ESC Expert Insights at ACC.22

ADAPT-TAVR (Edoxaban Versus Dual Antiplatelet Therapy For Valve Thrombosis And Cerebral Thromboembolism After Transcatheter Aortic-valve Replacement)

Insights by Davide Capodanno

With transcatheter aortic valve implantation (TAVI) now offered to a sizeable proportion of patients with severe aortic stenosis, doubts remain on the optimal pharmacological strategy to prevent thromboembolic complications such as leaflet thrombosis and cerebral embolisation; in particular, whether these complications are best prevented by anticoagulant or antiplatelet therapy is unclear.

The ADAPT-TAVR trial was a multicenter, open-label randomized trial comparing the direct oral anticoagulant edoxaban versus dual antiplatelet therapy with aspirin and clopidogrel in TAVI patients without an existing indication to chronic oral anticoagulation. The primary endpoint, leaflet thrombosis documented by cardiac computed tomography at 6 months from TAVI, occurred in 9.8% patients on edoxaban and 18.4% of patients on DAPT, a numerical difference that was not statistically significant (p=0.076).

The secondary endpoint of new cerebral embolisation documented by cerebral magnetic resonance imaging also did not differ between edoxaban and dual antiplatelet therapy. There was no relationship between subclinical leaflet thrombosis and neurologic outcomes.

Overall, the results of the ADAPT-TAVR trial suggest that subclinical leaflet thrombosis is an imaging phenomenon that does not seem to affect clinical outcomes and should not mandate routine screening or dictate the antithrombotic therapy for prevention or treatment after TAVR.

APOLLO (Magnitude And Duration Of Effects Of A Short-interfering RNA Targeting Lipoprotein(a))

Insights by Isabel Goncalves

Elevated lipoprotein(a) (Lp(a)) is found in approximately 20% of the general population and is associated with increased risk of atherosclerosis and aortic stenosis.

The APOLLO trial (Magnitude And Duration Of Effects Of A Short-interfering RNA Targeting Lp(a): A Placebo-controlled Double-blind Dose-ranging Trial) was a first-in-man, phase 1 study of a short interfering RNA, SLN360, targeting hepatocytes to reduce the production of apolipoprotein(a).
It included 32 subjects (53% females, mean age 50 years, 9% hypertension, 3% diabetes) without known cardiovascular disease, and a Lp(a) level ≥150 (median 224) nmol/L.

Participants were randomized to placebo (n=8) or single doses of SLN360 30mg (n=6), 100mg (n=6), 300mg (n=6), or 600mg (n=6) subcutaneously. Participants were assessed for 5 months.

Those who received the highest doses (300 and 600mg) had Lp(a) reductions of 96% and 98%; after 5 months the levels remained 71% and 81% lower than baseline, respectively. The highest doses also reduced LDL about 20-25%. No serious safety concerns were reported, and the most common adverse effects were mild injection site reactions.

In summary, the short interfering RNA SLN360 was well tolerated, and a dose-dependent lowering of Lp(a) concentrations was observed. The findings support further studies of this siRNA, focusing e.g. on larger number of patients, diverse populations, longer follow-up, multidosage and ultimately clinical outcomes.

Lp(a) testing has traditionally not been included in the routine cardiovascular risk assessment since there were no therapies available to address it. This and other new studies may make us change this approach in the future.

BIOGUARD-MI (The Clinical Effect Of Arrhythmia Monitoring After Myocardial Infarction)

Insights by Elena Arbelo

Observational data have suggested that incident arrhythmias are a better predictor of adverse cardiovascular events in patients suffering a myocardial infarction (MI).  The BIO|GUARD-MI trial was evaluated whether continuous cardiac arrhythmia monitoring using an insertable cardiac monitor (ICM) was capable of reducing a composite endpoint of cardiovascular death or acute unscheduled hospitalization for heart failure, arrhythmia, acute coronary syndrome, stroke, major bleeding or systemic embolism in high risk post-MI patients, defined by a CHA₂DS₂-VASC score >4 in men or >5 in women.

