Wood Street Clinic Blog

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Device that detects congestion in the lung improves heart failure outcomes

In patients with heart failure, use of an investigational device that monitors the accumulation of fluid in the lungs appeared to cut heart failure-related hospitalizations by more than half, meeting the study's primary endpoint, and reduced deaths from any cause by 39 percent per year compared with standard assessment and treatment, researchers reported at the American College of Cardiology's 65th Annual Scientific Session.

The Edema Guard Monitor alerts patients to an increase in fluid in the lungs, also called pulmonary congestion or edema, before they have symptoms, said Michael K. Shochat, M.D., of Hillel Yaffe Heart Institute in Hadera, Israel, and lead author of the study. Shochat is also president of RS Medical Monitoring, the Israel-based company that manufactures the Edema Guard Monitor.

"By the time a patient shows clinical signs of pulmonary congestion, the condition is already at an advanced stage," Shochat said. "Many patients need emergency hospitalization and have a high probability of sustaining irreversible damage to the heart and lungs. In this study, patients who used the Edema Guard Monitor started taking medication well before pulmonary congestion reached an advanced stage."

The Edema Guard Monitor--a stand-alone device--measures lung impedance, or resistance to electrical current, Shochat said. Healthy, air-filled lungs are highly resistant to electrical current, whereas lungs swollen by fluid are less resistant. In pulmonary congestion, the lungs gradually become more and more swollen by fluid. Existing techniques for monitoring worsening pulmonary congestion, such as periodic chest X-rays or computed tomography (CT) scans of the lungs, are costly or not highly effective. Preliminary studies had suggested that lung impedance-guided treatment could reduce hospitalizations for heart failure.

"This study shows for the first time that a noninvasive lung impedance monitor can be used to detect pulmonary congestion in its earliest stages and that adequate medical treatment at that early stage can significantly reduce both hospitalizations and mortality," Shochat said.

The IMPEDANCE-HF trial was conducted at two medical centers in Israel and included 256 patients with chronic heart failure whose hearts were pumping blood at less than half of the normal rate. Patients were 67 years of age on average, and 80 percent were male. Before patients were randomized, they received three months of treatment through outpatient clinics to achieve maximal doses of guideline-directed medications to manage congestive heart failure. All patients attended monthly outpatient visits during which a technician measured their lung congestion using the Edema Guard Monitor and their physician performed a standard clinical assessment.

Patients were randomly assigned to one of two groups. In the treatment group, medication was prescribed or adjusted at each visit based on the results of clinical assessment and lung congestion measurement with the Edema Guard Monitor. In the control group, medication was prescribed or adjusted based on clinical signs of lung congestion. The primary endpoint was hospitalizations due to heart failure. Secondary endpoints were hospitalizations and deaths from any cause. The average follow-up time was 48 months in the treatment group and 39 months in the control group.

In the treatment group compared with the control group, hospitalizations due to heart failure decreased by 58 percent during the first year of treatment, and the frequency of heart failure-related hospitalization decreased by 56 percent per year during the entire follow-up period, meeting the study's primary endpoint. For the entire follow-up period, deaths from heart failure were reduced by 62 percent per year and deaths from any cause decreased by 39 percent per year in the treatment group compared with the control group.

The hope is that patients will eventually be able to use the device at home to measure their lung impedance once or twice a day, Shochat said.

A limitation of the study is that it excluded patients with less severe heart failure, or those whose hearts were pumping blood at more than half of the normal rate, and that the results cannot be extended to that group of patients, Shochat said. Results from an ongoing randomized trial of the Edema Guard Monitor in patients with less severe heart failure are expected in 2019.

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Two atrial fibrillation ablation techniques equal on efficacy and safety

Two established techniques for correcting the root cause of the heart rhythm disorder atrial fibrillation show similar effects and safety outcomes, according to research presented at the American College of Cardiology's 65th Annual Scientific Session.

The study, called FIRE AND ICE, is the largest randomized trial to compare radiofrequency and cryoballoon ablation, two techniques designed to treat atrial fibrillation by disabling small portions of the heart that generate out-of-sync electrical signals. Radiofrequency ablation uses heat energy to disable the targeted heart tissue, while the cryoballoon, a newer technique, uses extreme cold to achieve the same effect. The trial revealed no differences between the two techniques for the study's primary outcomes--the recurrence of an irregular heart rhythm or the need for medication or subsequent procedures to address atrial fibrillation. It was funded in part by Medtronic, which makes the cryoballoon device.

"The FIRE AND ICE trial demonstrated that the cryoballoon, a newer, easier-to-use ablation catheter, worked as well as the established technology, which ultimately means that more patients can be treated for atrial fibrillation without having [to go to a] specialized cardiac center," said Karl-Heinz Kuck, M.D., Ph.D., head of cardiology at St. Georg Hospital in Hamburg, Germany, and the study's lead author. "In addition, there was, in general, a low risk of procedural complications in both groups, demonstrating that catheter ablation has become much safer over the years."

Atrial fibrillation, estimated to affect more than 33 million people worldwide, is an irregular heart rhythm that can cause fatigue, lightheadedness, shortness of breath, chest pain and an increased risk for stroke. Although medications and lifestyle changes can help manage the condition's risk factors and symptoms, about 30 percent of patients do not benefit from available medications or cannot take them due to side effects or other reasons. Ablation is one option for treating these patients. During ablation, a physician threads a small medical device through a vein in the groin to kill a small number of cells around the heart's pulmonary veins, preventing them from issuing electrical signals that are out of sync with the rest of the heart.

The trial, conducted in eight European countries, enrolled 769 patients needing ablation for intermittent atrial fibrillation. Patients were randomly assigned to receive either the radiofrequency or cryoballoon technique; both patients and physicians were aware of which technique was being used. The two groups were similar in terms of demographic factors, such as age and gender, as well as health status, based on parameters such as body mass index, blood pressure and various measures of heart function.

In addition to using different methods for disabling the target heart tissue, the two techniques involved different procedures to help the physician locate the target tissue. For radiofrequency procedures, physicians were guided by 3-D electroanatomical mapping to create tissue lesions in a point-by-point ablation approach. For cryoballoon procedures, physicians used a type of X-ray imaging known as fluoroscopy to create tissue lesions in a single-step ablation approach.

Outcomes were assessed through in-person patient visits conducted three months after the procedure, six months after the procedure and every six months thereafter. Each visit included an electrocardiogram test to assess heart rhythm and function, as well as the use of a Holter monitor, in which the patient wears a monitor for 24 hours to check for any abnormal heart rhythm. Patients were tracked for just over 18 months, on average.

The results revealed no significant difference in the rates of recurrence of an irregular heart rhythm or the need for medication or subsequent procedures to address atrial fibrillation, outcomes that collectively occurred in 64.1 percent of patients receiving radiofrequency ablation and 65.4 percent of cryoballoon patients within 12 months after the procedure.

There were also no significant differences in the overall safety profile of the two techniques. Safety was assessed with a composite endpoint of death, stroke and procedure-related serious adverse events; 87.2 percent of patients receiving radiofrequency ablation and 89.8 percent of cryoballoon patients had not experienced any of these safety endpoints by 12 months after the procedure.

In both groups, there was generally a low rate of procedure-related complications such as infection, dangerous heart rhythms or accumulation of fluid in the heart. However, patients receiving cryoballoon ablation were significantly more likely to experience injury to the phrenic nerve, which can affect the functioning of the diaphragm and require patients to use an artificial ventilator. Such injuries occurred in 2.7 percent of cryoballoon patients and zero patients receiving radiofrequency ablation. In all but one of these cases, functioning was restored by 12 months post-operation.

The study revealed some significant procedural differences between the two techniques. Because it involved 3-D anatomical mapping, radiofrequency ablation required about five minutes less fluoroscopy time and, thus, exposed patients and physicians to radiation for a shorter period of time, though Kuck said that the overall usage of fluoroscopy was relatively limited in both groups, at 21.7 minutes and 16.6 minutes total on average for the cryoballoon and radiofrequency procedures, respectively. Cryoablation was associated with a shorter overall procedure time by 18 minutes per procedure, on average, and a similarly reduced amount of time in which the catheter was present inside the heart's left atrium while the ablation was carried out.

"The procedure time was interesting because there are more cost pressures on the healthcare system for more efficient tools that keep procedures short and predictable," Kuck said.

Kuck said the findings could help inform future medical guidelines on the use of different catheter ablation techniques for treating atrial fibrillation. One limitation of the study is that it did not investigate ablation for treating patients with more advanced stages of atrial fibrillation. A separate trial would be needed to assess the ablation techniques' effectiveness and safety for that patient population, he said.

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No improvements with losmapimod after heart attack

Patients taking losmapimod, an anti-inflammatory drug currently being developed, for 12 weeks following a heart attack did not show improvements in the trial's primary endpoint, the rate of cardiovascular death, subsequent heart attack or urgent coronary revascularization, which includes placement of a stent or coronary artery bypass surgery, according to research presented at the American College of Cardiology's 65th Annual Scientific Session.

