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CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the SEQUOIA-HCM Trial.

Table of contents for the The SEQUOIA-HCM Trial summary:

Visual abstract
Summary
References

Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy

Martin S. Maron, M.D., Ahmad Masri, M.D., Michael E. Nassif, M.D., Roberto Barriales-Villa, M.D., Ph.D., Michael Arad, M.D., Nuno Cardim, M.D., Ph.D., Lubna Choudhury, M.D., +26, for the SEQUOIA-HCM Investigators

https://www.nejm.org/doi/full/10.1056/NEJMoa2401424

Relevant Literature Relevant Guidelines2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy (HCM)

2023 ESC Guidelines for the management of cardiomyopathies: Developed by the task force on the management of cardiomyopathies of the European Society of Cardiology

Study RationalHCM with LVOTO remains difficult to treat. Invasive therapies, under the umbrella term of septal reduction therapies (SRT), include surgical myectomy and percutaneous alcohol septal ablation. While they effectively relieve LVOT gradients and associated symptoms, they have associated risks and are done at a few high-volume centers. Conversely, historically utilized medications (beta blockers, non-dihydropyridine calcium channel blockers, and disopyramide) have suboptimal relief of LVOT gradients and symptoms.

Mavacamten, a cardiac myosin ATPase inhibitor, was approved by the FDA in 4/29/2022 based on the EXPLORER-HCM trial showing improvement in symptoms and exercise capacity. Aficamten has the same mechanism of action as mavacamten, with a few potential advantages:

shallow dose response relationship: smaller reductions in LVEF as dose is increased;
shorter half-life: steady state in 2 weeks (compared to 4-6 weeks with mavacamten);
does not interact with the cytochrome p450 system (no drug-drug interactions).

Objectives The primary goal was to evaluate the efficacy and safety of aficamten in adult patients with symptomatic obstructive HCM. The efficacy was assessed by changes in peak oxygen uptake during cardiopulmonary exercise testing and numerous secondary endpoints (see below). Safety was assessed by reporting adverse events during the study period.

| Details | | Trial Type | International, double-blind, randomized, placebo-controlled trial involving 80 sites | | Randomization | Randomly assigned in a 1:1 ratio to receive aficamten or placebo | | Dosage | The starting dose of aficamten was 5 mg, with three subsequent opportunities (at weeks 2, 4, and 6) to increase the dose by 5-mg increments, to a maximum dose of 20 mg | | Follow-up | Patients were followed during the 24-week treatment period and during a 4-week washout period at the end of the trial. | | Interim Analyses | No interim analyses were performed |

Enrollment Criteria * Patients between the ages of 18 and 85 years * Confirmed clinical diagnosis of HCM * Left ventricular wall thickness of at least 15 mm in the absence of pressure overload or other discernible causes * Left ventricular ejection fraction of at least 60% * Left ventricular outflow tract gradients of at least 30 mmHg at rest and at least 50 mmHg after the Valsalva maneuver * NYHA II-III * Decreased exercise capacity * Defined by a predicted peak oxygen uptake of 90% or less on the basis of age and sex

Outcomes Primary end point: The change from baseline to week 24 in the peak oxygen uptake as assessed during cardiopulmonary exercise testing

Secondary end points:

Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS):
1. change from baseline -> week 24
2. change from baseline -> week 12
NYHA functional class:
- improvement from baseline of at least one class at week 24
- improvement from baseline of at least one class at week 12
LVOT gradient after Valsalva:
- change from baseline -> week 24
- change from baseline -> week 12
- decrease in gradient to < 30 mmHg after Valsalva at week 24
- decrease in gradient to < 30 mmHg after Valsalva at week 12
Duration of eligibility for SRT during the 24-week treatment period among patients who were eligible for such therapy at baseline
- eligibility defined by NYHA functional class III or IV disease and a LVOT tract gradient (at rest or after the Valsalva maneuver) of ≥50 mmHg
Total workload as assessed by cardiopulmonary exercise testing: change at week 24

Statistical Analysis1. The trial was designed with at least 90% power to detect the between-group difference in the change from baseline in the peak oxygen uptake at week 24 of 1.5 ml/kg of body weight/min, with a standard deviation of 3.5 ml/kg/min, at a two-sided type I error level of 0.05. 2. The primary analysis tested the null hypothesis that there would be no between-group difference with respect to the primary end point in the full analysis set. 3. To adjust for multiplicity, hierarchical testing was utilized. Only if the primary end point showed a significant treatment effect at a two-sided P value of less than 0.05, then the secondary end points would be tested sequentially at a two-sided level of 0.05.

Notable Baseline Characteristics* A total of 543 patients were screened for eligibility at 101 sites in 14 countries, of whom 282 underwent randomization and received aficamten or placebo. * The most common reasons for exclusion: + inadequately elevated LVOT gradients after the Valsalva maneuver; + not meeting cardiopulmonary exercise testing criteria. * Overall, the mean age was 59.1 years, 59.2% were men, and 79.1% identified as White. * 25% of patients had a family history of HCM, with 17.5% having a pathogenic sarcomeric variant. * Overall, the baseline mean resting LVOT gradient was 55 mmHg and mean LVOT gradient with Valsalva was 83 mmHg. The baseline mean left ventricular ejection fraction (LVEF) was 75%. * At screening, 61.3% of the patients were receiving beta-blockers, 28.7% were receiving calcium channel blockers, and 12.8% were receiving disopyramide. * At the end of the dose-escalation phase (week 8), 3.6%, 12.9%, 35.0%, and 48.6% of the patients assigned to the aficamten group were receiving aficamten at a dose of 5 mg, 10 mg, 15 mg, and 20 mg, respectively. * Most patients were NYHA Class II – 78.9%. * Intervention and placebo groups were comparable across baseline characteristics.

Primary OutcomeThe primary endpoint, mean change from baseline to week 24 in peak VO2 uptake, for aficamten vs. placebo, was: 1.8 vs. 0.0 mL/kg/min, least square mean difference: 1.7 mL/kg/min (p < 0.0001).

Secondary Outcomes* Change in Kansas City Cardiomyopathy Questionnaire-clinical summary score (KCCQ-CSS) at week 24: 12 vs. 5 (p < 0.001) * LVOT gradient ≤30 mm Hg after Valsalva at week 24: 49.3% vs. 3.6% (p < 0.001) * Change in LVOT gradient at week 24: -47.6 vs. 1.8 mm Hg (p < 0.001) * Geometric mean proportional change in NTproBNP at week 24: 0.20 vs. 0.20 (p > 0.05) * Serious adverse events: 5.6% vs. 9.3%

Adverse EventsSerious adverse events were reported in 8 patients (5.6%) in the aficamten group and in 13 patients (9.3%) in the placebo group.

The number of patients who had at least one adverse event after the start of administration of aficamten or placebo was 105 (73.9%) in the aficamten group and 99 (70.7%) in the placebo group.
- Atrial fibrillation: 2.8% vs. 2.9%
- Ventricular fibrillation 0% vs. 0.7
- Palpitations: 7.0% vs. 2.9%
- Hypertension: 7.7% vs. 2.1%
At week 24, the LVEF in the aficamten group was modestly lower than that in the placebo group (least-squares mean difference, –4.8 percentage points; 95% CI, –6.3 to –3.2)
After the 4-week washout period, there was no marked difference between the groups in the LVEF (least-squares mean difference, –1 percentage points; 95% CI, –2 to 0).
A transient reduction of less than 50% in the LVEF occurred in 5 patients (3.5%) in the aficamten group and in 1 patient (0.7%) in the placebo group
7 patients (4.9%) in the aficamten group underwent a per protocol dose reduction on the basis of the site echocardiographic evaluation.
None of the patients in the aficamten group with a LVEF of less than 50% had an interruption of treatment or an exacerbation of heart failure.

The trial was designed to estimate the treatment effects of early initiation and later initiation of DOACS and provide qualitative data to guide clinicians.

The study ultimately found that the incidence of compositive of stroke, systemic embolism, hemorrhage, or death at 30 days was estimated to be in the range from 2.8% points lower to 0.5% points higher (95% CI) with the early use of DOACS than with later use
Based on this, early treatment can be supported
Comparing the 90 day outcomes to the 30 day, there was not an excessive risk associated with early anticoagulation use within this period

Limitations & Considerations

This study excludes individuals who received therapeutic anticoagulation at baseline
Limited statistical power to explore the subgroups
Trial population was predominantly from European centers with a higher proportion of White participants
Those with parenchymal hemorrhage were excluded so these results on anticoagulation cannot be extrapolated to this group

The results of this trial indicate that aficamten at a dose of 5-20 mg daily improved exercise capacity as assessed by cardiopulmonary exercise testing over a 24-week treatment period compared with placebo among patients with symptomatic HCM, the majority of whom were already on background therapy. These results are very promising and another option to our armamentarium for HCM management. Due to it’s improved pharmacokinetic properties as compared to mavacamten, aficamten may allow more patients to be able to tolerate and utilize a myosin inhibitor. A future head to head comparison with mavacamten as well as understanding of cost-benefit of these drugs would be helpful for clinicians when they are deciding on the management of their HCM patients.

Indik JH, Wang A, Geske JB, et al. Mavacamten in Symptomatic Patients With Obstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2022;79(16):1565-1575. doi: 10.1016/j.jacc.2022.02.024

Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2020;396(10253):759-769. doi: 10.1016/S0140-6736(20)31792-X

Desai MY, Owens A, Geske JB, et al. Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy. J Am Coll Cardiol. 2022;80(2):95-108. doi: 10.1016/j.jacc.2022.04.048

Maron MS, Masri A, Nassif ME, et al. Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy. N Engl J Med. 2024;390(20):1849-1861. doi: 10.1056/NEJMoa2401424

Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2020;142(25). doi: 10.1161/CIR.0000000000000937

Ommen SR, Ho CY, Asif IM, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guideline. Circulation. 2024;149(23). doi: 10.1161/CIR.0000000000001250

Arbelo E, Protonotarios A, Gimeno JR, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503-3626. doi: 10.1093/eurheartj/ehad194

Summary By:

Dr. Anna Radakrishnan, Internal Medicine Resident, Mount Sinai
Dr. Akiva Rosenzveig, Internal Medicine Resident, Cleveland Clinic Foundation

Visual Abstract By:

Dr. Sahitya Allam, Cardiology Fellow, Cooper Medical Center

Trial Tweets:

Dr. Apoorva Gangavelli, Internal Medicine Resident, Emory University

Moderator:

Dr. Shazli Khan, Cardiology Fellow, Westchester Medical Center

Promo By:

Dr. Atefeh Ghorbanzadeh, Internal Medicine Resident, Capital Health Regional Medical Center

Under the Guidance Of:

Dr. Ronaldo Correa Fabiano, Hospitalist, Brigham and Women’s Hospital

Supported House Faculty:

Dr. Teodora Donisan, Cheif Cardiology Fellow, Mayo Clinic
Dr. Sukriti Banthiya, Cardiology Fellow, Ascension Providence

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Table of contents for the The FINEARTS-HF Trial summary:

Visual abstract
Summary
References
Credits
Twitter Archive

October 3, 2024

Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction

S.D. Solomon, J.J.V. McMurray, M. Vaduganathan, B. Claggett, P.S. Jhund, A.S. Desai, A.D. Henderson, C.S.P. Lam, B. Pitt, M. Senni, F. Amarante, P. Kolkhof, and P. Viswanathan et al

https://www.nejm.org/doi/full/10.1056/NEJMoa2407107

Relevant Literature

Relevant Guidelines

2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure: Executive Summary

Recommendation for MRAs (Referenced studies that support the recommendation are summarized in the Online Data Supplements.)

COR LOE Recommendation 1 A

In patients with HFrEF and NYHA class IIIV symptoms, an MRA (spironolactone or eplerenone) is recommended to reduce morbidity and mortality, if estimated glomerular filtration rate is > 30 mL/min/1.73 and serum potassium is < 5.0 mEq/L. Careful monitoring of potassium, renal function, and diuretic dosing should be performed at initiation and closely monitored thereafter to minimize risk of hyperkalemia and renal insufficiency.

Take-Home Message No. 2

Mildly reduced LVEF has new medication recommendations, including use of SGLT2i (Fig. 2). SGLT2i has a COR 2a in HF with mildly reduced EF (HFmrEF). Weaker recommendations (COR 2b) are made for ARNi, ACEi, ARB, MRA, and beta-blockers in this population.

ACC/AHA 2022 Guidelines:

For HFrEF, MRAs hold a Class I recommendation (strong evidence) for patients with NYHA class II-IV heart failure
For HFpEF, MRAs are assigned a Class IIb recommendation, indicating that they may be considered, especially in those with elevated filling pressures (e.g., BNP levels)

Rationale:

Heart failure (HF) with mildly reduced or preserved ejection fraction (EF ≥40%) presents a treatment challenge. While therapies such as SGLT2 inhibitors have shown benefits, there remains a gap in effective treatments specifically targeting this population. Steroidal mineralocorticoid receptor antagonists (like spironolactone) have shown benefits in HF with reduced EF, but their efficacy in preserved EF is unclear. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, has shown promise in chronic kidney disease and HF with diabetes, prompting investigation in this broader HF population.

Objective:

The primary goal was to determine if finerenone could reduce the composite endpoint of worsening HF events (defined as unplanned HF-related hospitalizations or urgent visits) and cardiovascular death in patients with mildly reduced or preserved EF.

Enrollment Criteria

Patients ≥40 years of age, symptomatic HF (New York Heart Association [NYHA] class II-IV), left ventricular EF ≥40%, elevated levels of natriuretic peptides (such as NT-proBNP), on diuretic therapy (for 30 days prior to randomization) and structural heart disease.
Patients were required to be on standard HF therapy, and those with severe chronic kidney disease (GFR <25), serum potassium > 5 mmol/L at any visit or recent use of mineralocorticoid receptor antagonists were excluded.

Outcomes

Primary Outcome: A composite of worsening HF events (first and recurrent unplanned hospitalizations or urgent visits for HF) and death from cardiovascular causes.
Secondary Outcomes: Included total HF events, change in symptoms (measured by the Kansas City Cardiomyopathy Questionnaire [KCCQ]), improvement in NYHA class, kidney function decline, cardiovascular death, and death from any cause.

Statistical Analysis

The trial was designed with 90% power to detect a 19% reduction in the primary outcome event rate in the finerenone group vs. placebo.
The primary analysis was performed based on an intention-to-treat approach and utilized the semiparametric proportional rates method, which considers both first and recurrent HF events to capture the full burden of disease.
Subgroup analyses were predefined, and 17 were analyzed based on characteristics like baseline EF, use of other therapies (e.g., SGLT2 inhibitors), and geographic region.
Secondary outcomes were tested in a hierarchical order (As listed in the above section).

Notable Baseline Characteristics

Of 6016 patients who underwent randomization, 6001were included; those who were excluded did not had severe violations of Good Clinical Practice guidelines
Mean age 72; 54% were male
Most patients were white (79%), from Eastern Europe (44%), NYHA functional class II (69%), III (30%)
Most characteristics were well matched. The finerenone group had 87.9 % of patients with HTN and 38.8 % with atrial fibrillation whereas the placebo group had 89.% with HTN and 37.6% with afib.

Primary Outcome

Finerenone significantly reduced the composite primary outcome (rate ratio 0.84; 95% CI 0.74-0.95; p=0.007).
HF events: 842 (finerenone) vs. 1024 (placebo); rate ratio 0.82; 95% CI 0.71-0.94; p=0.006.
Cardiovascular deaths: 242 (8.1%) vs. 260 (8.7%); hazard ratio 0.93 (95% CI 0.78-1.11).

Secondary Outcomes

Improved symptom score (KCCQ): +1.6 points (p<0.001).
No significant difference in NYHA class improvement, kidney outcomes, or death from any cause.

Here is a table summarizing the different endpoints of the study:

Adverse Events

Hyperkalemia: hyperkalemia was higher in the finerenone group

this is consistent with findings from other studies involving finerenone, such as the FIDELIO-DKD and FIGARO-DKD trials

Hypokalemia: Interestingly, finerenone was associated with a reduced risk of hypokalemia compared to placebo.
Other Adverse Events: The trial also reported adverse events such as hypotension and hyponatremia, which occurred more frequently in the finerenone group than in the placebo group.
Reduction in Heart Failure Events and Cardiovascular Death: Finerenone significantly reduced the composite rate of heart failure (HF) events (first or recurrent hospitalizations) and cardiovascular (CV) death compared to placebo. The event rate was 14.9 per 100 patient-years in the finerenone group versus 17.7 in the placebo group, demonstrating a 16% relative risk reduction in this primary outcome (Rate Ratio 0.84, p=0.007).
All-Cause Mortality: Though there was a numerical reduction in all-cause mortality in the finerenone group (16.4% vs. 17.4%), this difference was not statistically significant
Improvement in Patient-Reported Outcomes: Finerenone showed modest improvement in quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), with a greater increase in scores compared to placebo
Renal Outcomes: While finerenone did not demonstrate a significant reduction in renal outcomes (e.g., progression of chronic kidney disease), the trial highlighted potential benefits in subgroups with comorbid kidney disease.
- In patients with low risk of kidney disease progression, finerenone did not result in a lower risk of secondary kidney outcome. However, it did reduce the risk of secondary kidney outcome in patients with kidney disease and diabetes.

Limitations

Lack of Mortality Benefit: did not demonstrate a significant reduction in cardiovascular mortality. This aligns with challenges faced by previous studies in this population
Low Use of SGLT2 Inhibitors: Only a small percentage of patients were on SGLT2 inhibitors, a therapy already known to benefit HFmrEF/HFpEF. Further studies are needed to explore the potential synergistic effects of combining finerenone with SGLT2 inhibitors.
Finerenone was associated with a higher rate of hyperkalemia (14.3% vs. 6.9%) and hypotension, which are important considerations in clinical practice, particularly in patients with chronic kidney disease.
Few black patients
NHYA Class is a physician-reported measure of functional status, so could be a less sensitive.
Underpowered subgroup analysis, interpret with caution.

