Hot Trials from the European Society of Cardiology Annual Congress
By Michael H. Crawford, MD, Editor
SYNOPSIS: Below are some highlights from four key studies presented in Barcelona, Spain, between Aug. 26 and Aug. 29, 2022, along with Dr. Crawford’s personal commentary on each.
PANTHER: P2Y12 inhibitor monotherapy vs. aspirin in patients with coronary artery disease. Researchers identified seven trials (ASCET, CADET, CAPRIE, DACAB, GLASSY, HOST-EXAM, and TiCAB) conducted in 492 sites in Europe, Asia, and North America. In these trials, researchers compared a P2Y12 inhibitor (clopidogrel or ticagrelor) to aspirin monotherapy as secondary prevention in patients with coronary artery disease (CAD). After exclusions, 24,325 patients were included, of whom 12,178 were assigned P2Y12 inhibitor (PYI) monotherapy and 12,147 aspirin monotherapy. The primary efficacy outcome was the composite of cardiovascular death, myocardial infarction, and stroke. Safety outcomes were major bleeding and net adverse clinical events (NACE).
After a median follow-up of 557 days, the primary outcome had occurred in 5.5% of PYI-treated patients and 6.3% of the aspirin group. The primary safety outcomes of major bleeding and NACE had occurred in 1.2% and 6.4%, respectively, in the PYI group vs. 1.4% and 7.2%, respectively, in the aspirin group. The investigators concluded long-term PYI monotherapy may be warranted instead of aspirin monotherapy for secondary prevention among CAD patients.
Consider post-procedural patients who have finished the recommended therapy with dual antiplatelet therapy after a coronary procedure, along with other CAD patients in whom secondary prevention antiplatelet therapy is indicated. The usual course of action for these groups is to move to aspirin monotherapy because of the large amount of data over many years that speak to its effectiveness. Recently, attention has been focused on the long-term risk of bleeding with aspirin. In addition to its antiplatelet effects, aspirin can erode the endothelium of the stomach and GI tract, leading to GI bleeding. Thus, attention has focused on PYI monotherapy instead because it does not cause this GI destruction and it has appeared to produce equal cardiovascular protective effects.
Now that at least some of the PYI agents are generic in the United States, this approach would alleviate the cost difference between PYI agents and aspirin. It remains unclear whether the infrequent genetic resistance to indirect PYI agents, such as clopidogrel, should be used to help decide what to use for monotherapy. However, this large analysis certainly supports the safety and efficacy of PYI monotherapy without genetic testing for secondary prevention.
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 were on a statin with well-controlled LDL cholesterol levels.
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 (> 135 mg/dL) was within the upper range of what is considered normal (less than 150 mg/dL) and includes borderline high level (< 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 reduced renal function.
The median LDL level was 75 mg/dL, which is good for when this trial was 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 IPE cost $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 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 (PPG) 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.
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 it 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.
INVICTUS: Investigation of rheumatic AF treatment using vitamin antagonists, rivaroxaban, or aspirin studies. The objective of this randomized, open-label, parallel study was to evaluate the effectiveness of rivaroxaban 20 mg/day vs. a vitamin K antagonist (international normalized ratio, 2-3.0) in patients with AF associated with rheumatic heart disease. Patients were at least age 18 years, had been diagnosed with rheumatic heart disease, and presented with at least one of the following: a CHA2DS2-VASc score > 1, mitral valve area less than 2 cm2, or echocardiographic evidence of spontaneous atrial contrast or left atrial thrombus. Researchers excluded patients with mechanical heart valves, who were taking dual antiplatelet therapy, who were pregnant, presented with marked renal insufficiency, or were contraindicated to the two drugs. The 4,531 patients enrolled were a mean age of 50 years; 72% were women.
Over the three-year follow-up period, the primary outcome of vascular death, stroke, systemic embolism, or MI occurred in 8.2% of the rivaroxaban group vs. 6.5% of the vitamin K antagonist group (P < 0.05). The event curves diverged at 18 months. The secondary outcome of vascular death occurred in 6.3% of the rivaroxaban group vs. 4.8% of the vitamin K group (P < 0.05). Ischemic stroke was 1.1% in the rivaroxaban group vs. 0.7% of the vitamin K group (P < 0.05). The investigators concluded vitamin K antagonists were superior to rivaroxaban in preventing adverse CV events in patients with AF associated with rheumatic heart disease. They also concluded these results support the current guideline recommendation to use vitamin K antagonists to prevent stroke in patients with rheumatic heart disease and AF.
Presumably, most of these patients had rheumatic mitral stenosis, for which the guidelines do recommend vitamin K antagonists over direct oral anticoagulants (DOAC). It is unclear whether vitamin K antagonists would be effective against other forms of rheumatic disease, such as mitral regurgitation or aortic stenosis/regurgitation. Also, there has been debate about patients with mitral annular calcification-associated mitral stenosis and AF. Hopefully, when the full publication of this study comes out, some of these nuances will be addressed. For now, I would avoid using DOACs in anyone with AF and mitral stenosis of any cause or a rheumatic etiology of their heart disease. n
Below are some highlights from four key studies presented in Barcelona, Spain, between Aug. 26 and Aug. 29, 2022, along with Dr. Crawford’s personal commentary on each.
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