The findings are from the initial phase of a losmapimod trial involving 3,500 patients. Because the trial failed to meet its primary endpoint, study authors said the second phase trial involving 22,000 patients will not go forward. However, in a finding that could warrant further study, the trial offers some evidence that the drug may benefit a subset of patients experiencing the most severe form of heart attack, ST-segment elevation myocardial infarction, or STEMI.

"Overall the results were neutral, showing no evidence of efficacy in our primary analysis," said Michelle O'Donoghue, M.D., a cardiologist and investigator in the TIMI Study Group at Brigham and Women's Hospital and the study's lead author. "We did, however, see intriguing signals toward there potentially being some efficacy in ST-elevation myocardial infarction patients. But because that signal was only within a smaller subgroup, we would need to validate those findings in a new study in order to confirm such an effect."

Although inflammation is a natural part of the body's response to injury, in some cases it can cause more harm than good. Inflammation is thought to increase cardiovascular risk after a heart attack by affecting the healing of heart muscle tissue, increasing the formation of plaque in the arteries and raising the likelihood that plaque will dislodge and cause another heart attack.

Losmapimod was developed to counteract these effects by inhibiting p38 mitogen-activated protein kinase, an enzyme present inside heart muscle cells and other cell types and that is activated by stressors such as a heart attack, heart failure or persistent high blood pressure. Earlier pilot studies involving several hundred patients suggested losmapimod could reduce inflammation in patients undergoing stenting procedures and hinted that it might help protect against major adverse cardiovascular events.

The new trial, LATITUDE-TIMI 60, the largest losmapimod study to date, was a randomized, double-blind staged phase 3 trial involving 3,500 patients hospitalized with an acute heart attack at 322 hospitals in 34 countries. Half of the patients received 7.5 milligrams of losmapimod twice daily and half received a placebo.

After 12 weeks, a preliminary analysis showed no differences in rates of cardiovascular death, subsequent heart attack or urgent coronary revascularization among the group receiving losmapimod as compared to those receiving a placebo.

Although the trial was not large enough to conclusively demonstrate effects in specific patient subgroups, O'Donoghue said further study on losmapimod's effects in the heart may help to identify particular cases in which it could be beneficial.

"We are intrigued by the potential signal towards benefit, which was supported, at least in concept, by an earlier study that showed favorable effects in terms of left ventricular function following myocardial infarction. Thus, it remains possible that losmapimod may have favorable effects on healing of the heart after a heart attack, but that would require a separate study," O'Donoghue said.

In addition, other drugs designed to curb the inflammatory response may yet show promise.

"Although our study showed no efficacy, I think these results are not to say that we won't eventually find a therapeutic agent that targets pathways related to inflammation and shows clinical benefit. There are other trials that are ongoing that are targeting other inflammatory pathways, and the hope is that one of those compounds will demonstrate clinical efficacy," O'Donoghue said.

The study had a relatively small size and short duration. Enrolling more patients could potentially have put the study in a better position to more thoroughly evaluate the drug's effects, particularly in patient subgroups. It is also possible that taking the drug for more than 12 weeks would have yielded more benefits for patients. Further study would be required to address these limitations.

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US prediction models for kidney injury following angioplasty hold up in Japan

Models developed by the American College of Cardiology NCDR CathPCI Registry to predict the likelihood of angioplasty patients developing acute kidney injury and acute kidney injury requiring dialysis have proven to be effective among patients in Japan. This finding suggests these models may have international application as a preventive tool, according to a study published in the Journal of the American College of Cardiology.

Acute kidney injury is a condition characterized by an abrupt or rapid decline in kidney function. It is the most common non-cardiac complication following angioplasty and is associated with an increased risk of other complications, as well as death. This condition often can be prevented, however, by administering fluids and using cholesterol-lowering medications before conducting the procedure. By knowing who is at highest risk for acute kidney injury, it is possible to take these steps and prevent this complication.

The prediction models from the NCDR CathPCI Registry were applied to records from 11,041 patients from the Japan Cardiovascular Database, a registry comprised of 16 centers, between September 2008 and May 2014. The acute kidney injury model used 11 variables for predicting this complication, including age, baseline presence of kidney impairment, a history of stroke or heart failure, and prior angioplasty. The acute kidney model involving dialysis used five variables: baseline presence of kidney impairment, diabetes, heart failure, presence of acute coronary syndrome, and cardiogenic shock.

Researchers found 10.1 percent of the patients experienced acute kidney injury and 1.5 percent had a kidney injury that required dialysis. Patients who experienced an acute kidney injury tended to be older, have more heart failure and kidney dysfunction prior to angioplasty, and a greater number of other medical conditions.

The study found that overall, the prediction model for acute kidney injury performed well. In the highest-risk group, the predicted incidence of acute kidney injury was 34 percent, compared to a 36 percent actual occurrence of the problem. Similar performance was observed among patients with and without acute coronary syndrome.

For patients with acute kidney injury requiring dialysis, the predicted risk was 4 percent, compared to a 9 percent observed incidence. This discrepancy showed that the model underestimated the risk of dialysis among the highest-risk patients. Once the model was adjusted properly, it was better able to stratify risk.

Taku Inohara, M.D., the study's lead author and a cardiologist at Keio University School of Medicine in Tokyo, said that "these findings support the use of the NCDR models in Japan" and pointed out that knowing a patient's risk for acute kidney injury enables the provider to tailor treatment accordingly. "Given the validity of the NCDR acute kidney injury models in Japan, future research on how to best leverage these insights about patient risk to minimize the onset of acute kidney injury is warranted," he said.

"This is an example of how registries, like NCDR, can provide important information that once it is validated - as it is in this paper - can change practice," said Valentin Fuster, M.D., Ph.D., Journal of the American College of Cardiology editor-in-chief.

In an accompanying editorial, Peter A. McCullough, M.D., M.P.H., FACC, vice chief of medicine at Baylor University Medical Center in Dallas, said that the study is "an excellent example of how the NCDR Registry can be used to generate meaningful tools for prediction of complications that are set up for external validation from populations outside of the United States." He adds that because there are increasing numbers of patients with advanced kidney disease undergoing angioplasty, "there is an urgent need for safer approaches for these high-risk patients."

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Evacetrapib fails to reduce major adverse cardiovascular events

Despite lowering low-density lipoprotein (LDL), known as "bad" cholesterol, while markedly increasing levels of high-density lipoprotein (HDL), or "good" cholesterol, a large clinical trial to investigate the cholesterol drug evacetrapib was discontinued early after a preliminary analysis showed it did not reduce rates of major adverse cardiovascular events, according to research presented at the American College of Cardiology's 65th Annual Scientific Session.

The favorable effects on cholesterol did not translate into any reduction in the study's primary endpoint: the amount of time until cardiovascular death, heart attack, stroke, coronary artery bypass surgery or hospitalization for chest pain due to unstable angina, a restriction in the flow of blood through the heart's arteries.

"Here we've got an agent that more than doubles the levels of good cholesterol and lowers bad cholesterol and yet has no effect on clinical events," said Stephen Nicholls, M.B.B.S, Ph.D., a professor at Australia's University of Adelaide, cardiologist at Royal Adelaide Hospital and the study's lead author. "We were disappointed and surprised by the results."

The study was a phase 3, randomized, double-blind trial conducted in approximately 540 global health centers involving more than 12,000 patients at high risk for serious cardiovascular problems. Participants were randomized to receive either 130 milligrams of evacetrapib or a placebo daily for at least 18 months. All patients also received standard medical therapy throughout the trial, which in a vast majority of cases included treatment with statins or other cholesterol-lowering drugs.

On average, patients taking evacetrapib lowered their LDL cholesterol by 37 percent and increased their HDL cholesterol by 130 percent compared with patients taking a placebo. However, there was no difference between the two groups in terms of the study's primary endpoint.

The findings make evacetrapib the third failure in a class of drugs known as cholesteryl ester transfer protein (CETP) inhibitors, which are designed to disrupt the natural process by which HDL cholesterol is converted into LDL cholesterol in the body. The first such drug, torcetrapib, was abandoned after a phase 3 clinical trial revealed it increased the risk of cardiovascular events and death. Development of a second CETP inhibitor, dalcetrapib, was stopped when a phase 2 clinical trial found the drug to be ineffective.

"There has been, and continues to be, a lot of confusion about what's going on with this class of drugs, since we don't yet have one that can be brought to the clinic to prevent heart attack and stroke in our patients," Nicholls said. "As we close out the trial, we're trying to understand how a drug that seems to do all the right things in terms of blood cholesterol levels doesn't then translate into reducing clinical events."

