Apixaban Plus P2Y12 Inhibitor and No Aspirin Safest for Patients with Both AFib and ACS
Patients at high risk for heart attacks, strokes, and blood clots who were treated with a novel blood thinner (apixaban) and an antiplatelet drug such as clopidogrel had a significantly lower risk of bleeding and being hospitalized compared with patients who received an older blood-thinning medication such as warfarin, according to research presented at the American College of Cardiology’s 68th Annual Scientific Session. In addition, patients who received clopidogrel without concurrent aspirin, which has been standard for these patients, had an additional 47 percent reduction in bleeding events with no increase in heart attacks, strokes, or blood clots when compared with patients who received aspirin.
The lowest rates of bleeding, with no increase in deaths or hospitalizations, were seen in patients who did not receive aspirin and were treated with apixaban plus a drug such as clopidogrel. In addition to the significant reduction in risk for bleeding and lower rates of stroke, patients treated with these two medications had no increase in heart attacks or blood clots.
“We have shown that when it comes to treating this high-risk patient population, less may be more,” said Renato D. Lopes, MD, PhD of the Duke Clinical Research Institute at Duke University School of Medicine in Durham, North Carolina, and the study’s lead author. “Our findings show that the combination of apixaban and a drug such as clopidogrel — without aspirin — is the safest treatment regimen for this difficult-to-treat group of patients, without significantly increasing ischemic events such as heart attacks, strokes, and blood clots. These results should reassure clinicians that it’s okay not to treat most of these patients with aspirin.”
Patients in the trial, known as AUGUSTUS, had both atrial fibrillation (AFib) and acute coronary syndrome (ACS).
Choosing the optimal treatment for patients with both AFib and ACS is challenging, Lopes said. These patients need to take a blood thinner to prevent stroke and blood clots, but blood thinners have not been shown to prevent blood clots in stents and are usually not recommended for patients with ACS. Treatment with aspirin plus clopidogrel or a similar drug — known as dual antiplatelet therapy (DAPT) — has been shown to reduce heart attacks and stent thrombosis in patients with ACS but not stroke associated with AFib. Moreover, combining a blood thinner with DAPT increases the risk of potentially life-threatening bleeding.
Most AFib treatment trials have excluded patients with ACS, while most ACS treatment trials have excluded patients with AFib, Lopes said, creating a gap in researchers’ understanding of how best to treat patients who have both conditions. Among the unanswered questions: whether a next-generation blood thinner such as apixaban is more effective than warfarin, and whether these patients fare better if they take aspirin plus a medication such as clopidogrel in addition to a blood thinner.
The AUGUSTUS trial was designed to answer both questions. It is the first randomized, double-blinded, placebo-controlled trial to test the effect of withdrawing aspirin from the treatment regimen for a patient population at high risk for bleeding as well as for heart attacks, strokes and blood clots, Lopes said.
The trial enrolled 4,614 patients in 33 countries, including the United States, Canada, Mexico, the United Kingdom, and other countries in Europe, Asia, and South America. Patients’ median age was 70 years and 71 percent were men. All patients had AFib requiring long-term treatment with a blood thinner, had experienced a recent episode of ACS and/or were having a stent inserted in a blocked artery.
All the patients had an indication to take medications to reduce the risk of blood clots in the arteries by inhibiting platelets. More than 92 percent were taking clopidogrel at baseline; the rest were taking one of the similar drugs (e.g., prasugrel, ticagrelor).
Within 14 days of an ACS episode or stent insertion, patients underwent random assignment twice: first, to receive either apixaban or warfarin and, second, to receive either a daily baby aspirin or a matching placebo. The aspirin-or-placebo treatment assignments were double blinded, meaning that neither the patients nor their doctors knew who was receiving which treatment. The apixaban-or-warfarin treatment assignments were not blinded because of the need for patients taking warfarin to get regular blood tests to check the drug’s effect on blood clotting.
All patients were treated for six months. This follow-up period was selected because most bleeding episodes, heart attacks, strokes, and blood clots occur during the first six months after an ACS episode, insertion of a stent or initiation of a blood-thinning medication, Lopes said.