Considerations

Exploration of Combination Therapy: Future studies should assess the benefits of finerenone when used in combination with other therapies, particularly SGLT2 inhibitors, which were underutilized in this trial.
Kidney Disease Progression: Given the overlap between heart failure and chronic kidney disease, further research is needed to evaluate finerenone’s role in modifying renal outcomes in HFmrEF/HFpEF. Additionally,
Further Trials in Subpopulations: Additional trials are needed to explore whether finerenone’s benefits extend to other heart failure subgroups, including those with different comorbidities (diabetes or advanced kidney disease)
Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure – American College of Cardiology (acc.org)
American Diabetes Association Professional Practice Committee. 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes-2024. Diabetes Care. 2024 Jan 1;47(Suppl 1):S219-S230. doi: 10.2337/dc24-S011. PMID: 38078574; PMCID: PMC10725805.
Finerenone Reduces Cardiovascular Death, HF Events in FINEARTS-HF Trial (ajmc.com)
Miller RJH, Howlett JG. Evolving role for mineralocorticoid receptor antagonists in heart failure with preserved ejection fraction. Curr Opin Cardiol. 2015 Mar;30(2):168-172. doi: 10.1097/HCO.0000000000000147. PMID: 25574896.
Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022 May 3;79(17):e263-e421. doi: 10.1016/j.jacc.2021.12.012. Epub 2022 Apr 1. Erratum in: J Am Coll Cardiol. 2023 Apr 18;81(15):1551. doi: 10.1016/j.jacc.2023.03.002. PMID: 35379503.
Pitt, B., Pfeffer, M.A., Assmann, S.F., et al. (2014). Spironolactone for Heart Failure with Preserved Ejection Fraction. New England Journal of Medicine, 370(15), 1383–1392. DOI: 10.1056/NEJMoa1313731
Solomon SD, Ostrominski JW, Vaduganathan M, Claggett B, Jhund PS, Desai AS, Lam CSP, Pitt B, Senni M, Shah SJ, Voors AA, Zannad F, Abidin IZ, Alcocer-Gamba MA, Atherton JJ, Bauersachs J, Ma CS, Chiang CE, Chioncel O, Chopra V, Comin-Colet J, Filippatos G, Fonseca C, Gajos G, Goland S, Goncalvesová E, Kang SM, Katova T, Kosiborod MN, Latkovskis G, Lee AP, Linssen GCM, Llamas-Esperón G, Mareev V, Martinez FA, Melenovský V, Merkely B, Nodari S, Petrie MC, Saldarriaga CI, Saraiva JFK, Sato N, Schou M, Sharma K, Troughton R, Udell JA, Ukkonen H, Vardeny O, Verma S, von Lewinski D, Voronkov LG, Yilmaz MB, Zieroth S, Lay-Flurrie J, van Gameren I, Amarante F, Viswanathan P, McMurray JJV. Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial. Eur J Heart Fail. 2024 Jun;26(6):1334-1346. doi: 10.1002/ejhf.3266. Epub 2024 May 11. PMID: 38733212.
Pitt B, Anker SD, Böhm M, Gheorghiade M, Køber L, Krum H, Maggioni AP, Ponikowski P, Voors AA, Zannad F, Nowack C, Kim SY, Pieper A, Kimmeskamp-Kirschbaum N, Filippatos G. Rationale and design of MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF): a randomized study of finerenone vs. eplerenone in patients who have worsening chronic heart failure with diabetes and/or chronic kidney disease. Eur J Heart Fail. 2015 Feb;17(2):224-32. doi: 10.1002/ejhf.218. PMID: 25678098.
Filippatos G, Anker SD, Böhm M, Gheorghiade M, Køber L, Krum H, Maggioni AP, Ponikowski P, Voors AA, Zannad F, Kim SY, Nowack C, Palombo G, Kolkhof P, Kimmeskamp-Kirschbaum N, Pieper A, Pitt B. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J. 2016 Jul 14;37(27):2105-14. doi: 10.1093/eurheartj/ehw132. Epub 2016 Apr 29. PMID: 27130705; PMCID: PMC4946749.

Summary by:

Dr. Georgia Vasilakis Tsatiris, Internal Medicine Resident, University of Pittsburgh Medical Center, @gmvasilakis

Dr. Swagata Patnaik, Internal Medicine Resident, Mount Sinai Hospital, @Swagata_P

Visual abstract by:

Dr. Mariam Riad, Cardiology Fellow, University of South Alabama, @MariamfrAdel

Trial Tweets, Promotion, & Archive by:

Dr. Saihariharan Nedunchezhian, Internal Medicine Resident, George Washington, @SaiNedu

Moderator of Twitter during CardsJC by:

Dr. Swagata Patnaik, Internal Medicine Resident, Mount Sinai Hospital, @Swagata_P

Interns:

Pacey Wetstein, Medical Student, Lake Erie College of Osteopathic Medicine

Under the guidance of House Chief:

Dr. Cali Clark, Cardiology Fellow, Allegheny Health Network, @CaliRClark

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Table of contents for the The STOPDAPT-3 Trial summary:

Visual abstract
Summary
References
Credits
Twitter Archive

August 9, 2024

An Aspirin-Free Versus Dual Antiplatelet Strategy for Coronary Stenting:

STOPDAPT-3 Randomized Trial

Masahiro Natsuaki, MD; Hirotoshi Watanabe , MD; Takeshi Morimoto , MD; Ko Yamamoto , MD;

Yuki Obayashi , MD; Ryusuke Nishikawa , MD; Kenji Ando , MD; Takenori Domei, MD; Satoru Suwa, MD; Manabu Ogita , MD; et al.

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.066720

| Randomized Control Trial | Population | Intervention | Outcomes | | TICO3 2020 | 3056 patients with ACS treated with DES | Ticagrelor monotherapy (90mg BID) after 3-month DAPT -or- ticagrelor-based 12-month DAPT | The primary outcome (1-year NACE, defined as a composite of major bleeding and adverse cardiac and cerebrovascular events: death, myocardial infarction, stent thrombosis, stroke, or target-vessel revascularization) occurred in 59 patients (3.9%) receiving ticagrelor monotherapy after 3-month DAPT and in 89 patients (5.9%) receiving ticagrelor-based 12-month DAPT (HR 0.66 [95% CI 0.48-0.92]; P = .01). This was a modest but statistically significant reduction in a composite outcome of major bleeding and cardiovascular events at 1 year. However, it should be noted that this was driven by statistically significant reduction in bleeding (HR 0.56 [95% CI 0.34-0.91]; P = .02), with no significant difference in adverse cardiac and cerebrovascular events (HR 0.69 [95% CI, 0.45-1.06]; P = .09). | | TWILIGHT4 2020 | 7119 patients with high-risk features who had PCI with DES and had now received 3 months of DAPT with ticagrelor plus aspirin, had been adherent and event-free | Ticagrelor plus placebo -or- ticagrelor plus aspirin for 12 months | The primary outcome (BARC Type 2, 3, or 5) occurred in 3.6% of NSTE-ACS patients receiving monotherapy and in 7.6% receiving dual therapy (HR 0.47 [95% CI 0.36-0.67; P < 0.001). In patients without NSTE-ACS, the primary outcome was also reduced in the monotherapy group (4.8% vs. 6.2%; HR 0.76 [95% CI 0.54-1.06; P = 0.11). The secondary outcome (composite of all-cause death, myocardial infarction, or stroke) among those with NSTE-ACS (4.3% vs. 4.4%; HR 0.97; 95% CI 0.74-1.28; P = 0.84) and without (3.1% vs. 3.2%; HR 0.96; 95% CI 0.61-1.49; P = 0.85) NSTE-ACS were similar between treatment arms irrespective of clinical presentation. Among patients with or without NSTE-ACS who have completed an initial 3-month course of DAPT following PCI with DES, ticagrelor monotherapy reduced clinically meaningful bleeding events without increasing ischaemic risk as compared with ticagrelor plus aspirin. The benefits of ticagrelor monotherapy with respect to bleeding events were more pronounced in patients with NSTE-ACS. | | T-PASS5 2024 | 2850 patient with ACS treated with DES | Ticagrelor monotherapy after <1 month of DAPT -or- 12 months of ticagrelor-based DAPT | The primary end point (net clinical benefit as a composite of all-cause death, myocardial infarction, definite or probable stent thrombosis, stroke, and major bleeding at 1 year after the index procedure in the intention-to-treat population) occurred in 40 patients (2.8%) in the group receiving ticagrelor monotherapy after <1-month DAPT, and in 73 patients (5.2%) in the ticagrelor-based 12-month DAPT group (HR 0.54 [95% CI, 0.37-0.80]; P<0.001 for noninferiority; P=0.002 for superiority). The occurrence of major bleeding was significantly lower in the ticagrelor monotherapy after <1-month DAPT group compared with the 12-month DAPT group (1.2% versus 3.4%; HR 0.35 [95% CI, 0.20-0.61]; P<0.001). This study provides evidence that stopping aspirin within 1 month for ticagrelor monotherapy is both noninferior and superior to 12-month DAPT for the 1-year composite outcome of death, myocardial infarction, stent thrombosis, stroke, and major bleeding, primarily because of a significant reduction in major bleeding, among patients with acute coronary syndrome receiving drug-eluting stent implantation | | SMART-CHOICE7 2019 | 2993 patients treated with DES | Aspirin plus a P2Y12 inhibitor for 3 months then P2Y12 inhibitor alone -or- DAPT for 12 months | The primary end point was major adverse cardiac and cerebrovascular events (a composite of all-cause death, myocardial infarction, or stroke) at 12 months after the index procedure. At 12 months, major adverse cardiac and cerebrovascular events occurred in 42 patients in the P2Y12 inhibitor monotherapy group and in 36 patients in the DAPT group (2.9% vs 2.5%; difference, 0.4% [1-sided 95% CI, -∞% to 1.3%]; P = .007 for noninferiority). There were no significant differences in all-cause death (21 [1.4%] vs 18 [1.2%]; HR 1.18[95% CI 0.63-2.21]; P = .61), myocardial infarction (11 [0.8%] vs 17 [1.2%]; HR 0.66 [95% CI, 0.31-1.40]; P = .28), or stroke (11 [0.8%] vs 5 [0.3%]; HR 2.23 [95% CI 0.78-6.43 P = .14) between the 2 groups. The rate of bleeding was significantly lower in the P2Y12 inhibitor monotherapy group than in the DAPT group (2.0% vs 3.4%; HR 0.58 [95% CI 0.36-0.92]; P = .02). There was no significant difference in the primary outcome but did show reduced rate of bleeding. | | STOPDAPT-28 2019 | 3045 patients treated with PCI | 1-month of DAPT followed by clopidogrel monotherapy -or- 12 months of DAPT with aspiring and clopidogrel | The primary end point was a composite of cardiovascular death, myocardial infarction (MI), ischemic or hemorrhagic stroke, definite stent thrombosis, or major or minor bleeding at 12 months. The major secondary cardiovascular end point was a composite of cardiovascular death, MI, ischemic or hemorrhagic stroke, or definite stent thrombosis and the major secondary bleeding end point was major or minor bleeding. One-month DAPT was both noninferior and superior to 12-month DAPT for the primary end point, occurring in 2.36% with 1-month DAPT and 3.70% with 12-month DAPT (absolute difference, -1.34% [95% CI, -2.57% to -0.11%]; hazard ratio [HR], 0.64 [95% CI, 0.42-0.98]), meeting criteria for noninferiority (P < .001) and for superiority (P = .04). The major secondary cardiovascular end point occurred in 1.96% with 1-month DAPT and 2.51% with 12-month DAPT (absolute difference, -0.55% [95% CI, -1.62% to 0.52%]; HR, 0.79 [95% CI, 0.49-1.29]), meeting criteria for noninferiority (P = .005) but not for superiority (P = .34). The major secondary bleeding end point occurred in 0.41% with 1-month DAPT and 1.54% with 12-month DAPT (absolute difference, -1.13% [95% CI, -1.84% to -0.42%]; HR, 0.26 [95% CI, 0.11-0.64]; P = .004 for superiority). Among patients undergoing PCI, 1 month of DAPT followed by clopidogrel monotherapy, compared with 12 months of DAPT with aspirin and clopidogrel, resulted in a significantly lower rate of a composite of cardiovascular and bleeding events, meeting criteria for both noninferiority and superiority. | | GLOBAL LEADERS9 2018 | 15968 patients treated PCI with DES for either stable CAD or ACS | Aspirin plus ticagrelor for 1 month followed by 23 months of ticagrelor monotherapy -or- Standard DAPT with clopidogrel or ticagrelor for 12 months followed by aspirin monotherapy for another 12 months | The primary endpoint at 2 years was a composite of all-cause mortality or non-fatal centrally adjudicated new Q-wave myocardial infarction. The secondary safety endpoint was site-reported bleeding assessed according to the Bleeding Academic Research Consortium criteria (grade 3 or 5). 304 (3.81%) participants in the experimental group had died or had a non-fatal centrally adjudicated new Q-wave myocardial infarction, compared with 349 (4.37%) participants in the control group (rate ratio 0.87 [95% CI 0.75-1.01]; p=0.073]). There was no evidence for a difference in treatment effects for the primary endpoint across prespecified subgroups of acute coronary syndromes and stable coronary artery disease (p=0.93). Grade 3 or 5 bleeding occurred in 163 participants in the experimental group and 169 in the control group (2.04% vs 2.12%; rate ratio 0.97 [95% CI 0.78-1.20]; p=0.77). Ticagrelor in combination with aspirin for 1 month followed by ticagrelor alone for 23 months was not superior to 12 months of standard dual antiplatelet therapy followed by 12 months of aspirin alone in the prevention of all-cause mortality or new Q-wave myocardial infarction 2 years after percutaneous coronary intervention. There was no statistically significant differences in the primary or secondary outcomes between the groups. | | MASTER-DAPT11 2021 | 4434 patients treated with DES who had already received 1 month of DAPT and were considered at high bleeding risk | Immediately discontinue DAPT and continue with single antiplatelet therapy -or- Continue DAPT for at least 2 additional months (standard therapy) with continuation of single antiplatelet therapy after | The three ranked primary outcomes were net adverse clinical events (a composite of death from any cause, myocardial infarction, stroke, or major bleeding), major adverse cardiac or cerebral events (a composite of death from any cause, myocardial infarction, or stroke), and major or clinically relevant nonmajor bleeding; cumulative incidences were assessed at 335 days. NACE occurred in 165 patients (7.5%) in the abbreviated-therapy group and in 172 (7.7%) in the standard-therapy group ([95% CI −1.80-1.33]; P<0.001 for noninferiority). A total of 133 patients (6.1%) in the abbreviated-therapy group and 132 patients (5.9%) in the standard-therapy group had a major adverse cardiac or cerebral event ([95% CI −1.29-1.51]; P=0.001 for noninferiority). Among the 4579 patients in the intention-to-treat population, major or clinically relevant nonmajor bleeding occurred in 148 patients (6.5%) in the abbreviated-therapy group and in 211 (9.4%) in the standard-therapy group ([ 95% CI, −4.40- −1.24]; P<0.001 for superiority). One month of dual antiplatelet therapy was noninferior to the continuation of therapy for at least 2 additional months with regard to the occurrence of net adverse clinical events and major adverse cardiac or cerebral events; abbreviated therapy also resulted in a lower incidence of major or clinically relevant nonmajor bleeding. |

Relavent Guidlines

2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines6

2023 ESC Guidelines for the management of acute coronary syndromes: Developed by the task force on the management of acute coronary syndromes of the European Society of Cardiology (ESC)10

Study Rationale

The optimal duration of DAPT after PCI remains highly debated. There is a balance between decreasing cardiovascular events and causing bleeding. This study seeks to elucidate the efficacy and safety monotherapy vs DAPT within 1 month of PCI.

Objectives

The study aims to assess patients with ACS or high bleeding risk to prasugrel monotherapy vs DAPT with aspirin and prasugrel. The coprimary endpoints were major bleeding (Bleeding Academic Research Consortium 3 or 5) for superiority and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke) for noninferiority with a relative 50% margin.

Trial

A physician-initiated, prospective, multicenter, open-label, adjudicator-blinded randomized clinical trial involving 72 centers in Japan
- 6002 patients screened and 5966 patients enrolled from January 2021 to April 2023; 2984 patients in the no-aspirin group and 2982 patients in the DAPT group

Intervention

Randomly assigned 1:1 to no-aspirin vs DAPT group

Enrollment Criteria

Included patients with ACS regardless of high risk bleeding (as defined by ARC criteria) or non-ACS with high risk bleeding with minimal exclusion criteria. Exclusion criteria of this study were the following; (1) patients with a known allergy to the study drugs, and (2) patients who were enrolled in the ongoing prospective clinical trials

Outcomes

Primary Outcomes: (1) Coprimary bleeding end point defined as the Bleeding Academic Research Consortium (BARC) type 3 or 5, and (2) coprimary cardiovascular end point defined as a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke.
- Secondary Outcomes: Composite of the coprimary bleeding and cardiovascular end points representing net adverse clinical outcomes. Myocardial infarction and stent thrombosis were defined by the ARC criteria. Stent thrombosis was applied to the stents implanted at the index procedure of this trial.

Statistical Analysis

Sample size was initially planned for 3110 patients, revised to 6000 based on observed event rates and the need for sufficient power to detect differences.
- Kaplan-Meier estimates and log-rank tests for cumulative incidence were used for analysis. Cox proportional hazards model estimated the hazard ratios.
- Significance levels were defined as a two-sided P-value for superiority in bleeding endpoints and a one-sided P-value for noninferiority in cardiovascular endpoints.
- The sensitivity analysis included full analysis set and per-protocol population, with adjustments for discontinuations and subgroup analyses.