The results raised no safety concerns for evacetrapib and did not reveal any major side effects. Nicholls said the findings could offer evidence challenging conventional thinking regarding the benefits of HDL cholesterol in protecting against cardiovascular problems. Another possible explanation is that existing treatments, such as statins, are already so effective at improving cardiovascular outcomes that it has become more difficult to further improve outcomes in high-risk patients. Alternatively, the results could indicate that evacetrapib's active ingredient or the biological pathway it is designed to affect simply has no effect on cardiovascular risk.

All study participants either had an acute coronary syndrome such as a heart attack or unstable angina 30 days to one year before enrolling; had cerebrovascular atherosclerotic disease, in which the arteries that supply blood to the brain become constricted; had peripheral vascular disease, a group of disorders affecting blood vessels outside of the heart and brain; or had both diabetes and coronary artery disease.

"We tested the drug in high-risk patients because they are the patients with the greatest need for new drugs above and beyond what we already use in our clinics," Nicholls said. "Low risk patients could be another group of patients that could potentially benefit from this drug, but we didn't test that and to do so would require an extraordinarily large study that asks a different question from the one our study was designed to address."

The study was funded by Eli Lilly, a company for which Nicholls has served as a consultant. Nicholls has received research support or consulting fees from other pharmaceutical companies including AstraZeneca, Amgen, Novartis, Cerenis and others.

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Tool to engage patients with chest pain in care decisions shows benefits

Patients visiting a hospital emergency department with chest pain who engaged with their physician in shared decision-making using a tool called Chest Pain Choice showed improved knowledge of their health status and follow-up care options compared with patients who received standard counseling from a physician without the use of this decision aid, according to research presented at the American College of Cardiology's 65th Annual Scientific Session.

Chest Pain Choice is the first patient-oriented tool designed to facilitate shared decision-making between physicians and patients in the context of chest pain, a complaint that accounts for about eight million emergency department visits and 20 percent of all hospital admissions each year in the United States. In addition to improving patient knowledge, the study's primary outcome, the decision aid substantially improved patient engagement and reduced the use of stress tests with no adverse effects on safety.

"From a human rights perspective, patients have made it clear that one way they interpret the idea of 'care with dignity' is being involved in their health care decisions," said Erik Hess, M.D., an emergency medicine physician and health services researcher at Mayo Clinic and the study's lead author. "This trial shows that doing so can have a beneficial effect on patient knowledge, as well as other outcomes such as patient engagement and, sometimes, appropriate utilization of testing. I would recommend that this intervention be adopted more widely."

The trial, which involved 899 patients visiting six emergency departments in five states, expanded upon a promising earlier pilot study conducted at Mayo Clinic, where the Chest Pain Choice tool was developed. The tool consists of a one-page printable information sheet that provides user-friendly descriptions and graphics depicting a patient's specific risk profile - for example, a pictogram to help patients visualize what it means to have a 2 percent risk of having a heart attack in the next 45 days - and their health management options. Based on a patient's initial test results and medical history, health care providers select the appropriate information sheet for a given patient and then use it to facilitate a dialogue with the patient and work together to determine the appropriate next steps.

"The tool itself doesn't recommend a specific management decision - it just makes transparent what the options are," Hess said. "By setting out all the options, the tool enables patients to participate in their care decisions to the degree that they wish."

When a patient visits the emergency department complaining of chest pain, a blood test can quickly determine whether a heart attack is underway. But in patients who are not experiencing a heart attack - which accounts for more than 90 percent of those who come to the emergency department with chest pain - further testing may be needed to determine whether the patient faces an increased risk of a heart attack or other serious heart problem in the near future. Chest Pain Choice was designed to help these patients.

The appropriate follow-up care for each patient depends on risk factors such as health conditions, family history and initial test results. Higher-risk patients may benefit from staying at the hospital overnight and undergoing intensive cardiovascular testing, while lower-risk patients may need to simply follow up with their primary care physicians for ongoing health management.

In part, the Chest Pain Choice intervention was developed as a way to reduce unnecessary testing and hospital admissions.

"Even low-risk patients are often admitted to the hospital and given more advanced cardiac testing," Hess said. "Over-testing of low-risk patients frequently results in false positive test results, which leads to unnecessary intensive and invasive testing, such as coronary angiography and repeat stress testing. This over-testing has been estimated to waste $3-10 billion annually."

In the trial, half of patients were randomly assigned to receive a physician discussion facilitated with Chest Pain Choice, while the other half received a standard physician consultation. Patients receiving Chest Pain Choice showed increased knowledge about their risk and options, answering 53 percent of questions on a questionnaire correctly, compared with 44.6 percent in the control arm. Patients receiving the decision aid were about twice as engaged in the decision-making process, as evaluated by an objective analysis of videotaped patient-physician interactions.

Patients were also asked to reflect on the experience of discussing their care with their physician and the degree to which they felt conflicted or uninformed about their options. Patients receiving Chest Pain Choice reported significantly better experiences in both measures, with 68.9 percent stating they would recommend the way that they and their physician had shared information and 43.6 percent feeling conflicted, compared with 61.2 percent and 46.4 percent, respectively, in the control arm.

"What we heard from our patients and patient advisory group when designing the tool is what they fear the most is not knowing what's going on or why they're getting various tests," Hess said. "When that happens, your imagination often blows the problem out of proportion and increases fear and anxiety. I think this tool helps patients better connect with their physician and calibrates their degree of anxiety to their objective level of risk - and in this way they are more knowledgeable of what's going on and can feel more in control."

Chest Pain Choice was associated with no major adverse cardiovascular events and led to a significantly lower proportion of patients receiving a stress test, performed in 37.4 percent of patients receiving the decision aid and 46.3 percent in the control arm, suggesting the intervention was successful in reducing unnecessary testing.

When physicians engaged with their patients in shared decision-making using Chest Pain Choice, the length of the consultation was 1.3 minutes longer on average. A limitation of the trial is that it did not assess whether increased consultation length alone had benefits apart from the use of the decision tool itself. Further research would be needed to address that question.

The study was funded by the Patient-Centered Outcomes Research Institute.

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Daily vitamin D-3 supplementation may benefit heart failure patients

For patients with chronic heart failure, daily supplementation with vitamin D-3 may improve heart function. This is the conclusion of a new study recently presented at the American College of Cardiology 65th Annual Scientific Session & Expo in Chicago, IL.
[A man holding a heart]
Daily supplementation with vitamin D-3 improved heart function for heart failure patients in the new study.

In the US, around 5.1 million people have heart failure, which occurs when the heart is unable to pump enough oxygen-rich blood around the body to support other organs.

The prognosis for heart failure patients is poor; around 50% of those diagnosed with the condition die within 5 years of diagnosis.

But according to Dr. Klaus Witte, of the University of Leeds School of Medicine in the UK, and colleagues, a daily vitamin D-3 supplement could benefit heart function for patients with chronic heart failure.

The researchers note that patients with heart failure often experience vitamin D deficiency; heart failure is most common among adults aged 65 and older, and older individuals tend to make less vitamin D-3 in response to sunlight than younger individuals.

To reach their findings, the team enrolled more than 160 patients who were being treated for heart failure at Leeds Teaching Hospitals National Health Service (NHS) Trust, where Dr. Witte is a consultant cardiologist.

For 1 year, 80 of the patients were asked to take a vitamin D-3 supplement every day, while the remaining patients were required to take a placebo.

Vitamin D-3, or cholecalciferol, is the form of vitamin D that is produced in the body in response to sunlight exposure.

At the end of the study period, the team used an echocardiogram to measure any changes in patients' heart function, including their ejection fraction - how well the heart pumps out blood with each heartbeat.

A healthy individual will normally have an ejection fraction of 60-70%, but the ejection fraction is impaired among people with heart failure. In this study, patients had an average ejection fraction of 26%.

While heart failure patients who took the placebo showed no improvement in cardiac function, those who took a daily vitamin D-3 supplement showed an improvement in ejection fraction, increasing from 26% to 34%.

Explaining what the results may mean for individuals with heart failure, Dr. Witte says:

"This is a significant breakthrough for patients. It is the first evidence that vitamin D-3 can improve heart function of people with heart muscle weakness - known as heart failure. These findings could make a significant difference to the care of heart failure patients."

The researchers say their results indicate that for some patients with heart disease, regular supplementation with vitamin D-3 may reduce their need for an implantable cardioverter defibrillator (ICD).

An ICD is battery-powered device that is implanted under the skin and connected to the heart with thin wires. The device monitors heart rhythm. On detecting any abnormalities, it delivers an electric shock to the heart, restoring normal rhythm.

"ICDs are expensive and involve an operation," says Dr. Witte. "If we can avoid an ICD implant in just a few patients, then that is a boost to patients and the NHS as a whole."

Medical News Today recently reported on a study suggesting that measuring levels of two components of vitamin D - total vitamin D and bioavailable vitamin D - could predict the risk of poor cardiovascular health.

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Deferred stenting shows no clinical benefit

Delayed or deferred stent implantation in patients experiencing the deadliest form of heart attack - ST-segment elevation myocardial infarction (STEMI) - failed to reduce death from any cause, hospitalization for heart failure, subsequent heart attacks or the need for a repeat procedure to restore blood flow to the heart, researchers reported at the American College of Cardiology's 65th Annual Scientific Session.