The trial’s primary endpoint was major or clinically relevant nonmajor bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH). The ISTH definition includes bleeding that results in death; occurs in a critical organ; or results in hospitalization, medical treatment or surgery for bleeding or a change in the patient’s anti-blood-clotting treatment. Secondary endpoints included a composite of death or hospitalization and a composite of death or stroke, heart attack, stent thrombosis or urgent treatment to unblock an artery.
Results for the primary safety endpoint showed that patients taking apixaban had a 31 percent reduction in risk compared with patients taking warfarin and that patients taking a placebo instead of aspirin had a 47 percent reduction in risk compared with those taking aspirin. The proportion of patients who had a bleeding episode was highest among patients treated with clopidogrel, warfarin and aspirin (18.5 percent), and lowest among those treated with clopidogrel, apixaban and placebo (7.3 percent).
The proportion of patients who died or were hospitalized was highest for patients treated with clopidogrel, warfarin and aspirin (27.5 percent) and lowest for those treated with clopidogrel, apixaban and placebo (22 percent). Patients treated with apixaban also had 50 percent lower risk of stroke compared with those taking warfarin.
A limitation of the study, Lopes said, is that it was not large enough to detect potential small differences in clinically important but rare outcomes such as stent thrombosis for individual patients.
The study was funded by Bristol-Myers Squibb and Pfizer, Inc. It was simultaneously published online in the New England Journal of Medicine at the time of presentation.
The ACC’s Annual Scientific Session took place March 16-18, 2019, in New Orleans, bringing together cardiologists and cardiovascular specialists from around the world to share the newest discoveries in treatment and prevention.
The American College of Cardiology (acc.org) envisions a world where innovation and knowledge optimize cardiovascular care and outcomes. As the professional home for the entire cardiovascular care team, the mission of the College and its more than 52,000 members is to transform cardiovascular care and to improve heart health. The ACC bestows credentials upon cardiovascular professionals who meet stringent qualifications and leads in the formation of health policy, standards and guidelines. The College also provides professional medical education, disseminates cardiovascular research through its world-renowned JACC Journals, operates national registries to measure and improve care, and offers cardiovascular accreditation to hospitals and institutions.
Apple Heart Study Gives Glimpse into How Wearable Technology May Help Flag Heart Rhythm Problems
Amid the explosive popularity of the Apple Watch and other wearable fitness devices, along with new health care apps designed to track heart rate and other health measures, consumers have more opportunities than ever to monitor their own health data and make decisions about what to do with the information. The Apple Heart Study was designed to evaluate how well the Apple Watch can identify and prompt subsequent clinical evaluation for atrial fibrillation (AFib), which is a leading cause of major stroke and hospitalizations. According to preliminary data from the study presented at the American College of Cardiology’s 68th Annual Scientific Session, the Apple Watch was able to detect AFib in a small group of people who had been alerted by the app as having an irregular heartbeat.
AFib is estimated to affect up to 6 million Americans, yet many people don’t know they have it. AFib can lead to blood clots, disabling stroke, heart failure, and other heart-related complications.
For this study, researchers at Stanford University School of Medicine specifically evaluated a mobile app that uses the watch’s existing light sensor technology (called photoplethysmography) to intermittently measure blood flow activity and detect subtle changes that might indicate an irregular contraction or heartbeat. The Apple Watch generates a tachogram, which is a plot of time between heart beats. If an irregular tachogram is seen, then more frequent tachogram collection occurs. The tachograms are analyzed by an algorithm to determine if an irregular rhythm may be present and, if so, a notification is sent to the watch.
The main study goals were to determine: the proportion of participants with an irregular pulse watch notification who have AFib on a subsequent electrocardiogram (ECG) patch worn at home, how well the algorithm on the watch matched the ECG findings and the percentage of patients who received a notification who went on to seek medical help through the app. Of the 419,297 people who self-enrolled in this prospective study between November 2017 and July 2018, 0.5 percent (nearly 2,100 participants) received an irregular pulse notification, which was triggered if the sensor detected 5 out of 6 repeat episodes (or tachograms) of an irregular pulse within a 48-hour period.
