In this journal scan, the late-breaking trials presented at the European Society of Cardiology (ESC) Congress, held in August 2023 in Amsterdam, Netherlands are presented. The trials are categorized according to the subset of cardiology. As more than 30 late-breaking trials were presented in ESC, we are presenting the trials in two volumes. In the initial volume I, heart failure trials – 8 (STEP HFPEF, QUEST, ATTRIBUTE CM, HEART FID, BUDAPEST CRT, CASTLE HTX, PUSH AHF, DICTATE AHF), Arrhythmia trials – 4 (FRAIL AF, NOAH AF NET 6, COP AF, ADVENT), Intravascular imaging- 3 (OCTIVUS, OCTOBER, ILUMIEN IV) are presented. Happy reading.
Heart Failure
STEP HFPEF Trial: Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity
N Kosiborod, SZ Abildstroom, BA Borlaug, J Butler, S Rasmussen, M Davies, et al. The STEP HFPEF trial.
N Engl J Med. 2023 Aug 25.
Abstract
Background: Heart failure with preserved ejection fraction is increasing in prevalence and is associated with a high symptom burden and functional impairment, especially in persons with obesity. No therapies have been approved to target obesity-related heart failure with preserved ejection fraction.
Methods: We randomly assigned 529 patients who had heart failure with preserved ejection fraction and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or higher to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The dual primary endpoints were the change from the baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary endpoints included the change in the 6-minute walk distance; a hierarchical composite endpoint that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level.
Results: The mean change in the KCCQ-CSS was 16.6 points with semaglutide and 8.7 points with placebo (estimated difference, 7.8 points; 95% confidence interval [CI], 4.8–10.9; p < .001), and the mean percentage change in body weight was −13.3% with semaglutide and −2.6% with placebo (estimated difference, −10.7 percentage points; 95% CI, −11.9 to −9.4; p < .001). The mean change in the 6-minute walk distance was 21.5 m with semaglutide and 1.2 m with placebo (estimated difference, 20.3 m; 95% CI, 8.6–32.1; p < .001). In the analysis of the hierarchical composite endpoint, semaglutide produced more wins than placebo (win ratio, 1.72; 95% CI, 1.37–2.15; p < .001). The mean percentage change in the CRP level was –43.5% with semaglutide and –7.3% with placebo (estimated treatment ratio, 0.61; 95% CI, 0.51–0.72; p < .001). Serious adverse events were reported in 35 participants (13.3%) in the semaglutide group and 71 (26.7%) in the placebo group.
Conclusions: In patients with heart failure with preserved ejection fraction and obesity, treatment with semaglutide (2.4 mg) led to larger reductions in symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo.
Comments: Heart failure with an ejection fraction (EF) of >50% is termed heart failure with preserved ejection fraction (HFpEF). This shares the clinical symptoms and signs of raised intracardiac pressures as seen in its counterpart heart failure with reduced ejection fraction (HFrEF, EF ≤40%). However, to date, the drugs that were found to be beneficial in HFREF were not found to be effective to the same extent in reducing mortality in HFpEF, thereby having an unmet need in its management. This showcases, that something beyond the myocardial component to be addressed in this entity (the contributing factors). Most of the patients with HFpEF have obesity (≈ 60%). This trial with a presumed hypothesis, does weight loss reduces heart failure symptoms was taken. The results were surprising, in that there was significant improvement in symptoms in patients taking semaglutide 2.4mg sc once weekly at the end of 52 weeks. The improvement was consistent across all the tertiles of obesity (body mass index above 30 kg/m2). The improvement was also expressed with reductions in c reactive protein (CRP) (due to a decrease in inflammation), and N terminal brain natriuretic peptide (NT pro-BNP) (a rise with a decrease in weight was expected) emphasizing that the drug has anti-inflammatory effects and reduces the stress over the myocardium. The limitation of the study is that only 5% of patients were on sodium-glucose cotransporter-2 inhibitors (SGLT2i) [the only other drug found to be effective in HFpEF apart from the slight benefit of use of the angiotensin receptor neprilysin inhibitor (ARNI)]. Several questions arise amidst the positivity of this beautiful trial. What is the (a) the long-term effect of the use of this drug? (there was no plateau observed in the primary endpoints, showing that they will be having the same effect in the long term). (b) risk of malignancy with the use of this drug? (patients were found to be at risk of medullary carcinoma of the thyroid on long-term use), (c) the gastrointestinal side effects of this drug? (13%–20% seen in previous trials) (d) whether the effect is additive to SLGT2 inhibitors or not is to be seen in a larger trial? (a larger population with the use of SGLT2 inhibitors in 30% population is in the pipeline). This trial emphasizes that obesity is not a cosmetic issue but a metabolic disorder needing aggressive management. Addressing it when present would reduce the effects and better outcomes in HFpEF.
QUEST Trial
Professor X.LI. Qiliqiangxin in patients with heart failure and reduced ejection fraction - the QUEST study Presented at European Society of Cardiology Congress, August 26, 2023, Amsterdam, Netherlands.