"The take-home message from this study is that deferred stent implantation cannot be recommended as a routine procedure for STEMI patients treated with primary percutaneous coronary intervention," said Henning Kelbaek, M.D., of Roskilde Hospital, University of Copenhagen, Denmark, and lead author of the study. "Our results completely rebut the promising findings of preliminary studies that suggested deferred stenting should translate to clinical benefit."

STEMI is a severe form of heart attack caused by prolonged blockage of blood supply in the heart. It requires immediate angioplasty, a non-surgical procedure in which a balloon is fed into the blood vessels through a catheter and inflated to open, narrowed or blocked arteries, allowing blood to flow. A stent is usually placed at the blockage site to keep the artery open. In the United States, about 250,000 people experience a STEMI every year.

After the blocked artery is opened, the blockage site often contains residual blood clots that may, when the stent is implanted, be displaced downstream into the small branches of the artery. If this happens, it can damage heart muscle and block small blood vessels. Previous small studies suggested that delaying stent implantation for a period of time ranging from several hours to several days after reopening the artery might reduce the risk of blood-flow disturbance. The thinking was that medication given during the delay might allow the residual blood clots to diminish, reducing the risk of a displaced clot damaging the small branches of the artery. The DANAMI-3-DEFER trial was the largest trial yet conducted to evaluate whether delaying stent implantation would improve patients' survival and reduce their risk of heart failure or another heart attack.

In the trial, which took place in Denmark, 1,234 patients (average age 61; 75 percent male) with acute STEMI symptoms of less than 12 hours' duration were randomly assigned to receive standard angioplasty with immediate stent implantation or angioplasty followed by stent implantation after a re-examination 24 to 48 hours later. After an average follow-up time of 43 months, 105 patients or 17 percent in the DEFER group and 109 or 18 percent in the standard treatment group met the primary endpoint, a composite of death from any cause, hospitalization for heart failure, a second heart attack, and unplanned repeat angioplasty, a nonsignificant difference.

Although the trial was the largest so far to address the issue of delayed stent implantation, it may not have been large enough to detect a difference between the two treatment groups, Kelbaek said. Another limitation is that the trial did not select patients who were at the highest risk for developing another arterial blockage, such as those over age 65, those who have had more than one heart attack or those known to have a large number of blood clots.

"We cannot rule out that a fraction of our patients who met these criteria might have benefitted from delayed stent placement, especially because we found a small improvement in heart-muscle function 18 months after treatment among patients who underwent deferred stenting," Kelbaek said.

The study was not powered to detect this improvement, but Kelbaek said he and his team would now look carefully for possible "hypothesis-generating" findings in subsets of patients - both those who might have benefitted from the deferred-treatment strategy and, equally important, those in whom this strategy might have worsened their condition.

The DANAMI-3-DEFER trial was funded by the Danish Agency for Science, Technology and Innovation and Danish Council for Strategic Research.

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

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No improvement in clinical outcomes with ischemic postconditioning

A large randomized controlled trial of ischemic postconditioning in patients who had experienced the deadliest form of heart attack - ST-segment elevation myocardial infarction (STEMI) - failed to show that this procedure significantly reduces death from any cause or hospitalization for heart failure, according to research presented at the American College of Cardiology's 65th Annual Scientific Session.

STEMI is a severe form of heart attack caused by prolonged blockage of blood supply in the heart. It requires immediate angioplasty, a non-surgical procedure in which a balloon is fed into the blood vessels through a catheter and inflated to open narrowed or blocked arteries, allowing blood to flow. A stent is often placed at the blockage site to keep the artery open. In the United States, about 250,000 people experience a STEMI every year.

Ischemic postconditioning is a variation on angioplasty that involves using 30-second bursts of blood flow interspersed with 30-second pauses to restore blood flow to the heart.

"Abrupt reperfusion by angioplasty may itself damage the heart muscle," said Thomas Engstrøm, M.D., Ph.D., of Rigshospitalet University of Copenhagen, Denmark, and lead author of the study. "The thinking was that performing the reperfusion in a gentle, graded fashion would protect the heart against reperfusion injury."

Studies suggest that up to 35 percent of patients may experience reperfusion injury during angioplasty, he said.

Earlier studies in STEMI patients showed that ischemic postconditioning improved ST-segment resolution - an important marker of arterial blockage on electrocardiogram - reduced damage to heart muscle, and in some patients limited the extent of reperfusion injury. It was unclear, however, whether these improvements ultimately reduced hospitalizations or improved patient survival.

The DANAMI-3 iPOST trial, which took place in Denmark, included 1,234 patients (average age 61; 79 percent male) with acute STEMI symptoms of less than 12 hours' duration who were randomly assigned to receive standard angioplasty or ischemic postconditioning prior to stent implantation in the blocked artery. The primary endpoint was a composite of death from any cause and hospitalization for heart failure. Patients were followed for a minimum of two years, with an average follow-up time of 39 months.

Deaths from any cause and hospitalizations for heart failure - the primary endpoint, were reduced by 7 percent in patients who received iPOST compared with those who received standard angioplasty, but this result did not reach statistical significance, Engstrøm said. Although the primary endpoint was not met, a statistically significant 4 percent improvement was seen in a secondary endpoint, left ventricular ejection fraction - a measure of how much blood is being pumped out of the left ventricle - in patients whose STEMIs involved the front wall of the left ventricle (the heart's main pumping chamber), he said.

"This may translate into improved survival over more years of follow-up," Engstrøm said.

This study was the first large clinical trial designed to evaluate clinical outcomes in STEMI patients, as opposed to surrogate endpoints such as ST-segment resolution, Engstrøm said. He said larger trials may be required to definitely establish whether ischemic postconditioning improves clinical outcomes.

A limitation of the study is that the physicians performing the angioplasties cannot be blinded to the treatment group that patients are assigned to, Engstrøm said.

The DANAMI-3 iPOST trial was funded by the Danish Agency for Science, Technology and Innovation and Danish Council for Strategic Research.

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International technology-based competition associated with more exercise

A competition that used technology to encourage and track physical activity was effective at helping participants lose weight and exercise more in both developed and developing countries, according to a study presented at the American College of Cardiology's 65th Annual Scientific Session.

The researchers analyzed the records of more than 68,000 people in 64 countries who competed in small teams to increase their daily physical activity levels during a 100-day technology-based "virtual race." They found that on average, participants increased their amount of walking by more than 3,500 steps per day, exercised nearly one additional day per week, lost just over 3 pounds and reduced their time spent sitting by about 45 minutes per day.

"Physical inactivity, sedentary lifestyles and obesity are massive global problems that affect high-, middle- and low-income countries," said Anand Ganesan, MBBS, Ph.D., associate professor at Flinders University in Adelaide, Australia, and the study's lead author. "We need tools to get people moving that are attractive to consumers, that are affordable and that work on a large scale. Our study suggests that by using technology in a clever way, perhaps we, as a community, can devise solutions to this problem."

The research is based on participant data for a 100-day international event known as Stepathlon. During annual Stepathlon events, participants are organized into workplace-based teams of five, issued an inexpensive pedometer and encouraged to increase their daily step count through an interactive, multi-platform application that engages them with frequent emails, quizzes and social media communication. Each five-person team competes with other teams around the world in a virtual race that culminates with prizes awarded in various categories at the end of the 100-day period.

"The idea is to increase physical activity and wellness, but in a fun and social way that builds on teamwork and camaraderie," Ganesan said. "Stepathlon combines a number of lessons that we know are important to helping people change their activity levels and lose weight - it uses the power of mobile technology to remind users of the need to move, it provides a social group that encourages moving, and it builds on the lessons we have learned about self-monitoring using pedometers."

Using data from Stepathlons held in 2012, 2013 and 2014, the research team analyzed participants' physical activity and weight before and after each 100-day Stepathlon event. The results revealed improvements in all four parameters measured - daily step count, number of days per week in which participants exercised, amount of weight lost and minutes per day spent sitting.

More than 90 percent of participants were from low- and middle-income countries, and the results were consistent across countries of all income levels. "To our knowledge, our study is the first to provide comparative data on the effectiveness of this kind of intervention in both the developed and developing world," Ganesan said.

The results were also consistent in both men and women and were similar across all three years studied.

Stepathlon is run by a start-up company in Mumbai, India, that charges a fee for participation. Generally, its fees - $62.50 per participant or $312.50 per team of five - are paid by companies that invite their workers to enroll as part of a workplace wellness program.

Ganesan said a key goal for future research is to evaluate whether the improvements were sustained after the Stepathlon ended. One limitation of the study is that researchers relied on self-reports from participants regarding weight and other parameters, rather than objective measurements. However, the large number of people included in the study and the fact that similar benefits were seen across all three years studied offer reassurance that the findings are robust, Ganesan said.