An estimated 1400 patients were to be enrolled and followed until 372 primary endpoints had occurred. However, the trial was stopped when only 218 events had occured because of an unexpectedly high rate of non-cardiovascular events in patients who received an implantable cardiac monitor. A total of 790 post-MI patients were enrolled and randomised (1:1) to ICM implantation or not, stratified by the presence or absence of ST-segment elevation at the index MI (49%/51% STEMI/NSTEMI). Group assignment was open-label but outcome assessment blinded.

At 2 years, the trial failed to show a reduction in the primary endpoint, although there appeared to be a trend. However, the prespecified sub-analysis by type of MI, showed that in NSTEMI patients derived a significant benefit from ICM (about a 30% reduction or CV outcomes) compared to STEMI patients. This was mainly due to a greater reduction of the coronary and heart failure worsening events. NSTEMI patients also showed a poorer profile in regards to risk factors and revascularization strategy compared to STEMI individuals.

CHAP (Antihypertensive Therapy For Mild Chronic Hypertension and Pregnancy Outcomes)

Insights by Isabel Goncalves

The Chronic Hypertension And Pregnancy (CHAP) project was an open-labeled, multicenter, randomized controlled trial designed to assess the benefits and potential harm of treating pregnant women with mild chronic hypertension aiming at a blood pressure <140/90mmHg. Women (n=2 408), with known mild chronic hypertension, at less than 23 weeks into their pregnancy were randomized to receive an anti-hypertensive therapy (n=1208) or no treatment (n=1200), unless blood pressure became ≥160/105. Groups were similar, most women overweight, 56% already taking antihypertensives at enrollment, 48% black, 28% non-Hispanic white, 20% Hispanic, 16% diabetic. Women randomized to anti-hypertensives had a 20% reduction in the primary outcome: the combined rate of severe preeclampsia, preterm birth, abruption and fetal or newborn death. The safety endpoint of babies small for gestational age was similar in both groups. In conclusion, treating pregnant women with mild hypertension reduced adverse pregnancy outcomes with NNT of 15, without impairing fetal growth.

This was the largest, most comprehensive, and diverse study of chronic mild hypertension in pregnancy until today. It is practice-changing supporting the need to treat, not only severe hypertension, but also mild chronic hypertension in pregnancy and to educate patients about its benefits. It would be interesting to see if the results are applicable even in other populations/ethnicities, e.g. Europe and Asia or at later stages of the pregnancy. The CHAP consortium will follow these women and possibly their children to assess long term effects, both potentially providing very valuable insights.

CLASP-TR (Transcatheter Treatment Of Tricuspid Regurgitation: One-year Results)

Insights by Victoria Delgado

Severe tricuspid regurgitation is associated with poor outcomes if left untreated. However many patients are not referred for surgery due to contraindications or very high operative risk. In the last years, several transcatheter therapies have been developed to provide a safe and feasible treatment alternative to patients with symptomatic severe tricuspid regurgitation deemed inoperable. One of these therapies is the transcatheter edge-to-edge repair which reduces tricuspid regurgitation by improving leaflet valve coaptation. The CLASP-TR showed sustained reduction in tricuspid regurgitation and improvement in clinical symptoms at 1 year follow-up after transcatheter edge-to-edge repair in 49 patients. All-cause mortality was 11% while heart failure hospitalizations rate was 16%. Reduction of tricuspid regurgitation by 2 or more grades was observed in 75% of patients and 86% of them remained with moderate tricuspid regurgitation or less. These improvements in tricuspid regurgitation were accompanied by improvements in quality of life and symptoms. The 2021 guidelines in valvular heart disease included transcatheter edge-to-edge repair as a therapy which may be considered for symptomatic severe tricuspid regurgitation in patients who are inoperable. The results of the CLASP-TR trial provide further evidence to support current recommendation.