Notable Baseline Characteristics

Of 6002 patients who underwent randomization, 5966 were included; those who were excluded did not receive PCI, were enrolled in another trial, or withdrew their consent
The baseline characteristics and medications were well balanced between the 2 groups, except for the lower prevalence of proton pump inhibitor use at discharge in the no-aspirin group than in the DAPT group (83.0% and 92.4%)
Mean age 71.6; 76.6% were male
75% ACS, 25% non-ACS (stable CAD)

Primary Outcome

At 1 month, the no-aspirin group was not superior to the DAPT group for the coprimary bleeding end point (4.47% and 4.71%; HR, 0.95 [95% CI, 0.75–1.20]; P superiority=0.66)
- The most frequent cause of bleeding was access site bleeding related to either PCI or non-PCI access site followed by cardiac tamponade, gastrointestinal bleeding, and other PCI-related bleeding
The 1-month incidence of the coprimary cardiovascular end point was 4.12% in the no-aspirin group and 3.69% in the DAPT group (HR, 1.12 [95% CI, 0.87–1.45]; P noninferiority=0.01)

Secondary Outcomes

There was no between-group difference in the incidence of all-cause death (2.28% and 2.11%; HR, 1.08 [95% CI, 0.77–1.52]) and major secondary end point representing net adverse clinical outcomes (7.14% and 7.38%; HR, 0.97 [95% CI, 0.80– 1.17]); the 1-month incidences of coronary events were 1.15% and 0.57% (HR, 1.83 [95% CI, 1.01–3.30]) for any unplanned coronary revascularization, 0.37% and 0.17% (HR, 2.20 [95% CI, 0.77–6.34]) for unplanned non–target-lesion revascularization, 0.71% and 0.44% (HR, 1.62 [95% CI, 0.81–3.23]) for definite or probable stent thrombosis, and 0.58% and 0.17% (HR, 3.04 [95% CI, 1.26–9.23]) for subacute definite or probable stent thrombosis in the no-aspirin group and in the DAPT group, respectively

| End Point | Experimental (No-aspirin) | Standard (DAPT) | [Risk Association] | P value | | Coprimary bleeding end point: BARC 3 or 5 bleeding | 133 (4.47%) | 140 (4.71%) | HR 0.95 (0.75–1.20) | 0.66 | | Coprimary cardiovascular end point: A composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke | 123 (4.12%) | 110 (3.69%) | HR 1.12 (0.87–1.45) | 0.01 | | Major secondary endpoint: A composite of cardiovascular death, myocardial infarction, definite stent thrombosis, ischemic stroke, or BARC 3 or 5 bleeding | 213 (7.14%) | 220 (7.38%) | HR 0.97 (0.80–1.17) | N/A |

Adverse Events

As defined by the major secondary endpoint

The trial was designed to assess the safety and efficacy of prasugrel monotherapy compared to DAPT within 1 month of PCI

The aspirin-free strategy using low-dose prasugrel compared with the DAPT strategy was not superior for major bleeding and noninferior for cardiovascular events within 1 month after PCI
However, the aspirin-free strategy was associated with a signal suggesting an excess of coronary events (3-fold higher rate of subacute definite or probable stent thrombosis in the no-aspirin arm (0.58% versus 0.17%; hazard ratio, 3.04 [95% CI, 1.26–9.23]), despite the use of intravascular imaging for optimization of stent deployment in 93% of patients)
There have been multiple recent studies dedicated to duration of DAPT, which mixed outcomes; current guidelines recommend at least 1 month of DAPT, longer if able. High risk bleeding patient may need shorter duration, while patient with complex CAD may need longer duration
Shared decision making, individual treatment plans will continue to be paramount in deciding post-PCI DAPT

Limitations & Considerations

This study was open-label, which may have influenced the treatment after assignment

There was increased use of proton-pump inhibitors in the DAPT group
Was not powered enough to evaluate coronary events, but small signal suggesting an excess of coronary events with the no-aspirin strategy relative to the DAPT strategy was based on the small number of patients with event in a few secondary end points
Reduced dosed of prasugrel (loading 20mg, maintenance 3.75mg) were used; these are only approved in Japan
- There is some evidence that suggests that the levels of prasugrel active metabolite obtained with the prasugrel 20/3.75-mg regimen would be insufficient to deliver a high level of platelet P2Y12 receptor blockade in the majority of patients, thereby risking markedly suboptimal levels of receptor blockade2
12% of patients were also receiving an oral anticoagulant drug at hospital discharge
Only 25% women
Natsuaki M, Watanabe H, Morimoto T, et al. An Aspirin-Free Versus Dual Antiplatelet Strategy for Coronary Stenting: STOPDAPT-3 Randomized Trial. Circulation. 2024;149:585-600.
Storey R. Antiplatelet Therapy After PCI: The Art and Science of De-Escalation. Circulation. 2024;149(8):601-604.
Kim B, Hong S, Cho Y, et al. Effect of Ticagrelor Monotherapy vs Ticagrelor With Aspirin on Major Bleeding and Cardiovascular Events in Patients With Acute Coronary Syndrome: The TICO Randomized Clinical Trial. JAMA. 2020;323(23):2407-2416.
Baber U, Dangas G, Angiolillo D. Ticagrelor alone vs. ticagrelor plus aspirin following percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes: TWILIGHT-ACS. Eur Heart J. 2020;41(37):3533-3545.
Hong S, Lee S, Suh Y, et al. Stopping Aspirin Within 1 Month After Stenting for Ticagrelor Monotherapy in Acute Coronary Syndrome: The T-PASS Randomized Noninferiority Trial. Circulation. 2024;149:562-573.
Lawton J, Tamis-Holland J, Bangalore S, et al. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021;145(3):e18-e114.
Hahn J, Song Y, Oh J, et al. Effect of P2Y12 Inhibitor Monotherapy vs Dual Antiplatelet Therapy on Cardiovascular Events in Patients Undergoing Percutaneous Coronary Intervention: The SMART-CHOICE Randomized Clinical Trial. JAMA. 2019;321(24):2428-2437.
Watanabe H, Domei T, Morimoto T, et al. Effect of 1-Month Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual Antiplatelet Therapy on Cardiovascular and Bleeding Events in Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial. JAMA. 2019;321(24):2414-2427.
Vranckx P, Valgimigli M, Jüni P, et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet. 2018;392(10151):940-949.
Byrne R, Rossello X, Coughlan J, et al. 2023 ESC Guidelines for the management of acute coronary syndromes: Developed by the task force on the management of acute coronary syndromes of the European Society of Cardiology (ESC). European Heart Journal. 2023;44(38):3720-3826.
Valgimigli M, Rigoli E, Heg D, et al. Dual Antiplatelet Therapy after PCI in Patients at High Bleeding Risk. N Engl J Med. 2021;385(18):1643-1655.

Summary by:

Elizabeth Davis, Cardiology Fellow, University of Texas Medical Branch, @EliDavisMD

Visual abstract by:

Yeo Yong Hao, Med-Peds Resident, Corewell Health William Beaumont University Hospital, @YeoYongHao

Trial Tweets, Promotion, & Archive by:

Mariana Garcia, Internal Medicine Resident, University of Wisconsin Madison, @MarianaGarcia_a

Moderator of Twitter during CardsJC by:

Jake Roberts, internal Medicine Resident, UCLA, @JakeRoberts_MD

Interns:

Tina Reddy, Internal Medicine Resident, Osler Residency at John Hopkins Hospital, @TinaKReddy

Diane Masket, Internal Medicine Resident, University of Chicago Northshore, @DianeMasket

Under the guidance of House Chief:

Claire Cambron, Cardiology Fellow, Oregon Health & Science University, @ClaireCambron

View Details

Table of contents for the The The ORBITA-2 Trial summary:

Visual abstract
Summary
References
Credits
Twitter Archive

Feb 28, 2023

A Placebo-Controlled Trial of Percutaneous Coronary Intervention for Stable Angina

Christopher A. Rajkumar, M.B., B.S., Michael J. Foley, M.B., B.S., Fiyyaz Ahmed-Jushuf, M.B., B.S., Alexandra N. Nowbar, Ph.D., Florentina A. Simader, M.D., John R. Davies, Ph.D., Peter D. O’Kane, M.D., Peter Haworth, M.B., B.S., Helen Routledge, M.D., Tushar Kotecha, Ph.D., Reto Gamma, M.D., Gerald Clesham, Ph.D., et al., for the ORBITA-2 Investigators*

https://www.nejm.org/doi/full/10.1056/NEJMoa2310610

Relevant literature

Relevant Guidelines

2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines

Objectives:

The study was designed to evaluate the efficacy of PCI compared with sham procedure in relieving angina among patients with stable angina not on antianginal medications.

Trial –

Conducted at 14 sites in the United Kingdom
923 patients screened, 439 enrolled to pre-randomization symptom assessment phase, 301 randomly assigned to PCI or placebo between 11/12/2018 to 6/17/2023

Intervention

Randomly assigned 1:1 to percutaneous intervention or placebo-controlled sham procedure following 2 week symptom assessment phase and cessation of all antianginal meds .
PCI group (n=151):
- - Angiographic and physiological complete revascularization of the target vessels was mandatedPhysiological assessment was performed pre and post procedure to identify the target vessel and to document complete revascularizationIntravascular imaging encouraged, but not requiredIn patients with multivessel disease, all vessels treated during index procedure
- Placebo-controlled sham procedure (n=150):
  - Patients remained sedated without any further intervention for 15 minutes

Enrollment Criteria

Inclusion criteria:
- Considered to be clinically suitable for PCI by the referring heart team
- Patients had angina or symptoms equivalent to angina
- Had anatomic evidence of at least one severe coronary stenosis identified on invasive diagnostic coronary angiography or coronary computed tomographic angiography
- Had evidence of ischemia on the basis of noninvasive imaging or invasive coronary physiological tests
Exclusion criteria
- Age younger than 18
- Recent acute coronary event (in last 6 months)
- Previous CABG
- Significant left main stem coronary disease
- Chronic total occlusion in target vessel
- Contraindication to PCI or DES implantation, CI to antiplatelet therapy
- Severe valvular disease
- Severe LV systolic impairment < 35%
- Severe respiratory disease
- Life expectancy < 2yrs, pregnancy, inability to consent

Outcomes

Primary Endpoint: Angina symptom score, an ordinal clinical outcome scale of health status associated with angina
- Angina symptom score: calculated on basis of number of angina episodes reported on a given day and the number of units of antianginal medication prescribed on that day
  - Higher number of episodes of angina or more antianginal medications led to a higher score
  - A patient with no episodes of angina and received no antianginal medications on a day had a score of 0
  - Also incorporated occurrence of unblinding owing to unacceptable angina requiring coronary angiography, occurrence of ACS, and death (which would result in the maximum score of 79).
Secondary Endpoints: Frequency of angina as reported by the patient with the use of smartphone application, initiation and/or subsequent titration of antianginal medications, treadmill exercise time, physician assessed severity of angina (according to CCS class), frequency of angina, physical limitation, angina stability, freedom from angina, quality of life, and stress echo score.

Statistical Analysis

Primary endpoint: analyzed by means of ordinal analysis of covariance, uses a cumulative probability model that does not impose distribution assumptions on the outcome
- If daily symptoms were not available, the last entered value was used as final follow-up value unless unblinding had occurred due to unacceptable angina or ACS or death
- Freedom from angina was assessed using logistic regression
Secondary endpoint: analyzed by means of ordinal analysis of covariance technique for ordinal secondary endpoint, CCS class; for analysis of freedom from angina, a logistic-regression model was used; for the other secondary endpoints, an ordinary least-squares model was used
- During the 2019 coronavirus pandemic, hospital research visits for treadmill exercise tests and echocardiography were suspended while national restrictions were in place

Baseline Characteristics

301 patients underwent randomization, 151 patients to the PCI group and 150 patients to the placebo group
Mean age of patients was 64 +/- 9 years; and 79% were male
At time enrollment, 290 had angina or CCS severity class II or III
Median number of antianginal agents prescribed for patients prior to enrollment was 1, equivalent to a median of 2 standardized antianginal units

Procedural Characteristics

Radial artery access used in 288 pts (96%)
Invasive physiological assessment performed in a median of 1 vessel per patient
Ischemic territories: identified via invasive physiological assessment and noninvasive functional testing:
- One territory: 242 pts (80%)
- Two territories: 52 pts (17%)
- Three territories: 7 pts (2%)
Coronary lesion characteristics:
- Mean % diameter stenosis assessed by quantitative coronary angiography was 61 +/- 18%
- FFR done in 349/383 target vessels (91%), with median FFR of 0.63 (interquartile range 0.49 to 0.75)
- IFR done in 352/383 target vessels (92%), with median IFR of 0.78 (interquartile range 0.55 to 0.87)
- intravascular imaging was performed in 69% of patients in PCI group. Median post-PCI FFR 0.89 and post PCI IFR 0.93
Complete revascularization occurred in all but 2 patients

Outcomes

Primary Outcome

Data available for 99.7% o~~i~~f the 22,823 patient-days in trial
At 12-week follow up, mean angina symptom score was 2.9 in PCI group and 5.6 in placebo group
- Odds ratio 2.21, 95% CI 1.41 to 3.47, P<0.001
Mean daily angina frequency was 0.3 episodes in PCI group and 0.7 episodes in placebo group
- Odds ratio 3.44, 95% CI 2.00 to 5.91
Mean daily use of antianginal medication was 0.2 in PCI group and 0.3 in placebo group
- Odds radio 1.21, 95% CI 0.70 to 2.10

Secondary Endpoint

Adverse Events

| Adverse event | PCI group (# of pts) | Placebo group (# of pts) | | Unblinding from unacceptable angina | 0 | 1 | | ACS | 4 | 6 | | Death | 0 | 0 | | Periprocedural MI (Type 4a) | 4 | 0 | | Spontaneous MI (Type 1) | 0 | 6 | | Stroke | 2 | 0 | | Pressure wire complications | 1 | 2 |

See comparison of serious adverse events above between two groups
In placebo group, there were 2 major periprocedural bleeding events and 2 spontaneous bleeding events in 4 patients who were receiving DAPT
The trial was designed to determine the effect of PCI alone in patients with stable angina and evidence of ischemia.
- The study ultimately found that PCI as a monotherapy in patients with stable angina resulted in lower angina symptom score than a sham procedure.
- The trial used a new end point, the angina symptom score with the use of the smartphone app, which was patient centered and minimized recall bias and maximized data completeness. A smartphone application was utilized by patients to log daily symptoms, including the frequency of angina episodes and their severity. This method simplified data collection and evaluation, offering valuable insights into the symptoms of stable angina. Furthermore, it provided a practical means of monitoring patient activity and optimizing the algorithms used to prescribe antianginal medications
- “Perhaps for angina relief, the first therapy administered – either antianginal medication or an antianginal procedure, such as PCI – has the greatest chance of efficacy.”
Limitations & Considerations
- Duration of follow up was only 12 weeks; daily data showed effect of PCI was immediate and sustained
- However, despite decades of technical advances in PCI, including the introduction of stents, the effect of PCI on treadmill exercise time in the blinded ORBITA-2 trial was still 37 seconds less than the 96-second effect attributed to balloon angioplasty in the unblinded Angioplasty Compared to Medicine (ACME) trial that was conducted three decades ago. The effect of PCI as monotherapy was a 59.5-second difference in the tread- mill exercise time as compared with placebo, which was similar to the 48 to 55 seconds achieved with a full-dose single antianginal medication.
- Trial required stopping antianginal medications, which is against guideline recommendations; yet this allowed PCI to be tested as antianginal monotherapy
- Withdrawal of antianginal medication may have led to unmeasured behavioral changes
- Use of nitroglycerin spray was not included in calculation of angina symptom score
- 80% of patients had ischemia in a single territory only
- Smartphone application was available in English only
Al-Lamee R, Thompson D, Dehbi HM, Sen S, Tang K, Davies J, Keeble T, Mielewczik M, Kaprielian R, Malik IS, Nijjer SS, Petraco R, Cook C, Ahmad Y, Howard J, Baker C, Sharp A, Gerber R, Talwar S, Assomull R, Mayet J, Wensel R, Collier D, Shun-Shin M, Thom SA, Davies JE, Francis DP; ORBITA investigators. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet. 2018 Jan 6;391(10115):31-40. doi: 10.1016/S0140-6736(17)32714-9. Epub 2017 Nov 2. Erratum in: Lancet. 2018 Jan 6;391(10115):30. PMID: 29103656.
Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA, Berman DS, Mancini GB, Weintraub WS; COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007 Apr 12;356(15):1503-16. doi: 10.1056/NEJMoa070829. Epub 2007 Mar 26. PMID: 17387127.
Maron DJ, Hochman JS, Reynolds HR, Bangalore S, O’Brien SM, Boden WE, Chaitman BR, Senior R, López-Sendón J, Alexander KP, Lopes RD, Shaw LJ, Berger JS, Newman JD, Sidhu MS, Goodman SG, Ruzyllo W, Gosselin G, Maggioni AP, White HD, Bhargava B, Min JK, Mancini GBJ, Berman DS, Picard MH, Kwong RY, Ali ZA, Mark DB, Spertus JA, Krishnan MN, Elghamaz A, Moorthy N, Hueb WA, Demkow M, Mavromatis K, Bockeria O, Peteiro J, Miller TD, Szwed H, Doerr R, Keltai M, Selvanayagam JB, Steg PG, Held C, Kohsaka S, Mavromichalis S, Kirby R, Jeffries NO, Harrell FE Jr, Rockhold FW, Broderick S, Ferguson TB Jr, Williams DO, Harrington RA, Stone GW, Rosenberg Y; ISCHEMIA Research Group. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med. 2020 Apr 9;382(15):1395-1407. doi: 10.1056/NEJMoa1915922. Epub 2020 Mar 30. PMID: 32227755; PMCID: PMC7263833.

Summary by: Dr. Cali Clark @CaliRClark and Dr. Hamza Patel @Hamza_Patel123

Visual abstract by: Dr. Christian Andersen @CFAndersenMD

Trial Tweets by: Dr. Rachel Goodman @goodmra1

Moderator of Twitter during CardsJC by: Dr. Hamza Patel @Hamza_Patel123

Promo by: Dr. Rachel Goodman @goodmra1

Under the guidance of House Chief: Dr. Alaa Diab @DrAlaaDiab & Director of CardsJC Dr. Devesh Rai, @DeveshRaiMD

Supported by House Faculty: Dr. Dinu Balanescu @dinubalanescu, Dr. Ty Sweeney @TySweeney6, Dr. Saahil Jumkhawala @saahilaj, and Dr. Eunice Dugan @EuniceDuganMD

View Details

Table of contents for the The The ORBITA-2 Trial summary:

Visual abstract
Summary
References
Credits
Twitter Archive

Feb 28, 2023

A Placebo-Controlled Trial of Percutaneous Coronary Intervention for Stable Angina

https://www.nejm.org/doi/full/10.1056/NEJMoa2310610

Relevant literature

Relevant Guidelines

Objectives:

The study was designed to evaluate the efficacy of PCI compared with sham procedure in relieving angina among patients with stable angina not on antianginal medications.

Trial –

Conducted at 14 sites in the United Kingdom
923 patients screened, 439 enrolled to pre-randomization symptom assessment phase, 301 randomly assigned to PCI or placebo between 11/12/2018 to 6/17/2023

Intervention

Randomly assigned 1:1 to percutaneous intervention or placebo-controlled sham procedure following 2 week symptom assessment phase and cessation of all antianginal meds .
PCI group (n=151):
- - Angiographic and physiological complete revascularization of the target vessels was mandatedPhysiological assessment was performed pre and post procedure to identify the target vessel and to document complete revascularizationIntravascular imaging encouraged, but not requiredIn patients with multivessel disease, all vessels treated during index procedure
- Placebo-controlled sham procedure (n=150):
  - Patients remained sedated without any further intervention for 15 minutes

Enrollment Criteria

Inclusion criteria:
- Considered to be clinically suitable for PCI by the referring heart team
- Patients had angina or symptoms equivalent to angina
- Had anatomic evidence of at least one severe coronary stenosis identified on invasive diagnostic coronary angiography or coronary computed tomographic angiography
- Had evidence of ischemia on the basis of noninvasive imaging or invasive coronary physiological tests
Exclusion criteria
- Age younger than 18
- Recent acute coronary event (in last 6 months)
- Previous CABG
- Significant left main stem coronary disease
- Chronic total occlusion in target vessel
- Contraindication to PCI or DES implantation, CI to antiplatelet therapy
- Severe valvular disease
- Severe LV systolic impairment < 35%
- Severe respiratory disease
- Life expectancy < 2yrs, pregnancy, inability to consent

Outcomes

Primary Endpoint: Angina symptom score, an ordinal clinical outcome scale of health status associated with angina
- Angina symptom score: calculated on basis of number of angina episodes reported on a given day and the number of units of antianginal medication prescribed on that day
  - Higher number of episodes of angina or more antianginal medications led to a higher score
  - A patient with no episodes of angina and received no antianginal medications on a day had a score of 0
  - Also incorporated occurrence of unblinding owing to unacceptable angina requiring coronary angiography, occurrence of ACS, and death (which would result in the maximum score of 79).
Secondary Endpoints: Frequency of angina as reported by the patient with the use of smartphone application, initiation and/or subsequent titration of antianginal medications, treadmill exercise time, physician assessed severity of angina (according to CCS class), frequency of angina, physical limitation, angina stability, freedom from angina, quality of life, and stress echo score.