It is the first randomized trial of traditional medicine (Qiliqiangxin) in China showing the benefit in heart failure patients with reduced ejection fraction (HFrEF). The drug is an extract obtained from eleven herbs with the proven benefit of improving symptoms and reducing N-terminal pro B type natriuretic peptide (NT pro-BNP) levels in a pilot study published in 2011. Later studies have shown beneficial effects like attenuation of myocardial fibrosis (like spironolactone) and cardiac remodeling (like RAAS blockers).
The presented QUEST trial evaluated the clinical efficacy and safety of this drug in HFrEF patients, across China and Hongkong across 133 hospitals enrolling 3,110 patients. The enrolled patients had a left ventricular ejection fraction (LVEF) of ≤40% and NT pro-BNP of ≥450 pg/ml and were on treatment for at least two weeks before the enrolment. The patients were stable heart failure patients. Randomized in 1:1 fashion (Qiliqiangxin four capsules, three times daily) (1,555) or placebo (1,555) over the already being used heart failure medications. The primary endpoint was a composite of rehospitalization for worsening heart failure or cardiovascular death.
The average age was 62 years and 72.1% were men. At baseline, the mean LVEF was 32%, and the median NT-proBNP was 1730.80 pg/ml. During a median follow-up of 18.3 months, the primary endpoint occurred in 389 patients (25.02%) in the qiliqiangxin group and 467 patients (30.03%) in the placebo group which was statistically significant (p < .001). This effect was due to decreased rehospitalizations for worsening heart failure (Hazard ratio HR, 0.76, p = .002) and cardiovascular death (HR, 0.83, p = .045) in the drug group. This effect was consistent across all the subgroups of the patients (based on age, NT-pro BNP level, and with or without the use of ARNIs). The decrease in serum NT-pro BNP level at three months compared to baseline (the secondary endpoint) was greater in the Qiliqiangxin group compared to the placebo (-444.00 vs. -363, p = .047), which was consistent with the previous pilot study. Analysis of safety endpoints demonstrated no significant difference in all-cause mortality (14.21% vs. 16.85%, p = .058). Qiliqiangxin capsules were well-tolerated, with no major differences between the two groups in adverse events including gastrointestinal symptoms, worsening renal function, and increased liver enzymes.
Comments
: This study was interesting to show a drug being beneficial in HFrEF with pleiotropic effects of the extract from eleven herbs.
However, which herb is showing the beneficial effect?
The side effects of the drug on long-term, interaction with allopathic medications,
can the number of drugs be reduced?
(12/day over the regular heart failure medications of five to six on an average per day which will be18–20 per day) should be studied.
ATTRIBUTE CM Trial: Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy (ATTRibute)-CM
Julian Gillmore. Attribute-CM: Acoramidis (AG10) in patients with transthyretin amyloid cardiomyopathy presented at European Society of Cardiology Congress, August 27, 2023, Amsterdam, Netherlands.
After a positive trial on tafamidis (ATTR-ACT), the next trial assessing the safety of Acoramidis was presented. The trial was randomized in a 2:1 fashion to placebo. The used drug was Acoramidis HCL (800 mg bid). Patients with a diagnosis of ATTR CM (wild type or variant) in NYHA class I–III and ATTR positive biopsy or 99mTc scan were enrolled. The patients were followed up for 30 months. The mean age of the patients was 73.8 years and 10% were females. Of them, 90.4% of patients had the wild variant, with NT pro-BNP of 2300, KCCQ baseline score of 71, and concomitant use of tafamidis in 18%. The primary endpoint of hierarchical analysis of all-cause mortality, the cumulative frequency of cardiovascular-related hospitalization, and change in NT pro-BNP, six-minute walk distance, had an overall win ratio favoring acoramidis (p < .0001). The change in NT pro-BNP was favorable and the improvement of six-minute walk distance was significant however all-cause mortality was nonstatistically significant.
Comments:
The trial showed positive results in favor of acoramidis. It comes as an alternative to tafamidis. A larger trial and head-to-head comparison, cost considerations to be of focus in the future.
HEART FID Trial: Ferric Carboxymaltose in Heart Failure with Iron Deficiency
Robert J. Mentz, Jyotsna Garg, Frank W. Rockhold, Javed Butler, Carmine G. De Pasquale, Justin A. Ezekowitz, Gregory D. Lewis, Eileen O’Meara, Piotr Ponikowski, Richard W. Troughton, Yee Weng Wong, Lilin She, Ph.D., et al., for the HEART-FID Investigators.
N Engl J Med. 2023; 389:975–986.
Abstract
Background: Ferric carboxymaltose therapy reduces symptoms and improves the quality of life in patients who have heart failure with a reduced ejection fraction and iron deficiency. Additional evidence about the effects of ferric carboxymaltose on clinical events is needed.