“The app continuously gathers data in the background without the wearer of the device doing anything, so it’s very opportunistic in this way,” said Mintu Turakhia, MD, associate professor of cardiovascular medicine, Stanford School of Medicine, and the study’s co-principal investigator, adding that the entire user experience, end-to-end was directly through the study application. “[Overall], this study improves our understanding of how this wearable technology and app works in the real-world setting and how well the technology can detect long periods of AFib. Notifications of heart rhythm irregularities were low, an important finding given concerns about over notification, and we were able to see what happened downstream after participants received a notification.”
Participants who got a notification were also prompted to contact the study doctor through the app. Based on a video consultation on their device, it was decided whether the person should wear an electrocardiogram (ECG) patch, sent by mail, to measure their heart’s activity and potentially identify AFib. Participants wore it for up to seven days and then sent it back to determine whether AFib was evident. In total, 658 participants were sent a patch and 450 were returned and included in the analyses. One-third (34 percent) of the participants who had received an irregular pulse notification on their Watch and wore the ECG patch over a week later were then found to have AFib based on the ECG reading, which researchers said is not entirely unexpected.
“AFib can come and go, particularly early on in the course of the disease. It’s not surprising for it to go undetected in subsequent ECG patch monitoring. So while only 34 percent of people who were still having [signs of] AFib on the ambulatory ECG, that doesn’t mean that 66 percent didn’t have AFib. It just means that AFib may not have been there at the time,” Turakhia said. “These parameters help us understand how we, as clinicians, should think about these notifications.”
When comparing pulse detections on the watch with simultaneous ECG patch recordings among 450 participants who wore both at the same time, researchers found that the positive predictive value for the tachogram was 71 percent, and the positive predictive value for the notification was 84 percent. This means if a notification occurred, 84 percent of the time, the ambulatory ECG monitor also showed AFib.
Of the participants who received an irregular pulse notification via the app to confer with a study doctor to determine next steps, about half ended up initiating contact with the study doctor, but researchers said the others may have sought care elsewhere. In subsequent surveys, 57 percent of people who got an alert said they sought medical attention outside of the study regardless of whether they had been seen virtually by a study doctor.
Participants were required to have an Apple Watch (series 1, 2 or 3) and a compatible iPhone (iPhone 5S or later), be age ≥22 and a U.S. resident. The newer Apple Watches that feature a built-in ECG app were not part of this study. Participants downloaded the application to their device and were subsequently given information about the study, questions to help verify their eligibility and prompts to provide signed consent. They were not included in the study if they said they were taking an anticoagulant for any reason or had current or prior AFib. Surveys were used to collect information about patient reported outcomes.
Notification rates in people under 40 years of age were very low (0.16 percent) and were more frequent in those over age 65 (just over 3 percent).
“This is encouraging because it tracks with our understanding of AFib as being more common as you get older,” Turakhia said, adding that the overall study population represented a striking cross section of cardiovascular risk.
Five percent had diabetes, 21 percent had high blood pressure, 1 percent had a prior stroke and 38 percent were obese based on body mass index.
About one-third of people who received a notification had a CHADS-VASc score of two or greater, which is used to predict the risk of stroke in people with AFib and is the threshold to start anticoagulation. People with AFib have more than five times the risk of having a stroke than someone without it.
There were several study limitations, including researchers’ reliance on self-reported data from participants. Researchers said they also did not reach their target enrollment of 500,000 participants, of which they hoped 75,000 would be age 65 and older. But they explained this virtual study is step one in creating the groundwork for future studies that look to leverage wearable technologies as a way to support heart health outside of the clinic. They said an obvious next step is to study how this technology can be used in complement with other technologies such as real-time ECG and other validated tools to manage heart rhythm problems.
“It really represents a paradigm shift for how clinical studies can be conducted,” Turakhia said. “We don’t have to bring people into a brick and mortar clinic and give the study intervention.”
The study was funded by Apple, Inc.
CardioMEMS Sensor Reliably Safe, Cuts Hospitalizations By More Than Half
In the year following placement of a CardioMEMS heart failure sensor — designed to wirelessly measure and monitor pulmonary artery pressures that can signal worsening heart failure — patients experienced a 58 percent reduction in hospitalization for heart failure, according to research presented at the American College of Cardiology's 68th Annual Scientific Session. Reductions in hospitalizations were seen in both men and women, across all ejection fraction ranges and regardless of race.