DIAMOND (Patiromer For The Management Of Hyperkalemia In Subjects Receiving Renin-angiotensin-aldosterone System Inhibitor Medications For HFrEF)

Insights by Carlos Aguiar

Hyperkalemia often compromises the use of renin-angiotensin-aldosterone system inhibitors (RAASi), especially mineralocorticoid receptor antagonists (MRA). These drugs have a class I indication for the treatment of heart failure with reduced ejection fraction (HFrEF) to prolong survival and reduce HF hospitalizations.

The DIAMOND trial was designed to assess whether in HFrEF patients with current or a history of hyperkalemia, patiromer, a novel potassium (K+) binder, can simultaneously control K+ levels, enable optimal RAASi therapy, and improve clinical outcomes. Due to the complexities of conducting clinical trials in the COVID-19 pandemic, the trail design was modified, and the primary endpoint changed to the mean difference in serum K+ from baseline between the two arms for the duration of the trial. DIAMOND enrolled 1195 patients in a single-blinded run-in phase of up to 12 weeks, where patients were optimized on RAASi therapy and patiromer. During this phase, 85% of patients could be optimized to guideline-recommended doses of RAASi, including the MRA. These 878 patients were then randomized double-blind to either continued patiromer treatment or placebo (patiromer withdrawal).

After a median of 27 weeks, patiromer treatment maintained lower serum K+ levels, and was associated with a lower incidence of hyperkalemia events and a greater proportion of patients being maintained on MRA at target doses. Whether patiromer-enabled optimization of guideline directed medical therapy in HFrEF patients who are unable to tolerate optimal RAASi therapy due to hyperkalemia is associated with improved outcomes remains to be confirmed, since DIAMOND was not adequately powered to answer this question.

FLAVOUR (Comparison Of Fractional Flow Reserve-guided And Intravascular Ultrasound-guided Percutaneous Coronary Intervention In Intermediate Coronary Artery Stenosis)

Insights by Davide Capodanno

Invasive coronary angiography has known limitations in assessing the significance of intermediate coronary stenoses (e.g., 40%-70% by visual estimation). Fractional flow reserve (FFR) and intravascular ultrasound are used to inform the need for percutaneous coronary intervention (PCI) providing functional (i.e., presence of ischemia) and anatomic (i.e., lesion geometry and plaque morphology) information, respectively. FFR and IVUS have never been compared head-to-head in this setting.

The FLAVOUR study was a trial of 1,682 patients with intermediate coronary stenosis randomized to receive PCI guided by FFR or by IVUS according to established criteria. The primary endpoint was a composite of all-cause death, myocardial infarction, and any revascularization at 24 months after randomization. The hypothesis of the trial was the noninferiority of FFR-guided PCI compared with IVUS-guided PCI. At 2 years, the primary endpoint occurred in 8.1% of patients in the FFR-guided group and 8.6% of patients in the IVUS-guided group. The difference met the predefined criteria for noninferiority of the FFR-guided strategy. Target lesion PCI was significantly lower with FFR than with IVUS. There were no differences in the rates of the primary endpoint between patients who received PCI and those who were treated with medical therapy.

Overall, the FLAVOUR trial suggests that ,in patients with intermediate coronary stenoses, determining the need for a stent based on coronary function rather than on the extent and morphology of coronary narrowing results in similar outcomes at 2 years and reduced use of medical resources.

GIPS-IV (Groningen Intervention Study For The Preservation Of Cardiac Function With Sodium Thiosulfate After STEMI)

Insights by Stefan James

At a late-breaking session at ACC today, a well performed, small, randomized, double-blind, multicenter trial investigated a significant unmet clinical need for patients with ST-segment elevation acute myocardial infarction.

The investigators should be congratulated for having performed a difficult trial during a challenging period of time.