Being physically active and maintaining a healthy weight are seen as important parts of a heart-healthy lifestyle. Obesity, physical inactivity and spending too much time sitting down have been associated with increased risk of cardiovascular disease, adverse cardiac events and death.

Ganesan receives financial support from the National Health and Medical Research Council of Australia. The researchers have no financial relationship with the start-up company Stepathlon, which provided data on an unrestricted basis for the purpose of scientific research.

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Higher volume of TAVR boosts key in-hospital outcomes

The more frequently a hospital performs a minimally invasive technique called transcatheter aortic valve replacement, or TAVR, to replace a damaged aortic heart valve, the better patients fare, on average, immediately after the procedure, researchers reported at the American College of Cardiology's 65th Annual Scientific Session.

TAVR is a procedure in which a surgeon threads a replacement valve to the heart mounted on a long, thin tube called a catheter that is placed in the groin or chest, avoiding open-heart surgery. TAVR was first approved by the U.S. Food and Drug Administration (FDA) in 2011 to treat patients with severe aortic valve stenosis - a problem that occurs when the valve in the heart's main artery doesn't open fully and forces the heart to work harder to pump blood - for whom standard surgical valve replacement is too risky.

"In a large data set of over 40,000 cases of TAVR performed in the first four years after the technology was approved by the FDA, we found that outcomes significantly improved first during the early learning phase. In addition, even after hospitals achieved a volume of 100 or so cases, there continued to be improvement in patient outcomes with higher procedure volume," said John D. Carroll, M.D., professor of medicine and director of interventional cardiology at the University of Colorado Hospital and lead author of the study.

The findings are important because they shed light for the first time on a key factor involved in determining patient outcomes following treatment with this novel procedure, Carroll said. This will help inform decisions by health care professionals, patients and payers about how to ensure the best outcomes for patients treated with this new technology, he said.

"These results support the view that the healthcare system as a whole benefits when hospitals perform procedures in higher volumes, improving outcomes," Carroll said.

When the FDA approved the first transcatheter aortic heart valve in November 2011, the national Transcatheter Valve Therapy (TVT) Registry was created to track patient outcomes from the use of the device. The registry, which is jointly maintained by the American College of Cardiology and the Society of Thoracic Surgeons, now contains data on over 50,000 patients whose TAVR procedures were performed at nearly 400 hospitals in the United States. The database is designed to provide information that can help hospitals improve the quality of care for patients with severe aortic stenosis and help patients make informed decisions about this new form of heart valve replacement. Carroll serves on the Steering Committee of the TVT Registry.

Carroll and his colleagues analyzed data for 43,000 patients in the database whose procedures were performed between November 2011 and July 2015. Patients whose procedures were performed for different types of valves or as emergency procedures were excluded from the analysis. The researchers looked at how many procedures each hospital performed and how often four outcomes - deaths, vascular complications, bleeding and stroke - occurred in the hospital following a TAVR procedure.

The average death rate following the procedure, adjusted to take account of varying patient risk levels, was 4.03 percent, Carroll said. Cumulative procedure volume at U.S. centers was a median of 80 cases, ranging from a handful of cases at some hospitals to more than 600 at the highest-volume centers, he said. Most hospitals established TAVR programs in the last four years, but some were active longer due to their participation in the original clinical research trials.

"Both unadjusted and risk-adjusted mortality showed a highly statistically significant association between volume and mortality," he said. In other words, generally speaking, performing a higher volume of TAVR procedures was associated with a lower death rate, he said. A similar association was seen for vascular and bleeding complications but not for stroke, which occurred at 2 percent.

The study has a number of limitations. First, the association of better outcomes with higher volume does not prove causality. The analysis attempted to control for other factors that could affect patient outcomes, such as differences in patient characteristics and the subsequent introduction of new valve technologies, but Carroll said these adjustments are not perfect. Second, the "early learning curve" could not be separated from the subsequent period that is commonly used to study the volume-outcome relationship. During the nearly four-year study period, the number of hospitals performing TAVR increased rapidly, and FDA-approved indications for the procedure expanded to include patients who could have surgery but were at high risk for serious complications or death from open-heart surgery, as well as those not eligible for conventional surgery. Furthermore, the technology itself was evolving, with several new models of the device coming onto the market while the study was underway.

"These findings are a first look at how procedure volume influences outcomes for a recently introduced technology," Carroll said.

Although procedure volume is important, volume is not a direct measure of quality, he said.

"The bottom line is not volume but the actual outcomes achieved at a center," he said. "In general, outcomes at U.S. centers are excellent. Furthermore, there are some lower-volume centers that have excellent outcomes and some higher-volume centers that do not have the best outcomes."

The TVT Registry provides quarterly reports to all participating hospitals, providing their results benchmarked against national averages. A major goal of the registry is to provide feedback to centers so they can continue to improve outcomes, Carroll said.

Currently, TAVR can be performed only at hospitals that meet qualifications laid out by the federal Centers for Medicare and Medicaid Services (CMS). A major question for CMS and professional societies, Carroll said, is whether to keep or revise these qualifications. The present study provides data and analysis that can help inform these decisions, he said. At the same time, rapid growth in the number of hospitals offering TAVR means that the vast majority of U.S. patients are reasonably close to more than one center that meets the CMS qualifications for providing TAVR, he said.

Researchers said further studies are also planned that use other methods to analyze the relationship between volume and outcomes, follow patients after discharge from the hospital, and assess how patient outcomes are affected as hospitals gain more experience with TAVR and the technology is refined over time.

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Genes causing high cholesterol are less common than previously thought

Only a small fraction of people with very high cholesterol can attribute their condition to a genetic mutation related to familial hypercholesterolemia, but individuals with these mutations face a high risk of developing early-onset coronary artery disease, according to research presented at the American College of Cardiology's 65th Annual Scientific Session.

The study, the largest gene sequencing analysis to date focused on individuals with very high cholesterol, demonstrates that familial hypercholesterolemia mutations are likely less common than previous studies had suggested. Despite the rarity of the mutations, however, the study illustrates the serious health consequences of familial hypercholesterolemia mutations, suggesting that genetic screening could help to identify and ward off early cardiovascular disease in affected individuals.

"Our findings suggest that if you performed widespread genetic screening of all individuals with very high LDL cholesterol, your yield would likely be low, but for the people who do have the mutations, the results could be quite meaningful," said Amit V. Khera, M.D., a cardiology fellow at Massachusetts General Hospital who performed the research with senior author Sekar Kathiresan, M.D., a Massachusetts General Hospital cardiologist and a geneticist at the Eli and Edythe L. Broad Institute of Harvard and MIT. "This knowledge would be relevant not only to people with familial hypercholesterolemia mutations but to their relatives as well."

The study's first objective was to determine the prevalence of a familial hypercholesterolemia mutation among people with low-density lipoprotein, or LDL, cholesterol levels of 190 mg/dl or higher, a level considered very high.

"Many clinicians assume that patients with LDL above 190 have a familial hypercholesterolemia mutation as the major driver," Khera said. "But there are a lot of other causes that can lead to this very high LDL, such as poor diet, lack of exercise and a variety of common genetic variants that each have a small impact on cholesterol but can add up to a big impact when they occur together."

Drawing upon genetic information from several large research studies, together representing more than 26,000 people, the team identified individuals with mutations in any of three known familial hypercholesterolemia genes. They found that of people with LDL of 190 or higher, just 2 percent had a familial hypercholesterolemia mutation.

Previous studies had suggested a mutation prevalence upwards of 25 percent, but those studies were limited to people with additional risk factors, such as a family history of high cholesterol, an abnormal physical exam or developing high cholesterol at an early age, in addition to current LDL of 190 or higher. This study is the largest to assess for familial hypercholesterolemia mutations among a broad population of people with elevated cholesterol.

The study's second objective was to examine the health impacts of having a familial hypercholesterolemia mutation, beyond the elevated cholesterol it causes. The researchers focused on early-onset coronary artery disease, or CAD, a condition in which plaque buildup causes the heart's main arteries to become constricted. CAD is considered early-onset when it occurs in men before age 55 or in women before age 65. Very high cholesterol is one of several known risk factors for CAD.

The results show that people with LDL of 190 or higher but no familial hypercholesterolemia mutation have a six times higher risk of early-onset CAD than people with LDL below 130, a level considered average. By contrast, people with LDL of 190 or higher who do have a familial hypercholesterolemia mutation face a 22 times higher risk of early-onset CAD. Although this increased risk is especially pronounced for those with LDL above 190, the study also found that people with a familial hypercholesterolemia mutation faced a substantially increased CAD risk even if their cholesterol level was only mildly elevated.

"One of the reasons for this increased risk is that if you have a mutation, your cholesterol is elevated from the time of birth," Khera said. "We think it is the cumulative exposure to LDL over the course of your lifetime that is the important factor here."

