginally - 0.6% - higher than in the general population.

In those with diabetes, use of cholesterol-lowering medications increased more than 10-fold, aspirin increased by 50%, and blood pressure-lowering medications increased up to four times during the study period.

Dr. Gyldenkerne said: "The risk of heart attack and premature death among patients with newly diagnosed type 2 diabetes and no previous cardiovascular disease was approximately halved from 1996 to 2011. In the same period, the difference in risk of heart attack and death for patients with diabetes, as compared to the general population, was narrowed substantially."

She noted that this was an observational study and causation cannot be assumed. Dr. Gyldenkerne said: "In addition to the use of preventive medications, other factors may have influenced the likelihood of heart attack and premature death. For example, stricter control of diabetes and lifestyle changes such as smoking cessation, physical activity, and healthier food may have contributed to the improved prognosis."

Sophia Antipolis, France - 28 Aug 2020: Influenza and pneumonia vaccinations are associated with fewer hospital deaths in patients with heart failure. That's the result of a study in nearly 3 million Americans released today at ESC Congress 2020.1

One out of five individuals will develop heart failure in their lifetime. An estimated 26 million people are affected worldwide.2 Heart failure is a serious condition in which the heart cannot pump blood around the body as well at it should. It leads to a build-up of fluid in the lungs, causing shortness of breath and coughing, and impacts people's quality of life, often requiring urgent hospitalisations.

Respiratory infections such as influenza and pneumonia make heart failure worse, and annual vaccinations are recommended.

"The COVID-19 pandemic has shone the spotlight on the importance of vaccination to prevent respiratory infections, particularly for people with diseases like heart failure," said study author Dr. Karthik Gonuguntla of the University of Connecticut.

While it is known that inoculations protect against respiratory infections, and that these infections exacerbate heart failure, few studies have compared outcomes of vaccinated versus unvaccinated patients. This study examined whether immunisations had any link with the risk of heart failure patients dying while in hospital.

The study included 2,912,137 patients with heart failure who had a hospital admission in 2010 to 2014. The average age was 70 years. Data were obtained from the National Inpatient Sample (NIS), which covers more than 95% of the US population.

Just 1.4% of patients in the study had the flu vaccine and 1.4% had the pneumonia vaccine. The researchers compared in-hospital death rates between heart failure patients who received flu and pneumonia vaccinations that year and those who did not.

Rates of in-hospital mortality were significantly lower in patients who received the flu vaccine (1.3%) compared to those who did not receive the flu vaccine (3.6%). Similarly, rates of in-hospital mortality were significantly lower in patients inoculated against pneumonia (1.2%) compared to those who were not inoculated (3.6%).

Dr. Gonuguntla said: "Our study provides further impetus for annual immunisations in patients with heart failure. Despite advice to do so, uptake remains low. Although large administrative databases like the NIS are prone to containing some errors, the data indicate that there is some distance to go before reaching 100% coverage."

He noted that serious reactions to flu and pneumonia vaccinations are very rare, happen within a few hours, and can be effectively treated.

Dr. Gonuguntla said: "Pneumonia and flu vaccines are vital to preventing these respiratory infections and protecting patients with heart failure. Although many people have rejected common and safe vaccines before COVID-19, I am optimistic that the pandemic has changed perceptions about the role of immunisations in safeguarding our health."