Apple Watch ECG App Rolls Out: The Healthcare Experiment Begins

Apple rolled out its electrocardiogram (ECG) app for the Apple Watch Series 4 yesterday with less fanfare but no fewer questions about how its first wearable consumer heart-monitoring tool will affect healthcare providers.

“The idea that wearables can be used by both patients and their healthcare providers to manage and improve heart health holds promise and should also be approached with caution to ensure information and data are used responsibly and in concert with other evidence-based tools and guidelines,” American College of Cardiology President C. Michael Valentine, MD, said in an Apple release.

To take an ECG similar to a single-lead reading, consumers simply hold their finger on the watch’s digital crown and, after 30 seconds, the heart rhythm is classified as either atrial fibrillation (AF), sinus rhythm, or inconclusive. The waveforms can be stored on an iPhone and shared in a PDF with physicians.

“The role that technology plays in allowing patients to capture meaningful data about what’s happening with their heart, right when it’s happening, like the functionality of an on-demand ECG, could be significant in new clinical care models and shared decision making between people and their healthcare providers,” Nancy Brown, CEO of the American Heart Association, said in the Apple release.

The updated Apple Watch also has a notification feature that checks for signs of AF and alerts the user if it detects an irregular rhythm on five rhythm checks over a minimum of 65 minutes.

Apple acknowledges that in the Apple Heart Study, however, the watch’s AF warning was not confirmed 20% of the time by an ECG patch simultaneously worn by study participants.

Physicians took to Twitter after the app went public yesterday, with Daniel Yazdi, MD, Brigham and Women’s Hospital, Boston, tweeting: “Single lead EKG useful for detecting arrhythmias, not sensitive for ischemia. Excited for this new granularity but benefit/harm of anticoagulation needs to be evaluated.”

Electrophysiologist Kevin Driver, MD, Charleston, West Virginia, tweeted: “Congrats @leftbundle and Apple Watch team. High quality ECG will recommend to patients.”

Others had a different view. Nishat Siddiqi, MD, University of Aberdeen, United Kingdom, tweeted: “The apple smart watch app for AF is exciting BUT those with the highest risk of AF are older than the average smartwatch user and the false positive rates are too high. So, as a cardiologist, I’ll end up reassuring lots of anxious young people they don’t have AF.”

Michael Katz, MD, @MGKatz036, tweeted, “Of course, as a heart rhythm specialist, I immediately installed the iOS update on Apple Watch to EKGs enabled. We are gonna get wrecked.”

In response to Katz’s tweet, private-practice cardiologist Kevin Woolf, MD, @kwoolfmd, replied: “Job security/kids through college.”

News that the irregular heart rhythm notifications are not intended for people who have been diagnosed with AF also prompted headlines in the Washington Post and groans on Twitter. Electrophysiologist Edward J. Schloss, MD, The Christ Hospital in Cincinnati, tweeted: “Huh? Apple Watch 4 is not designed for the people in which it has the most utility.”

Electrophysiologist Paul Zei, MD, Brigham and Women’s Hospital and Harvard University, both in Boston, tweeted simply, “Oh, The irony…”

When Apple unveiled the app in September, Medscape Editor-in-Chief Eric Topol, MD, Scripps Research Institute, La Jolla, California, cautioned that the ECG feature could increase the chance of false-positives and detect cases of low-risk AF that don’t need to be treated.

Medscape columnist and electrophysiologist John Mandrola, MD, from Baptist Health, Louisville, Kentucky, said the app could misdiagnose patients because of inaccurate readings or lead to overtreatment of patients. Still, over time, “we may learn important things about arrhythmia from all these data. Similarly, people will gain more health literacy when it comes to their heart rhythm.”

In granting de novo clearance for the new ECG app in less than a month’s time, the US Food and Drug Administration stated that it is not intended for people younger than 22 years, a point that some on Twitter suggested could be easily worked around by changing the watch’s user settings.

When first unveiling the updates this September, Apple Chief Operating Officer Jeff Williams heralded the watch as the “ultimate guardian for your health.”

Apple executives sounded a more moderate tone yesterday.

“Apple Watch has helped so many people around the world and we are humbled that it has become such an important part of our customers’ lives,” Williams said in Apple’s statement. “With the release of these heart features, Apple Watch takes the next step in empowering people with more information about their health.”