The authors tested the hypothesis that sodium thiosulfate, a strong antioxidant, would attenuate reperfusion injury and reduce myocardial infarct size when administered at the time of primary PCI. The hypothesis was based on studies in experimental animals. In total, 380 patients underwent randomization and infarct size could be determined in 226.

The trial was negative as the primary endpoint, infarct size measured with Cardiac MRI at 4 months after randomization, did not differ between the active compound and placebo-treated patients. The study was prematurely terminated and did not achieve its own pre-specified power criteria and the mean infarct size was very small in both groups.

Overall, sodium thiosulfate was relatively well-tolerated and there were no major serious safety issues. The trial did not include PK data, or mechanistic or biomarker data (except for BNP at follow up), which could potentially have provided some insights in inflammatory or oxidative stress states

The most important experiences for the investigators and for the readers are related to the challenge of correctly estimating event rates since this and many similar trials tend to be under powered. Reducing infarct size with any pharmacological intervention in the era of effective mechanical and pharmacological reperfusion therapy is very difficult.

IVVE (Randomized Controlled Trial Of Influenza Vaccine In Patients With Heart Failure To Reduce Adverse Vascular Events)

Insights by Giuseppe Rosano

Previous studies and population-wide studies have demonstrated that influenza vaccination reduces mortality and morbidity in patients with cardiovascular disease.

The IVVE study was a randomized controlled trial to assess the benefits of the flu vaccination in patients with heart failure. The study was conducted in countries across Asia, Africa and the Middle East and included 5,129 patients with heart failure. Patients were allocated to receive a flu shot or a placebo annually for up to three years, though they were also allowed to get a flu shot outside of the trial. The primary endpoint was unusual for a heart failure study and consisted of a composite of death from cardiovascular causes, non-fatal heart attack or non-fatal stroke. Overall, no significant difference in the rates of the primary end-point was detected between those who had received a flu vaccine and those who had not. Separate analyses found that rates of pneumonia were 42% lower and hospitalisations were 15% lower among those who received the influenza vaccination. There was also a significant reduction in the first primary endpoint and a reductions in all-cause and cardiovascular death in favour of the flu vaccination when the analysis was limited to periods of peak influenza.

The results of this study support the current guidelines recommendation of influenza vaccination in patients with heart failure

POISE-3 (Efficacy And Safety Of Tranexamic Acid In Patients Undergoing Noncardiac Surgery)

Insights by Victoria Delgado

The POISE-3 answered two very relevant clinical questions in daily clinical practice: 1) can tranexamic acid reduce the risk of bleeding without increasing the risk of MACE in patients undergoing non-cardiac surgery; 2) is it safe to maintain antihypertensive medication through the surgery? More than 9000 patients with increased risk of bleeding and cardiovascular events undergoing non-cardiac surgery were recruited around the world. To answer the first question, patients were randomized to two doses of tranexamic acid or to placebo. The efficacy combined endpoint of bleeding was less frequently reported among patients treated with tranexamic acid as compared to placebo while there were no differences for the safety combined endpoints events (including myocardial infarction, thromboembolic events and nonhaemorrhagic stroke). To answer the second question, it is known that hypotension during surgery is associated with worse outcomes while stopping antihypertensive medication prior to surgery may be associated with increased risk of complications due to hypertension. The investigators compared patients following a strategy of keeping the antihypertensive medication throughout the admission for surgery and patients in whom the antihypertensive medication was stopped prior to surgery. The results showed no differences in rates of major adverse cardiovascular events between the two strategies. These results will have an impact on clinical practice.

SODIUM-HF (Study Of Dietary Intervention Under 100 Mmol In Heart Failure)

Insights by Giuseppe Rosano

The SODIUM-HF Study was designed to assess the effects of dietary sodium reduction on cardiovascular-related hospital admissions and all-cause mortality within 12 months, quality-of-life, New York Heart Association (NYHA) functional class and the 6-min walk distance.
It was a pragmatic, multinational, open-label, randomised trial; the trial recruited 841 HF patients from 26 sites. Patients were recruited if they had chronic heart failure determined by local clinical guidelines and by clinicians.