Methods: In this double-blind, randomized trial, we assigned ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency, in a 1:1 ratio, to receive intravenous ferric carboxymaltose or placebo, in addition to standard therapy for heart failure. Ferric carboxymaltose or placebo was given every six months as needed based on iron indexes and hemoglobin levels. The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to six months in the six-minute walk distance. The significance level was set at 0.01.
Results: We enrolled 3,065 patients, of whom 1532 were randomly assigned to the ferric carboxymaltose group and 1,533 to the placebo group. Death by month 12 occurred in 131 patients (8.6%) in the ferric carboxymaltose group and 158 (10.3%) in the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean (±SD) change from baseline to six months in the six-minute walk distance was 8 ± 60 and 4 ± 59 m, respectively (Wilcoxon–Mann–Whitney p = .02; unmatched win ratio, 1.10; 99% CI, 0.99–1.23). Repeated dosing of ferric carboxymaltose appeared to be safe with an acceptable adverse-event profile in the majority of patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (413 patients [27.0%] in the ferric carboxymaltose group and 401 [26.2%] in the placebo group).
Conclusions: Among ambulatory patients who had heart failure with a reduced ejection fraction and iron deficiency, there was no apparent difference between ferric carboxymaltose and placebo concerning the hierarchical composite of death, hospitalizations for heart failure, or six-minute walk distance.
Comments: This trial is of a surprise to the cardiologists, contrary to the evidence so far and guidelines emphasizing the importance of iron therapy (Class IIa to Class I based on the IRON MAN trial and FERIC HF). This trial showed modest improvement in outcomes compared to placebo. The drug appeared to be safe. Further research on the topic appears warranted.
BUDAPEST CRT Upgrade Trial: Upgrade of Right Ventricular Pacing to Cardiac Resynchronization Therapy in Heart Failure: A Randomized Trial
Béla Merkely, Robert Hatala, Jerzy K Wranicz, Gábor Duray, Csaba Földesi, Zoltán Som, et al.
Eur Heart J. ehad591.
Abstract
Background and Aims: De novo implanted cardiac resynchronization therapy with a defibrillator (CRT-D) reduces the risk of morbidity and mortality in patients with left bundle branch block, heart failure, and reduced ejection fraction (HFrEF). However, among HFrEF patients with right ventricular pacing (RVP), the efficacy of CRT-D upgrade is uncertain.
Methods: In this multicenter, randomized, controlled trial, 360 symptomatic (New York Heart Association class II–IVa) HFrEF patients with a pacemaker or implantable cardioverter defibrillator (ICD), high RVP burden ≥20%, and a wide, paced QRS complex duration ≥150 ms were randomly assigned to receive CRT-D upgrade (n = 215) or ICD (n = 145) in a 3:2 ratio. The primary outcome was the composite of all-cause mortality, heart failure hospitalization, or <15% reduction of left ventricular end-systolic volume assessed at 12 months. Secondary outcomes included all-cause mortality or heart failure hospitalization.
Results: Over a median follow-up of 12.4 months, the primary outcome occurred in 58/179 (32.4%) in the CRT-D arm versus 101/128 (78.9%) in the ICD arm [odds ratio 0.11; 95% confidence interval (CI) 0.06–0.19; p < .001]. All-cause mortality or heart failure hospitalization occurred in 22/215 (10%) in the CRT-D arm versus 46/145 (32%) in the ICD arm (hazard ratio 0.27; 95% CI 0.16–0.47; p < .001). The incidence of procedure- or device-related complications was similar between the two arms [CRT-D group 25/211 (12.3%) vs. ICD group 11/142 (7.8%)].
Conclusions: In pacemaker or ICD patients with significant RVP burden and reduced ejection fraction, an upgrade to CRT-D compared to ICD therapy reduced the combined risk of all-cause mortality, heart failure hospitalization, or absence of reverse remodeling.
Comments: This trial shows that in patients (pacemaker or ICD) with increased RVP better to shift to CRT-D in patients having reduced ejection fraction. Approximately, 2/3rd had a pacemaker and the remaining ICD. At one year, patients who were given CRT-D had a significant reduction of the primary composite endpoint. The effect was consistent across the various subgroups including patients with atrial fibrillation (56% of the population). The efficacy of this modality in atrial fibrillation has answered the unexplored subset of CRT-D. The number needed to treat (NNT) to prevent an event was 4.7. Though there was no decrease in mortality, there was a decrease in HF hospitalizations. The echocardiographic parameters also improved in the CRT-D group with a decrease in LVEDV and a larger increase in LVEF (≈11%). The procedure was successful in 98%. Long enrolment time, open-label design, and crossovers are some of the limitations. Upgrading to CRT-D from RV pacing improves outcomes in pacing-induced cardiomyopathy. This result would change the guidelines.
CASTLE HTx: Catheter Ablation in End-stage Heart Failure with Atrial Fibrillation
Sohns C, Fox H, Marrouche NF, et al., on behalf of the CASTLE HTx Investigators. Catheter ablation in end-stage heart failure with atrial fibrillation. N Engl J Med 2023; 389: 1380–9.
