Linda Peckel

 -a fixed-dose combination of 2 lipid-lowering agents with complementary mechanisms of action is effective for high-risk cardiovascular patients who fail to meet lipid goals with conventional statin therapies. The ATP citrate lyase inhibitor bempedoic acid, delivered in combination with the cholesterol absorption inhibitor ezetimibe (typically used as an add-on to statin therapy) lowered low-density lipoprotein (LDL) cholesterol by 38% compared to placebo, according to lead author Christie Ballantyne, MD, of Baylor College of Medicine in Houston, Texas, who presented the results of the phase 3 trial at the European Atherosclerosis Society 2019 Congress on May 27th.

A total of 301 patients at high risk for heart attack or stroke (measured as clinical disease with a history of familial hypercholesterolemia and LDL levels above 2.6 mmol/L, or no clinical disease, with multiple risk factors and LDL above 3.4 mmol/L) were randomized to the combination therapy, either agent alone, or placebo. The majority of patients (65%) were already taking a statin, many at the maximal dose.

At the end of 12 weeks, the combination of bempedoic acid/ezetimibe (180 mg/10 mg) reduced LDL-C by 36.2%, which was significantly greater than ezetimibe alone (23.2%), bempedoic acid alone (17.2%), or placebo, which actually increased LDL by 1.8%. The fixed combination also demonstrated greater reduction in non-high-density lipoprotein and high sensitivity C-reactive protein than either agent alone or placebo.

“The results of this study show that a fixed combination of bempedoic acid and ezetimibe, two oral lipid-lowering agents with complementary mechanisms of action, has the potential to meet the needs of high risk patients who are unable to attain LDL cholesterol goal with currently available therapies,” Dr. Ballantyne said.

The efficacy of the 2-agent combination is also supported by data from a 

that showed additional LDL-C lowering when bempedoic acid was added to ongoing treatment with ezetimibe. (ref)

Bempedoic acid/ezetimibe was well tolerated and presents a good therapeutic option for patients who are unable to tolerate conventional statin therapies, in addition to those who are already taking statins. “The fixed combination is also a convenient once-daily option for patients,” Dr. Ballantyne added.

Efficacy and safety of bempedoic acid + ezetimibe fixed-dose combination in patients at high CVD risk and with elevated LDL-C receiving maximally tolerated statin therapy. 

Paper presented at 87th EAS Congress: May 26-29, 2019; Maastricht, The Netherlands. Abstract EAS19-1133.
	 

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MAASTRICHT, The Netherlands--The significant combined effect of bempedoic acid and ezetimibe on LDL-C in patients at high risk for CV events may suggest a new era of non-statin therapy. 

Fixed-dose Lipid-lowering Combination Bests Either Drug Alone 

 - Elevated levels of plasma lipoprotein(a) (Lp[(a]) have been linked to risk for cardiovascular (CV) disease. Although it has historically been thought that this elevated risk is related to both the atherogenic and prothrombotic effects of Lp(a), a recent study found that antiplatelet and antithrombin therapies to reduce Lp(a) levels are not associated with any significant impact on CV outcomes, including heart attack and stroke. Results of the large-scale European study were presented May 27th at the 87th Annual Congress of the European Atherosclerosis Society (EAS). 

The proposed prothrombic and atherogenic effects of Lp(a) have been difficult to separate. Thus, the current study sought to determine whether Lp(a) actually has significant prothrombic effects. “Antiplatelet and antithrombin therapies are part of the routine evidence-based management of patients at high and very high risk of cardiovascular events,” explained Brian Ference, MD, a cardiologist and genetic epidemiologist and Executive Director of the Centre for Naturally Randomised Trials at Cambridge University, who presented the latest data. “Given current understanding of the biology of lipoprotein(a), a key question is whether these treatments are likely to influence cardiovascular risk associated with high lipoprotein(a) levels,” he said.

Using a pool of 480,000 people of European descent from the UK Biobank database, 375,000 of whom were identified as having high Lp(a) levels using a single assay, the study showed that high Lp(A) levels were not associated with increased risk of thrombotic outcomes such as deep vein thrombosis or pulmonary embolism. This trend persisted in the cohort regardless of whether they carried gene variants for platelet activation, or for Factor II and Factor V genes for prothrombin disorders. Taken together the results seem to argue against a clinically significant prothrombotic effect for Lp(a) “Based on the results of our analysis, in which lipoprotein(a) levels were measured with the same sensitive assay, concomitant antiplatelet therapy should not have any effect on the amount that lipoprotein(a) must be reduced to achieve clinically meaningful benefit in a short-term trial,” Dr. Ference reported.

