By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: Below are some highlights from two key studies presented in Barcelona, Spain, between Aug. 26 and Aug. 29, 2022, along with Dr. Crawford’s personal commentary on both.
REDUCE-IT: Reduction of cardiovascular events with icosapent ethyl intervention. The authors of this trial compared icosapent ethyl (IPE) to placebo for reducing serum triglyceride (TG) levels and cardiovascular (CV) events in stable patients with high TG (135 mg/dL to 499 mg/dL). Eligible subjects had been diagnosed with a CV disease or were at high risk for developing it (e.g., diabetes plus one other risk factor). Also, subjects already were on a statin with well-controlled LDL cholesterol levels (i.e., lower than 100 mg/dL). The 8,179 patients enrolled were randomized to IPE 2 g twice a day or placebo.
The mean reduction in TG on IPE was 39 mg/dL vs. a gain of 4.5 mg/dL on placebo. The primary outcome of CV death, myocardial infarction (MI), stroke, coronary revascularization, or unstable angina was 17% for IPE patients vs. 22% for placebo patients (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.68-0.83; P < 0.0001).
Secondary outcomes for IPE vs. placebo were CV death or MI (9.6% vs. 12.4%; P < 0.001), all MI (6.1% vs. 8.7%; P < 0.001), revascularization (5.3% vs. 7.8%; P < 0.001), all-cause mortality (6.7% vs. 7.6%; P = 0.09), and major bleeding (2.7% vs. 2.1%; P = 0.06). These results were consistent among those with diabetes, prior MI, and across the spectrum of kidney function. The investigators concluded using 2 g of IPE twice a day was superior to placebo for lowering TG levels and preventing CV events and CV death in patients with moderately elevated TG levels and either known CV disease or at high risk for developing it, and who were on a statin with well-controlled LDL cholesterol levels.
COMMENTARY
This formulation of IPE carries a higher level of purified eicosapentaenoic acid (4 g/day) than was tested in other clinical trials, including those with n-3 fatty acid supplements. This probably explains why this is the first non-LDL-targeted trial to show a CV benefit, although other trials are ongoing. Also of interest was the lower level of TG for entry into the trial (greater than 135 mg/dL) was within the upper range of what is considered normal (< 150 mg/dL) and includes borderline high level (lower than 200 mg/dL).
The authors excluded those with levels greater than 500 mg/dL, presumably to avoid dealing with pancreatitis during the study period. Patients with a history of pancreatitis were excluded, as were those with severe heart failure, liver disease, uncontrolled diabetes, and markedly worse renal function.
The median LDL level was 75 mg/dL, which is good for when this trial started, but 71% of the cohort were secondary prevention patients for whom we now believe the LDL target should be < 70 mg/dL. If this cohort recorded a lower LDL level, would the results have been as robust?
The investigators performed a cost effectiveness analysis, assuming the price of IPE is $4 a day. The quality-adjusted life years for IPE and placebo were 3.34 and 3.27, respectively. IPE was cost effective in most simulations they ran.
Finally, although major bleeding was slightly higher on IPE, but not quite statistically significant, safety seems relatively favorable at this dose. Expect to see the next iteration of the prevention guidelines to include this therapy for selected patients.
eBRAVE-AF: Smartphone app more than doubles detection of atrial fibrillation (AF) vs. standard screening. eBRAVE-AF was a site-less, randomized study of 5,551 individuals (median age = 65 years; 31% were women) who owned a smartphone.
Entry criteria included age 50-90 years, no known AF, not on anticoagulants, and a CHA2DS2-VASc score of ≥ 1 for men and ≥ 2 for women. Smartphone screening was compared to usual screening for the ability to detect AF, which then was treated with oral anticoagulants (OAC). There was a dedicated study app on smartphones to trigger randomization and initiate a crossover phase.
Participants were randomly assigned to sequential six-month periods of digital and conventional AF screening. Digital screening involved using the smartphone’s photoplethysmographic sensor, which required putting a finger on the camera twice a day for two weeks, then twice a week. Reminder notifications were used.
If the results were abnormal, participants were mailed a patch to record a 14-day ECG, which they returned by mail. If this test showed AF, subjects were sent to their local physician, who was not involved in the study, to decide on therapy. The primary efficacy endpoint was newly diagnosed AF leading to OAC therapy.
The primary endpoint occurred in 1.33% of the digital cohort and 0.63% of the conventional screening cohort (odds ratio [OR], 2.12; 95% CI, 1.19-3.76; P = 0.01). Also, digitally detected AF predicted major adverse cardiac and cerebrovascular events.
The investigators concluded digital smartphone screening for AF more than doubles the detection rate of treatment-relevant AF in an older population compared to conventional screening.
COMMENTARY
I have experienced a marked increase in the number of patients I am seeing because their smartphone detected AF. Upon further ambulatory ECG testing, most of these patients exhibit atrial premature beats, not AF. Thus, the smartphones my patients use are sensitive, but not very specific, for AF. Few of my patients use the ancillary devices that display an ECG, which can be recorded and sent for analysis via smartphone. The beauty of the device in this study is that patients used the built-in camera to detect AF via an app. Thus, the patient does not need the most recent model of smartphones with built-in or peripheral-detecting devices.
Although the results of this study are impressive, the definition of conventional screening was unclear. Also of interest was the low yield of the smartphone screening. Although more than double conventional screening, it was only 1.3% of older individuals with CHA2DS2-VASc scores who were in the treatable range. Whether this will make a difference in outcomes remains to be established.
Some highlights from two key studies presented in Barcelona, Spain, between Aug. 26 and Aug. 29, 2022, along with Dr. Crawford’s personal commentary on both.
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