Key Points

• Statin therapy is in wide use globally to prevent cardiovascular events in patients with elevated cholesterol levels. Despite an abundance of data proving their effect, many patients exhibit caution in starting the therapy due to concerns of muscle pain and weakness.
• The CTT meta-analysis of 23 trials, spanning over 150,000 patients demonstrated a small increase in the frequency with which muscle weakness and pain were reported in the first year of therapy. This increase did not persist beyond one year.
• Investigators adjudicated the etiology of muscle pain and weakness in the individual trials, finding that only 1 in 15 reports were truly caused by the statin therapy.

Continue reading →

Key Points

• Transradial access has emerged as the preferred initial access method for coronary angiography, largely due to evidence supporting its association with reduced bleeding risk. However, the difference between transradial and transfemoral access with regards to mortality is not clear. The RTC study was an individual patient data meta-analysis to examine the effect of transradial vs transfemoral access on 30-day mortality and bleeding risk.
• Transradial access resulted in reduced 30-day mortality and major bleeding compared to transfemoral. This result was seen regardless of indication for angiography (ie, ACS vs non-ACS) or whether or not PCI was performed. The reduction in mortality was especially substantial in patients with significant baseline anemia.

Continue reading →

Key Points

• The PARADISE-MI trial randomized patients to receive sacubitril/valsartan or ramipril after high-risk myocardial infarction. The initial results demonstrated no significant benefit of sacubitril/valsartan, however examination of adjudicated events demonstrated a trend toward benefit with sacubitril/valsartan.
• A post-hoc win ratio analysis of the primary results were presented at the 2022 European Society of Cardiology Congress, in which the primary outcome was analyzed in a hierarchical order as opposed to a composite.
• Sacubitril/valsartan was compared to ramipril on a patient-by-patient basis, and resulted in an estimated unmatched win ratio of 1.17, demonstrating a larger number of “wins” with respect to the primary outcomes, when compared to ramipril.
• These results do not replace the initial neutral trial results, but can be rather used to aid in decision-making.

Continue reading →

Key Points

• Antiplatelet therapy is a cornerstone of secondary prevention in patients with known CAD, but it is incompletely understood whether aspirin should be the preferred agent as compared to oral P2Y12 inhibitors. The PANTHER collaborative initiative was an individual patient data meta-analysis which sought to assess the effect of ASA vs PSY12 inhibitor monotherapy on long-term cardiovascular outcomes in patients with known CAD.
• Treatment with oral P2Y12 inhibitor therapy, as compared to ASA, resulted in lower composite CV events (including MI, CV death, and stroke) and similar bleeding risk, although with specifically reduced risk of GI bleeding and hemorrhagic stroke. The reduced composite CV events were largely driven by a significant reduction in MI in the P2712 inhibitor group.

Continue reading →

Key Points

• Given the increased thrombotic risk in COVID patients, there has been substantial interest around the potential use of antithrombotic agents in the treatment of critically ill patients with COVID. The COVID PACT study assessed the effect of full-dose vs standard-dose prophylactic anticoagulation, as well as the addition of antiplatelet therapy with clopidogrel vs no additional therapy, on both thrombotic and bleeding events in COVID patients in the ICU.
• Treatment with full-dose anticoagulation resulted in lower thrombotic rates of thrombotic events in COVID ICU patients. There was no difference in rates of fatal or life-threatening bleeding, but there was an increased rate of GUSTO moderate or severe bleeding in patients treated with full-dose anticoagulation.

Continue reading →

Key Points:

• In this pre-specified MASTER DAPT sub-study, patients with high bleeding risk and high ischemic risk who were treated with PCI with an Ultimaster stent were randomized to either standard care dual antiplatelet therapy (DAPT) or abbreviated DAPT starting after 30 days of DAPT post PCI.
• The three co-primary endpoints included the following at fifteen months: a) net adverse clinical events (NACE), b) major adverse cardiac and cerebral events (MACCE), and c) major or clinically relevant non-major bleeding (MCB).
• Treatment with abbreviated DAPT was not significantly different from standard DAPT for NACE and MACCE in patients with high ischemic risk. Abbreviated DAPT resulted in lower major or nonmajor bleeding. There were no significant differences between the patients with high ischemic risk and those without.