These findings are likely to have a significant impact on clinical trial design for hyperlipidemia by altering the current practice of enrolling patients with cardiovascular disease who are already taking antiplatelet therapy, he concluded.

Mendelian randomization analysis of lipoprotein(a) lowering and cardiovascular risk stratified by LDL cholesterol, gender, and antiplatelet therapy: implications for clinical outcome trials. 

Paper presented at 87th EAS Congress: May 26-29, 2019; Maastricht, The Netherlands; Abstract  EAS19-0777.

MAASTRICHT, The Netherlands-Study results suggest that clinical trials of novel treatments targeting Lp(a) will not be affected by subjects with CV disease receiving antiplatelet therapy.

From 87th EAS: High Lipoprotein(a) Levels not Linked to Increased Prothrombotic Effects

âLarge scale screening for atrial fibrillation (AF) is feasible using smartphone apps already available, according to authors of one of the largest population studies on AF ever conducted.

"Using digital technology only, we were able to reach a large population very quickly and collect clinically meaningful and actionable data, without the need for medical infrastructure,” reported lead author Tine Proesmans, MASc, of the Mobile Health Unit at Hasselt University in Belgium on May 11th at the 2019 Heart Rhythm Society meeting.

More than 60 000 participants from the general population in Belgium were screened and enrolled using only existing communications, ie, local and national newspapers, over a 2-week period. All participants gained access to the approved smartphone app (FibriCheck® by Qompium) by scanning a code provided in the advertisements. Participants were instructed to measure heart rhythm for 8 days at regular intervals twice daily as well as when experiencing symptoms. The smartphone technology allowed for the flexibility to take measurements “anytime, anywhere, and at a fraction of the cost" of using traditional healthcare resources, Dr Proesmans emphsized.

Each event was recorded and classified as 

regular rhythm, possible AF, irregular rhythm 

 During the recorded time period, 72% percent of participants had no symptoms, while 27% showed persistent AF. A total of 581 participants (73%) had paroxysmal AF, with 111 detected on the first pulse-plethysmography (PPG)-measurement. All participants received a written report with a copy of rhythm traces and a physician-based conclusion regarding their AF pattern.

Participants had an average age of 48.5 years (± 14.7 years) and the group was ~58% male. Average age of the group identified as having AF was ~62 years (± 10.9 years) and ~76% male.

Importantly, 72% of the AF participants experienced no symptoms.

An estimated 33.5 million adults are affected by AF annually. Not only did this trial demonstrate the efficacy of the AF screening modality, but it also showed how smartphone technology can be easily utilized for very low-cost screening, monitoring, and treatment applications across broad populations. "It's fascinating to see the impact that PPG technology is having on clinical practice,” Dr Proesmans observed. “Using digital tools in a very structured way enables us to outpace any other traditional methodology to screen or prescreen patients and guide them into an appropriate care pathway." The trial is continuing into phase II, where participants will be sent follow-up questionnaires to map the decision-making process of screening AF-positive participants and their physicians.

Proesmans T, Verbrugge F, Vandercoort P, et al.  DIGITAL-AF II: Results From A Real-life Digital Atrial Fibrillation Screening And Outcome Registry In The General Population.

In this study, among participants with smartphone-detected AF, 72% had experienced no symptoms. This technology-based screening approach could have legs.

Novel Smartphone Trial Design Collects Large-Scale AF Data Very Rapidly

The addition of surgical ablation to cardiac surgery in patients with atrial fibrillation (AF) increased the chance of maintaining sinus rhythm and reduced risk of stroke at 5 years, according to PRAGUE-12 study lead author Pavel Osmancik, MD, PhD, of the Charles University and University Hospital Kralovske Vinohrady, in Prague, Czech Republic. Dr Osmancik presented the long-term outcomes of the PRAGUE-12 study at the recent 2019 Heart Rhythm Society Meeting in San Francisco.

Atrial fibrillation, an independent risk factor for all-cause mortality, stroke, heart failure. and increased hospitalizations, is found in about 10% of all patients with indications for cardiac surgery and 2% of the general population.