The research team used their genetic sequencing results to estimate that 412,000 of about 14 million adult Americans with an untreated LDL of 190 or higher have a familial hypercholesterolemia mutation.

The study's findings raise the question of whether screening for the mutations in all individuals with a high LDL would be desirable. Khera noted that a major goal of 'precision medicine' is to identify subsets of a population who face an increased disease risk and then design prevention and treatment strategies to address those specific risks. Identifying individuals with high LDL who carry a familial hypercholesterolemia mutation may represent one such opportunity. But while screening for a familial hypercholesterolemia mutation could potentially help doctors and patients work proactively to try to reduce CAD risk, there are a host of psychological and ethical issues to take into consideration before widespread implementation, Khera said.

Limitations of the study are that it focused on patients with early-onset CAD, rather than all CAD patients, and that it defined familial hypercholesterolemia as having a mutation in 1 of 3 genes for the disease: LDLR, APOB and PCSK9; ongoing work may identify additional genes that play an important role. Lastly, authors did not have access to detailed physical exam and family history features of study participants to enable direct comparisons to previous studies.

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Higher calcium intake 'may protect seniors from CVD, but not stroke, fractures'

When it comes to dietary calcium intake, there is good and bad news for older adults; while higher calcium consumption may lower the risk for cardiovascular disease, it does not reduce stroke or fracture risks.
[An older woman drinking milk]
Older adults may benefit from a lower CVD risk with a higher calcium intake, but it may not lower the risks for stroke and fractures.

This is the conclusion of a new study recently presented at Endo 2016 - the annual meeting of The Endocrine Society, held in Boston, MA.

Calcium is one of the body's most important minerals. Around 99% of the body's calcium supply aids the structure and functioning of bones and teeth, while the remaining 1% supports various metabolic functions, including cell signaling, blood clotting, muscle contraction, nerve function, heartbeat regulation and hormonal secretion.

Dairy products - such as milk, yogurt and cheese - are rich sources of calcium and make up most of Americans' calcium intake.

Green leafy vegetables, such as kale, broccoli, Chinese cabbage, turnip greens, collards and bok choy, are also good sources of the mineral, as are salmon, sardines - canned with bones - almonds, brazil nuts and sunflower seeds.

Calcium is also available as dietary supplements, primarily in the form of carbonate and citrate.

According to the National Institutes of Health (NIH), men aged 51-70 should aim to have 1,000 mg of calcium daily, increasing to 1,200 mg from the age of 71. Women's recommended daily intake of calcium is 1,200 mg daily from the age of 51.

Previous studies have suggested that higher calcium intake in older age may protect heart health, as well as reduce the risk of fractures.

However, such evidence has been conflicting. Last September, for example, Medical News Today reported on research that claims increasing calcium intake does not improve seniors' bone health.

"Moreover, participants in previous studies were from populations that had calcium-rich diets," notes the lead author of this latest study, Dr. Sung Hye Kong, of the Department of Internal Medicine at Seoul National University Hospital in South Korea.

For their study, Dr. Kong and colleagues set out to investigate how high calcium intake affects the risks for cardiovascular disease (CVD), stroke and fractures among older adults from a population with a low calcium intake.

How much calcium is in your food?

8 oz of plain, low-fat yogurt contains 415 mg of calcium 1.5 oz of cheddar cheese contains 301 mg A 3-oz serving of salmon contains 181 mg.

Learn more about calcium

To do so, the team analyzed data of 2,199 men and 2,704 women aged 50 and older - without a history of CVD or stroke - who were part of Korea's Ansung and Ansan Cohort Study. Beginning in 2001, the study followed participants for an average of 13 years.

The team assessed the dietary calcium intake of participants, determined through a food frequency questionnaire. Every 2 years, participants underwent health examinations and interviews, from which the researchers identified any CVD, stroke or fracture events.

Compared with subjects who had a lower calcium intake, those who had a higher calcium intake had a significantly lower risk of CVD, according to the results. However, no significantly reduced fracture or stroke risks were identified for those with a higher calcium intake.

These findings remained after the team accounted for numerous factors that may influence heart health and fractures, including age, body mass index (BMI), intake of fruits and vegetables, protein and sodium intake, total energy intake and women's menopausal status and use of hormonal therapy.

In October 2014, MNT reported on a study suggesting that a high milk intake may increase the risk of fractures and premature death.

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Rates of death and stroke equivalent for surgery and TAVR at two years

Intermediate-risk patients with severe aortic stenosis who receive minimally invasive transcatheter aortic valve replacement, known as TAVR, have similar rates of death and disabling strokes after two years compared with those undergoing standard open heart surgical replacement, according to a study presented at the American College of Cardiology's 65th Annual Scientific Session. Patients receiving TAVR also experienced shorter hospital stays and lower incidence of some major complications compared with those undergoing surgery.

Data from this non-inferiority trial - the first to evaluate TAVR in patients who are considered intermediate-risk - suggests TAVR is at least as safe and effective as surgery in these patients. Overall, the primary endpoint of all-cause death and disabling strokes was comparable at two years, 19.3 percent for TAVR and 21.1 percent for surgery. Among TAVR patients with transfemoral placement of the valve - the least invasive of two approaches in which the device is implanted through a small incision in the groin - the combined rate of death and disabling stroke was lower, 16.8 for TAVR compared with 20.4 percent for surgery (p-value=0.05).

"For the past five years, TAVR has been growing in use and acceptance largely based upon clinical evidence from multiple randomized controlled trials, but these have been limited to patients at the highest risk for surgery," said Martin B. Leon, M.D., professor of medicine and director of the Center for Interventional Vascular Therapy at Columbia University Medical Center-New York Presbyterian Hospital and co-principal investigator of the PARTNER trials. "Here, we demonstrate outcomes related to death and stroke, which are equivalent in these patients and may be superior in the transfemoral group."

To perform TAVR, a surgeon threads a replacement valve to the heart through a catheter placed in the groin or chest. TAVR is currently approved for patients with severe aortic stenosis - narrowing of the valve in the heart's main artery - whose health profile makes them ineligible or high-risk candidates for open-heart valve replacement surgery.

In this randomized controlled PARTNER 2A trial, outcomes using the SAPIEN XT valve were compared with open-heart surgery valve replacement among 2,032 intermediate-risk patients treated between December 2011 and November 2013 at 57 sites, all but two in the U.S. Patients were randomly assigned; 1,011 to TAVR and 1,021 to surgery. Of those in the TAVR group, 76 percent underwent transfemoral placement, and the rest had transthoracic placement in which the new valve is thread through a cut in the chest wall.

"When we compare transthoracic TAVR patients to those having surgery, they are about the same, so whatever benefit achieved related to lower rates of death and strokes was clearly in the transfemoral group," Leon said.

Researchers also found significant differences in secondary clinical endpoints looking at time in the hospital, valve function and major complications, some favoring TAVR, some surgery. For example, TAVR patients spent less time in the hospital overall - the average time in the ICU was two days with TAVR versus four days with surgery, and the average hospitalization for TAVR was six days compared to nine days with surgery. TAVR also appeared to improve the aortic valve areas more than surgery, meaning that the quality of the valve's performance was better as measured by echocardiography during follow-up points through two years.

Compared to surgery, TAVR also yielded significantly lower rates of acute kidney injury, severe bleeding events and new onset atrial fibrillation, a heart rhythm problem that is a common complication of open procedures. The surgery group, on the other hand, had fewer major vascular complications and leakage around the valve (para-valvular regurgitation).

The heart team discussed each individual case to determine if patients were indeed intermediate-risk. Baseline characteristics were comparable. All patients were followed for at least two years and will continue to be followed for five years.

"The two-year follow-up allows enough time to accurately assess the relative performance of these two valve replacement therapies," Leon said, adding that he suspects these findings will potentially affect clinical guidelines for TAVR in the future. "We know surgery is good, but it is still a major procedure and for many patients, a less-invasive approach may be the preferred alternative. As we continue to evolve the procedure and technology, it's important to know whether TAVR is an effective alternative in these lower risk patients."

Aortic stenosis happens when the aortic valve narrows or is blocked and therefore does not open fully. As a result, the amount of blood that can flow through the valve into the aorta and out to the body is restricted. If the condition is untreated, which usually involves valve replacement, the risk of death is 25 percent the first year after symptoms appear, and the risk rises to 50 percent the second year.

Roughly 1 in 5 patients undergoing surgical aortic valve replacement in the U.S. are estimated to be intermediate-risk; so together, intermediate- and high-risk patients comprise the top quartile of all patients needing an aortic valve replacement.

The study was funded by Edwards LifeSciences.

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Anti-inflammatory drug does not reduce risk of major cardiovascular events following heart attack

Michelle L. O'Donoghue, M.D., M.P.H., of Brigham and Women's Hospital, Boston, and colleagues evaluated the efficacy and safety of the anti-inflammatory drug losmapimod on cardiovascular outcomes in patients hospitalized after a heart attack. The study was published online by JAMA, and is being released to coincide with its presentation at the American College of Cardiology's 65th Annual Scientific Session & Expo.