Sumbul Desai, MD, Apple’s vice president of health, remarked, “We are confident in the ability of these features to help users have more informed conversations with their physicians. With the ECG app and irregular rhythm notification feature, customers can now better understand aspects of their heart health in a more meaningful way.”

https://www.medscape.com/viewarticle/906206#vp_1

A good word for proton pump inhibitors from anticoagulant patients

Anticoagulation patients at risk for upper gastrointestinal (GI) bleeding saw their risk reduced by more than a third when a proton pump inhibitor (PPI) was added to oral anticoagulant therapy, according to a retrospective analysis of Medicare claims.

In addition, the choice of anticoagulant can be important for outcomes, reported Wayne Ray, PhD, of Vanderbilt University Medical Center in Nashville, and colleagues. During 754,389 person-years of therapy, they found that the highest risk of upper GI hemorrhage was associated with rivaroxaban (Xarelto) but not apixaban (Eliquis), dabigatran (Pradaxa), or warfarin (Coumadin).

Ray noted in a Vanderbilt new release that an estimated 1% to 1.5% of patients on oral anticoagulants will experience upper GI bleeds every year, and anticoagulant choice and PPI co-therapy could affect the risk of upper GI tract bleeding, a frequent and potentially serious complication of oral anticoagulant treatment. The study, published online in JAMA, found that adding a PPI reduced overall bleeding across all anticoagulants, for an incidence rate ratio of 0.66 and a risk reduction of 34%.

“For patients starting oral anticoagulant treatment, both PPI co-therapy and anticoagulant choice can materially affect risk of upper gastrointestinal bleeding hospitalization,” Ray told MedPage Today. “These factors are particularly important for patients with elevated gastrointestinal risk and argue for a GI evaluation prior to initiating oral anticoagulant treatment.”

Ray also noted that without an added PPI the incidence of hospitalization for upper GI bleeding was 4% per year, while adding a PPI reduced the rate to 2.8% per year.

The retrospective analysis looked at hospitalizations for upper GI bleeds among Medicare beneficiaries in the period 2011-2015. The researchers identified 1,643,123 patients with 1,713,183 new episodes of oral anticoagulant treatment for conditions such as atrial fibrillation.

The mean age in the cohort was 76.4, and atrial fibrillation accounted for 870,330 person-years (74.9%) of follow-up. Women accounted for 56.1% of person-years of follow-up.

Warfarin was by far the most commonly used anticoagulant, Ray and co-authors found. Overall, 1,058,807 anticoagulation patients had no PPI co-therapy vs 239,672 with co-therapy, for a follow-up of 754,389 person-years without co-therapy.

During no PPI co-therapy, the adjusted incidence of hospitalization for upper GI bleeding (n=119) was 115 per 10,000 person-years (95% CI 112-118).

Comparing PPI co-therapy (264,447 person-years) with no co-therapy, the researchers found the overall risk of upper GI bleeding hospitalizations (n=2,245) was lower with co-therapy, for an incidence rate ratio (IRR) of 0.66 (95% CI 0.62-0.69).

Compared with the results of other anticoagulants without PPI co-therapy, hospitalization per 10,000 person-years was highest for rivaroxaban (n=1278) at 144 (IRR 1.97) and lowest for apixaban (n=279) at 73. “Because rivaroxaban is given as a single daily dose intended to maintain 24-hour therapeutic levels, the relative peak plasma concentrations are higher than those for other oral anticoagulants,” Ray and associates explained.

The corresponding hospitalization incidence for dabigatran (n=629) was 120 per 10,000 person-years and for warfarin (n=4,933), 113 per 10,000 person-years.

The association of anticoagulant choice and PPI co-therapy with hospitalization for upper GI bleeding varied according to patients’ underlying disease, with absolute differences driven by the upper quartile of risk.

“For these patients, the difference in the annual incidence of hospitalization for upper gastrointestinal tract bleeding between the treatment strategies with the lowest and the highest gastrointestinal safety (rivaroxaban treatment without PPI and apixaban treatment with PPI, respectively) was 2.1 hospitalizations per 100 person-years,” the authors wrote. “These findings indicate the potential benefits of a gastrointestinal bleeding risk assessment before initiating anticoagulant treatment.”

Ray noted that oral anticoagulants can be extremely valuable in preventing an ischemic stroke — “which is one thing you really do not want to have happen, and we can’t lose sight of that.”