Statistical Analysis

Primary endpoint: analyzed by means of ordinal analysis of covariance, uses a cumulative probability model that does not impose distribution assumptions on the outcome
- If daily symptoms were not available, the last entered value was used as final follow-up value unless unblinding had occurred due to unacceptable angina or ACS or death
- Freedom from angina was assessed using logistic regression
Secondary endpoint: analyzed by means of ordinal analysis of covariance technique for ordinal secondary endpoint, CCS class; for analysis of freedom from angina, a logistic-regression model was used; for the other secondary endpoints, an ordinary least-squares model was used
- During the 2019 coronavirus pandemic, hospital research visits for treadmill exercise tests and echocardiography were suspended while national restrictions were in place

Baseline Characteristics

301 patients underwent randomization, 151 patients to the PCI group and 150 patients to the placebo group
Mean age of patients was 64 +/- 9 years; and 79% were male
At time enrollment, 290 had angina or CCS severity class II or III
Median number of antianginal agents prescribed for patients prior to enrollment was 1, equivalent to a median of 2 standardized antianginal units

Procedural Characteristics

Radial artery access used in 288 pts (96%)
Invasive physiological assessment performed in a median of 1 vessel per patient
Ischemic territories: identified via invasive physiological assessment and noninvasive functional testing:
- One territory: 242 pts (80%)
- Two territories: 52 pts (17%)
- Three territories: 7 pts (2%)
Coronary lesion characteristics:
- Mean % diameter stenosis assessed by quantitative coronary angiography was 61 +/- 18%
- FFR done in 349/383 target vessels (91%), with median FFR of 0.63 (interquartile range 0.49 to 0.75)
- IFR done in 352/383 target vessels (92%), with median IFR of 0.78 (interquartile range 0.55 to 0.87)
- intravascular imaging was performed in 69% of patients in PCI group. Median post-PCI FFR 0.89 and post PCI IFR 0.93
Complete revascularization occurred in all but 2 patients

Outcomes

Primary Outcome

Data available for 99.7% o~~i~~f the 22,823 patient-days in trial
At 12-week follow up, mean angina symptom score was 2.9 in PCI group and 5.6 in placebo group
- Odds ratio 2.21, 95% CI 1.41 to 3.47, P<0.001
Mean daily angina frequency was 0.3 episodes in PCI group and 0.7 episodes in placebo group
- Odds ratio 3.44, 95% CI 2.00 to 5.91
Mean daily use of antianginal medication was 0.2 in PCI group and 0.3 in placebo group
- Odds radio 1.21, 95% CI 0.70 to 2.10

Secondary Endpoint

Adverse Events

See comparison of serious adverse events above between two groups
In placebo group, there were 2 major periprocedural bleeding events and 2 spontaneous bleeding events in 4 patients who were receiving DAPT
The trial was designed to determine the effect of PCI alone in patients with stable angina and evidence of ischemia.
- The study ultimately found that PCI as a monotherapy in patients with stable angina resulted in lower angina symptom score than a sham procedure.
- The trial used a new end point, the angina symptom score with the use of the smartphone app, which was patient centered and minimized recall bias and maximized data completeness. A smartphone application was utilized by patients to log daily symptoms, including the frequency of angina episodes and their severity. This method simplified data collection and evaluation, offering valuable insights into the symptoms of stable angina. Furthermore, it provided a practical means of monitoring patient activity and optimizing the algorithms used to prescribe antianginal medications
- “Perhaps for angina relief, the first therapy administered – either antianginal medication or an antianginal procedure, such as PCI – has the greatest chance of efficacy.”
Limitations & Considerations
- Duration of follow up was only 12 weeks; daily data showed effect of PCI was immediate and sustained
- However, despite decades of technical advances in PCI, including the introduction of stents, the effect of PCI on treadmill exercise time in the blinded ORBITA-2 trial was still 37 seconds less than the 96-second effect attributed to balloon angioplasty in the unblinded Angioplasty Compared to Medicine (ACME) trial that was conducted three decades ago. The effect of PCI as monotherapy was a 59.5-second difference in the tread- mill exercise time as compared with placebo, which was similar to the 48 to 55 seconds achieved with a full-dose single antianginal medication.
- Trial required stopping antianginal medications, which is against guideline recommendations; yet this allowed PCI to be tested as antianginal monotherapy
- Withdrawal of antianginal medication may have led to unmeasured behavioral changes
- Use of nitroglycerin spray was not included in calculation of angina symptom score
- 80% of patients had ischemia in a single territory only
- Smartphone application was available in English only
Al-Lamee R, Thompson D, Dehbi HM, Sen S, Tang K, Davies J, Keeble T, Mielewczik M, Kaprielian R, Malik IS, Nijjer SS, Petraco R, Cook C, Ahmad Y, Howard J, Baker C, Sharp A, Gerber R, Talwar S, Assomull R, Mayet J, Wensel R, Collier D, Shun-Shin M, Thom SA, Davies JE, Francis DP; ORBITA investigators. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet. 2018 Jan 6;391(10115):31-40. doi: 10.1016/S0140-6736(17)32714-9. Epub 2017 Nov 2. Erratum in: Lancet. 2018 Jan 6;391(10115):30. PMID: 29103656.
Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA, Berman DS, Mancini GB, Weintraub WS; COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007 Apr 12;356(15):1503-16. doi: 10.1056/NEJMoa070829. Epub 2007 Mar 26. PMID: 17387127.
Maron DJ, Hochman JS, Reynolds HR, Bangalore S, O’Brien SM, Boden WE, Chaitman BR, Senior R, López-Sendón J, Alexander KP, Lopes RD, Shaw LJ, Berger JS, Newman JD, Sidhu MS, Goodman SG, Ruzyllo W, Gosselin G, Maggioni AP, White HD, Bhargava B, Min JK, Mancini GBJ, Berman DS, Picard MH, Kwong RY, Ali ZA, Mark DB, Spertus JA, Krishnan MN, Elghamaz A, Moorthy N, Hueb WA, Demkow M, Mavromatis K, Bockeria O, Peteiro J, Miller TD, Szwed H, Doerr R, Keltai M, Selvanayagam JB, Steg PG, Held C, Kohsaka S, Mavromichalis S, Kirby R, Jeffries NO, Harrell FE Jr, Rockhold FW, Broderick S, Ferguson TB Jr, Williams DO, Harrington RA, Stone GW, Rosenberg Y; ISCHEMIA Research Group. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med. 2020 Apr 9;382(15):1395-1407. doi: 10.1056/NEJMoa1915922. Epub 2020 Mar 30. PMID: 32227755; PMCID: PMC7263833.

Summary by: Dr. Cali Clark @CaliRClark and Dr. Hamza Patel @Hamza_Patel123

Visual abstract by: Dr. Christian Andersen @CFAndersenMD

Trial Tweets by: Dr. Rachel Goodman @goodmra1

Moderator of Twitter during CardsJC by: Dr. Hamza Patel @Hamza_Patel123

Promo by: Dr. Rachel Goodman @goodmra1

Under the guidance of House Chief: Dr. Alaa Diab @DrAlaaDiab & Director of CardsJC Dr. Devesh Rai, @DeveshRaiMD

Supported by House Faculty: Dr. Dinu Balanescu @dinubalanescu, Dr. Ty Sweeney @TySweeney6, Dr. Saahil Jumkhawala @saahilaj, and Dr. Eunice Dugan @EuniceDuganMD

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Table of contents for the The STEP-HFpEF Trial summary:

Visual abstract
Summary
References
Credits
Twitter Archive

https://www.nejm.org/doi/full/10.1056/NEJMoa2310234

Relevant literature

Atrial fibrillation (AF) is a significant risk factor for embolic events (stroke and systemic). The thromboembolic event risk is proportional to the patient’s risk for stroke and also to the burden of AF, which is related to the total time in AF but more importantly to the continuous AF rhythm duration.1 It is well known that anticoagulation in patients with AF is effective in reducing embolic events without significantly increasing the risk of major bleeding compared to placebo, aspirin, or aspirin plus clopidogrel, conferring a net clinical benefit for anticoagulation.2 Studies have shown that direct oral anticoagulants (DOACs) are at least as effective as warfarin but with significantly fewer safety events.2-4 Prior to the popularization of DOACs, in patients considered to be high risk for bleeding and warfarin use, aspirin demonstrated a questionable effectiveness in reducing embolic events compared to placebo but it caused fewer major bleeding than DAPT (aspirin plus clopidogrel).5,6 The optimal management of subclinical AF with an episodic duration between 6 minutes and 24 hours, however, remains unclear.

Relevant Guidelines

2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines
Device-detected subclinical atrial tachyarrhythmias: definition, implications and management—an European Heart Rhythm Association (EHRA) consensus document

Briefly, the decision of anticoagulation should be based on:

The diagnosis of atrial fibrillation (AF) and risk for thromboembolic events (CHA2DS2VASc score or equivalent).

For patients without a diagnosis of AF but asymptomatic atrial high rate episodes (AHRE)* (subclinical AF) anticoagulation decision is based on the:

The burden (duration) and thromboembolic risk (CHA2DS2VASc score or equivalent)

*AHRE: Typically detected by reliable monitor devices (telemetry, pacemaker, defibrillators, recorders)

Anticoagulation is recommended (high risk for thromboembolic events >2% annually):

In patients with atrial fibrillation documented by ECG plus CHA2DS2VASc ≥ 2 for man and CHA2DS2VASc ≥ 3 without anticoagulation contraindication

In patients without a previous diagnosis of atrial fibrillation but asymptomatic atrial high rate episodes (AHRE) (episode ≥ 24 hr, detected by a reliable monitor device) plus CHA2DS2VASc ≥ 2 for man and CHA2DS2VASc ≥ 3 without anticoagulation contraindication

Anticoagulation is reasonable (intermediate risk 1-2 % annually):

In patients with atrial fibrillation plus CHA2DS2VASc 2 for men and CHA2DS2VASc 2 for women without anticoagulation contraindication
Persistent afib in the setting of acute medical illness or postoperative – individual risk assessment of bleeding risk, thromboembolic risk, and close follow-up are factors when short-term anticoagulation is being considered

Anticoagulation is contraindicated:

The risk for major bleeding outweighs the anticoagulation clinical benefits in patients with anticoagulation afib indication, or
Afib in patients with low risk for thromboembolic events (CHA2DS2VASc 0 for men and CHA2DS2VASc ≤ 1 for women)
In patients without a previous diagnosis of atrial fibrillation but AHRE (episode < 5 min) regardless of the CHA2DS2VASc score.

Literature/Guideline gap (uncertainty)

Patients without afib but asymptomatic AHRE between 5 min and 24 hr

Figure 1. 2023 ACC/AHA/ACCP/HRS Guidelines

Study Rationale:

Subclinical atrial fibrillation is associated with an increased risk of stroke, systemic embolism, and atrial fibrillation development. However, it is unknown if anticoagulation in patients with subclinical atrial fibrillation with a duration between 6 min and 24 hr has a clinical benefit.

Objectives:

Investigate the efficacy and safety of apixaban vs aspirin in patients with subclinical atrial fibrillation detected by implanted cardiac devices/monitors.

Trial – The ARTESIA Trial

Phase IV, prospective, international multicenter (247 sites, 16 European and North American countries), parallel, double-blind, randomized trial

Intervention

Patients were randomly assigned to:
Aspirin 81 mg daily plus placebo-apixaban

Apixaban 5 mg twice daily (or 2.5 mg BID, if indicated) plus placebo-aspirin.

Enrollment Criteria

If subclinical atrial fibrillation ≥ 24 hr or clinical atrial fibrillation developed (symptoms) patient became ineligible, therefore the apixaban or aspirin was stopped, follow-up was continued, treatment with an open-label anticoagulant was initiated, and these patients were censored in the analysis.

Enrollment

Patients were recruited at the time of pacemaker or defibrillator follow-up visit or after identification of eligible patients by review of local pacemaker databases.

Study follow-up/outcome assessment

Follow-up visits at 30 days from enrollment, then every 6 months, when patients were assessed for outcome events and with questions to verify stroke-free status. Follow-up endpoint expected (not achieved) until 248 primary events have occurred (expected ~36 months).

Primary Outcome

Efficacy: Composite of stroke (including TIA with evidence of cerebral infarction on diffusion-weighted MRI) and systemic embolism
Safety: Major bleeding as defined by the ISTH criteria

Secondary Outcome:

Ischemic stroke
Myocardial infarction (MI)
Vascular death Total death (vascular and non-vascular) Composite of stroke, MI, systemic embolism, and total death
Composite of stroke, MI, systemic embolism, total death and major bleeding

Outcome assessment

Stroke, systemic embolism, and major bleeding events were adjudicated by a committee of experts who were unaware of the trial-group assignments.

Statistical Analysis

Sample size was calculated from ASSERT data:

A study population of 4000 patients has 80% power to detect a relative reduction of 35% in the risk of stroke or systemic embolism in the apixaban group, assuming a risk of 2.75% per patient-year in the control group, a crossover frequency of 8.5%, and the occurrence of 248 primary-outcome events in the two groups.
Primary outcomes presented using the Kaplan-Meier curve and hazard ratio (HR with 95% CI) comparisons between the groups’ treatment effects were derived by the Cox proportional hazards model. Significance defined by 2-sided p ≤ 0.05
Intention-to-treat analysis for primary efficacy outcome.

Baseline Characteristics

mean age was 76.8±7.6 years
36.1% women
mean CHA2DS2-VASc score was 3.9±1.1

Trial Patients

4012 patients underwent randomization with 2015 to the apixaban group and 1997 to the aspirin group
- Apixaban or aspirin was permanently discontinued due to the development of subclinical afib lasting > 24hrs to clinical afib in 24.3% of patients in the apixaban group and 23.8% of patients in the aspirin group (median time to discontinuation was 18.3mos).
- The trial medication was discontinued for other reasons in 34.1 % of patients in the apixaban group and 34.9% of patients in the aspirin group.
- 22.7% and 21.9% of patients died during the follow-up period in the apixaban and aspirin groups, respectively.
- The mean (±SD) duration of follow-up was 3.5±1.8 years for the intention-to-treat analysis and 2.5±1.8 years for the on-treatment analysis.

Outcomes

Primary Outcome

The primary outcome of stroke or systemic embolism was measured in the intention to treat population (all patients who underwent randomization with censoring for the development of subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation).
This occurred at a rate of 0.78% per patient-year and 1.24% per patient-year in the apixaban and aspirin groups respectively ( HR= 0.63; 95% CI 0.45 to 0.88; P=0.007).
The rates of ischemic or unknown stroke were similar with HR= 0.62; 95% CI, 0.43 to 0.91.
By using the modified Rankin scale with scores of 3-6, 18 of 55 strokes in the apixaban group and 36 of 84 stroked in the aspirin group were disabling or fatal. This was 49% lower in the apixaban group (hazard ratio, 0.51; 95% CI, 0.29 to 0.88).
Rates of death were similar between the two groups

Major Bleeding:

The risk of major bleeding was assessed according to the definition of the International Society on Thrombosis and Haemostasis and was measured in the on-treatment population (underwent randomization and received at least one dose of the assigned drug with follow‐up censored 5 days after permanent discontinuation of trial medication for any reason)
Major bleeding occurred at a rate of 1.71% per patient-year with apixaban and 0.94% per patient-year with aspirin (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P = 0.001).
Most bleeding events responded to supportive care (including transfusions) and hemodynamic instability at presentation was uncommon.
Fatal bleeding occurred in 5 patients with apixaban and 8 patients with aspirin.

ARTESIA Conclusions

In this trial involving patients with risk factors for stroke who were found to have subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin by 37%. There is also a lower risk of disabling or fatal stroke in the apixaban group by 49%. The apixaban group had a higher risk of major bleeding, but most incidents responded to supportive care.

Limitations and considerations:

There was a high rate of discontinuation for various reasons in the trial but both the intention to treat and on treatment analysis showed a significant reduction in stroke or systemic embolism.
Lastly, the results of this trial are only relevant to patients with implantable cardiac devices that can detect subclinical AF and it is unclear how these results will translate to patients at high risk of stroke with wearable monitors or other devices.
2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines | Circulation. 2024.
Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation. 1991;84(2).
Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet (London, England). 1996;348(9028).
SJ C, J E, C J, et al. Apixaban in patients with atrial fibrillation. The New England journal of medicine. 2011;364(9).
S C, J P, R H, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet (London, England). 2006;367(9526).
SJ C, J P, RG H, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. The New England journal of medicine. 2009;360(20).
Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet (London, England). 1994;343(8899).
CB G, JH A, JJ M, et al. Apixaban versus warfarin in patients with atrial fibrillation. The New England journal of medicine. 2011;365(11).
RP G, CT R, E B, et al. Edoxaban versus warfarin in patients with atrial fibrillation. The New England journal of medicine. 2013;369(22).
P K, T T, A G, et al. Anticoagulation with Edoxaban in Patients with Atrial High-Rate Episodes. The New England journal of medicine. 2023;389(13).
JS H, RD L, CB G, et al. Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation. The New England journal of medicine. 2024;390(2).

Summary by: Dr. Ronaldo Filho @Ronaldo_CFF and Dr. Maani Kamal @Kamal_mz

Visual abstract by: Dr. Shivani Hanchate @HanchateShivani

Trial Tweets by: Dr. Paul Montana @PaulMontanaMD

Moderator of Twitter during CardsJC by: Dr. Yetunde Kemi Fatade @joyfuldockemi

Promo by: Student Doctor Shivani Reddy @ShivaniReddy_1

Under the guidance of House Chief: Dr. Gurleen Kaur @GurleenKaur_96 & Director of CardsJC Dr. Devesh Rai, @DeveshRaiMD

Supported by House Faculty: Dr. Ahmed Ghoneem @a_h_ghoneem, Dr. Colin Blumenthal @CBlumenthal2, and Dr. Sukriti Banthiya @sukritibanthiya

Faculty experts:

Dr. Hafiza Khan @HafizaKMD

Dr. Mayank Kansal @mmkansal

Dr. Kamala Tamirisa @KTamirisaMD

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Table of contents for the The SELECT Trial summary:

Visual abstract
Summary
References
Credits
Twitter Archive

**Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes****

A. Michael Lincoff, M.D., Kirstine Brown‑Frandsen, M.D., Helen M. Colhoun, M.D.,

John Deanfield, M.D., Scott S. Emerson, M.D., Ph.D., Sille Esbjerg, M.Sc.,

Søren Hardt‑Lindberg, M.D., Ph.D., G. Kees Hovingh, M.D., Ph.D.,

Steven E. Kahn, M.B., Ch.B., Robert F. Kushner, M.D., Ildiko Lingvay, M.D., M.P.H.,

Tugce K. Oral, M.D., Marie M. Michelsen, M.D., Ph.D., Jorge Plutzky, M.D.,

Christoffer W. Tornøe, Ph.D., and Donna H. Ryan, M.D.,

for the SELECT Trial Investigators*

https://www.nejm.org/doi/full/10.1056/NEJMoa2306963

Relevant literature

Obesity is associated with various cardiovascular (CV) risk factors as type 2 diabetes and hypertension. It is also independently associated with cardiovascular morbidity and mortality.1 GLP-1 agonists such as semaglutide are known to be highly effective in weight loss in both diabetic and non-diabetic patients. They are also known to be associated with reduced cardiovascular mortality in patients with type 2 diabetes, however cardiovascular benefit of these agents in non-diabetic patients have yet to be explored.

In a meta-analysis6 of eight trials with 60080 patients (ELIXA, LEADER, SUSTAIN-6, EXSCEL, Harmony Outcomes, REWIND, PIONEER 6, and AMPLITUDE-O) , treatment with a GLP-1 receptor agonist led to a 14% relative risk reduction in three-point MACE (HR 0·86 [95% CI 0·80–0·93]; p<0.001 . GLP-1 receptor agonist use led to a reduction in components of the composite MACE endpoint separately including risk of death from cardiovascular causes, fatal or non-fatal myocardial infarction, and fatal or non-fatal stroke. Furthermore, treatment with a GLP-1 receptor agonist reduced the risk of death from any cause and risk of hospital admission for heart failure.