Abstract
Background: The role of catheter ablation in patients with symptomatic atrial fibrillation and end-stage heart failure is unknown.
Methods: We conducted a single-center, open-label trial in Germany that involved patients with symptomatic atrial fibrillation and end-stage heart failure who were referred for heart transplantation evaluation. Patients were assigned to receive catheter ablation and guideline-directed medical therapy or medical therapy alone. The primary endpoint was a composite of death from any cause, implantation of a left ventricular assist device, or urgent heart transplantation.
Results: A total of 97 patients were assigned to the ablation group and 97 to the medical-therapy group. The trial was stopped for efficacy by the data and safety monitoring board one year after randomization was completed. Catheter ablation was performed in 81 of 97 patients (84%) in the ablation group and 16 of 97 patients (16%) in the medical-therapy group. After a median follow-up of 18.0 months (interquartile range, 14.6–22.6), a primary end-point event had occurred in eight patients (8%) in the ablation group and 29 patients (30%) in the medical-therapy group (hazard ratio, 0.24; 95% CI, 0.11–0.52; p < .001). Death from any cause occurred in six patients (6%) in the ablation group and 19 patients (20%) in the medical-therapy group (hazard ratio, 0.29; 95% CI, 0.12–0.72). Procedure-related complications occurred in three patients in the ablation group and one patient in the medical-therapy group.
Conclusions: Among patients with atrial fibrillation and end-stage heart failure, the combination of catheter ablation and guideline-directed medical therapy was associated with a lower likelihood of a composite of death from any cause, implantation of a left ventricular assist device, or urgent heart transplantation than medical therapy alone.
Comments: This trial has shown that ablation of symptomatic AF in end-stage HF would have benefits in decreasing all-cause mortality, the need for left ventricular assist device implantation, and the need for urgent transplantation when compared with medical therapy alone. The effect was consistent despite significant crossover between the treatment arms leading to early termination of the trial. This is an extension of the positive findings of the CASTLE-AF trial (the patients listed for heart transplantation were excluded) to end-stage HF patients. Whether this benefit will be replicated in asymptomatic AF patients is unclear. Generalizing the trial findings is of concern in view of the study being from a single center and of small sample size.
PUSH AHF Trial
Jozine Ter Maaten. PUSH-AHF: Natriuresis guided therapy in acute heart failure Presented at European Society of Cardiology Congress, Amsterdam, Netherlands, August 28, 2023.
It is an open-label trial assessing whether the natriuresis-based diuretic therapy efficacy in patients with acute heart failure (AHF) will improve outcomes or not. A total of 310 patients (45% female) having AHF and requiring intravenous loop diuretics were assigned to natriuresis-guided therapy or standard care. In natriuresis guided arm, the urine sodium was assessed at set time points, and intensification of therapy was done if levels were low. The strategy at the end of the trial didn’t improve clinical outcomes. Further studies are required on this strategy.
DICTATE-AHF Trial
Z.Cox. DICTATE-AHF: Early Dapagliflozin Initiation in Acute Heart Failure. Presented at the European Society of Cardiology Congress, Amsterdam, Netherlands, August 28, 2023
The efficiency of the intravenous diuretic therapy was enhanced after the addition of Dapagliflozin in patients with Acute decompensated heart failure. Patients with and without diabetes, irrespective of the left ventricular ejection fraction having ADHF were enrolled in 1:1 fashion to dapagliflozin (10 mg/day) or placebo. About 230+ patients, with a median age of 65 years were followed up for 30 days. Type 1 diabetes patients were excluded; 72% had type 2 diabetes, the left ventricular ejection fraction less than 40% was seen in 52%, the mean eGFR was 53 ml/min/m2 and the furosemide dose initially was 80 mg. The diuretic efficiency (the primary outcome) was calculated as cumulative weight change divided by cumulative loop diuretic dose and expressed as kg/40 mg IV furosemide equivalent. The odds ratio was 0.65, p = .06. The cumulative dose of diuretic in the dapagliflozin group compared to placebo was 560 versus 800 mg, p = .006. The trial though did not achieve a significant primary outcome, the efficiency of diuretics was improved, as seen in previous trials of empagliflozin (EMPULSE and EMPAG HF trial). There was no change in the 30-day readmission rate. The SGLT2 inhibitors are an established component of guideline-directed medical therapy in both subsets of HF (HFpEF and HFrEF), an earlier initiation of the drug in ADHF rather than delaying initiation in outpatient is of benefit. Further studies are needed to confirm the current data.
ARRHTHYMIA
FRAIL AF Trial
Ms. L. Joosten. The FRAIL-AF randomized controlled trial. Presented at the European Society of Cardiology Congress, Amsterdam, Netherlands, August 27, 2023
The elderly people with high bleeding risk who were on Vitamin K antagonists, when switched on to novel oral anticoagulants had more bleeding. A total of 1330 frail elderly patients with a mean age of 83 years who were being managed with VKA, were randomized to either continue VKA or to switch on to NOAC. Females were 38.8%. The choice of NOAC was left to the treating doctor. Patients with valvular atrial fibrillation and severe renal impairment were excluded. When the primary outcome was assessed, the major and clinically relevant nonmajor bleeding events occurred more in the NOAC group compared to the VKA group (101 vs. 62 events, HR = 1.69). The trial was stopped prematurely following a futility analysis by the data safety and medical regulatory board. When the efficacy was assessed (in terms of thromboembolic events) it was not significant (16 vs.13).