Continue reading →

Key Points

• Understanding the future risk of myocardial infarction and death for patients with established coronary artery disease is a cornerstone of modern cardiology.
• The PRE18FFIR study attempted to pool PET-CTA images into patients’ established invasive and noninvasive coronary images to predict the risk of future myocardial infarction, death, and coronary revascularization.
• 704 patients from 4 countries were enrolled into this prospective cohort study
• While the technique was not able to accurately demonstrate the risk of future myocardial infarction, the authors were able to find an association with increased coronary activity on PET scans and both all-cause mortality and cardiac mortality.

Continue reading →

Key Points:

• Current risk estimating algorithms exclude causal effects and therefore do not accurately estimate baseline cardiovascular risk caused by LDL and systolic blood pressure (SBP)

• Using artificial intelligence to train algorithms on the causal effect of modifiable targets of disease can for the 1st time produce algorithms that accurately predict risk and benefit

• These updated algorithms could be used to prescribe specific actions to alter the trajectory of cardiovascular disease, including identifying the optimal timing, duration and intensity of LDL and SBP lowering.

Continue reading →

Key Points

• Selective XIa inhibitor Milvexian may innovate the field of oral anticoagulation by uncoupling hemostasis from thrombosis and potentially providing protection from ischemic events with reduced bleeding risk among patients with acute non-lacunar stroke.
• The Phase 2 AXIOMATIC-SSP trial (n=2,366) compared 5 doses of Milvexian (25 mg once daily, or 25, 50, 100, 200 mg twice daily) against placebo daily for 90 days among patients within 48 hours from acute non-lacunar stroke or TIA. Milvexian was not found to have a statistically significant dose-response in the reduction of the primary outcome (clinical ischemic stroke during treatment or infarct identified on brain MRI at 90 days), though Milvexian at the doses of 50 mg and 100 mg twice daily did result in numerically lower event rates, compared to placebo. BARC 3 or 5 rates were similar to placebo with most doses of Milvexian compared to placebo, with numerically higher bleeding rates with Milvexian 200 mg twice daily.

Continue reading →

Key Points

• Selective XIa inhibitor Asundexian may innovate the field of oral anticoagulation by uncoupling hemostasis from thrombosis and potentially providing protection from thromboembolic events without increasing bleeding risk among patients with acute non-cardioembolic stroke.
• The Phase 2 PACIFIC-STROKE trial (n=1,808) compared Asundexian 10 mg, 20 mg and 50 mg versus placebo (on top of antiplatelet therapy) among patients suffering from acute non-cardioembolic stroke. Overall, all doses of Asundexian appeared safe as with non-statistically different rates of major and clinically-meaningful non-major ISTH bleeding compared to placebo. At the same time, however, even the highest dose of Asundexian did not achieve a statistically significant reduction in the primary ischemic outcome, namely reducing the incidence of symptomatic ischemic stroke or covert brain infarct (detected by MRI) at 6 months from the index event. Nonetheless, secondary exploratory analyses of Asundexian 50 mg suggested a dose-dependent reduction in the risk of recurrent symptomatic ischemic strokes and TIAs. Adequately powered Phase 3 data are needed to understand whether Asundexian may provide additional protection from recurrent ischemic events among patients who have acute non-cardioembolic strokes.

Continue reading →

Key Points

• While DOACs have revolutionized the field of atrial fibrillation for patients with non-valvular disease, the equally important population of patients with valvular atrial fibrillation has traditionally been excluded from randomized trials and represent a fundamental unmet need at the global level, since rheumatic heart disease affects 40 million people around the world, primarily concentrated in low- and middle-income countries (LMIC).
• The INVICTUS trial finally provided randomized evidence that VKA like warfarin should remain the standard of care for patients with valvular atrial fibrillation in the setting of mitral stenosis. In this study, rivaroxaban was found to have a significantly higher rate of the primary outcome of stroke, systemic embolism, myocardial infarction or death, compared to VKA (8.26% vs 6.46% per year), with cross-over of the Kaplan-Meier curves at about 18 months, and a resulting mean survival time (RMST) of difference-75 days in favor of VKA (95% CI -117 to -34; p<0.001). The mortality benefit of VKA became most apparent starting around 3 years of observation time.

