Journal Scan 2021

Introduction

The year 2021 has been an eventful year for the therapy of heart failure. New data on the SGLT2 inhibitor empagliflozin (EMPEROR trials) was released, proving the usefulness of this drug in heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), in patients with or without diabetes. In addition, early data on dapagliflozin in HFpEF (PRESERVED-HF) has shown its utility in HFpEF as well. Therefore, the scan shall begin with the latest on heart failure.

Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial

Circulation. 2021, January 26;143(4):326-336.

Milton Packer, Stefan D Anker, Javed Butler, Gerasimos Filippatos, João Pedro Ferreira, Stuart J Pocock, Peter Carson, Inder Anand, Wolfram Doehner, Markus Haass, Michel Komajda, Alan Miller, Steen Pehrson, John R Teerlink, Martina Brueckmann, Waheed Jamal, Cordula Zeller, Sven Schnaidt, Faiez Zannad

Background: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, with or without diabetes, but additional data are needed about the effect of the drug on inpatient and outpatient events that reflect worsening heart failure.

Methods: We randomly assigned 3,730 patients with class II to IV heart failure with an ejection fraction of ≤40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to recommended treatments for heart failure, for a median of 16 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points.

Results: Empagliflozin reduced the combined risk of death, hospitalization for heart failure, or an emergent/urgent heart failure visit requiring intravenous treatment (415 vs 519 patients; empagliflozin vs placebo, respectively; hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.67-0.87; P < .0001). This benefit reached statistical significance at 12 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (HR, 0.67; 95% CI, 0.50-0.90; P = .008) and that required a vasopressor or positive inotropic drug or mechanical or surgical intervention (HR, 0.64; 95% CI, 0.47-0.87; P = .005). As compared with placebo, fewer patients in the empagliflozin group reported intensification of diuretics (297 vs 414 [HR, 0.67; 95% CI, 0.56-0.78; P < .0001]). Additionally, patients assigned to empagliflozin were 20% to 40% more likely to experience an improvement in New York Heart Association functional class and were 20% to 40% less likely to experience worsening of New York Heart Association functional class, with statistically significant effects that were apparent 28 days after randomization and maintained during long-term follow-up. The risk of any inpatient or outpatient worsening heart failure event in the placebo group was high (48.1 per 100 patient-years of follow-up), and it was reduced by empagliflozin (HR, 0.70; 95% CI, 0.63-0.78; P < .0001).

Conclusions: In patients with heart failure and a reduced ejection fraction, empagliflozin reduced the risk and total number of inpatient and outpatient worsening heart failure events, with benefits seen early after initiation of treatment and sustained for the duration of double-blind therapy. Registration: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Comments: The EMPEROR-Reduced study, like DAPA-HF, has demonstrated the significant survival benefits provided by SGLT2i in HFrEF irrespective of diabetic status. While head-to-head comparison of empagliflozin vs dapagliflozin is not available, this trial looked at a sicker patient population and still demonstrated significant benefits. Empagliflozin, therefore, joins dapagliflozin in the “four pillars of heart failure therapy” algorithm consisting of RAS inhibitor (preferably ARNI), beta blocker, MRA, and SGLT2i in both diabetics and nondiabetics.

Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status: Results From the EMPEROR-Reduced Trial

Circulation. 2021 January 26;143(4):337-349.

Stefan D Anker, Javed Butler, Gerasimos Filippatos, Muhammad Shahzeb Khan, Nikolaus Marx, Carolyn SP Lam, Sven Schnaidt, Anne Pernille Ofstad, Martina Brueckmann, Waheed Jamal, Edimar A Bocchi, Piotr Ponikowski, Sergio V Perrone, James L Januzzi, Subodh Verma, Michael Böhm, João Pedro Ferreira, Stuart J Pocock, Faiez Zannad, Milton Packer

Background: Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events.

Methods: Patients with class II to IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes.

Results: Of the 3,730 patients enrolled, 1,856 (50%) had diabetes, 1,268 (34%) had prediabetes (hemoglobin A1c [HbA1c] 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 [95% CI, 0.60-0.87] and 0.78 [95% CI, 0.64-0.97], respectively, P-interaction = .57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome (P-interaction = .40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia.

Conclusions: In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c. Registration: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Comments: Like dapagliflozin, empagliflozin too demonstrated major renal protective effects in patients with HFrEF, irrespective of diabetes. Thus, both the SGLT2i proven to have major cardiac benefits in HFrEF also have major renal benefits.

Cardiac and Kidney Benefits of Empagliflozin in Heart Failure Across the Spectrum of Kidney Function: Insights From EMPEROR-Reduced

Circulation. 2021 January 26;143(4):310-321.