NOAH-AF NET 6Trial: Anticoagulation with Edoxaban in Patients with Atrial High-rate Episodes
Kirchhof P, Toennis T, Goette A, et al. Anticoagulation with Edoxaban in patients with atrial high-rate episodes. N Engl J Med. 2023;389(13):1167–1179.
Abstract
Background: Device-detected atrial high-rate episodes (AHREs) are atrial arrhythmias detected by implanted cardiac devices. AHREs resemble atrial fibrillation but are rare and brief. Whether the occurrence of AHREs in patients without atrial fibrillation (as documented on a conventional electrocardiogram [ECG]) justifies the initiation of anticoagulants is not known.
Methods: We conducted an event-driven, double-blind, double-dummy, randomized trial involving patients 65 years of age or older who had AHREs lasting for at least 6 minutes and who had at least one additional risk factor for stroke. Patients were randomly assigned in a 1:1 ratio to receive edoxaban or placebo. The primary efficacy outcome was a composite of cardiovascular death, stroke, or systemic embolism, evaluated in a time-to-event analysis. The safety outcome was a composite of death from any cause or major bleeding.
Results: The analysis population consisted of 2,536 patients (1,270 in the edoxaban group and 1,266 in the placebo group). The mean age was 78 years, 37.4% were women, and the median duration of AHREs was 2.8 hours. The trial was terminated early, at a median follow-up of 21 months, based on safety concerns and the results of an independent, informal assessment of futility for the efficacy of edoxaban; at termination, the planned enrollment had been completed. A primary efficacy outcome event occurred in 83 patients (3.2% per patient-year) in the edoxaban group and 101 patients (4.0% per patient-year) in the placebo group (hazard ratio, 0.81; 95% CI, 0.60–1.08; p = .15). The incidence of stroke was approximately 1% per patient-year in both groups. A safety outcome event occurred in 149 patients (5.9% per patient-year) in the edoxaban group and 114 patients (4.5% per patient-year) in the placebo group (hazard ratio, 1.31; 95% CI, 1.02–1.67; p = .03). ECG-diagnosed atrial fibrillation developed in 462 of 2,536 patients (18.2% total, 8.7% per patient-year).
Conclusions: Among patients with AHREs detected by implantable devices, anticoagulation with edoxaban did not significantly reduce the incidence of a composite of cardiovascular death, stroke, or systemic embolism as compared with placebo, but it led to a higher incidence of a composite of death or major bleeding. The incidence of stroke was low in both groups.
Comments: Approximately one-fifth of patients with implanted devices have atrial high-rate events (AHRE). The occurrence of these episodes will increase the stroke risk compared to the normal population. This trial was taken with a hypothesis, does giving anticoagulants to these patients would protect them from stroke without documented evidence of atrial fibrillation, is a novel insight indeed. The trial was stopped prematurely given safety and futility issues. The trial demonstrated no reduction in cardiovascular death, stroke, or systemic embolism but had higher major bleeding events in patients receiving edoxaban. Some points to be noted are, that despite the patient population being at higher risk of stroke based on a CHA2DS2-VASc score of 4, the incidence of primary outcome in the placebo group was lower than expected. This emphasizes that these populations are at low risk of stroke and atrial fibrillation itself carries an increased stroke risk, and increased thrombus burden compared to the AHRE. The ECG for detection of atrial fibrillation was taken every six months. The AHRE is to be given importance because 20% of them will end up having atrial fibrillation. The trial cannot be generalized to other NOACs, further studies are required in this gray zone.
COP-AF Trial: Effect of Colchicine on Perioperative Atrial Fibrillation and Myocardial Injury After Non-cardiac Surgery in Patients Undergoing Major Thoracic Surgery (COP-AF): An International Randomized Trial
David Conen, Michael Ke Wang, Ekaterina Popova, Matthew TV Chan, Giovanni Landoni, Juan P Cata, et al.
Lancet. 2023 Aug 25; S0140-6736(23)01689-6.
Abstract
Background: Higher levels of inflammatory biomarkers are associated with an increased risk of perioperative atrial fibrillation and myocardial injury after non-cardiac surgery (MINS). Colchicine is an anti-inflammatory drug that might reduce the incidence of these complications.