Continue reading →

Key Points

• Selective XIa inhibitor Asundexian may innovate the field of oral anticoagulation by uncoupling hemostasis from thrombosis and potentially providing protection from ischemic events without increasing bleeding risk among patients with acute myocardial infarction.

• The Phase 2 PACIFIC-AMI trial (n=1,601) compared Asundexian 10 mg, 20 mg and 50 mg versus placebo (on top of dual antiplatelet therapy) among patients suffering from acute myocardial infarction. Overall, all doses of Asundexian seemed to be safe as they had similar rates of BARC 2, 3 and 5 bleeding compared to placebo. However, even the highest dose of Asundexian did not result in a significant reduction in the primary ischemic outcome of cardiovascular death, MI, stroke or stent thrombosis (compared to placebo), perhaps due to a low event rate. Adequately powered Phase 3 data are therefore needed to understand whether Asundexian may provide additional protection from ischemic events among patients who have acute coronary syndromes.

Continue reading →

Despite major advances in the implementation of artificial intelligence (AI) in Cardiology, from both a clinical and research perspective, no clinical trials to data have proven its benefit or efficacy in this space. The investigators of EchoNet-RCT sought to rectify this, by conducting and publishing the first randomized clinical trial studying the implementation of AI for the practice of clinical cardiology. In a Hot Line Session at the 2022 European Society of Cardiology Congress, Dr. David Ouyang (Smidt Heart Institute, Cedars-Sinai, Los Angeles) presented the results of their trial, testing the fidelity and accuracy of echocardiograms read by artificial intelligence.

Echonet-Dynamic is the proprietary AI software studied in the trial. The programming of the deep-learning algorithm had previously been published in NATURE. The software was trained on echocardiogram videos to assess cardiac function and determine left ventricular ejection fraction. Prior results showed the AI to accurately read ejection fractions with a mean absolute error of 4.1 – 6%. In order to reproduce the results and minimize error, the algorithm employs multiple cardiac cycles in its determination of ejection fraction.

In this prospective randomized control trial assessing Echonet-Dynamic in clinical use, the investigators sought to determine how often AI-generated LVEF was changed by the reading cardiologist. These changes would then be compared against changes the cardiologists made to the sonographer-generated LVEFs. To achieve this, 3495 echocardiograms obtained by cardiac sonographers were randomized in a 1:1 fashion to undergo LVEF tracings by the sonographer or by the AI. These scans were then sent to the reading cardiologist, who was blinded to the source of the EF assessment, for final interpretation. To assess the adequacy of blinding, the cardiologists were asked to choose whether the thought the EF assessment was AI-guided or sonographer-guided at the end of each scan, and chose correctly only 32.3% of the time.

The primary efficacy outcome was the change in initial EF (AI or sonographer-guided) vs. final EF assessment by the cardiologist. The AI-guided EF required a substantial change 16.8% of the time, compared to 27.2% in the sonographer-guided arm (mean difference -10.5% (95% CI -13.2% – 7.7%), p<0.001) meeting significance for both non-inferiority and superiority. The mean absolute difference of EF percentage points was also significant, favoring AI-generated assessments (2.79 vs 3.77, p<0.001). A pertinent secondary outcome was the time it took for reading cardiologists to overread each scan, and as expected, more time was spent reading the sonographer-guided scans (64 seconds vs 54 seconds, p<0.001.  Subgroup analyses by patient characteristics and echo characteristics demonstrated consistent results in favor of AI-generated assessments.

The authors concluded that LVEF assessment by a proprietary AI algorithm was both noninferior and superior to an initial sonographer assessment, as cardiologists were less likely to change these assessments overall. As this was a single-center study, it is unclear how generalizable these results would be, and whether they can be externally validate. Still, this trial is promising for the future of AI in cardiology, and as Dr. Ouyang stated, the technology could “be very effective at not only improving the quality of echo reading output but also increasing efficiencies in time and effort spent by sonographers and cardiologists by simplifying otherwise tedious but important tasks”.