“On the other hand,” he added, “they have potentially very dangerous side effects. What we’ve done with this study is show that clinicians can focus on a high-risk population and significantly improve care for those patients with the addition of a PPI.”

Important Because of Large Patient Numbers

Asked for her perspective, Suneal K. Agarawal, MD, of Baylor College of Medicine in Houston, who was not involved in the research, said: “This a very important study because it reinforces with large numbers of patients what gastroenterologists have assumed for some time, that PPIs reduce GI bleeding. The COGENT trial showed that a PPI reduced GI bleeding in patients on antiplatelet medication, and now we have data on the role of PPIs in anticoagulant as well as antithrombotic therapy.”

The Medicare-based analysis had several limitations, the authors said, including the potential misclassification of anticoagulant treatment, PPI co-therapy, and non-steroidal anti-inflammatory drug use, since these variables were determined from filled prescriptions, and Medicare restricts reimbursement for many over-the-counter drugs. In addition, confounding could also have been present by unmeasured factors, such as aspirin exposure and Helicobacter pylori infection.

Furthermore, bleeding risk was measured with a disease risk score, an internal measure suitable for risk stratification within the Medicare cohort and not studied in other populations, Ray and co-authors noted. In terms of generalizability, the cohort excluded patients previously hospitalized for GI bleeding or who switched to a different anticoagulant during the study period. In addition, its Medicare population had a greater prevalence of anticoagulant treatment and GI bleeding risk compared with younger populations.

The study was supported in part by a grant from the National Heart, Lung, and Blood Institute.

Ray reported having no conflicts of interest; one co-author reported funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Rheumatology Research Foundation.

• Primary Source

  JAMA

  Source Reference: Ray WA, et al “Association of oral anticoagulants and proton pump inhibitor cotherapy with hospitalization for upper gastrointestinal tract bleeding” JAMA 2018; doi:10.1001/jama.2018.17242.

https://www.medpagetoday.com/cardiology/prevention/76810

Akebia to host special shareholder meeting

Special Shareholder Meeting to vote on the merger with Biopharmaceuticals will be held in Boston on December 11 at 11 am.
https://thefly.com/landingPageNews.php?id=2834179

Centene to hold a meeting

2019 Financial Guidance & Investor Day will be held in New York on December 14 at 8:30 am. Webcast: https://edge.media-server.com/m6/p/zsdxjzqz
https://thefly.com/landingPageNews.php?id=2834175

Catalyst Pharmaceuticals to hold a conference call

Conference call to discuss the Company’s commercialization plans for Firdapse will be held on December 13 at 8:30 am.
https://thefly.com/landingPageNews.php?id=2834173

Prophylaxis May Cut Cardiotoxicity Risk in HER+ Breast Cancer

The frequency of cardiotoxicity declined significantly with prophylactic antihypertensive medication for patients with early HER2-positive breast cancer treated with anthracycline-containing chemotherapy, but not trastuzumab (Herceptin), a randomized trial showed.

Although the trial did not meet the primary endpoint of cardiotoxicity in all treated patients, the incidence decreased by about half in patients who received anthracycline-containing adjuvant or neoadjuvant therapy and cardiovascular prophylaxis with a beta-blocker or angiotensin converting enzyme (ACE) inhibitor. Patients who received trastuzumab (Herceptin) without an anthracycline had a similar rate of cardiotoxicity whether they received one of the antihypertensive drugs or placebo, reported Pamela M. Munster, MD, of the University of California San Francisco, and colleagues.

“Our primary endpoint was similar for all cohorts,” Munster said at the San Antonio Breast Cancer Symposium (SABCS). “However, cardiotoxicity-free survival [CFS versus placebo] is comparable, with a hazard ratio of 0.71 for carvedilol and 0.74 for lisinopril, with a nonsignificant P-value.”

“Cardiotoxicity-free survival was longer with carvedilol or lisinopril than with placebo in patients who received anthracycline-containing regimens, but no differences were seen with the non-anthracycline regimens,” she added. “In patients with HER2-positive breast cancer treated with trastuzumab and anthracyclines, the addition of lisinopril or carvedilol should be considered.”

Two separate studies presented at the 2018 American College of Cardiology meeting in Orlando reported that cardiotoxicity from breast cancer drugs was about half as likely with prophylactic use of heart drugs in higher-risk patients, as well as an early trend for less cardiac damage.