The PRAGUE-12 study was a prospective, randomized clinical trial to assess a protocol of coronary artery disease (CAD) surgery or valve surgery plus ablation for AF vs cardiac surgery alone, over a 5-year follow up period. The one-year results first presented in 2012 showed that ablation was safe, Dr. Osmancik said, adding that “secondly, the ablation was effective in terms of having more sinus rhythm at one year...but there was no clinical effect.” The study's primary endpoint was a composite of cardiovascular (CV) death, stroke, hospitalization for heart failure or severe bleeding. Secondary endpoints included the elements of the primary endpoint plus AF recurrence.

At the end of 5 years, a total 108 patients had been treated with surgical ablation plus appendage exclusion using the MAZE procedure, compared to 99 who underwent surgery alone. Among surgical patients who also had ablation, the composite endpoint was observed less frequently than in those having surgery alone, although the difference was not significant after adjusting for competing risks.

While all components of the composite primary endpoint (CV death, stroke, hospitalization for heart failure, severe bleeding) were less frequent in number in the ablation group, only the difference in stroke reached statistical significance (5.6% vs 14.1%; SHR 0.32; 95% CI 0.12-0.84).

An important finding in the secondary endpoint analysis, Dr. Osmancik said, was that “the incidence of stroke was decreased in surgically ablated patients, and this decrease remained significant even after adjustment for all covariables including history of myocardial infarction and coronary artery disease.”

Dr Osmancik proposed that all patients who are candidates for cardiac surgery with a history of AF should also undergo surgical ablation since older trials have confirmed the procedure’s safety and efficacy in achieving sinus rhythm “But now,” he added, “we can also see that in the long term it [ablation] is associated with better survival, at least with decreased rate of stroke in the future.”

 Osmancik P, Budera P, Talavera D, et al. Five-year outcomes in cardiac surgery patients with arrial fibrillation undergoing concomitant surgical ablation versus no ablation: The long-term follow-up of the PRAGUE-12 study. Heart Rhythm (2019), doi: 

https://doi.org/10.1016/j.hrthm.2019.05.001.

Heart Rhythm Society Interivew with Dr Pavel Osmancik

The 5-year PRAGUE-12 study outcomes show that LAA ablation in cardiac surgery patients with a history of atrial fibrillation reduces stroke rate vs cardiac surgery alone.

PRAGUE-12 at 5 Years: Stroke Rate Reduced, Sinus Rhythm Maintained 

Renal artery denervation, when used in conjunction with pulmonary vein isolation increased likelihood of freedom from atrial fibrillation (AF) at 12 months compared with pulmonary vein isolation alone, in patients with atrial fibrillation and hypertension.

 Jonathan S. Steinberg, MD, adjunct professor of medicine at the University of Rochester School of Medicine and Dentistry and director of SMG Arrhythmia Services at Summit Medical Group of New Jersey presented this finding at the 40th Annual Heart Rhythm Scientific Sessions held in San Francisco last week.

Hypertension is a common comorbidity in patients with AF and contributes negatively to clinical outcomes and response to therapies, Dr Steinberg told the audience at the May 9th late breaking clinical trials session. Pulmonary vein isolation is a standard procedure used in these patients who have not achieved optimal response to previous antiarrhythmic pharmacotherapies, but it, too, often fails to produce durable results.

Early limited studies showed that renal artery denervation significantly reduced sympathetic tone in patients with AF and hypertension, but negative findings from the 

 prompted questions about the efficacy of renal denervation. This outcome led Dr Steinberg and colleagues from multiple sites in Russia, Poland, and Germany, to test the hypothesis in a large, single-blind, longitudinal, randomized clinical trial. For the ERADICATE-AF (Evaluate renal artery denervation in addition to catheter ablation to eliminate atrial fibrillation) trial, they randomly assigned 302 patients with paroxysmal AF and hypertension to receive catheter ablation alone or catheter ablation plus renal denervation.

Hypertension was defined as systolic BP ≥130 mm Hg and/or diastolic BP ≥80 mm Hg despite taking at least one antihypertensive medication (median = 2). The primary endpoint was freedom from AF recurrence at 12 months, free of antiarrhythmic therapy. Key secondary endpoints included procedure complications and blood pressure control at 6 and 12 months.