Methods: COP-AF was a randomized trial conducted at 45 sites in 11 countries. Patients aged 55 years or older and undergoing major non-cardiac thoracic surgery were randomly assigned (1:1) to receive oral colchicine 0·5 mg twice daily or matching placebo, starting within four hours before surgery and continuing for 10 days. Randomization was done with the use of a computerized, web-based system, and was stratified by center. Health-care providers, patients, data collectors, and adjudicators were masked to treatment assignment. The coprimary outcomes were clinically important for perioperative atrial fibrillation and MINS during 14 days of follow-up. The main safety outcomes were a composite of sepsis or infection and non-infectious diarrhea. The intention-to-treat principle was used for all analyses.
Findings: Between February 14, 2018 and June 27, 2023, we enrolled 3,209 patients (mean age 68 years [SD 7], 1656 [51.6%] male). Clinically important atrial fibrillation occurred in 103 (6.4%) of 1,608 patients assigned to colchicine, and 120 (7.5%) of 1,601 patients assigned to placebo (hazard ratio [HR] 0.85, 95% CI 0.65–1.10; absolute risk reduction [ARR] 1·1%, 95% CI -0.7 to 2.8; p = .22). MINS occurred in 295 (18·3%) patients assigned to colchicine and 325 (20.3%) patients assigned to placebo (HR 0.89, 0.76–1.05; ARR 2.0%, -0.8 to 4.7; p = .16). The composite outcome of sepsis or infection occurred in 103 (6·4%) patients in the colchicine group and 83 (5·2%) patients in the placebo group (HR 1·24, 0.93–1.66). Non-infectious diarrhea was more common in the colchicine group (134 [8.3%] events) than in the placebo group (38 [2.4%]; HR 3.64, 2.54–5.22).
Interpretation: In patients undergoing major non-cardiac thoracic surgery, administration of colchicine did not significantly reduce the incidence of clinically important atrial fibrillation or MINS but increased the risk of mostly benign non-infectious diarrhea.
Comments: Perioperative atrial fibrillation (AF) and myocardial injury after noncardiac surgery (MINS) are more common in patients with elevated inflammatory biomarkers and have been associated with worse short- and long-term postoperative outcomes. Whether the cardioprotective effect of colchicine is seen in this aspect given the recent positive results of COLCOT and Lodoco trial led to continued interest. This trial did not show any protective benefit of colchicine compared to placebo. Some points to be considered in interpreting the trial. There is variability in postoperative cardiac monitoring across the sites enrolled in the trial. Less than 50% of patients underwent electrocardiography on day 3, so the total events of AF might be undercounted. Increased drug discontinuation is also to be kept in mind before ruling out any effect of the anti-inflammatory agent. The discontinuation was due to increased noninfectious diarrhea. Further trials are needed before concluding no benefit of anti-inflammatory drugs in this subset of patients.
ADVENT Trial: Pulsed Field or Conventional Thermal Ablation for Paroxysmal Atrial Fibrillation
Vivek Reddy. ADVENT: Pulsed Field Ablation vs Thermal Ablation (RF/Cryo) for Paroxysmal AF. Presented at the European Society of Cardiology Congress, Amsterdam, Netherlands, August 27, 2023
Abstract
Background: Catheter-based pulmonary vein isolation is an effective treatment for paroxysmal atrial fibrillation. Pulsed-field ablation, which delivers microsecond high-voltage electrical fields, may limit damage to tissues outside the myocardium. The efficacy and safety of pulsed-field ablation as compared with conventional thermal ablation are not known.
Methods: In this randomized, single-blind, noninferiority trial, we assigned patients with drug-refractory paroxysmal atrial fibrillation in a 1:1 ratio to undergo pulsed field ablation or conventional radiofrequency or cryoballoon ablation. The primary efficacy endpoint was freedom from a composite of initial procedural failure, documented atrial tachyarrhythmia after a three-month blanking period, antiarrhythmic drug use, cardioversion, or repeat ablation. The primary safety endpoint included acute and chronic device- and procedure-related serious adverse events.
Results: A total of 305 patients were assigned to undergo pulsed field ablation, and 302 were assigned to undergo thermal ablation. At one year, the primary efficacy endpoint was met (i.e., no events occurred) in 204 patients (estimated probability, 73.3%) who underwent pulsed field ablation and 194 patients (estimated probability, 71.3%) who underwent thermal ablation (between-group difference, 2.0 percentage points; 95% Bayesian credible interval, −5.2 to 9.2; posterior probability of noninferiority, >0.999). Primary safety end-point events occurred in six patients (estimated incidence, 2.1%) who underwent pulsed field ablation and four patients (estimated incidence, 1.5%) who underwent thermal ablation (between-group difference, 0.6 percentage points; 95% Bayesian credible interval, −1.5 to 2.8; posterior probability of noninferiority, >0.999).
Conclusions: Among patients with paroxysmal atrial fibrillation receiving a catheter-based therapy, pulsed-field ablation was non-inferior to conventional thermal ablation concerning freedom from a composite of initial procedural failure, documented atrial tachyarrhythmia after a three-month blanking period, antiarrhythmic drug use, cardioversion, or repeat ablation and concerning device- and procedure-related serious adverse events at one year.