‘Nice,’ but Not Enough?

The results are “very nice” but did not address the key issue for patients with breast cancer treated with anthracyclines and/or trastuzumab, said Steven Vogl, MD, a medical oncologist who practices in the Bronx in New York City.

“You’ve shown that you have fewer decreases in [left ventricular ejection fraction, LVEF], so you can give more trastuzumab, but did these interventions prevent dyspnea, heart failure — something that bothered the patient?” Vogl asked.

Acknowledging that his point was well taken, Munster said investigators struggled over the selection of the primary endpoint and ultimately decided that LVEF was more practical to assess than “subjective symptoms” in a community-based clinical trial involving 127 practices across the U.S.

“We will now analyze, do we in the long term actually have symptomatic changes, or is it just left ventricular ejection fraction?” she added.

Vogl continued, “There is considerable controversy about whether longer trastuzumab is better than shorter, but the bulk of the data suggest, at least for patients with the worse prognosis — positive nodes or bigger tumors — longer is better. In that situation, if that’s correct, then it’s good to give these [cardiovascular drugs] because then you get to give longer trastuzumab, regardless of whether they prevent symptoms or severe congestive heart failure — if you’re going to do the echocardiograms.”

Background and Results

Adjuvant trastuzumab remains standard of care for patients with early-stage HER2-positive breast cancer. The drug’s potential for cardiotoxicity requires monitoring and often leads to dose interruption and/or discontinuation, Munster noted. Results of several small studies suggested that treatment-induced cardiotoxicity might be prevented by prophylaxis with an ACE inhibitor or beta blocker, which are widely used to treat hypertension and heart failure.

Designing a randomized, multicenter, community-based trial of cardiovascular prevention posed several challenges, she continued. Reports about the frequency and severity of cardiotoxicity with HER2-targeted regimens varied widely. Evolving changes in practice pattern preferences for adjuvant neoadjuvant regimens have led to variation by geography and practice setting. Selection of regimens might be influenced by perceived or actual cardiac risk factors of patients with HER2-positive tumors.

Ultimately, investigators designed a randomized, double-blind, placebo controlled community-based trial involving patients with early HER2-positive breast cancer treated with trastuzumab. The design included stratification by use of anthracycline-containing chemotherapy. Patients were randomized to lisinopril (Zestril), carvedilol (Coreg and Coreg CR), or placebo, beginning day 1 of trastuzumab treatment and continuing for 52 weeks.

The trial had a primary endpoint of cardiotoxicity, defined as an absolute 10% decrease in LVEF from baseline or a 5% absolute decrease if LVEF fell below 50%. Eligible patients had early HER2-positive breast cancer and planned treatment with trastuzumab for 1 year, adjuvant or neoadjuvant cytotoxic therapy, LVEF ≥50, systolic blood pressure ≥90 mm Hg, and pulse ≥60 bpm.

Investigators randomized 468 patients 1:1:1 to placebo, lisinopril 10 mg, or carvedilol 10 mg. A total of 193 patients discontinued treatment before 52 weeks, including 86 patients who had a decrease in cardiac function. The patients remained in follow-up and 181 were eligible for efficacy analysis. Munster said 189 of 468 patients received anthracycline-containing chemotherapy in addition to trastuzumab.

The primary analysis showed similar rates of cardiotoxicity for the three treatment arms: 32% for placebo, 29% for carvedilol, and 30% for lisinopril. The carvedilol and lisinopril groups had nonsignificant trends toward better CFS, but neither difference achieved statistical significance:

• Carvedilol: HR 0.71 (95% CI 0.47-1.07, P=0.052)
• Lisinopril: HR 0.74 (95% CI 0.48-1.12, P=0.076)

The prespecified analysis by anthracycline use showed significant advantages for treatment with either cardiovascular agent versus placebo. Patients who received anthracycline-containing chemotherapy in addition to trastuzumab had a 51% reduction in the CFS hazard with carvedilol (95% CI 0.27-0.89, P=0.009) and a 47% reduction with lisinopril (95% CI 0.30-0.94, P=0.015). Cardiovascular prophylaxis did not affect CFS in the patients who received trastuzumab without an anthracycline.

Interruption of trastuzumab therapy occurred significantly more often in the placebo group (26.3% vs 15.4% with carvedilol and 17.3% with lisinopril, P=0.01). Anthracycline use accounted for most of the difference, as trastuzumab interruption occurred in 40.3% of the placebo group versus 19.7% of the carvedilol group and 23.0% of the lisinopril group.