Study Objectives

To evaluate if semaglutide 2.4 mg subcutaneously once weekly is superior to placebo when added to standard of care for preventing major adverse cardiovascular events in patients with established CVD and overweight or obesity but without diabetes.

Trial design has been published previously.7

– Multi-center, double-blind, randomized, placebo-controlled, event-driven superiority trail

– 804 participating clinical sites in 41 countries

Enrollment Criteria

Intervention

o 1:1 double-blinded non-stratified randomization to receive either 2.4mg semaglutide SC weekly or placebo

o Initial dose of 0.24mg weekly x 4 weeks, uptitrated to 0.5, 1.0, 1.7, and eventually 2.4mg every 4 weeks

§ If significant adverse effects encountered, patients could be placed on slower uptitration, pause treatment, or continue reduced maintenance dose therapy

o Placebo/semaglutide discontinued if:

Patients became/planned to become pregnant
Developed pancreatitis
Calcitonin level ≥ 100 ng/L
Patients were to continue on treatment if diabetes was diagnosed after initiation of treatment/placebo

Primary Outcome

Composite of death from cardiovascular causes, nonfatal MI, nonfatal stroke, (assessed in time-to-first-event analysis)

Secondary Outcome: (all assessed in time-to-first-event analysis)

Death from cardiovascular causes
Composite heart failure end-point (death from CV causes or hospitalization/urgent medical visit for heart failure)
Death from any cause

Statistical Analysis

o Event-driven trial designed to provide 90% power to detect relative risk reduction of 17% for primary endpoint (HR 0.83) at overall one-sided significance level of 0.025

o Required minimum 1225 primary end-point events accrued

o Intention-to-treat analysis performed

o Hazard ratios and 95% confidence intervals generated with Cox proportional hazard model

Baseline Characteristics

17604 patients randomized between Oct. 2018 and March 2021 (8803 semaglutide, 8801 placebo arm)
Mean age 61.6±8.9 years, 12,732 (72.3%) were male.
Mean BMI 33.3±5.0, 12,580 patients (71.5%) met the BMI criterion for obesity (≥30).
More than three quarters of the patients had had a previous myocardial infarction, and nearly one quarter had chronic heart failure.
Mean follow-up of 39.8±9.4 months.

Outcomes

Primary and Secondary Outcome

Patients in the semaglutide study arm experienced a significantly lower rate of the primary outcome (cardiovascular composite end-point) (6.5% vs 8.0%, HR 0.80 (95% CI 0.72-0.90)

No significant difference in rates of cardiac death (HR 0.85, 95% CI 0.71-1.01) however significantly lower rates of heart failure (HR 0.82, 95% CI 0.71-0.96) and all-cause mortality (HR 0.81, 95% CI 0.71-0.93)

Adverse Events

Rates and types of adverse events were fairly similar between control and intervention groups
Permanent premature discontinuation of semaglutide or placebo occurred in 2351 patients (26.7%) in the semaglutide group and 2078 (23.6%) in the placebo group
In obese and overweight patients with cardiovascular comorbidities but without diabetes, treatment with weekly semaglutide was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months.

Limitations and Considerations

BMI cutoff used is in between the typical cutoffs for overweight and obese
Limited generalizability given that the majority of patients included were Caucasian, with only 12.5% African American
male predominant population studied, with only 27.7% females
It remains to be demonstrated if treatment with semaglutide has a cardioprotective and preventative benefit in patients who do not have pre-existing cardiovascular disease
Powell‐Wiley TM, Poirier P, Burke LE, et al. Obesity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2021;143:e984‐e1010.
Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med. 2015;373(1):11-22. doi:10.1056/nejmoa1411892
Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, et al. Efficacy of Liraglutide for Weight Loss Among Patients With Type 2 Diabetes: The SCALE Diabetes Randomized Clinical Trial. JAMA. 2015;314(7):687-699. doi:10.1001/jama.2015.9676
Sorli C, Harashima SI, Tsoukas GM, Unger J, Karsbøl JD, Hansen T, Bain SC. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017 Apr;5(4):251-260. doi: 10.1016/S2213-8587(17)30013-X. Epub 2017 Jan 17. PMID: 28110911.
Wilding JPH, Batterham RL, Calanna S, Davies M, Gaal LFV, Lingvay I, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/nejmoa2032183
Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomeswith GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomized trials. Lancet Diabetes Endocrinol 2021; 9: 653-62.
Ryan DH, Lingvay I, Colhoun HM, et al. Semaglutide effects on cardiovascular outcomes in people with overweight or obesity (SELECT) rationale and design. Am Heart J 2020; 229: 61-9.

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Table of contents for the The STEP-HFpEF Trial summary:

Visual abstract
Summary
References
Credits
Twitter Archive

November 28th 2023

*Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity1*

M.N. Kosiborod, S..Z. AbildstrØm, B.A. Borlaug, J. Butler, S. Rasmussen, M. Davies, G.K Hovingh, D.W. Kiltman, M.L. Lindegaard, D.V. Moller, S.J Shah, M.B. Treppendahl, S. Verma, W. Abhayaratna, F.Z. Ahmed, V. Chopra, J. Ezekowitz, M. Fu, H. Ito, M. Lelonek, V. Melenovksy, B. Merkely, J. Nunez, E. Perna, M. Schou, M. Senni, K. Sharma, P. Van der Meer, D. von Lewinski, D. Wolf, and M.C Petrie, for the STEP-HFpEF Trial Committees and Investigators*

https://www.nejm.org/doi/full/10.1056/NEJMoa2306963

Relevant literature

The STEP-HFpEF group has previously published the study design and baseline patient characteristics of this RCT2
1. Relevant RCT’s below:

Relevant Guidelines

2022 AHA/ACC/HFSA Guidelines of the Management of Heart Failure: A Report of the ACC/AHA Joint Committee on Clinical Practice Guidelines.8

2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure9

Study Rationale

The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing in the U.S., accounting for over half of all cases of heart failure.10,11 Many patients with HFpEF have the obesity phenotype.12,13 Growing evidence suggests that obesity and excess visceral adiposity are more than coexisting conditions in HFpEF, playing a significant role in the development and disease progression of HFpEF.13 HFpEF with obesity phenotype is characterized by greater symptom severity, worse functional capacity, more adverse hemodynamics, and greater risk of heart failure hospitalization than those with HFpEF without obesity.14,15 There are limited medications available to help patients with HFpEF, particularly the obesity phenotype. This study investigated whether the use of pharmacotherapies specifically targeting obesity7 can help reduce symptoms and physical limitations in this HFpEF phenotype.

Study Objectives

The study aims to assess efficacy of treatment with Semaglutide (a GLP1-receptor agonists) on symptoms, physical limitations, exercise function, and weight loss in patients with HFpEF and obese phenotype.

Trial – The STEP-HFpEF Trial
- Conducted at 96 sites in 13 countries in Asia, Europe, North America, and South America
- Randomized 529 patients between March 2021 and March 2022.
Intervention
Randomly assigned 1:1 to subcutaneous Semaglutide 2.4 mg once-weekly for 52 weeks or placebo
1. Semaglutide treatment was initiated at a dose of 0.25mg once-weekly for the first 4 weeks. The dose was then escalated every 4 weeks with the aim of reaching the maintenance dose (2.4 mg) by week 16.
Randomization was stratified according to baseline body mass index (BMI) <35kg/m2 vs. ≥35kg/m2

Enrollment Criteria

Primary Outcome

Primary Outcomes: Dual primary endpoints including change in KCCQ-CSS questionnaire score and percentage change in body weight from baseline at 52 weeks.
- KCCQ-CSS questionnaire: 23-item instrument that quantifies heart failure-related symptoms (frequency, severity, and recent changes), physical function, quality of life, and social function. Scores are ranked from a range of 0 to 100, with higher scores reflecting better health status.

Secondary Outcome:

Secondary Outcomes: Changes in waist circumference, body fat, body lean mass, and metabolic risk factors including levels of plasma glucose, insulin sensitivity, serum lipids, and blood pressure

Statistical Analysis

Full details previously published2 and can also be found in the STEP group statistical analysis plan at NEJM.org
1. Statistical analysis approach sought strong control for type I error
2. All endpoints addressing intervention efficacy were analyzed using intention-to-treat approach
3. All endpoints addressing intervention safety were analyzed using per-protocol approach
4. Efficacy endpoints analyzed using 2 estimands
  1. Treatment Policy Estimand: intention to treat analysis; these results are presented in the primary text and tables/figures
  2. Trial Product Estimand: per-protocol analysis; these results presented in supplementary table 4
5. Sample size: Using certain assumptions and previously validated methods, it was determined that a sample size of 516 would provide 90% power to detect a 4.1 mean difference in change in KCCQ-CSS and 99% power to detect a 9.9% mean difference in change in body weight
  1. Alpha of 0.05 was split between the two primary endpoints, 0.04 for KCCQ-CSS and 0.01 for body weight
6. Primary analysis model for the dual primary endpoints is a linear regression analysis of covariance
  1. Missing data points filled using an established and previously described2 imputation modelthat uses baseline characteristics, prior endpoint data, and group data to produce an unfavorable value
7. Statistical testing hierarchy
  1. Used treatment policy estimand results
8. Confirmatory secondary endpoints were meant to represent the overall clinical benefit/harm of the intervention. Thus, a composite endpoint analyzed via hierarchical testing was utilized
  1. For excellent overviews of the basics of composite endpoints and hierarchical testing, check out these Tweetorials by Akiva Rosenzveig
    1. https://x.com/AkivaRosenzveig/status/1651645980582748175?s=20
    2. https://x.com/AkivaRosenzveig/status/1663605151750340608?s=20

Baseline Characteristics

Baseline demographics and clinical characterizations were similar in both treatment groups. About 56.1% were women and 95.8% where white.
14.6% of the participants qualified for participation based on elevated filling pressures, 13.4% based on hospitalization for heart failure within 12 months in combination with ongoing diuretic treatment or echocardiographic abnormalities (or both), and 72.0% based on NT-proBNP levels plus echocardiographic abnormalities
Median body weight and BMI of participants were 105.1 kg and 37.0kg/m2, respectively
At baseline, patients had substantial degree of heart failure related symptoms, physical limitations, and poor exercise tolerance

Outcomes

Primary Outcome

Co-primary endpoints for Semaglutide vs placebo from baseline to week 52:

Change in KCCQ-CSS 16.6 points vs 8.7 points (estimated difference, 7.8 points; 95% CI 4.8 to 10.9, p<0.001)

Mean percentage change in body weight: -13.3% vs -2.6% (p<0.001)

Secondary Outcomes

Change in 6-minute walk distance from baseline to week 52: 21.5 m vs 1.2 m (95% CI 8.6 to 32.1; p<0.001)

Semaglutide favored over placebo on all components of the hierarchical composite end point (death, heart failure events, change in KCCQ-CSS, and 6MWD), with a difference of at least 15 points in the change in KCCQ-CSS contributing the most to Semaglutide’s benefit. Overall win ratio of 1.72 (95% CI, 1.37 to 2.15; p<0.001)

43.5% Reduction of CRP level with Semaglutide vs 7.3% reduction with placebo at 52 weeks

Semaglutide achieved greater percentage reduction in NT-proBNP from baseline to week 52 (-20.9%) vs. placebo (-5.3%; 95% CI 0.71 to 0.98)

Adverse Events

Serious adverse events were reported in 13.3% of Semaglutide and 26.7% in the placebo group. Overall, the discontinuation rate for serious adverse events between Semaglutide and placebo was similar.
The trial was designed to estimate the treatment effects of once-weekly subcutaneous Semaglutide among obese patient with HFpEF.
1. This study ultimately found that once-weekly subcutanoues Semaglutide was superior to placebo in improving body weight (~11% greater weight loss) and patient-oriented quality of life (QoL) outcomes including KCCQ-CSS and 6MWD at 52 weeks in HFpEF patients with obesity phenotype.
Adverse events were reported in 13.3% patients in the Semaglutide group vs 26.7% in the placebo group.

Limitations and Considerations

The number of non-white participants was low, which may limit the generalizability of results.
The trial was not adequately powered to evaluate clinical events such as hospitalization for heart failure or urgent visits, however a nonsignificant reduction in HF hospitalizations was noted in the Semaglutide group vs. placebo.
The percentage of patients treated with SGLT2 inhibitors was low. A separate trial is investigating once-weekly Semaglutide 2.4 mg compared with placebo in obese patients with HFpEF and type 2 diabetes is ongoing. It will be important to determine the roles of GLP-1 agonisms as compared to SGLT2i in this patient population.
The study was only studied over one year time frame. Semaglutide requires continued use of medication to maintain weight loss, with prior trials demonstrating discontinuation of medication associated with weight gain within 6 months to 1 year16. It will be important to continue monitoring side effect tolerability of the medication in the long term.
It is unclear whether the symptomatic improvements favoring Semaglutide over placebo were driven by the weight loss alone or an additional intrinsic benefit of the medication. Future studies investigating the effect of GLP-1 agonism on more heart failure endpoints will be needed.
Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023;389(12):1069-1084. doi:10.1056/nejmoa2306963
Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Christensen L, Davies M, et al. Design and Baseline Characteristics of STEP-HFpEF Program Evaluating Semaglutide in Patients With Obesity HFpEF Phenotype. JACC: Hear Fail. 2023;11(8):1000-1010. doi:10.1016/j.jchf.2023.05.010
Sorli C, Harashima S ichi, Tsoukas GM, Unger J, Karsbøl JD, Hansen T, et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017;5(4):251-260. doi:10.1016/s2213-8587(17)30013-x
Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med. 2015;373(1):11-22. doi:10.1056/nejmoa1411892
Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, et al. Efficacy of Liraglutide for Weight Loss Among Patients With Type 2 Diabetes: The SCALE Diabetes Randomized Clinical Trial. JAMA. 2015;314(7):687-699. doi:10.1001/jama.2015.9676
O’Neil PM, Birkenfeld AL, McGowan B, Mosenzon O, Pedersen SD, Wharton S, et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet. 2018;392(10148):637-649. doi:10.1016/s0140-6736(18)31773-2
Wilding JPH, Batterham RL, Calanna S, Davies M, Gaal LFV, Lingvay I, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/nejmoa2032183
Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. doi:10.1161/cir.0000000000001063
McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Hear J. 2023;44(37):3627-3639. doi:10.1093/eurheartj/ehad195
Redfield MM, Borlaug BA. Heart Failure With Preserved Ejection Fraction. JAMA. 2023;329(10):827-838. doi:10.1001/jama.2023.2020
Roger VL. Epidemiology of Heart Failure. Circ Res. 2021;128(10):1421-1434. doi:10.1161/circresaha.121.318172
Kitzman DW, Nicklas BJ. Pivotal Role of Excess Intra-Abdominal Adipose in the Pathogenesis of Metabolic/Obese HFpEF ∗. JACC: Hear Fail. 2018;6(12):1008-1010. doi:10.1016/j.jchf.2018.08.007
Borlaug BA, Jensen MD, Kitzman DW, Lam CSP, Obokata M, Rider OJ. Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. Cardiovasc Res. 2022;118(18):3434-3450. doi:10.1093/cvr/cvac120
Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA. Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction. Circulation. 2017;136(1):6-19. doi:10.1161/circulationaha.116.026807
Reddy YNV, Lewis GD, Shah SJ, Obokata M, Abou-Ezzedine OF, Fudim M, et al. Characterization of the Obese Phenotype of Heart Failure With Preserved Ejection Fraction: A RELAX Trial Ancillary Study. Mayo Clin Proc. 2019;94(7):1199-1209. doi:10.1016/j.mayocp.2018.11.037 16. Wilding JPH, Batterham RL, Davies M, Gaal LFV, Kandler K, Konakli K, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes, Obes Metab. 2022;24(8):1553-1564. doi:10.1111/dom.14725

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Table of contents for the The Stellar Trial summary:

Visual abstract
Summary
References
Credits
Twitter Archive

September 2023

Calorie Restriction with or without Time-Restricted Eating in Weight Loss

Deying Liu, M.D., Yan Huang, M.S., Chensihan Huang, M.D., Shunyu Yang, M.D., Xueyun Wei, M.D., Peizhen Zhang, M.D., Dan Guo, M.D., Jiayang Lin, M.D., Bingyan Xu, M.D., Changwei Li, Ph.D., Hua He, Ph.D., Jiang He, M.D., Ph.D., et al.

https://www.nejm.org/doi/full/10.1056/NEJMoa2114833

Relevant literature

Study Rationale

Identification of an alternative and feasible dietary intervention for weight loss.

Study Objectives

The study aims to assess whether time-restricted eating with calorie restriction as compared with daily calorie restriction alone for the effects on weight loss and metabolic risk factors in obese patients.

Trial
- Conducted in Guangzhou, China and was approved by the IRB at Nanfang Hospital of Southern Medical University.
- Participants were recruited via promotional leaflets, information on the internet, and community screenings
Intervention
Randomly assigned 1:1 to time-restricted eating regimen or daily-calorie restriction regimen for 12 months
1. Interventions for both groups:
  1. Prescribed diet:
    1. 1500-1800kcal diet per day for men; 1200-1500kcal diet per day for women
    2. Combination of 40-55% of calories from carbohydrates, 15-20% from protein, 20-30% from fat
  2. All participants received dietary counseling by trained health coaches for duration of trial and information booklets with portion advice, sample menus and attended health-education sessions monthly
  3. Instructed to maintain usual daily physical activity throughout trial
  4. First 6 months:
    1. Required to write daily dietary log, photograph food, note time of meals on custom app
    2. Two researchers used this information to assess dietary intake
    3. Participants received follow-up telephone calls or app messages 2x/week and met with health coach every 2 weeks for adherence assessment and aid
    4. Received one protein shake per day
  5. Second 6 months:
    1. Maintain diet regimens
    2. Fill out lot with pictures and mealtimes 3 days per week
    3. Participants received follow-up telephone calls and app messages 1x/week and met with health coach monthly
2. Time-restricted eating group:
  1. Instructed to consume prescribed calories from 8:00 am to 4:00 pm each day
  2. Only non-caloric beverages permitted outside 8hr period
3. Daily-calorie restriction only group:
  1. Instructed to consume prescribed calories without time restriction
4. Adherence based on number of days participant met requirements as above

Enrollment Criteria

Inclusion criteria: age 18-75, BMI 28-45
Exclusion criteria: acute or chronic viral hepatitis, malignant tumors, diabetes, serious liver dysfunction, chronic kidney disease, current smoking, serious cardiovascular or cerebrovascular disease within 6 months before randomization, severe GI disease or GI surgery within 12 months, active participation in a weight-loss program, use of medications that affect weight or energy balance, and current or planned pregnancy

Primary Outcome

Primary Outcome: Difference between the two groups in the change from baseline in body weight at 12 months

Secondary Endpoints:

Secondary Outcomes: Changes in waist circumference, body fat, body lean mass, and metabolic risk factors including levels of plasma glucose, insulin sensitivity, serum lipids, and blood pressure

Statistical Analysis

Intention to treat analysis. Data were presented as least-squares means with 95% confidence intervals for continuous variables. The 95% confidence intervals are not adjusted for multiple comparisons and should not be used to infer definitive treatment effects. A two-sided P value of less than 0.05 was considered to indicate statistical significance for the primary outcome.