Key Points

• Allopurinol had previously shown an improvement in exercise time and qualitative chest pain assessment in patients with ischemic heart disease.
• ALL-HEART randomized over 5,700 patients without gout to receive allopurinol in addition to usual care versus usual care alone. The dose of the xanthine oxidase inhibitor was up-titrated to a total of 600 mg daily.
• The primary outcome, a composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death, was not found to be different between the two groups, suggesting no benefit for the drug, and likely settling the question for good.

Continue reading →

Key Points

• There has been a theoretical concern of potential increased amyloid deposition via neprilysin inhibition in patients using sacubitril/valsartan. In the PERSPECTIVE study, patients with HFpEF and HFmrEF were treated with either sacubitril/valsartan or valsartan. Their cognitive function (as assessed by comprehensive CogState testing) as well as brain amyloid peptide deposition by PET and MRI were determined at three years.
• Treatment with sacubitril/valsartan was not associated with any significant differences in cognitive function via CogState testing or in global amyloid deposition as determined by PET scan at three years.

Sacubitril/Valsartan is now standard of care in patients with heart failure with reduced ejection fraction (HFrEF), and within the past year has also gained FDA approval in the treatment of patients with preserved EF as well. The mechanism of sacubitril involves neprilysin inhibition, and neprilysin is additionally involved in the proteolytic degradation of amyloid peptides. As such, a theoretical concern of sustained neprilysin inhibition via the use of sacubitril/valsartan has been the potential accumulation of amyloid peptides in the brain with subsequent cognitive impairment. In a breaking presentation at the 2022 European Society of Cardiology Conference today, Dr. John McMurray (University of Glasgow) and his team presented “Efficacy and Safety of LCZ696 Compared to Valsartan on Cognitive Function in Patients With Chronic Heart Failure and Preserved Ejection Fraction,” or the PERSPECTIVE trial.

The PERSPECTIVE study (NCT02884206) was a multicenter, randomized, double-blind, active-controlled study assessing the cognitive impact of sacubitril/valsartan compared to valsartan alone in heart failure patients with mid-range or preserved ejection fraction. All recruited patients were adults >60 years old with symptomatic heart failure and EF >40% with either an NT-proBNP >200 pg/mL or a hospitalization for HF within the last year. Some relevant exclusion criteria included elevated serum potassium >5.4mmol/L, eGFR <25 ml/min, or severe hypo- or hypertension. Other neurocognitive-relevant criteria included consent to APOE4 genetic testing, lack of preexisting substantial cognitive impairment (known dementia syndrome or MMSE <24), and absence of contraindication to MRI.

A total of 592 patients were randomized; 297 patients were included in the valsartan cohort, and 295 in the sacubitril/valsartan cohort. Prior to randomization, in the run-in phase, each patient was initiated in 80 mg valsartan BID for 1-5 weeks and then sacubitril/valsartan (49/51mg BID) for 2-4 weeks to ensure tolerance. The mean age was 72, and the pre-existing average MMSE score was 28. CogState cognitive testing was performed every 3 months, PET scans were performed at the outset and at 18 and 36 months, and MRIs were also performed at 18 and 36 months. The primary outcome of CogState global cognition composite score at 36 months was not statistically different between the two groups. Similarly, there were no differences in secondary outcomes, including the standardized uptake value ratio (SUVR) of the global cortical composite in amyloid PET imaging of the brain. In individual components of the brain, sacubitril/valsartan resulted in significantly lower rates of amyloid deposition by the SUVR method, including the cingulum (p=0.003).  No new safety concerns were identified relative to previous trials. 25% of patients discontinued treatment in the sacubitril/valsartan arm, as did 30% in the valsartan arm alone.

When discussing the implications of the study at the ESC, Dr. McMurray stated: “This largely theoretical concern that sacubitril/valsartan might cause accumulation of amyloid peptides in the brain with resulting cognitive dysfunction is, I think, disproved by this trial.”