Inflammation stimulated by the enzyme p38 mitogen-activated protein kinase (MAPK) is implicated in atherogenesis (the process of forming atheromas, plaques in the inner lining of arteries) and plaque destabilization. Pilot data in a phase 2 trial in patients with non-ST elevation myocardial infarction (NSTEMI; a certain pattern on an electrocardiogram following a heart attack) indicated that the p38 MAPK inhibitor losmapimod lessens inflammation and may improve outcomes. In this phase 3 trial, Dr. O'Donoghue and colleagues randomly assigned patients who had been hospitalized with an acute MI and had at least 1 additional predictor of cardiovascular risk to either twice-daily losmapimod (n = 1,738) or matching placebo (n = 1,765) on a background of guideline-recommended therapy. Patients were treated for 12 weeks and followed up for an additional 12 weeks. The study was conducted at 322 sites in 34 countries. Part A of the trial consisted of a group (n = 3,503) to provide an initial assessment of safety and exploratory efficacy before considering progression to part B (approximately 22,000 patients).

Among the 3,503 patients in part A, the primary end point (a composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization with the principal analysis specified at week 12) occurred by 12 weeks in 123 patients treated with placebo (7 percent) and 139 patients treated with losmapimod (8.1 percent). The on-treatment rates of serious adverse events were 16 percent with losmapimod and 14.2 percent with placebo.

The authors write that the results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population.

"In this trial, losmapimod did not reduce the risk of recurrent major adverse cardiovascular events through 12 weeks of treatment in patients hospitalized with acute MI. Furthermore, there was no evidence that losmapimod reduced the incidence of any secondary outcomes including all-cause mortality. Therefore, our findings do not support a strategy of p38 MAPK inhibition with losmapimod in patients hospitalized with MI."

"Because inflammation is believed to play a key role in atherogenesis, there remains intense interest to identify an anti-inflammatory therapeutic that will reduce the risk of cardiovascular events. However, because inflammation acts along multiple redundant and interconnected pathways, the identification of an appropriate target may be difficult, and it is challenging to predict clinical efficacy prior to phase 3 testing."

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Phase 2 results of AC6 gene transfer in patients with heart failure published

Renova Therapeutics, a biopharmaceutical company developing gene therapy treatments for cardiovascular and metabolic diseases, announced the publication of Phase 2 clinical trial results of AC6 gene transfer for the treatment of patients with heart failure and reduced ejection fraction in JAMA Cardiology. This trial was funded via a public-private partnership between the National Institutes of Health's National Heart, Lung, and Blood Institute and Renova Therapeutics. Results indicate that, through a one-time administration, AC6 gene transfer safely increased heart function beyond optimal heart failure therapy.

AC6 gene transfer involves infusing an inactivated adenovirus vector encoding human adenylyl cyclase type 6 (Ad5.hAC6) into the arteries that feed the heart during cardiac catheterization, a commonly performed procedure. Renova Therapeutics will develop AC6 gene transfer as an investigational product known as RT-100.

AC6 is a protein found in cardiac muscle cells that regulates heart function and appears to be down-regulated in heart failure patients. Dr. H. Kirk Hammond, Professor of Medicine at the University of California - San Diego and cardiologist at the Veterans Affairs San Diego Healthcare System, and his colleagues developed the method of gene transfer designed to up-regulate AC6 content in the heart, performed extensive preclinical studies and ran the clinical trial. Dr. Hammond is a co-founder of Renova Therapeutics and serves as a consultant to the company.

The randomized, double-blind, placebo-controlled trial included 56 patients who were studied for up to one year at seven medical centers throughout the United States. The trial assessed the safety of five doses of Ad5.hAC6 versus placebo in patients with symptomatic heart failure. Forty-two participants received Ad5.hAC6; 14 received a placebo.

The trial demonstrated that two endpoints showed differences between the two highest doses of AC6 (combined) versus placebo:

AC6 gene transfer increased left ventricular peak -dP/dt (p=0.029). This is a direct measure of the heart's ability to fill. AC6 gene transfer increased left ventricular ejection fraction in participants with non-ischemic heart failure (p=0.024). Non-ischemic heart failure is a type of heart failure not associated with extensive coronary artery disease.

In addition, symptoms of heart failure were reduced 12 weeks after therapy in Ad5.hAC6 participants (p=0.0005) but not in placebo subjects.

For all trial participants, there were no differences in rates of serious adverse events between the AC6 and placebo groups. Morbidity and mortality - key safety measures in the trial - showed:

After one year of follow-up, one death of 42 (2.4%) in the AC6-treated group and one death of 14 (7.1%) in the placebo group had occurred (p=0.40). The annual heart failure hospital admission rate was 9.5% in the treatment group versus 28.6% in the placebo group (p=0.10).

"We are thrilled about the publication of the Phase 2 data in JAMA Cardiology, which supports RT-100's potential to increase function of the failing heart," said Jack W. Reich, Ph.D., CEO and Co-founder of Renova Therapeutics. "We appreciate the National Institutes of Health's National Heart, Lung, and Blood Institute's support for this work, which was key to the success thus far, both in the early stages and in this clinical trial."

Heart failure afflicts more than 28 million people globally and is the only cardiovascular disease that is increasing in prevalence.1 It is the most common cause for emergency hospital admissions in patients 65 and older.

Larger trials are warranted to assess the safety and efficacy of AC6 gene transfer for patients with heart failure. Renova Therapeutics is committed to bringing to market a single-dose treatment to safely increase heart function and looks forward to advancing to pivotal trials for RT-100 AC6 gene transfer.

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'Good' cholesterol may not always protect against heart disease

High levels of "good cholesterol," or high-density lipoprotein, are unlikely to protect people from heart disease if their bloodstream also contains high levels of a newly identified biomarker of inflammation in the arteries.
[good and bad cholesterol]
Maintaining levels of HDL cholesterol is important, but we may need to factor in GlycA, too.

This is the conclusion of research recently presented at the American College of Cardiology 2016 Scientific Sessions in Chicago, IL.

Inflammation of the artery walls raises the risk of a heart attack or stroke because it increases the chance of plaque on the arterial walls rupturing. If this happens, it can lead to the formation of blood clots and a blockage in the blood flow.

Cholesterol is a waxy, fat-like substance. The human body needs some cholesterol, but if there is too much, it can collect within the arteries, leading to heart disease and stroke. Heart disease is the number one cause of death in the US.

Low-density lipoprotein (LDL) - also known as "bad" cholesterol - is found in high levels in 33.5% of American adults, according to the Centers for Disease Control and Prevention (CDC).

On the other hand, high levels of high density lipoprotein (HDL), or "good" cholesterol, are thought to provide anti-inflammatory protection in the arteries.

Many people do not realize that their cholesterol is too high, because there are no symptoms. Exercising, eating a healthy diet and not smoking can help reduce cholesterol levels.

Individuals can increase their HDL levels through dietary measures such as consuming foods rich in omega-3s and following a Mediterranean diet, with a high proportion of plant-based foods and healthy fats, such as olive oil. Limiting intake of salt and red meat also helps.

Researchers from the Intermountain Medical Center Heart Institute in Salt Lake City, UT, used a test called NMR spectroscopy to measure lipoprotein particles and glycoprotein acetylation, or GlycA, in 2,848 patients.

Fast facts about cholesterol

Total cholesterol levels should be less than 200 mg/dL LDL levels should be less than 100 mg/dL HDL levels should be 60 mg/dL or higher.

Learn more about cholesterol

Participants had an average age of 63 years; 66% were male, and 65% had coronary artery disease.

Findings revealed a higher risk of heart attack or stroke among those with high levels of the biomarker GlycA.

The results suggest that an interaction may occur between GlycA and small HDL particles, restricting the capacity of HDL to act as an anti-inflammatory and increasing the chance of a heart attack or stroke.

Dr. Brent Muhlestein, co-director of cardiovascular research at the Intermountain Medical Center Heart Institute, explains that historically, C-reactive protein has been used as an indicator of inflammation in the body and a predictor of heart-related problems.

Now, it seems that GlycA, a marker of inflammation identified through NMR, could also predict adverse events such as heart attack or stroke.

Dr. Muhlestein describes GlycA as "a new particle we didn't know much about."

Now that research has established epidemiologic associations, he calls for further research to find ways to assess and understand how it works and how it interacts in the bloodstream.

The next step for researchers is to find out whether C-reactive protein and GlycA impact inflammation and heart disease independently.

Dr. Muhlestein says:

"The results of our study reinforce the importance of the recommendations we offer to our patients working to reduce inflammation in their arteries by exercising regularly and eating heart-healthy foods."

Medical News Today recently reported on research suggesting that too few Americans are using drugs to reduce their levels of "bad" or LDL cholesterol.