Baseline Characteristics

139 patients were randomly assigned to time restricted eating (69) or daily calorie restriction (70). Of the total number, 135 completed 6 months of intervention and 118 completed the full 12 months of intervention.
Baseline demographic and clinical characteristics were similar in both treatment groups.
Mean age was 31.9 and the mean weight was 88.2kg
Adherence: calculated as the mean percentage of days participants adhered to both the prescribed calories and eating period
- 84.0 +/- 16.1% in the time-restricted eating group
- 83.8 +/- 12.6% in the daily calorie restriction group

Outcomes

Primary Outcome

The mean weight change from baseline to 12 months was –8.0 kg (95% CI –9.6 to –6.4) in the time-restricted eating group and –6.3 kg (CI –7.8 to –4.7) in the daily calorie restriction group.
No significant difference between the two groups in weight change (net difference –1.8 kg, 95% CI –4.0 to 0.4; p=0.11)
Subgroup analysis showed weight changes were similar for the two groups
Waist circumference and BMI changes were similar between the two groups
Body fat mass at 12 mo was reduced by 5.9 kg (95% CI –7.1 to –4.7) from baseline in time-restricted eating group and by 4.5 kg (95% CI, -5.6 to –3.3) in the daily calorie restriction group; no substantial differences in the two groups
Body composition:
- Both diets led to loss of lean mass, abdominal visceral fat, subcutaneous fat, and liver fat; no differences between the two groups
- Both groups had similar measures of trunk fat and appendicular lean mass at 12 months
Cardiometabolic risk factors:
- Both groups associated with reduced systolic and diastolic blood pressures over 12 months, no substantial between-group differences
- Fasting glucose levels, 2hr postprandial glucose levels, scores on insulin disposition index and HOMA-IR, and lipid levels were similar in the two groups

Adverse Events

No deaths or serious adverse events were reported during the trial
Occurrences of mild adverse events like fatigue, dizziness, headache, decreased appetite, upper abdominal pain, dyspepsia, and constipation were similar in the two groups
The trial was designed to determine if time-restricted eating with caloric restriction as compared to daily caloric restriction alone resulted in a greater change from baseline in body weight.
- The study ultimately found there was no statistically significant difference in change from baseline body weight at 12 months when adhering to a time-restricted eating regimen as compared to daily calorie restriction.
- Based on this, the authors conclude the weight loss documented in both groups is explained by the caloric restriction alone, and not the time-restriction.
Limitations & Considerations
- This study excluded patients with diabetes or cardiovascular disease, and thus cannot be generalized to these patient populations, many of which often struggle with obesity.
- This study cannot be generalized to persons of other races or ethnic groups.
- Total energy expenditure was not assessed during this trial.
- Physical activity was not controlled in this trial in efforts to examine the effects of diet regimens on weight loss in isolation.
Johnston BC, Kanters S, Bandayrel K, et al. Comparison of Weight Loss Among Named Diet Programs in Overweight and Obese Adults: A Meta-analysis. JAMA. 2014;312(9):923–933. doi:10.1001/jama.2014.10397
Lowe DA, Wu N, Rohdin-Bibby L, et al. Effects of Time-Restricted Eating on Weight Loss and Other Metabolic Parameters in Women and Men With Overweight and Obesity: The TREAT Randomized Clinical Trial. JAMA Intern Med. 2020;180(11):1491–1499. doi:10.1001/jamainternmed.2020.4153

Summary by: Dr. Cali Clark @CaliRClark and Dr. Hamza Patel @Hamza_Patel123

Visual abstract by: Dr. Christian Andersen @CFAndersenMD

Trial Tweets by: Dr. Rachel Goodman @goodmra1

Moderator of Twitter during CardsJC by: Dr. Hamza Patel @Hamza_Patel123

Promo by: Dr. Rachel Goodman @goodmra1

Under the guidance of House Chief: Dr. Alaa Diab @DrAlaaDiab & Director of CardsJC Dr. Devesh Rai, @DeveshRaiMD

Supported by House Faculty: Dr. Dinu Balanescu @dinubalanescu, Dr. Ty Sweeney @TySweeney6, Dr. Saahil Jumkhawala @saahilaj, and Dr. Eunice Dugan @EuniceDuganMD Faculty experts: Dr. Martha Gulati @DrMarthaGulati, Dr. Alison Bailey @a_l_bailey, Dr. Seth Martin @SethShayMartin, Dr. Eugenia Gianos @EugeniaGianos

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CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the STELLAR Trial Table of contents for the The Stellar Trial summary: […]

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CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the ELAN Trial Table of contents for the The ELAN Trial summary: […]

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CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the RAPID-HF Trial Table of contents for the The CLEAR Trial summary: […]

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This Journal Club was hosted in collaboration with the American Society of Preventive Cardiology. For more information about the ASPC, visit www.aspconline.org.

Table of contents for the The CLEAR Trial summary:

Visual abstract
Summary
References
Credits
Twitter Archive

Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients

April 13, 2023

S.E. Nissen, A.M. Lincoff, D. Brennan, K.K. Ray, D. Mason, J.J.P. Kastelein, P.D. Thompson, P. Libby, L. Cho, J. Plutzky, H.E. Bays, P.M. Moriarty, V. Menon, D.E. Grobbee, M.J. Louie, C.-F. Chen, N. Li, L.A. Bloedon, P. Robinson, M. Horner, W.J. Sasiela, J. McCluskey, D. Davey, P. Fajardo-Campos, P. Petrovic, J. Fedacko, W. Zmuda, Y. Lukyanov, and S.J. Nicholls, for the CLEAR Outcomes Investigators

Link to Manuscript

What is Bempedoic acid?
1. Bempedoic Acid: for Whom and When

Relevant literature

Relevant guidelines

2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Solution Set Oversight Committee

2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines

2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS)

Note that these guidelines are not included in the standard therapy protocol

Study Rationale

Recent data suggest that bempedoic acid has an LDL-lowering effect. However, cardiovascular outcome data related to this medication was missing. The CLEAR trial was conducted to determine the effect of bempedoic acid on cardiovascular events.

Objective

Determine the safety and efficacy of bempedoic acid versus placebo in patients who are statin intolerant and either have cardiovascular disease or are at high-risk for cardiovascular disease.
1. Statin-intolerance defined as being unable or unwilling to receive statins owing to an adverse effect that had started or increased during statin therapy and resolved or improved after statin therapy was discontinued

The CLEAR Outcomes Trial

Patients assigned to oral bempedoic acid 180 mg daily or placebo
Followed for a median of 40.6 months
Of note, bempedoic acid has a similar end-goal to statins but is a prodrug activated in the liver and not in most peripheral tissues

Enrollment Criteria

Statistical Analysis

Intention-to-treat analysis. Differences between the placebo and bempedoic acid groups for the primary outcome were assessed for statistical significance at p<0.05.
Hierarchical statistical analysis.
- Sequential analysis was run for the primary end point and the six secondary endpoints
- In order to progress, statistical significance was required at each step

Randomization

4-week run in period of a single-blind placebo
- Those with unacceptable adverse effects or <80% adherence were then ineligible for randomization and excluded from trial
Randomized 1:1 bempedoic acid vs. placebo

Notable Baseline Characteristics (Intervention vs. Control)

Age: 65.5 vs. 65.5 years
Women: 48.1% vs. 48.4%
White race: 91.5% vs. 90.8%
LDL cholesterol: 139 vs. 139 mg/dL
HDL cholesterol: 49.6 vs. 49.4 mg/dL
TG: 159.5 vs. 158.5 mg/dL
CV risk category
- Primary prevention: 30% vs. 30.2%
- Secondary prevention: 70% vs. 69.8%
Statin use: 22.9% vs. 22.5%
Ezetimibe use: 11.5 vs. 11.6%
T2DM: 45% vs. 46.3%
Inadequately controlled DM*: 19.4% vs. 19.6%

* Defined as Diabetes Mellituswith an HbA1C greater than or equal to 7 at baseline.

Outcomes

*Of note, details of non-fatal myocardial infarction (e.g. spontaneous vs. Procedure-related) are not reported

Adverse Events (Intervention vs. Control)

The incidence of gout and cholelithiasis were higher with bempedoic acid than with placebo, as were the incidences of increases in serum creatinine, uric acid, and hepatic-enzyme levels.

Myalgias – 5.6% vs. 6.8%
Discontinuation of the trial regimen because of myalgia – 1.8% vs. 1.9%
Renal impairment – 11.5% vs. 8.6%
Hyperuricemia – 10.9% vs. 5.6%
Gout – 3.1% vs. 2.1%
Cholelithiasis – 2.2% vs. 1.2%

Change from baseline in lab results after 6 months

Uric acid – 0.76±1.2 vs. -0.03±1.0
Creatinine – 0.05±0.2 vs. 0.01± 0.2

There was no difference in the incidence of tendinopathy, as has been seen in prior trials.

Tendinopathy– 1.7% vs. 1.8%
Adjudicated tendon rupture– 1.2% vs. 0.9%

A difference in the rate of fatal and nonfatal hemorrhagic stroke was detected:

Fatal and nonfatal non-hemorrhagic stroke – 1.7% (bempedoic acid) vs. 2.1% (placebo)

Conclusions

The percent reduction in the LDL cholesterol was greater with bempedoic acid than placebo by 21%
The risk of the composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization was 13% lower with bempedoic acid than with placebo over a median of 3.4 years
Bempedoic acid was superior to placebo in reducing the risk of secondary end-point events, including the three-component composite endpoint of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke, along with, fatal or nonfatal myocardial infarction, and coronary revascularization
Similar effects of bempedoic acid were seen in patients using concomitant ezetimibe and very-low-dose statins
The percentage of patients with myalgias was similar in both groups, however incidences of gout, cholelithiasis, and serum elevations in creatinine, uric acid, and hepatic enzymes were higher with bempedoic acid than placebo
Limitations & Considerations
Only included patients who reported they were unable or unwilling to take statins. This resulted in elevated baseline mean LDL cholesterol level (139 and 139 mg/dL in each arm). The effects of bempedoic acid on CV events in populations with lower LDL cholesterol levels and in patients taking conventional therapeutic doses of statins were not studied.
Predominately White cohort (> 90%)
Use of composite outcomes.
Strength: randomized controlled trial, almost 50% women in each group
Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med. 2023;388(15):1353-1364. doi:10.1056/NEJMoa2215024
Ray KK, Bays HE, Catapano AL, et al. Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. N Engl J Med. 2019;380(11):1022-1032. doi:10.1056/NEJMoa1803917
Alexander JH. Benefits of Bempedoic Acid – Clearer Now. N Engl J Med. 2023;388(15):1425-1426. doi:10.1056/NEJMe2301490
Ballantyne CM, Laufs U, Ray KK, Leiter LA, Bays HE, Goldberg AC, Stroes ES, MacDougall D, Zhao X, Catapano AL. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol. 2020 Apr;27(6):593-603. doi: 10.1177/2047487319864671. Epub 2019 Jul 29. PMID: 31357887; PMCID: PMC7153222.
Ballantyne CM, Banach M, Mancini GBJ, Lepor NE, Hanselman JC, Zhao X, Leiter LA. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study. Atherosclerosis. 2018 Oct;277:195-203. doi: 10.1016/j.atherosclerosis.2018.06.002. Epub 2018 Jun 12. PMID: 29910030.
Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, Robinson PL, Ballantyne CM; CLEAR Harmony Trial. Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. N Engl J Med. 2019 Mar 14;380(11):1022-1032. doi: 10.1056/NEJMoa1803917. PMID: 30865796.
François Mach et. al, 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS), European Heart Journal, Volume 41, Issue 1, 1 January 2020, Pages 111–188, https://doi.org/10.1093/eurheartj/ehz455
Ruscica M, Sirtori CR, Carugo S, Banach M, Corsini A. Bempedoic Acid: for Whom and When. Curr Atheroscler Rep. 2022;24(10):791-801. doi:10.1007/s11883-022-01054-2

Trial summary by Christian Faaborg Andersen MD and Rachel Goodman, MD

Visual abstract by Cali Clark, DO, MBA

Trial tweets by Hamza Patel, MD

Promo by Apurva Bhavana Challa and Pacey Wetstein

House Chief: Alaa Diab, MD

FIT experts: Paul Marano, MD , Kayla Riggs, MD , Usman Hasnie, MD , and Allison Bigeh, DO

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Table of contents for the The TRILUMINATE Trial summary:

Visual abstract
Summary
References
Credits
Twitter Archive

**Transcatheter Repair for Patients with Tricuspid Regurgitation: The TRILUMINATE Pivotal Randomized clinical trial****

March 4, 2023

Authors: Paul Sorajja, Brian Whisenant, Nadira Hamid, Hursh Naik, Raj Makkar, Peter Tadros, Matthew J. Price, Gagan Singh, Neil Fam, Saibal Kar, Jonathan G. Schwartz, Shamir Mehta, Richard Bae, Nishant Sekaran, Travis Warner, Moody Makar,George Zorn, Erin M. Spinner, Phillip M. Trusty, Raymond Benza, Ulrich Jorde, Patrick McCarthy, Vinod Thourani, Gilbert H.L. Tang, Rebecca T. Hahn, and David H.Adams

Link to Manuscript: https://www.nejm.org/doi/full/10.1056/NEJMoa2300525

Untreated severe tricuspid regurgitation (TR) has been associated with poor quality of life and long-term survival. 1
Severe TR can cause right sided heart failure leading to fatigue and peripheral edema.
Per the 2021 European Society of Cardiology and European Association for Cardiothoracic Surgery guidelines, for patients who are symptomatic with isolated, severe TR without severe right ventricular dysfunction, surgery is a class I recommendation. 2
However, many patients present more clinically decompensated despite the use of intravenous diuretics that increase the risk of surgery including right ventricular dysfunction and hepatorenal dysfunction
Mortality rates for isolated tricuspid valve surgery have ranged from 8-10% in certain studies.3, 4
Treatment of TR with transcatheter edge-to-edge repair (TEER) uses a transvenous approach and approximates the tricuspid valve leaflets by using a clip to hold the leaflets together, to reduce the amount of actual regurgitation
Initial single-arm studies of TEER have shown significant reduction in amount of TR, hospitalization rates, NYHA class, 6-minute walk test, and symptoms. 5, 6

*Current Guidelines for surgical treatment of TR*

Study Rationale

The clinical benefit of TEER compared to conservative therapy (ie, diuretics) in severe, isolated TR is unknown.

Objective

The TRILUMINATE study aims to evaluate the safety and effectiveness of TEER in symptomatic patients with severe TR compared to medical therapy alone.

Trial:

International, multi-center randomized controlled trial

Intervention

Tricuspid TEER was done with the TriClip Tricuspid Valve Repair system, with a 25-French delivery catheter to place one or more TriClip devices on the tricuspid-valve leaflets. The goal was to permanently appose the tricuspid valve leaflets with the use of echocardiographic and fluoroscopic guidance.
The procedure was done via the femoral vein and patients were placed under general anesthesia.

Enrollment Criteria

Patients with TR that was confirmed by an independent echocardiography lab as severe, were symptomatic (NYHA class II-IV), had a pulmonary artery systolic pressure <70 mmHg, received stable (≥30 days) guideline-directed medical therapy for heart failure, had no other cardiovascular conditions in need of surgical correction (i.e., severe aortic stenosis or mitral regurgitation), and were at intermediate or greater surgical risk.
Surgical risk was determined by the local heart team, which consisted of board-certified specialists in cardiac surgery, interventional cardiology, echocardiography, and heart failure.
Clinical follow up was done at 1, 6, and 12 months with each appointment aimed at the assessment of symptoms, 6-minute walk test, and quality-of-life measurement with the Kansas City Cardiomyopathy Questionnaire (KCCQ).

Statistical Analysis

A sample of 350 patients would provide 84% power to show superiority of TEER to the control, with a two-sided alpha level of 0.05.
Primary endpoint analysis was done with the Finkelstein-Schoenfeld method and a win ratio, along with the use of the intention-to-treat population based on their assigned treatment.
Analyses were also done in a per-protocol population, as-treated population, and an attempted-procedure population.

Participant Characteristics:

Mean age – 78±7 years (51- 96 years)
Women – 54.9%
Functional tricuspid regurgitation – 323/344 (93.9%)
Hypertension – 283 patients (80.9%)
Atrial fibrillation – 315 patients (90%)
Previous mitral or aortic valve interventions – 129 patients (36.9%)
Hospitalization for heart failure <1 year of enrollment – 88 patients (25.1%)
History of cardiac implantable electronic rhythm device – 52 patients (14.9%)

Outcomes

Conclusions

Tricuspid TEER is safe in patients with severe TR, reduced the severity of TR to moderate or less and was associated with a significant improvement in quality of life.
TEER with TriClip may be a promising minimally invasive therapy for patients with severe TR who are not eligible for tricuspid valve surgery.

Limitations & Considerations

Potential bias in patient’s perception of their health status in open-label design.
Hawthorne effect may have contributed to improved management of the disease in the intervention arm.
Results may not apply to patients with anatomical or hemodynamic findings that differ from those utilized in selection criteria during enrollment into trial.
Long-term follow up is required to assess survival and hospitalizations for heart failure beyond 1 year.
There is a need for future studies to help identify which patients and specifically anatomies are most suited to treatment.
Topilsky Y, Maltais S, Medina Inojosa J, et al. Burden of tricuspid regurgitation in patients diagnosed in the community setting. JACC Cardiovasc Imaging 2019;12:433-442.
Vahanian A, Beyersdorf F, Praz F, et al. 2021 ESC/EACTS guidelines for the management of valvular heart disease. Eur Heart J 2022;43:561-632.
Zack CJ, Fender EA, Chandrashekar P, et al. National trends and outcomes in isolated tricuspid valve surgery. J Am Coll Cardiol 2017;70:2953-2960.
Kilic A, Saha-Chaudhuri P, Rankin JS, Conte JV. Trends and outcomes of tricuspid valve surgery in North America: an analysis of more than 50,000 patients from the Society of Thoracic Surgeons database. Ann Thorac Surg 2013;96:1546-1552.
Nickenig G, Weber M, Lurz P, et al. Transcatheter edge-to-edge repair for reduction of tricuspid regurgitation: 6-month outcomes of the TRILUMINATE single-arm study. Lancet 2019;394:2002-2011.
Lurz P, Stephan von Bardeleben R, Weber M, et al. Transcatheter edge-to-edge repair for treatment of tricuspid regurgitation. J Am Coll Cardiol 2021;77:229-239.