At the end of 12 months, more patients remained free of AF (off medication) in the renal artery denervation with catheter ablation group (71.4%) than in the group receiving catheter ablation alone (57.8%). Systolic and diastolic blood pressure control was also improved at both 6 and 12 months in the group that underwent both procedures.  Twice as many patients with catheter ablation alone were hospitalized (11.7% v 5.2%) for cardiovascular reasons.

Dr. Steinberg concluded that renal denervation is “reasonable to employ” as a method to enhance the success of catheter ablation in patients with AF and hypertension.

 Steinberg JS, Shabanov V, Ivanickiy E, et al. Evaluate renal artery denervation in addition to catheter ablation to eliminate atrial fibrillation. In: Heart Rhythm Society Annual Scientific Sessions: Late Breaking Clinical Trials Session 1; May 8-11, 2019; San Francisco. S-LBCT01-03
	

 Bakrus GL, Townsend RR, Liu M, et al. Impact of renal denervation on 24-hour ambulatory blood pressure: Results from SYMPLICITY HTN-3. JACC 2014;64:1071-1078. 

https://doi.org/10.1016/j.jacc.2014.05.012

SAN FRANCISCO--Study results reported at the 40th HRS Scientific Sessions showed at 1 year, more patients remained AF-free in the renal  denervation/catheter ablation group than in the group receiving catheter ablation alone (71.4% vs 57.8%). 

ERADICATE-AF: Renal Artery Denervation Improves Results of Catheter Ablation in Atrial Fibrillation with Hypertension

â Burden of atrial fibrillation (AF) was reduced by 85% at 6 months by transcutaneous electrical stimulation of the vagus nerve, compared to a sham procedure.

 The finding was reported by Stavros Stavrakis, MD, PhD, associate professor of medicine in the Heart Rhythm Institute at the University of Oklahoma Health Sciences Center in Oklahoma City, at a May 9th session during the 40th Heart Rhythm Scientific Sessions in San Francisco.

AF represents the most common clinical arrhythmia in humans, attended by increases in morbidity and mortality as well as by deficits in quality of life. Previous studies have shown that vagus nerve stimulation (VNS) can suppress AF in animals and a proof-of-concept study in humans showed that 1 hour of low-level transcutaneous electrical stimulation (LLTS) of the auricular branch of the vagus nerve at the tragus of the ear significantly reduced atrial fibrillation duration and levels of serum inflammatory cytokines.

Speaking on behalf of the investigators from the TRanscutaneous Electrical vAgus nerve sTimulation to suppress Atrial Fibrillation (TREAT-AF) trial, Dr Stavrakis presented data from the sham controlled double-blind randomized trial showing that VNS reduced all measures of AF burden at 3 and 6 months, as well as both daily and total AF duration vs a sham procedure. Median AF burden was reduced by 75% in the active vs sham treatment arm. LLTS also modified heart rate variability and reduced the level of TNF-Î± cytokines, although there were no significant between-group differences in other types of cytokines. See primary and key secondary endpoints in 

For the current randomized control trial, 26 patients with paroxysmal AF self-administered active electrical stimulation just below the discomfort threshold (20Hz) via an ear clip attached to the for 1 hour daily for 6 hours, and 27 administered sham therapy via the ear lobe.  Mean age of the participants was 65 years.

Two patients in the sham group and one in the active therapy group died during the trial, none from cardiovascular causes. No device-related adverse effects were reported.

Dr Stavrakis closed by stating that further studies are indicated to optimize patient selection and discriminate at baseline between responders and nonresponders to maximize efficacy of this modality.

Stavrakis S, Stoner JA, Humphre MB, et al. Transcutaneous electrical vagus nerve stimulation to suppress atrial fibrillation (TREAT-AF): a randomized clinical trial. In: Heart Rhythm Society Annual Scientific Sessions: Late Breaking Clinical Trials Session 1; May 8-11, 2019; San Francisco. S-LBCT01-01.

Stavrakis S, Humphrey MB, Scherlag BJ, et al. Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J Am Coll Cardiol 2015;65:867-875.

SAN FRANCISCO― Results of the TREAT-AF trial showed burden of AF was reduced by 85% at 6 months using transcutaneous electrical stimulation of the vagus nerve, vs a sham procedure; findings were showcased at the 40th HRS Scientific Sessions.