At the end of the study there was no difference in the primary outcome of mortality and hospitalisation and no difference in the individual components of the primary outcome. Also, no difference in 6-min walk distance between the low sodium diet group and the usual care group was detected. A modest effect on quality-of-life assessed by KCCQ and a very modest effect on NYHA improvement by 1 class were seen. Therefore, SODIUM-HF demonstrated that in ambulatory patients with HF, a dietary intervention to reduce sodium intake did not reduce clinical events. Despite a modest benefit on quality-of-life, no effect on exercise capacity was detected.

The results of this study should lead us to rethink our strategy of Na-restriction in patients with heart failure.

VALOR-HCM and MAVA-LTE

Insights by Carlos Aguiar

Mavacamten is a targeted inhibitor of cardiac myosin. It decreases the number of myosin-actin cross-bridges and reduces excessive contractility.

In the EXPLORER-HCM trial, 30 weeks of mavacamten treatment improved exercise capacity, left ventricular outflow tract (LVOT) obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy (HCM). Two additional studies on mavacamten were presented at ACC this year and expand the clinical benefits of this disease-specific drug.

The first, VALOR-HCM, was designed to assess the safety and efficacy of adding mavacamten to maximally tolerated medical therapy among 112 patients with obstructive HCM who remained severely symptomatic and were thus being considered for septal reduction therapy (SRT). The primary endpoint was a composite of SRT guideline eligibility or the patient decision to proceed with SRT after 16 weeks. Mavacamtem significantly reduced the primary endpoint and improved symptoms and quality of life.

The other mavacamtem study presented at ACC is an interim analysis of the 5-year extension of EXPLORER-HCM. Over a median follow-up of 62 weeks, the LVOT gradient was reduced to less than 30 mm Hg in 83.5% of patients, the NYHA class improved by at least one class in 68% of patients, and NT-proBNP was reduced by 63%. Mavacamten was also well tolerated with no new or unexpected adverse events reported.

This drug is currently under review by the US FDA and has the potential to change guidelines for the management of obstructive HCM.

Wrap-up Basic and Translational Science

Insights by Carol Ann Remme

At ACC2022, the Basic and Translational Science program includes sessions dedicated to the emerging field of cardio-oncology, discussing not only the potential cardiotoxic effects of cancer and cancer therapies, but also the concept of reverse cardio-oncology, where cardiovascular disease may increase cancer risk and worsen its outcome.

In two other sessions, novel mechanisms and therapeutic strategies for heart failure are discussed, including RNA-based therapies, mesenchymal stromal cells and stem cells.

In the Young Investigator Awards session on Basic and Translational Science, five excellent studies were presented. Jae Hyung Cho (Los Angeles, USA) showed that exosomes secreted by cardiosphere-derived cells improve diastolic function and reduce ventricular arrhythmias by attenuating ventricular fibrosis in rats with HFpEF, and that this beneficial effect could be recapitulated by MicroRNA-16, the most abundant microRNA in these exosomes. Maddalena Conte (Naples, Italy) identified isolated aortic valve amyloidosis as a unique pathology distinct from cardiac amyloidosis and showed that a local, rather than systemic production of serum amyloid A1 may play an important role. Neha Hafeez (Pittsburgh, USA) unravelled the pathogenic mechanisms for the observed association of a single nucleotide polymorphism with disease outcome in pulmonary arterial hypertension. Olivia Ly (Chicago, USA) developed an approach to generate mature iPSC-derived atrial cardiomyocytes in order to investigate how mutations in the gene NPPA cause atrial fibrillation. Finally, David Rawnsley (St Louis, USA) showed that intermittent fasting is protective in cardiac lipotoxicity by attenuating protein aggregate, suggesting a link between lipid overload and the autophagy-lysosome pathway.