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Table of contents for the CANARY Trial summary:

Visual abstract
Summary
References
Credits
Twitter Archive

*Catheter-Directed Thrombolysis vs. Anticoagulation in Patients With Acute Intermediate-High–risk Pulmonary Embolism: The CANARY Randomized Clinical Trial*

October 19, 2022

Authors: Parham Sadeghipour, Yaser Jenab, Jamal Moosavi, Kaveh Hosseini, Bahram Mohebbi, Ali Hosseinsabet, Saurav Chatterjee, Hamidreza Pouraliakbar, Shapour Shirani, Mehdi H Shishehbor, Azin Alizadehasl, Melody Farrashi, Mohammad Ali Rezvani, Farnaz Rafiee, Arash Jalali, Sina Rashedi, Omid Shafe, Jay Giri, Manuel Monreal, David Jimenez, Irene Lang, Majid Maleki, Samuel Z Goldhaber, Harlan M Krumholz, Gregory Piazza, Behnood Bikdeli

Link to Manuscript: https://jamanetwork.com/journals/jamacardiology/article-abstract/2797198

Relevant Literature – CANARY Trial

The role of reperfusion therapy (also known as “escalation of care”) for the treatment of intermediate-high risk pulmonary embolism (PE) is not well established.
Catheter-directed thrombolysis (CDT) refers to the administration of a thrombolytic drug directly into the pulmonary arterial circulation, generally over 24-48 hours, with a maximal dosage of thrombolytic. This is different from systemic thrombolysis, which involves the peripheral intravenous administration of thrombolytics, with higher doses of medication over a shorter period of time. The thrombolytics currently used are alteplase, tenecteplase, reteplase, urokinase, and streptokinase.
In patients with submassive or intermediate-risk PE (defined as patients without acute hypotension but with biologic and/or imaging evidence of acute right ventricular dysfunction), systemic thrombolysis has been shown to improve hemodynamic outcomes, but is associated with an elevated risk of intra- and extracranial hemorrhage.1
The goal of CDT is to achieve reperfusion similar to systemic thrombolysis, while decreasing the rate of major and intracranial bleeding, by delivering a localized, lower thrombolytic dose.1
CDT has been proven to have favorable hemodynamic outcomes and lower bleeding complications in patients with submassive/intermediate-high risk PE. There are currently no data to support short-term mortality benefits with catheter-based approaches for the treatment of PE.3
Prior trials evaluating CDT in the treatment of acute PE have focused on imaging surrogates for improved short-term outcomes, such as RV:LV ratio. There is uncertainty regarding the long-term improvement of RV function after treatment with CDT compared with systemic thromboloysis or anticoagulation monotherapy.1

Relevant Guidelines – CANARY Trial

European Society of Cardiology Guidelines (2019)6
- Surgical embolectomy or CDT should be considered for patients with hemodynamic deterioration on anticoagulation treatment (Class IIa, level C)
- Percutaneous CDT should be considered for patients with high-risk PE, in whom thrombolysis is contraindicated or has failed (Class IIa, level C)
American Heart Association Scientific Statement (2019)1
- If patients deteriorate (hemodynamic, respiratory, or RV function), more intensive therapies, including thrombolysis, catheter-based or surgical embolectomy, and mechanical circulatory support, should be strongly considered.
- Among those who remain hemodynamically stable, a careful assessment for factors that elevate the risk of decompensation should be undertaken, including elevated pulmonary embolism severity index (PESI) or simplified PESI score, severe PE-related functional impairment, and objective signs of severely diminished end-organ perfusion or stroke volume. In those who meet these criteria and have non-prohibitive bleeding risk, systemic thrombolysis or CDT may be considered to improve RV performance immediately.

Study Rationale – CANARY Trial

There is limited evidence regarding durable effects on improving RV function with CDT compared with anticoagulation monotherapy in patients with acute intermediate-high-risk PE.

Objective – CANARY Trial

The CANARY trial aimed to compare the effect of CDT plus anticoagulation to anticoagulation monotherapy on biologic and echocardiographic measures of RV strain (serum NT-pro-BNP, serum troponin, RV/LV ratio) in acute intermediate-high–risk PE.

Trial: – CANARY Trial

Open-label, parallel-group, masked-end point, and randomized
Performed in two cardiovascular centers in Tehran, Iran

Intervention

Therapy with unfractionated heparin was started in all potentially eligible patients prior to randomization
Patients were randomized to anticoagulation monotherapy or CDT:

Anticoagulation monotherapy

Twice-daily subcutaneous enoxaparin (1 mg/kg) for the first 48 hours after enrollment
Subsequent transition to oral anticoagulant was left to the discretion of treating physicians

CDT

Transfer to the catheterization laboratory within 60 minutes of randomization
Catheter(s) placed via femoral artery: one catheter for unilateral and two catheters for bilateral PE
Infusion of alteplase at 0.5 mg/h per catheter plus a fixed dose of unfractionated heparin at 500 U/h
Transition to twice-daily enoxaparin (1 mg/kg) for the first 48 hours after completion of fibrinolytic therapy in patients without procedural complications or hemodynamic instability
Subsequent transition to oral anticoagulant was left to the discretion of treating physicians

Enrollment Criteria

Inclusion criteria

Age ≥ 18 years old with acute intermediate-high risk PE confirmed by CTPA and symptoms onset ≤ 14 days
NT-proBNP ≥ 600 pg/mL and high-sensitivity troponin T ≥ 14 pg/mL for patients aged < 75 years and ≥ 45 pg/mL for those ≥ 75 years
RV/LV ratio >0.9 in CTPA
Simplified PESI ≥ 1
Randomized within 48 hours since initiation of anticoagulation therapy
Not enrolled in another blinded randomized trial
Willing to participate and consent

Exclusion criteria

Pulmonary emboli diagnosed with modalities other than CTPA
Pulmonary emboli limited to segmental and sub-segmental branches of pulmonary arteries
High-risk or massive PE
Severe renal dysfunction with CrCl < 30 mL/min
Terminal illness, as assessed by treating clinicians
Surgery within the prior 2 weeks
Platelet count < 50,000/ìL
Any absolute contraindication for fibrinolytic therapy: active internal bleeding, history of intracranial hemorrhage, ischemic stroke within the past 3-months, cerebral aneurysm, primary or metastatic intracranial malignancy, presence of signs or symptoms of acute aortic dissection, or major trauma or head injury in the prior 3-weeks
Evidence of right heart thrombi
Allergic reaction to study medications
Lack of withdrawal of informed consent

Outcomes

Primary
- The proportion of patients with RV/LV ratio > 0.9 at 3 months
Secondary
- The proportion of patients with RV/LV ratio > 0.9 at 72 hours after randomization
- The proportion of patients with unrecovered RV at 3-months
- All-cause mortality at 3-months

Statistical Analysis

A sample size of 144 patients in each group (288 total) would be needed to reach a power of 80%
Categorical variables were analyzed using Chi-square or Fisher exact test
Continuous variables were analyzed with T-test
After completion of enrollment but before analyzing the trial data, it was planned to conduct a random-effect meta-analysis from CDT arms of prior randomized trials (ULTIMA, OPTALYSE-PE, SUNSET-PE) plus the current trial, to assess the pooled relative frequency of bleeding events

Note: Due to the COVID-19 pandemic and its strain on the healthcare system, it was decided to stop recruitment in February 2020. The 3-month outcomes were analyzed in patients with valid values. Other outcomes were analyzed on all randomly assigned patients.

Participant Characteristics:

Outcomes

Proportion of patients with RV/LV ratio > 0.9 at 3-month follow-up: 4.3% vs. 12.8%; OR 0.31 (CI 0.06-1.69; P=0.24)

Secondary Outcomes

Proportion of patients with RV/LV ratio > 0.9 at 72 hours: 27.0% vs. 52.1%; OR 0.34 (CI 0.14-0.80; P=0.01)
Proportion of patients with unrecovered RV function at 3-month follow-up: 6.2% vs. 28.2%; OR 0.18 (CI 0.06-0.77; P=0.009)
All-cause mortality at 3-months: 0% vs. 6.5%; OR -6.50 (-13.06-6.14, P=0.40)

Safety Outcomes

1 case of Bleeding Academic Research Consortium (BARC) type 3a major bleeding (nonfatal GI bleed) occurred in the CDT group
No fatal or intracranial bleeding occurred in either group
3 cases of minor bleeding (vascular access-site hematoma, BARC type 2) occurred in the CDT group

Adverse Events

Pooled frequency of bleeding events (including ULTIMA, OPTALYSE-PE, SUNSET-PE, and CANARY trials)

Fatal bleeding: 0.02% (95% CI, 0-1.15%)
Intracranial hemorrhage: 0.44% (95% CI, 0-2.17%)
Major bleeding: 1.76% (95% CI, 0.20%-4.27%)

Conclusions

There was no statistically significant difference in the proportion of patients with RV/LV ratios > 0.9 in the CDT group vs. anticoagulation monotherapy group, at 3 months follow up. However, CDT was associated with a statistically significant decrease in the proportion of patients with RV/LV ratio > 0.9 at 72 hours after randomization.
CDT was also associated with more echocardiographic RV recovery at 3-month follow-up, when compared to anticoagulation monotherapy.

Limitations & Considerations

The main limitation of the CANARY trial was stopping enrollment prematurely due to the COVID-19 pandemic, resulting in recruiting a total of 94 patients, and leading to an underpowered trial.
Women were underrepresented in the trial, accounting for only 29% of the patient sample.
Majority of the sample had a low baseline bleeding risk profile, which may represent selection bias.
Due to logistical limitations, the 6-minute walk test at 3-month follow-up was only performed in one enrolling center.
Giri J, Sista AK, Weinberg I, et al. Interventional Therapies for Acute Pulmonary Embolism: Current Status and Principles for the Development of Novel Evidence: A Scientific Statement From the American Heart Association. Circulation. 2019;140(20):E774-E801. doi:10.1161/CIR.0000000000000707
Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-1411. doi:10.1056/NEJMOA1302097
Pei DT, Liu J, Yaqoob M, et al. Meta-Analysis of Catheter Directed Ultrasound-Assisted Thrombolysis in Pulmonary Embolism. Am J Cardiol. 2019;124(9):1470-1477. doi:10.1016/J.AMJCARD.2019.07.040
Kucher N, Boekstegers P, Müller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129(4):479-486. doi:10.1161/CIRCULATIONAHA.113.005544
Piazza G, Hohlfelder B, Jaff MR, et al. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. JACC Cardiovasc Interv. 2015;8(10):1382-1392. doi:10.1016/J.JCIN.2015.04.020
Konstantinides S V., Meyer G, Bueno H, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543-603. doi:10.1093/EURHEARTJ/EHZ405

The published archive features curated twitter highlights from the journal club event.

SUMMARY:

Dr. Saahil Jumkwala, Internal medicine resident, Rutgers New Jersey Medical School

Dr. Karla Asturias, Internal Medicine Resident, Pennsylvania Hospital

VISUAL ABSTRACT:

Dr. Justin Brilliant, Internal Medicine Resident, The Johns Hopkins Hospital

JOURNAL CLUB PROMO GRAPHIC:

Student doctor, Anusha Gandhi, Baylor College of Medicine

TWEET PREPARATION:

Dr. Sukriti Banthiya, Internal Medicine Resident, Ascension Providence in Michigan

HOUSE JONES CHIEF FELLOW:

Dr. Teodora Donisan, Cardiology Fellow, Mayo Clinic

HOUSE JONES FACULTY

Dr. Tommy Das, Cardiology fellow, Cleveland Clinic

DIRECTOR of JOURNAL CLUB:

Dr. Devesh Rai, @DeveshRaiMD, Cardiology fellow at Rochester General Hospital

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Table of contents for the ECMO-CS Trial summary:

Visual abstract
Summary
References
Credits
Twitter Archive

Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock: Results of the ECMO-CS Randomized Clinical Trial

Petr Ostadal, Richard Rokyta, Jiri Karasek, Andreas Kruger, Dagmar Vondrakova, Marek Janotka, Jan Naar, Jana Smalcova, Marketa Hubatova, Milan Hromadka, Stefan Volovar, Miroslava Seyfrydova, Jiri Jarkovsky, Michal Svoboda, Ales Linhart and Jan Belohlavek and for the ECMO-CS Investigators

LINK: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.062949

Relevant Literature – ECMO-CS Trial

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a means of mechanical circulatory support (MCS) for patients with cardiogenic shock (SCAI stages D-E) that has become widely adopted internationally. There is limited evidence comparing early VA-ECMO with a more conservative strategy in patients with cardiogenic shock. The current role of ECMO includes complete hemodynamic support to reverse the deleterious effects of organ hypoperfusion in cardiogenic shock and hopeful recovery of intrinsic cardiac function or as a bridge to more durable left ventricular assist devices or heart transplants.1
To date, MCS options, including intra-aortic balloon pumps (IABP) and Impella used for cardiogenic shock, have not been shown to have mortality benefits. In the IABP-SHOCK II trial, no difference in all-cause mortality was seen at 30 days for patients in cardiogenic shock from acute MI treated with IABP when compared to the control group.2 Furthermore, in the IMPRESS trial, all-cause mortality was the same between Impella and IABP for patients with cardiogenic shock from STEMI undergoing primary PCI.3 For patients with worsening cardiogenic shock, particularly worsening biventricular function refractory to inotropes or other MCS options mentioned above (transition from SCAI stage D to E, see Figure 1), VA-ECMO is a feasible option.

Relevant Guidelines – ECMO-CS Trial

There are currently no standardized guidelines for choosing MCS in cardiogenic shock. The European Society of Cardiology (ESC) for Heart Failure (2021) recommends that for early hemodynamic stabilization for cardiogenic shock, ventilatory support is a class IIA recommendation, considering inotropes/vasopressors is a class IIB recommendation, and short-term MCS is a class IIA recommendation.4

Study Rationale – ECMO-CS Trial

There is limited evidence comparing early VA-ECMO with a more conservative strategy in patients with cardiogenic shock.
A meta-analysis of cohort studies has shown that ECMO is effective in patients with severe cardiogenic shock and may have a higher 30-day survival rate when compared to the use of IABP alone.3

Objective – ECMO-CS Trial

The aim of the ECMO-CS trial was to compare early conservative therapy with the use of inotropes and vasopressors for hemodynamic stabilization and immediate insertion of ECMO in the setting of rapidly deteriorating cardiogenic shock.

Trial: – ECMO-CS Trial

Randomized, multicenter, investigator-initiated clinical trial without industry involvement.
Conducted in four centers in the Czech Republic.

Hypothesis

Immediate ECMO insertion in the case of severe cardiogenic shock would be associated with improved outcomes in the primary composite endpoint.

Intervention

1:1 randomization of 117 patients into immediate VA-ECMO therapy (N = 58) vs early conservative therapy (N = 59).
In the early conservative group, VA-ECMO could be used downstream in case of a further worsening of hemodynamic status, defined as a rise of serum lactate by 3 mmol/L in comparison with the lowest value during the past 24 hours.

Enrollment Criteria

Outcomes

Primary
- Composite: Death from any cause, resuscitated cardiac arrest, and implantation of another MCS device
Secondary
- Composite: All-cause mortality or resuscitated cardiac arrest
- Bleeding, leg ischemia, or stroke

Statistical Analysis

All analyses were performed with intention-to-treat with all patients and events occurring until 30 days from randomization
Categorical variables: Pearson Chi-Squared or Fisher’s exact test
Continuous variables: T-test or Mann-Whitney test
Time to occurrence of primary composite endpoint: Kaplan-Meier method and compared using a log-rank test
95% Confidence intervals and hazard ratios were calculated with the cumulative risk function and Cox proportional hazard model, respectively.

Participant Characteristics:

Outcomes

Composite Endpoint: 63.8% vs. 71.2% [HR] 0.72, 95% CI 0.46-1.12)
- All-cause mortality: 50% vs. 47.5% (HR 1.11, 95% CI 0.66-1.87)
- Another MCS: 17.2% vs. 42.4% (HR 0.38, 95% CI 0.18-0.79)
- Resuscitated circulatory arrest: 10.3% vs. 13.6% (HR 0.79, 95% CI 0.27-2.28)

Secondary Outcomes

Composite: All-cause mortality or resuscitated cardiac arrest: 53.4% vs. 54.2% (p > 0.05)
Bleeding, leg ischemia, or stroke: 37.9% vs. 23.7% (p = 0.10)

Adverse Events

Conclusions

The immediate insertion of VA-ECMO in patients with SCAI stage D or E cardiogenic shock was not associated with improved outcomes in comparison with early conservative therapy. The study was limited by a high crossover rate of 39%, open-label status, and low rates of left ventricular venting. Further trials are necessary to elucidate the optimal management strategy in patients with cardiogenic shock.

Limitations & Considerations

The study population was homogeneously white and mostly male, which limits the generalizability of results to other racial or ethnic groups.
The average age of patients was 66 years old, and therefore, younger patients may be more likely to survive the cardiogenic shock.
The sample size of 122 patients was too small for subgroup analyses.
This study was done only in the Czech Republic, and the results may not be generalizable beyond the study population.
Patients in the conservative arm could be crashed onto ECMO if clinically indicated. The high crossover rate makes interpretation of the primary outcome difficult.
Patients who were only in stage D and stage E cardiogenic shock were studied; therefore, data can not be extrapolated to any other stages of cardiogenic shock.
Since there was a large proportion of patients who crossed over from the conservative group (39% of patients) to the VA-ECMO group with a similar mortality rate compared to prior studies that have investigated the mortality rate on ECMO (~50%), the delay of escalation to ECMO until inotropes and other MCS options are attempted may be plausible and much of the mortality on ECMO may be attributed to its complications.
Left ventricular venting during ECMO support was not standardized or defined in the protocol leading to varying use of other mechanical support in the ECMO arm; this may impair the results of the trial. In turn, the use of a left ventricular venting strategy increased the number of patients meeting the primary outcome in the ECMO arm, which could confound the interpretation of results as left ventricular venting is an optimal strategy to unload the left ventricle to promote myocardial recovery.
There was an early separation of the Kaplan-Meier curves between both groups before converging at the 15-day mark from randomization; therefore, if there was no crossover, then there may have been a statistically significant mortality benefit of ECMO over conservative therapy.
The stratification of patients into the etiology of cardiogenic shock (MI vs. acute on chronic heart failure vs. valvular disease vs. myocarditis vs. cardiac tamponade vs. arrhythmias etc.) could make the results more applicable in practice tailored more to each patient (albeit, limited by sample size when designing a randomized controlled trial).
Chakaramakkil, M. J., & Sivathasan, C. (2018). ECMO and short-term support for cardiogenic shock in heart failure. Current cardiology reports, 20(10), 1-8.
Thiele, H., Zeymer, U., Neumann, F. J., Ferenc, M., Olbrich, H. G., Hausleiter, J., et al. (2012). Intraaortic balloon support for myocardial infarction with cardiogenic shock. New England Journal of Medicine, 367(14), 1287-1296.
Ouweneel, D. M., Schotborgh, J. V., Limpens, J., Sjauw, K. D., Engström, A. E., Lagrand, W. K., et al. (2016). Extracorporeal life support during cardiac arrest and cardiogenic shock: a systematic review and meta-analysis. Intensive care medicine, 42(12), 1922-1934.
McDonagh, T. A., Metra, M., Adamo, M., Gardner, R. S., Baumbach, A., Böhm, M., et al. (2021). 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. European heart journal, 42(36), 3599-3726.

The published archive features curated twitter highlights from the journal club event.

SUMMARY:

Dr. Saahil Jumkwala, Internal medicine resident, Rutgers New Jersey Medical School

Dr. Justin Brilliant, Internal medicine resident, Johns Hopkins

VISUAL ABSTRACT:

Dr. Sukriti Banthiya, Internal medicine resident, Ascension Providence in Michigan

JOURNAL CLUB PROMO GRAPHIC:

Dr. Karla Asturias, Internal medicine resident, Pennsylvania Hospital.