Adverse events associated with carvedilol and lisinopril were consistent with their known safety profiles. Fatigue, dizziness, headache, cough, and hypertension were more common with lisinopril than with carvedilol.

SABCS session moderator Giuseppe Curigliano, MD, PhD, of the European Institute of Oncology in Milan, called the findings “provocative and potentially practice changing.”

The study was supported by the National Cancer Institute and the University of South Florida.

Munster and co-authors disclosed no relevant relationships with industry.

• Primary Source

  San Antonio Breast Cancer Symposium

  Source Reference: Munster P, et al “A randomized, community-based trial of an angiotensin-converting enzyme inhibitor, lisinopril, or beta-blocker, carvedilol, for the prevention of cardiotoxicity in patients with early-stage HER2-positive breast cancer receiving adjuvant trastuzumab” SABCS 2018; Abstract GS5-01.

https://www.medpagetoday.com/meetingcoverage/sabcs/76813

BriaCell Positive Phase 2 Data on Lead Cancer Med i n Combo at SABCS

• Interim data indicate an excellent safety profile for the combination regimen in advanced breast cancer patients. Initial efficacy data is expected in first quarter of 2019;
• Confirmed positive proof-of-concept with Bria-IMT™ Monotherapy demonstrates promising anti-tumor activity with excellent safety and tolerability in advanced breast cancer patients.

BriaCell Therapeutics Corp. (“BriaCell” or the “Company“) (TSX-V:BCT) (OTCQB:BCTXF), an immuno-oncology focused biotechnology company with a proprietary targeted immunotherapy technology, announces the presentation of initial safety data in the combination study of its lead candidate, Bria-IMT™, with pembrolizumab [KEYTRUDA^®; manufactured by Merck & Co., Inc. (NYSE: MRK)] and confirmation of positive proof of concept data of Bria-IMT™ for advanced breast cancer at the 2018 San Antonio Breast Cancer Symposium (SABCS^®). The combination study is listed in ClinicalTrials.gov as NCT03328026.

“I am very excited about our data continuing to show robust biological activity of Bria-IMT™ in advanced breast cancer,” commented Dr. Bill Williams, BriaCell’s president & CEO. “These findings also reinforce our product development strategy for Bria-OTS™, BriaCell’s novel off-the-shelf personalized immunotherapy, by showing predictability of the anti-tumor responses in patients using a relatively simple and inexpensive HLA test.

“Based on the data of three proof of concept studies to-date, Bria-IMT™ has shown the ability to produce powerful immune responses and elicit tumor regression even in heavily pre-treated patients with very advanced disease. We are highly confident of our strategy to use Bria-IMT™ in combination with KEYTRUDA^®, an approved treatment for multiple cancer indications, and expect synergistic activity of this combination in patients with advanced breast cancer. We look forward to additional clinical data and expect to share details at upcoming scientific meetings.”

Highlights of the Poster Presentation at SABCS^®

Initial safety data on the Bria-IMT™/KEYTRUDA^® combination study and additional confirmatory Phase I/IIa data from the Bria-IMT™ monotherapy study, a subset of which was the subject of a previous press release, was presented this morning in detail by Saveri Bhattacharya, DO, assistant professor of Medical Oncology at Thomas Jefferson University and researcher at the NCI-designated Sidney Kimmel Cancer Center – Jefferson Health.

Title: Initial safety and efficacy of a phase I/IIa trial of a modified whole tumor cell targeted immunotherapy in patients with advanced breast cancer

Bria-IMT™ Combination Study with KEYTRUDA^®: In the combination therapy study, five patients have been treated with the Bria-IMT™/KEYTRUDA® combination to date.  Initial data on the combination of the Bria-IMT™ regimen with KEYTRUDA^® suggests the combination is very safe and well tolerated. The study remains ongoing.

BriaCell is on track to present initial efficacy data on the combination in 1Q19.

https://globenewswire.com/news-release/2018/12/06/1663095/0/en/BriaCell-Presents-Positive-Efficacy-Data-with-Lead-Cancer-Drug-Candidate-in-Phase-IIa-Monotherapy-and-Excellent-Initial-Safety-Data-in-Combination-with-KEYTRUDA-at-a-Major-Breast-C.html