Comments: Catheter-based ablation therapy is an effective management strategy for patients with paroxysmal atrial fibrillation. However, the risk of pulmonic vein stenosis is of concern. This trial showed that pulsed field ablation (PFA) therapy is non-inferior to thermal ablation. It is the first randomized trial with the Farapulse system though previous studies have shown the efficacy of PFA. Eighty patients were rolled in to make the operators familiar with the procedure. The PFA was associated with shorter mean times for the total procedure, left atrial dwell time, and ablation time with increased fluoroscopy time (which was reduced with increased experience of the operator). The predominantly nonthermal mechanism of PFA has generated interest in its viability as a safer technique with less risk of esophageal or phrenic nerve injury. It appears to be specific to myocardial tissue unlike the other modalities and there lies its advantage over the collateral damage seen with thermal ablation. Although noninferiority safety was demonstrated, there were too few serious adverse periprocedural events in either treatment arm to test for superiority. There were no clinical episodes of pulmonic vein stenosis in either treatment arm, despite the significantly less narrowing of the pulmonic vein in the PFA system arm. The follow-up beyond a year may provide the long-term safety as well as the efficacy of each technique. The findings cannot be generalized to other PFA systems and in patients with persistent AF, a potential area for further investigation. PFA is due for FDA approval already received CE approval in Europe. Further larger studies are required.
Intravascular Imaging
OCTIVUS Trial: Optical Coherence Tomography-guided or Intravascular Ultrasound Guided Percutaneous Coronary Intervention
Kang DY, Ahn JM, Yun SC, et al. Optical Coherence Tomography-Guided or Intravascular Ultrasound-Guided Percutaneous Coronary Intervention: The OCTIVUS Randomized Clinical Trial. Circulation. 2023;148(16):1195-1206.
Circulation. 2023.
Abstract
Background: Intravascular imaging-guided percutaneous coronary intervention (PCI) with intravascular ultrasound (IVUS) or optical coherence tomography (OCT) showed superior clinical outcomes compared to angiography-guided PCI. However, the comparative effectiveness of OCT-guided and IVUS-guided PCI regarding clinical outcomes is unknown.
Methods: In this prospective, multicenter, open-label, pragmatic trial, we randomly assigned 2008 patients with significant coronary-artery lesions undergoing PCI in a 1:1 ratio to undergo either an OCT-guided or IVUS-guided PCI. The primary endpoint was a composite of death from cardiac causes, target-vessel-related myocardial infarction, or ischemia-driven target-vessel revascularization at one year, which was powered for noninferiority of the OCT group as compared with the IVUS group. Safety outcomes were also assessed.
Results: At one year, primary end-point events occurred in 25 of 1,005 patients (Kaplan–Meier estimate, 2.5%) in the OCT group and 31 of 1,003 patients (Kaplan–Meier estimate, 3.1%) in the IVUS group (absolute difference, −0.6 percentage points; upper boundary of one-sided 97.5% confidence interval, 0.97 percentage points; p < .001 for noninferiority). The incidence of contrast-induced nephropathy was similar (14 patients [1.4%] in the OCT group vs. 15 patients [1.5%] in the IVUS group, p = .85). The incidence of major procedural complications was lower in the OCT group than in the IVUS group (22 [2.2%] vs. 37 [3.7%], p = .047), although imaging procedure-related complications were not observed.
Conclusions: In patients with significant coronary-artery lesions, OCT-guided PCI was non-inferior to IVUS-guided PCI concerning the incidence of a composite of death from cardiac causes, target-vessel-related myocardial infarction, or ischemia-driven target-vessel revascularization at one year. The selected study population and lower-than-expected event rates should be considered in interpreting the trial.
Comments
: Intravascular imaging helps in optimizing the implantation of the stents and thereby reducing the MACE. IVUS has robust evidence. Whether the use of OCT-guided PCI has similar outcomes was studied in this trial. It showed that OCT-guided PCI is non-inferior to IVUS-guided PCI. Assessing according to the location of the lesion, presence of bifurcation, calcium, and renal failure might show the use of a particular imaging modality.
OCTOBER Trial: OCT or Angiography Guidance for PCI in Complex Bifurcation Lesions
Holm NR, Andreasen LN, Neghabat O, et al. OCT or Angiography Guidance for PCI in Complex Bifurcation Lesions. N Engl J Med. 2023;389(16):1477-1487.
Abstract
Background: Imaging-guided percutaneous coronary intervention (PCI) is associated with better clinical outcomes than angiography-guided PCI. Whether routine optical coherence tomography (OCT) guidance in PCI of lesions involving coronary-artery branch points (bifurcations) improves clinical outcomes as compared with angiographic guidance is uncertain.
Methods: We conducted a multicenter, randomized, open-label trial at 38 centers in Europe. Patients with a clinical indication for PCI and a complex bifurcation lesion identified using coronary angiography were randomly assigned in a 1:1 ratio to OCT-guided PCI or angiography-guided PCI. The primary endpoint was a composite of major adverse cardiac events (MACE), defined as death from a cardiac cause, target-lesion myocardial infarction, or ischemia-driven target-lesion revascularization at a median follow-up of 2 years.