Student doctor, Akiva Rosenzveig, New York Medica College

TWEET PREPARATION:

Dr. Karla Asturias, Internal medicine resident, Pennsylvania Hospital.

HOUSE JONES CHIEF FELLOW:

Dr. Teodora Donisan, Cardiology fellow, UCSF

HOUSE JONES FACULTY

Dr. Tommy Das, Cardiology fellow, Cleveland Clinic

DIRECTOR of JOURNAL CLUB:

Dr. Devesh Rai, @DeveshRaiMD, Cardiology fellow at Rochester General Hospital

View Details

ADVOR CardsJC CardioNerds PromoTable of contents for the ADVOR Trial summary:

Visual abstract
Summary
References
Credits
Twitter Archive

September 29, 2022

Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomised, trial

Prof Alexandre Mebazaa, MD, Beth Davison, PhD, Prof Ovidiu Chioncel, MD, Prof Alain Cohen-Solal, MD, Rafael Diaz, MD, Prof Gerasimos Filippatos, MD, Prof Marco Metra, MD, Prof Piotr Ponikowski, MD, Prof Karen Sliwa, MD, Prof Adriaan A Voors, MD, Christopher Edwards, BS, Maria Novosadova, MD, Koji Takagi, MD, Prof Albertino Damasceno, MD, Hadiza Saidu, MBBS, Prof Etienne Gayat, MD, Prof Peter S Pang, MD, Prof Jelena Celutkiene, MD, Gad Cotter, MD

Link to Manuscript

Relevant Literature – STRONG-HF Trial

The first few weeks to months after an acute heart failure hospitalization are a valuable yet vulnerable period for patients.
While current guidelines recommend early follow-up for patients after discharge for initiation and titration of guideline-directed medical therapy, there is a paucity of data and guidance regarding the timeline and goals for up-titration.

Relevant Guidelines – STRONG-HF Trial

Relevant Guidelines:
- 2022 AHA/ACC/HFSA Joint Committee Guidelines7: “In patients being discharged after hospitalization for worsening HF, an early follow-up, generally within 7 days of hospital discharge, is reasonable to optimize care and reduce rehospitalization” (Class 2a, LOE B-NR)
  - “Multidisciplinary systems of care that promote improved communication between health care professionals, systematic use and monitoring of GDMT, medication reconciliation, and consistent documentation are examples of patient safety standards that should be ensured for all patients with HF transitioning out of the hospital.”
- The 2021 Heart Failure Association of the ESC8 recommends the following:

Study Rationale – STRONG-HF Trial

There is little data behind recommended explicit practices of early follow-up post-discharge for AHF hospitalization. There is a similar lack of data in best practices for optimizing GDMT in the immediate post-discharge period.

Objective – STRONG-HF Trial

To compare high-intensity early follow-up from AHF hospitalization with rapid up-titration of GDMT to target doses within 2-3 weeks of discharge to standard post-discharge care.

Trial9: – STRONG-HF Trial

Multinational: 14 countries and 87 hospitals
1. Open-label trial
2. 1:1 parallel-group randomization

Intervention

Usual care: discharge and follow-up according to local practice for 90 days
1. High-intensity care: algorithm-based treatment
  1. Optimization of oral heart failure therapies:
    1. First dose adjustment immediately after randomization (within 2 days before anticipated hospital discharge) — prescribed at least half of optimal dose of BB, ACE/ARB/ARNi, and MRA
    2. Two weeks after randomization, uptitration to full target dose of BB, ACE/ARB/ARNi, and MRA, as tolerated
Frequent visits with circulating NT-proBNP measured
1. Assessed by the study team at 1, 2, 3, and 6 weeks after randomization for safety and tolerability by full physical exam and lab assessment of NTproBNP, electrolytes, kidney function, and Hgb
2. Diurtics increased based on congestion on physical exam and NT-proBNP

Enrollment Criteria

Outcomes

Primary Outcome
- 180-day heart failure readmission or all-cause death
Secondary Outcomes
- Change in quality of life from baseline to day 90 (EQ-5D visual analog scale)
- Change in 180-day all-cause death
- Change in 90-day heart failure readmission or all-cause mortality
- Safety endpoint of incidence of treatment-emergent adverse events up to 90 days

Statistical Analysis

Intention-to-treat protocol
Countries combined into regions for analysis, given the sparseness of events in some countries
Protocol amended to increase sample size and change primary endpoint from 90-day to 180-day mid-way given lower than expected event rate
The trial terminated when approximately 1000 patients had 90-day follow-up data given larger than expected risk reduction of the primary endpoint in the high-intensity care group

Participant Characteristics:

The study terminated early due to larger than expected difference in the risk of the primary endpoint between the groups
- The study terminated early due to larger than expected difference in the risk of the primary endpoint between the groups
- N = 1085 (542 to high intensity, 536 to usual care)
- Average age: 63.0 ±13.6
- Male: 662 (61%)
- Race/Ethnicity: 77% white, 21% Black, ≤1% all other
- Average LVEF: 36.3% (±12.52%)
  - LVEF ≤40%: 68%
  - LVEF >50%: 15% Ischemic cardiomyopathy: 48%
- Ischemic cardiomyopathy: 48%
Rates of up-titration of meds:
1. Percentage of patients on target dose of medication by day 90:
  1. Reni angiotensin aldosterone inhibition:
    1. High-intensity group: 55%
    2. Usual care group: 2%
  2. Beta-blockers:
    1. High-intensity group: 49%
    2. Usual care group: 4%
  3. Mineralocorticoid receptor antagonist:
    1. High-intensity group: 84%
Usual care group: 46%
Average visits in 90 days: 4.8 in high intensity group vs 1.0 in usual care group
Adjustment treatment effect in vitals and labs:
Systolic blood pressure (mmHg): -5.4 (-7.2 to –3.5), p < 0.0001
Diastolic blood pressure (mmHg): -2.3 (-3.5 to –1.1), p = 0.0001
Pulse (bpm): -5.8 (-7.3 to –4.3), p < 0.0001
NYHA class: 1.36 (1.22 to 1.53), P < 0.0001
Bodyweight (kg): -1.36 (-1.91 to –0.80), p < 0.0001
NT-proBNP (pg/mL): 0.77 (0.67 to 0.89), P = 0.0003

Outcomes

Secondary Outcomes

Adverse Events

Adverse events in 223/542 patients in the high-intensity group (41%) vs. 158/536 in the usual care group (29%)
Most commonly observed adverse events: cardiac failure, hypotension, hyperkalemia, renal impairment, with non-significant differences in occurrences between groups
- Hypotension 5% vs. <1%
- Hyperkalemia 3% vs. 0
- Renal impairment 3% vs. <1%
- Bradycardia 0.7% vs. 0.4%

Conclusions

In this multinational, randomized, open-label trial involving patients discharged following acute heart failure admission, rapid up-titration of guideline-directed medical therapy with scheduled follow-up to achieve specific target doses in the first 90 days was associated with a reduction in 180-day all-cause death or heart failure readmission, improved quality of life, and reduced symptom burden. There was no significant difference in serious adverse outcomes.

Limitations & Considerations

Early termination of the study given the large treatment effect and concern that it was unethical not to offer high-intensity treatment to both cohorts.
The composite primary endpoint was not powered to evaluate the difference in 180-day all-cause mortality alone.
The open-label trial design was necessary based upon intervention, though it may influence the results of self-reported symptom burden as a secondary endpoint.
SGLTi approval came late in the study and therefore was not prescribed to most patients in the trial.
Generalizability/feasibility is limited by the availability of resources at individual health centers, though it offers the opportunity to explore the role of telemedicine and the involvement of non-physician care team members in GDMT up-titration.
Logeart D, Berthelot E, Bihry N, et al. Early and short-term intensive management after discharge for patients hospitalized with acute heart failure: a randomized study (ECAD-HF). Eur J Heart Fail. Jan 2022;24(1):219-226. doi:10.1002/ejhf.2357
Bistola V, Simitsis P, Parissis J, et al. Association between up-titration of medical therapy and total hospitalizations and mortality in patients with recent worsening heart failure across the ejection fraction spectrum. Eur J Heart Fail. Jul 2021;23(7):1170-1181. doi:10.1002/ejhf.2219
Yamaguchi T, Kitai T, Miyamoto T, et al. Effect of Optimizing Guideline-Directed Medical Therapy Before Discharge on Mortality and Heart Failure Readmission in Patients Hospitalized With Heart Failure With Reduced Ejection Fraction. Am J Cardiol. Apr 15 2018;121(8):969-974. doi:10.1016/j.amjcard.2018.01.006
Carubelli V, Lombardi C, Specchia C, et al. Adherence and optimization of angiotensin converting enzyme inhibitor/angiotensin II receptors blockers and beta-blockers in patients hospitalized for acute heart failure. ESC Heart Fail. Jun 2021;8(3):1944-1953. doi:10.1002/ehf2.13223
Gayat E, Arrigo M, Littnerova S, et al. Heart failure oral therapies at discharge are associated with better outcome in acute heart failure: a propensity-score matched study. Eur J Heart Fail. Feb 2018;20(2):345-354. doi:10.1002/ejhf.932
Kimmoun A, Takagi K, Gall E, et al. Temporal trends in mortality and readmission after acute heart failure: a systematic review and meta-regression in the past four decades. Eur J Heart Fail. Mar 2021;23(3):420-431. doi:10.1002/ejhf.2103
Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. doi:doi:10.1161/CIR.0000000000001063
McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. European Heart Journal. 2021;42(36):3599-3726. doi:10.1093/eurheartj/ehab368
Mebazaa A, Davison B, Chioncel O, et al. Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomised, trial. The Lancet. doi:10.1016/S0140-6736(22)02076-1

The published archive features curated twitter highlights from the journal club event.

SUMMARY:

Dr. Anjali Agarwalla, Internal medicine resident, University of Pennsylvania

VISUAL ABSTRACT:

Dr. Ty Sweeney, Internal medicine resident, Johns Hopkins Bayview Medical Center

JOURNAL CLUB PROMO GRAPHIC:

Student doctor Adrianna Mares, medical student, The University of Texas at El Paso

Student doctor Chelsea Amo Tweneboah, medical student, St. George’s University,

TWEET PREPARATION:

Dr. Gurleen Kaur, Internal medicine resident, Brigham Women’s Hospital

Dr. Kahtan Fadah, Internal medicine resident, Texas Tech University

HOUSE JONES CHIEF FELLOW:

Dr. Jessie Holtzman, Chief resident, UCSF

HOUSE JONES FACULTY

Dr. Devesh Rai, @DeveshRaiMD, Cardiology fellow at Rochester General Hospital

DIRECTOR of JOURNAL CLUB:

Dr. Devesh Rai, @DeveshRaiMD, Cardiology fellow at Rochester General Hospital

View Details

ADVOR CardsJC CardioNerds PromoTable of contents for the ADVOR Trial summary:

Visual abstract
Summary
References
Credits
Twitter Archive

September 29, 2022

Acetazolamide in Acute Decompensated Heart Failure with Volume Overload

Wilfried Mullens, M.D., Ph.D., Jeroen Dauw, M.D., Pieter Martens, M.D., Ph.D., Frederik H. Verbrugge, M.D., Ph.D., Petra Nijst, M.D., Ph.D., Evelyne Meekers, M.D., Katrien Tartaglia, M.Sc., Fabien Chenot, M.D., Samer Moubayed, M.D., Riet Dierckx, M.D., Ph.D., Philippe Blouard, M.D., Pierre Troisfontaines, M.D., et al., for the ADVOR Study Group

Link to Manuscript

Relevant Literature – ADVOR Trial

Loop diuretics are the mainstay of acute decongestive therapy in patients with heart failure and volume overload, recommended by current guidelines recommend for use in acute decompensated heart failure. Though chronic diuretic therapy is not associated with reduced mortality, timely administration of diuretic therapy in hospitalized patients and diuresis to euvolemia are associated with improved outcomes.
Some have proposed sequential diuretic therapy as a more effective decongestive strategy, particularly in diuretic-resistant volume overload; however, insufficient data currently supports this practice.

Relevant Guidelines – ADVOR Trial

2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure
- “Diuretic treatment should be started with an initial IV dose of furosemide, or equivalent dose of bumetanide or torsemide, corresponding to 1-2 times the daily oral dose taken by the patient before admission.” (Class I LOE C)
- “If the diuretic response remains inadequate… concomitant administration of other diuretics acting at different sites, namely thiazides or metolazone or acetazolamide, may be considered. However, this combination requires careful monitoring of serum electrolytes and renal function.”

Study Rationale – ADVOR Trial

The carbonic anhydrase inhibitor acetazolamide reduces renal tubular sodium reabsorption and has been proposed to augment the diuretic effect of co-administered loop diuretics.
Small, observational studies have shown improvement in sodium excretion among patients receiving both loop diuretics and carbonic anhydrase inhibitors.

Objective – ADVOR Trial

To evaluate whether the addition of acetazolamide to standardized intravenous loop diuretic therapy improves successful decongestion rates among patients with acute decompensated heart failure.

Trial – ADVOR Trial

27 trial sites in Belgium
1:1 parallel-group randomization
Double-blind
Placebo-controlled

Intervention

Acetazolamide 500 mg IV bolus or matched placebo was administered once daily immediately after randomization and during the next two days or until complete decongestion.
- Complete decongestion was defined as the absence of clinical signs of fluid overload other than trace edema.
All participants had home diuretics stopped at randomization and subsequently received an IV loop diuretic at double the maintenance dose administered once daily immediately after randomization and then as a split dose separated by ≥ 6 hours on each of the subsequent two days.
- Acetazolamide or placebo was administered concurrently with the first dose of loop diuretics each day.
- Loop diuretic dose was escalated per protocol if cumulative urine output over the 30-48 hours following the initial diuretic dose failed to exceed 3.5 liters and signs of fluid overload were still present.
Other heart failure medications, including neurohormonal blockade, were left unadjusted during the treatment phase of the study.

Enrollment Criteria

Outcomes

Primary Outcome
- Successful decongestion, defined by an absence of signs of volume overload (i.e., no more than trace edema, no residual pleural effusion, and no residual ascites).
Secondary Outcomes
- Composite of death from any cause or rehospitalization for heart failure within 3 months.
- Combined renal safety endpoint of doubling of baseline creatinine, ≥ 50% reduction in eGFR, or the initiation of renal replacement therapy.

Statistical Analysis

Outcomes stratified by LV EF ≤ or > 40% and trial center.
Goal enrollment of 519 participants to reach 80% power in detecting a difference of 10% in the number of participants achieving successful decongestion.
Intention-to-treat protocol.

Participant Characteristics:

N = 519 (enrollment target met)
- Acetazolamide group: n = 259
- Placebo group: n = 260
Average age: 78.2 ± 8.9
Male: 62.6%
Race: 99% white
Average systolic BP: 127 ± 21 mm Hg
Median (IQR) home maintenance dose (furosemide equivalent)
- Acetazolamide group: 80 (40-120) mg
- Placebo group: 60 (40-100) mg
LV EF ≤40%: 43.2%
Mean (IQR) eGFR: 39 (29-52)

Outcomes

Adverse Events

Combined renal safety endpoint was met in 7 (2.7%) participants in the acetazolamide group compared to 2 (0.8%) in placebo group (P = 0.10)
There were similar, low rates of hypokalemia and hypotension between groups
Rates of adverse events related to placebo or acetazolamide during three months follow-ups were similar and low

Conclusions

In this multicenter, randomized, placebo-controlled trial involving patients with acute decompensated heart failure and volume overload, the addition of acetazolamide to standardized intravenous loop-diuretic therapy was associated with a higher incidence of successful decongestion within three days after randomization and at discharge without increased risk of adverse events.
Acetazolamide use was also associated with a decreased hospital stay.

Limitations & Considerations

Although strong evidence shows incomplete decongestion at discharge is associated with worse outcomes, there was no significant difference in risk of death or rehospitalization between groups, even though the acetazolamide group had a higher rate of successful decongestion.
- Of note, the mortality rate in ADVOR was lower than that in DOSE and CARRESS-HF
The trial results may not be generalizable to new diagnosis HF patients who are diuretic-naïve, given that diuretic-naïve patients were excluded from this trial.
Important conclusions from subgroup analyses:
- Subgroup analysis suggests that acetazolamide is not superior among patients with a greater likelihood of diuretic resistance, including:
  - Participants receiving > 60 mg of furosemide or equivalent as a home maintenance dose
  - Participants who have ischemic cardiomyopathy, particularly with a reduced ejection fraction
  - Participants who have eGFR ≥ 39 mL/min/1.73 m2
- The treatment effect for female participants was also non-significant in the subgroup analysis
The trial was limited by suboptimal use of RAAS inhibitor (52.0%) and MRA (41.6%), as well as exclusion of patients using SGLT2i, given that these medications were not approved for HF when the trial was initiated.Participants were nearly exclusively white, with minimal racial and ethnic diversity, which may limit the generalizability of these findings. Future trials should seek greater diversity in enrollment.
Mullens, Wilfried, et al. “Rationale and design of the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial.” European journal of heart failure 20.11 (2018): 1591-1600.
Felker, G. Michael, et al. “Diuretic strategies in patients with acute decompensated heart failure.” New England Journal of Medicine 364.9 (2011): 797-805.
Bart, Bradley A., et al. “Ultrafiltration in decompensated heart failure with cardiorenal syndrome.” New England Journal of Medicine 367.24 (2012): 2296-2304.
Matsue, Yuya, et al. “Time-to-furosemide treatment and mortality in patients hospitalized with acute heart failure.” Journal of the American College of Cardiology 69.25 (2017): 3042-3051.
Verbrugge, Frederik H., et al. “Acetazolamide to increase natriuresis in congestive heart failure at high risk for diuretic resistance.” European journal of heart failure 21.11 (2019): 1415-1422.
McDonagh, Theresa A., et al. “2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC.” European heart journal 42.36 (2021): 3599-3726.
Mullens, Wilfried, et al. “Rationale and design of the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial.” European journal of heart failure 20.11 (2018): 1591-1600.

The published archive features curated twitter highlights from the journal club event.

SUMMARY:

Dr. Ty Sweeney, Internal medicine resident, Johns Hopkins Bayview Medical Center

VISUAL ABSTRACT:

Dr. Gurleen Kaur, Internal medicine resident, Brigham Women’s Hospital

JOURNAL CLUB PROMO GRAPHIC:

Student doctor Adrianna Mares, medical student, The University of Texas at El Paso

Student doctor Chelsea Amo Tweneboah, medical student, St. George’s University,

TWEET PREPARATION:

Dr. Kahtan Fadah, Internal medicine resident, Texas Tech University

Dr. Anjali Agarwalla, Internal medicine resident, University of Pennsylvania

HOUSE JONES CHIEF FELLOW:

Dr. Jessie Holtzman, Chief resident, UCSF

HOUSE JONES FACULTY

Dr. Devesh Rai, @DeveshRaiMD, Cardiology fellow at Rochester General Hospital

DIRECTOR of JOURNAL CLUB:

Dr. Devesh Rai, @DeveshRaiMD, Cardiology fellow at Rochester General Hospital

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