Heart failure affects nearly 6 million Americans. CardioMEMS is a small sensor that is placed directly into a patient's pulmonary artery. In a minimally invasive outpatient procedure, doctors use the femoral vein in the groin to thread the sensor up to the heart. Once implanted, the device can detect rising pressures in the pulmonary artery, which can be an early warning of fluid backing up in the lungs and pending onset of congestive heart failure even before symptoms of shortness of breath or weight gain are reported. Pressures are recorded and transmitted electronically from a patient's home to a secure website so health care providers can review the readings and proactively adjust medical therapies to keep patients at their target pressures.
This prospective, open-label trial was initiated as a post-approval study to evaluate the efficacy and safety of the CardioMEMS sensor in clinical practice per U.S. FDA mandates. The device was approved by the FDA in May 2014 for use in patients who have New York Heart Association (NYHA) Class III heart failure that limits daily life and who have been hospitalized for heart failure in the previous year. The study included 1,200 patients at 104 clinical sites in the U.S. Participants were an average of 69 years old and included 38 percent women, 17 percent non-white, 30 percent with preserved ejection fraction (HFpEF) and 53 percent with reduced ejection fraction.
"This study was done in a large number of patients with substantial representation of women and minorities and showed the device to be not only safe but markedly effective in keeping people out of the hospital," said David Shavelle, MD, associate professor at Keck School of Medicine of USC and the study's lead author. "Our findings further validate the concept that remote monitoring of pulmonary artery pressures, which is a surrogate to a patients' volume status, allows adjustment of medical therapy in a timely manner to prevent future heart failure hospitalizations. This represents an important advance in heart failure management, as these patients are at very high risk of hospitalizations and complications."
The primary efficacy endpoint was heart failure hospitalization rates in the year after the sensor was implanted compared to the year before. Heart failure is among the top conditions that result in hospitalizations among people age 65 years and older. Patients in the study had an average of 1.24 heart failure hospitalizations in the year prior to implant and 0.52 hospitalizations in the year after having the device implanted. This translated to a 58 percent reduction in heart failure-related hospitalizations, researchers said. Similar reductions in hospitalizations were seen in patients with the greatest burden of hospitalizations (more than two hospitalizations in the previous year).
"Having the device cut the risk of hospitalizations by more than half," Shavelle said. "The benefits of lower hospitalizations were seen across all subgroups of patients, and we also validated that this treatment can decrease hospitalizations in patients with HFpEF."
The sensor prevented hospitalizations regardless of patients' ejection fraction, preserved ejection fraction (50 percent or higher, which is considered normal), reduced ejection fraction (<40 percent) or mid-range ejection fraction (41-50 percent). Ejection fraction is a measure of how well the heart squeezes blood out of the heart to the body. There were also clear benefits for females and racial/ethnic minorities. Females had a 61 percent reduction in heart failure hospitalization and blacks had a reduction of 53 percent.
Additionally, patients with or without an implantable cardioverter defibrillator or cardiac resynchronization therapy defibrillator and those with an ischemic or non-ischemic cardiomyopathy also saw lower rates of hospitalizations with the CardioMEMS sensor.
Moreover, having the device also appeared to reduce all-cause hospitalizations for conditions like pneumonia, chronic obstructive pulmonary disease or arrhythmias by 28 percent. Other analyses showed the combined rate of heart failure-related hospitalizations or death also dropped by 44 percent after the sensor was placed.
"If you can maintain more normal cardiac filling pressures and less heart stress, you are less likely to be seriously affected and need hospitalization for other conditions such as lung disease or liver disease, which are affected by heart function," Shavelle said. "We believe that having the sensor monitored by their care team also encourages patients to follow their medication plan and gives them a sense of security that is particularly important for those living far away from a hospital."
The CardioMEMS sensor also met its safety endpoint: freedom from device or system-related complications or sensor failure at one year. To assess safety, researchers tracked whether there were any device or system-related complications and episodes of sensor failure where they were unable to get pressure readings from the device even after troubleshooting the external electronics. Based on the data, only four patients had device- or system-related complications, and there was only one episode of sensor failure, Shavelle said. Reported another way, at one year post-implant, study participants had 99.7 percent freedom from device/system-related complications and 99.9 percent freedom from sensor failure.