Results: We assigned 1,201 patients to OCT-guided PCI (600 patients) or angiography-guided PCI (601 patients). A total of 111 patients (18.5%) in the OCT-guided PCI group and 116 (19.3%) in the angiography-guided PCI group had a bifurcation lesion involving the left main coronary artery. At two years, a primary end-point event had occurred in 59 patients (10.1%) in the OCT-guided PCI group and 83 patients (14.1%) in the angiography-guided PCI group (hazard ratio, 0.70; 95% CI, 0.50–0.98; p = .035). Procedure-related complications occurred in 41 patients (6.8%) in the OCT-guided PCI group and 34 patients (5.7%) in the angiography-guided PCI group.
Conclusions: Among patients with complex coronary-artery bifurcation lesions, OCT-guided PCI was associated with a lower incidence of MACE at two years than angiography-guided PCI.
Comments: This trial has shown that OCT-guided PCI for true bifurcation lesions (left main involvement was seen in 18%) is better than angiography-guided bifurcation PCI across the subsets (left main and non-left main), (single vs. two stents). The OCT was performed three times (plan procedure, wire position, and post-stenting) (increased contrast use). Bifurcation PCI has an increased risk of malapposition, carinal shift, strut covering the ostium, and side branch access through the proximal or distal strut. The need for intravascular imaging is of utmost importance to improve the outcomes. The trial was in favor of OCT, but some points of the trial to be noted before concluding applicability in all bifurcation lesion PCI. All patients underwent kissing balloon inflation, even those who had single stent implantation. (which is not done routinely as per the existing guidelines). Two-thirds of patients had two stents deployed contrary to the evidence (the EBC MAIN trial had only 22%). The OCT is to be used only in complex bifurcation PCI following this trial. Increased contrast use with OCT did not appear to influence cardiovascular outcomes. This may be, however, of concern in patients with chronic kidney disease.
ILUMIEN IV Trial: Optical Coherence Tomography-guided Versus Angiography-guided PCI
Ali ZA, Landmesser U, Maehara A, et al. Optical coherence tomography-guided versus angiography-guided PCI. N Engl J Med. 2023;389(16):1466-1476.
Abstract
Background: Data regarding clinical outcomes after optical coherence tomography (OCT)–guided percutaneous coronary intervention (PCI) as compared with angiography-guided PCI are limited.
Methods: In this prospective, randomized, single-blind trial, we randomly assigned patients with medication-treated diabetes or complex coronary-artery lesions to undergo OCT-guided PCI or angiography-guided PCI. A final blinded OCT procedure was performed in patients in the angiography group. The two primary efficacy endpoints were the minimum stent area after PCI as assessed with OCT and target-vessel failure at two years, defined as a composite of death from cardiac causes, target-vessel myocardial infarction, or ischemia-driven target-vessel revascularization. Safety was also assessed.
Results: The trial was conducted at 80 sites in 18 countries. A total of 2,487 patients underwent randomization: 1,233 patients were assigned to undergo OCT-guided PCI, and 1,254 to undergo angiography-guided PCI. The minimum stent area after PCI was 5.72 ± 2.04 mm2 in the OCT group and 5.36 ± 1.87 mm2 in the angiography group (mean difference, 0.36 mm2; 95% CI, 0.21–0.51; p < .001). Target-vessel failure within two years occurred in 88 patients in the OCT group and in 99 patients in the angiography group (Kaplan–Meier estimates, 7.4% and 8.2%, respectively; hazard ratio, 0.90; 95% CI, 0.67–1.19; p = .45). OCT-related adverse events occurred in one patient in the OCT group and two patients in the angiography group. Stent thrombosis within two years occurred in six patients (0.5%) in the OCT group and 17 patients (1.4%) in the angiography group.
Conclusions: Among patients undergoing PCI, OCT guidance resulted in a larger minimum stent area than angiography guidance, but there was no apparent between-group difference in the percentage of patients with target-vessel failure at two years.
Comments: The trial results were contrary to the OCTIVUS and OCTOBER trials presented in the same hotline session. The OCT-guided PCI failed to show improved clinical outcomes compared to angiography-guided PCI despite having improved angiographic, imaging, and procedural outcomes (stent thrombosis). The OCTIVUS trial showed that OCT is non-inferior to IVUS in terms of target vessel failure and superior to IVUS in terms of major procedural complications. The OCTOBER trial showed a major reduction of MACE in complex bifurcation lesions compared to angiography-guided PCI. Coming to the trial, the statistical power to detect the difference between the two groups is insufficient as the target vessel revascularization was much less than expected (7.5% vs. 12%). A long follow-up and a larger population are to be included in a future study to conclude the efficacy of intravascular imaging particularly OCT as the IVUS has robust evidence in this aspect of improved outcomes. The OCT has a definite edge over IVUS about the procedure outcomes when it fits in hands with the best experience.