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Vitamin D levels could predict risk of poor cardiovascular health

The risk of heart attack, stroke, heart failure and other cardiac events could be predicted by measuring levels of two vitamin D components, suggest researchers from the Intermountain Medical Center Heart Institute in Salt Lake City, UT.
[A man holding his heart]
Low levels of total and bioavailable vitamin D may predict poor cardiovascular health, say researchers.

Lead researcher Dr. Heidi May, a cardiovascular epidemiologist at the Institute, and colleagues found that individuals with low levels of both total vitamin D and bioavailable vitamin D were more likely to experience poor cardiovascular outcomes.

Bioavailable vitamin D is vitamin D that has been absorbed into the bloodstream but has not attached to surrounding proteins.

The researchers recently presented their findings at the American College of Cardiology Scientific Sessions in Chicago, IL.

To reach their results, Dr. May and colleagues analyzed the vitamin D levels of 4,200 individuals aged 52-76. Of these, around a quarter had diabetes and around 70% had coronary artery disease.

The team focused on measuring the participants' levels of various vitamin D metabolites - elements of the vitamin that are produced during metabolism - and assessed whether they were associated with future cardiac events.

The researchers explain that only 10-15% of total vitamin D has the ability to act on target cells during metabolism; most vitamin D metabolites are attached to vitamin D binding proteins.

The team says it is important to assess the proportion of these "unbound" vitamin D metabolites - such as bioavailable vitamin D - that is available to pursue target cells.

From their analysis, the researchers found that measuring both total levels of vitamin D and levels of bioavailable vitamin D demonstrated the highest accuracy for predicting the risk of cardiac events.

In other words, individuals with low levels of both total vitamin D and bioavailable vitamin D were at greatest risk for heart attack, stroke, heart failure and even cardiovascular death, compared with people whose levels of these vitamins were high.

Commenting on the results, Dr. May says:

"This study is the first research that evaluates the association of vitamin D metabolites with cardiovascular events. And evaluating usable vitamin D could mean the difference on the amount of vitamin D prescribed, if it's prescribed at all."

The researchers say their findings build on previous research associating low vitamin D levels with poor heart health. However, they call for future studies to further investigate this link in non-white populations, noting that past studies have shown the effects of vitamin D metabolites vary between white people and those of other ethnicities.

Last November, Medical News Today reported on a study suggesting that vitamin D levels below 15 ng/mL are associated with poor heart health.

And another study published last year suggested vitamin D supplements may improve exercise performance and reduce the risk of heart disease.

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Study explores cholesterol lowering therapies for patients with muscle-related statin intolerance

Steven E. Nissen, M.D., of the Cleveland Clinic, and colleagues identified patients with muscle-related adverse effects from statins and compared lipid-lowering efficacy for two nonstatin therapies, ezetimibe and evolocumab. The study was published online by JAMA, and is being released to coincide with its presentation at the American College of Cardiology's 65th Annual Scientific Session & Expo.

A significant proportion of patients with clinical indications for statin treatment report inability to tolerate evidence-based doses, most commonly because of muscle-related adverse effects, reported by 5 percent to 20 percent of patients. These patients typically report muscle pain or weakness when treatment is initiated or dosage increased and relief when the drug is discontinued or the dosage reduced. Patients with muscle-related intolerance often refuse to take statins despite elevated low-density lipoprotein cholesterol (LDL-C) levels and a high risk of major cardiovascular events. Current management may include very low or intermittent administration of statins or use of ezetimibe, but these strategies seldom achieve reductions recommended by current guidelines.

For this study, the researchers conducted a two-stage randomized clinical trial that included 511 adult patients with uncontrolled LDL-C levels and a history of intolerance to 2 or more statins. Phase A involved a 24-week crossover procedure in which patients were randomly assigned to atorvastatin (20 mg) or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, patients were randomly assigned to evolocumab (420 mg monthly, by injection) or oral ezetimibe (10 mg daily) for 24 weeks.

In phase A, the researchers observed a 43 percent rate of discontinuation for intolerable muscle symptoms with atorvastatin but not placebo. However, 27 percent of patients reported similar symptoms with placebo but not atorvastatin, demonstrating that reported muscle symptoms are not always related to statin use. "Since statin-associated muscle symptoms are dose-related, the rate observed in [this trial] for atorvastatin (20 mg) may underestimate the problem, particularly for patients needing high-intensity statin therapy, such as those enrolled in the trial."

During the second phase of the study, the authors found that evolocumab produced significantly larger reductions in levels of LDL-C and other lipoproteins compared to ezetimibe. Both coprimary end points (the average percent change in LDL-C level from baseline to the average of weeks 22 and 24 levels and from baseline to week 24 levels) showed a 17 percent reduction with ezetimibe and a more than 50 percent reduction with evolocumab. Despite very high baseline values, the LDL-C goal of less than 70 mg/dL was achieved in nearly 30 percent of evolocumab-treated patients and 1.4 percent of ezetimibe-treated patients.

Muscle symptoms were reported in 29 percent of ezetimibe-treated patients and 21 percent of evolocumab-treated patients. Active study drug was stopped for muscle symptoms in 7 percent of ezetimibe-treated patients and 0.7 percent of evolocumab-treated patients.

"These findings demonstrate that both drugs are unlikely to provoke muscle symptoms and can be administered successfully in such patients, although with significant differences in lipid-lowering efficacy. Since a minority of patients achieved optimal LDL-C levels despite treatment with evolocumab, it may be worth exploring the addition of ezetimibe to evolocumab for those patients requiring further LDL-C reduction. It should be noted that neither ezetimibe nor evolocumab is approved for reduction of major adverse cardiovascular events," the authors write.

"Further studies are needed to assess long-term efficacy and safety."

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Treating depression may reduce heart disease risk

Heart disease and depression are both serious and prevalent conditions; mounting evidence infers that they are connected. Depression has been shown to increase the likelihood of developing heart disease later in life. A new study looks in depth at this relationship.
[Illustration of a heart in black and red]
Treating depression early might help reduce the chances of developing cardiac problems.

An estimated 6.7% of American adults suffered one or more major depressive episodes in 2014.

Additionally, around 1 in 4 deaths in the US is attributed to some form of heart disease.

Depression and heart disease are not only incredibly common, they also appear to be intrinsically linked.

After a heart attack or heart failure, some individuals who have never been troubled by depression can find themselves under its spell.

Conversely, people who have suffered from depression seem more likely to develop heart problems later in life.

A new study, carried out at the Intermountain Medical Center Heart Institute in Salt Lake City, UT, investigates this relationship further.

Depression and cardiac risk

Researcher Heidi May, PhD, a cardiovascular epidemiologist, wanted to examine whether treating depression reduces the chances of developing heart disease.

An additional question that May set out to answer was whether brief encounters with depression still have the ability to increase the risk of heart problems further down the line.

To investigate these questions, May delved into data from Intermountain Healthcare's depression registry, containing information from more than 100,000 patients. This information source proved essential for the success of the research, as May explains: "There's little publicly available data about this question."

From the database, the team used data from the 7,550 patients who had filled in at least two depression questionnaires over the course of 2 years. The individuals were then divided into four groups: never depressed, no longer depressed, remained depressed and became depressed.

The patients were followed to observe whether they later developed cardiovascular problems including stroke, heart attack or heart failure.

Treating depression reduces cardiac risk

The results showed that individuals who were no longer depressed had similar rates of heart disease as those who had never been depressed (4.6% and 4.8%, respectively). However, in the group of individuals who had become depressed during the study or remained depressed, the rates of cardiac disease were higher (6% and 6.4%, respectively).

In other words, treatment for depression resulted in a decreased level of cardiovascular risk that was roughly equivalent to someone who did not have depression.

May summarizes the results as follows:

"Our study shows that prompt, effective treatment of depression appears to improve the risk of poor heart health."

Past research has shown that depression increases the chances of cardiovascular health issues in the long-term but, as May explains, "knowing that alleviating the symptoms of depression reduces a person's risk of heart disease in the short term, too, can help care providers and patients commit more fully to treating the symptoms of depression."

The findings will be presented at the 2016 American College of Cardiology Scientific Sessions in Chicago, IL, on April 2nd.

May hopes to continue research in this field. She notes that the results of the current study are observational, and full clinical trials will be necessary to investigate the interplay between depression and heart disease further.

A complex web of factors

There is a swarm of potentially confounding variables that must be studied and controlled before solid conclusions can be drawn. For instance, individuals with depression are more likely to be obese; according to the Centers for Disease Control and Prevention (CDC), 43% of depressed adults are obese.

Of course, obesity comes with its own range of related cardiac issues. Lack of exercise is another factor that can increase the risk of heart disease and obesity, and also increase the chances of depression. The web between these factors will be no mean feat to unfurl.

Once these factors have been controlled for, and the results are in, the best methods of treating depression will still need to be discussed. Certain antidepressant medications can, themselves, cause changes in weight. The story certainly is a complex one.

Medical News Today recently covered research investigating whether depression and bipolar disease might raise heart disease risk in teens.

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