An ongoing study is evaluating the use of the CardioMEMS sensor for patients with other classes of heart failure (NYHA Class II and IV) and for patients at risk but without a prior hospitalization for heart failure.
This study was funded by Abbott Vascular.
Three New Studies Confirm Clinical Utility of AliveCor's KardiaMobile Device and AI Algorithms
AliveCor, the leader in FDA-cleared personal electrocardiogram technology (ECG), announced three new studies that demonstrate both the clinical utility and workflow advantages of its mobile ECG platform.
The Lancet's EClinicalMedicine published research from the University of Edinburgh and NHS Lothian which demonstrated that in a randomized controlled trial of 243 people — who presented to 10 hospitals in the UK with heart palpitations or pre-syncope — ECGs taken with KardiaMobile after discharge allowed doctors to diagnose 56 percent of patients in 9.5 days on average. This compared to patients who received standard care, where 10% were diagnosed in an average of 43 days. The research also found that cost per-treated patient using KardiaMobile could also be reduced by nearly $1,200. The researchers concluded that KardiaMobile "should be considered part of ongoing care to all patients presenting acutely with unexplained palpitations or pre-syncope."
Two studies were presented at the American College of Cardiology Scientific Sessions in New Orleans:
• Dr. Ronald Karlsberg from the Cardiovascular Research Foundation of Southern California, demonstrated that AliveCor's Remote Patient Monitoring platform, KardiaPro, can be integrated into an Electronic Health Records platform (EPIC) to allow KardiaMobile ECGs to be analyzed, interpreted, and recorded into the patient's medical record for more robust documentation and treatment decision making. Simultaneously, AliveCor announced the latest version of KardiaPro which supports reimbursement under the newest Remote Patient Monitoring CPT codes.
• AliveCor data scientists, in collaboration with Mayo Clinic, showed that KardiaMobile Generation 2 — AliveCor's six lead mobile ECG (pending 510(k) clearance) — can accurately measure the QT interval, which, when prolonged, is associated with sudden cardiac death. AliveCor trained a deep neural network using ECG data from over 200,000 Mayo Clinic patients to predict the QT interval. The algorithm was then tested on prospectively collected ECG data from 323 patients in Mayo Clinic's Heart Rhythm Clinic. The neural network's QT prediction from KardiaMobile Generation 2 ECG data was comparable to the QT measured from a traditional 12-lead ECG. This research presents a convenient and accurate means for early detection of long QT syndrome, for which millions of patients are at risk of due to use of certain medications including antibiotics and antidepressants.
AliveCor continues to lead the digital health industry with new products. In September 2018, AliveCor announced that it is developing KardiaMobile Gen 2, a six-lead, consumer-facing ECG device — pending FDA clearance — that gives patients and physicians even more detailed information about heart health. KardiaMobile Generation 2 was demonstrated at the American College of Cardiology Scientific Sessions in New Orleans.
AliveCor, Inc. is pioneering the creation of FDA-cleared machine learning techniques to enable proactive heart care and is recognized around the world for transforming cardiac care. The FDA-cleared KardiaMobile is the most clinically validated mobile ECG solution on the market. It is recommended by leading cardiologists and used by people worldwide for accurate ECG recordings. KardiaMobile, and KardiaBand, when paired with the Kardia app provide instant analysis for detecting AFib and normal sinus rhythm in an ECG. Kardia is the first AI-enabled platform to help clinicians manage patients for the early detection of AFib. KardiaBand is the first FDA-cleared medical device accessory for Apple Watch. The new KardiaPro platform is the only Remote Patient Monitoring platform that works with the existing devices that patients use. KardiaPro now supports reporting for contemporary CPT codes including 99091 and 99457. AliveCor owns pending patent applications and issued patents covering ideas presented in this press release including issued U.S. Patent Numbers 9,839,363; 9,572,499; 9,986,925; 9,833,158; 9,351,654; 9,220,430; and 9,579,062. AliveCor is a privately-held company headquartered in Mountain View, California. For more information, visit alivecor.com.