Faiez Zannad, João Pedro Ferreira, Stuart J Pocock, Cordula Zeller, Stefan D Anker, Javed Butler, Gerasimos Filippatos, Sibylle Jenny Hauske, Martina Brueckmann, Egon Pfarr, Janet Schnee, Christoph Wanner, Milton Packer

Background: In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin reduced cardiovascular death or heart failure (HF) hospitalization and total HF hospitalizations, and slowed the progressive decline in kidney function in patients with HF and a reduced ejection fraction, with and without diabetes. We aim to study the effect of empagliflozin on cardiovascular and kidney outcomes across the spectrum of kidney function.

Methods: In this prespecified analysis, patients were categorized by the presence or absence of chronic kidney disease (CKD) at baseline (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m² or albumin-to-creatine ratio >300 mg/g). The primary and key secondary outcomes were: (1) a composite of cardiovascular death or HF hospitalization (primary outcome); (2) total HF hospitalizations; and (3) eGFR slope. The direct impact on kidney events was investigated by a prespecified composite kidney outcome (defined as a sustained profound decline in eGFR, chronic dialysis, or transplant). The median follow-up was 16 months.

Results: Of 3,730 patients who were randomized to empagliflozin or placebo, 1,978 (53%) had CKD. Empagliflozin reduced the primary outcome and total HF hospitalizations in patients with and without CKD: hazard ratio (HR) = 0.78 (95% CI, 0.65-0.93) and HR = 0.72 (95% CI, 0.58-0.90), respectively (interaction P = .63). Empagliflozin slowed the slope of eGFR decline by 1.11 (0.23-1.98) mL/min/1.73 m²/yr in patients with CKD and by 2.41 (1.49-3.32) mL/min/1.73 m²/yr in patients without CKD. The risk of the composite kidney outcome was reduced similarly in patients with and without CKD: HR = 0.53 (95% CI, 0.31-0.91) and HR = 0.46 (95% CI, 0.22-0.99), respectively. The effect of empagliflozin on the primary composite outcome and key secondary outcomes was consistent across a broad range of baseline kidney function, measured by clinically relevant eGFR subgroups or by albuminuria, including patients with eGFR as low as 20 mL/min/1.73 m². Empagliflozin was well tolerated in CKD patients.

Conclusions: In EMPEROR-Reduced, empagliflozin had a beneficial effect on the key efficacy outcomes and slowed the rate of kidney function decline in patients with and without CKD, and regardless of the severity of kidney impairment at baseline. Registration: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Comments: This article subanalyzed the results of the EMPEROR-Reduced study and demonstrated that the beneficial effects of empagliflozin on HF and renal function were seen regardless of severity of baseline kidney disease. Even patients with eGFR of 20 mL/min/1.73 m² benefited from empagliflozin. These findings gain significance as patients with such severe kidney disease are usually excluded from outcome studies. DAPA-HF, for example, excluded patients with eGFR <30 mL/min/1.73 m².

Influence of Neprilysin Inhibition on the Efficacy and Safety of Empagliflozin in Patients With Chronic Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial

Eur Heart J. 2021 February 11;42(6):671-680.

Milton Packer, Stefan D Anker, Javed Butler, Gerasimos Filippatos, Joao Pedro Ferreira, Stuart J Pocock, Hans-Peter Brunner-La Rocca, Stefan Janssens, Hiroyuki Tsutsui, Jian Zhang, Martina Brueckmann, Waheed Jamal, Daniel Cotton, Tomoko Iwata, Janet Schnee, Faiez Zannad, EMPEROR-Reduced Trial Committees and Investigators

Aims: We evaluated the influence of sacubitril/valsartan on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition with empagliflozin in patients with heart failure and a reduced ejection fraction.

Methods and Results: The EMPEROR-Reduced trial randomized 3,730 patients with heart failure and an ejection fraction ≤40% to placebo or empagliflozin (10 mg/day), in addition to recommended treatment for heart failure, for a median of 16 months. A total of 727 patients (19.5%) received sacubitril/valsartan at baseline. Analysis of the effect of neprilysin inhibition was 1 of 12 prespecified subgroups. Patients receiving a neprilysin inhibitor were particularly well treated, as evidenced by lower systolic pressures, heart rates, N-terminal prohormone B-type natriuretic peptide, and greater use of cardiac devices (all P < .001) when compared with those not receiving sacubitril/valsartan. Nevertheless, when compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure in patients receiving or not receiving sacubitril/valsartan (hazard ratio 0.64 [95% CI 0.45-0.89], P = .009 and hazard ratio 0.77 [95% CI 0.66-0.90], P = .0008, respectively, interaction P = .31). Empagliflozin slowed the rate of decline in estimated glomerular filtration rate by 1.92 ± 0.80 mL/min/1.73 m²/year in patients taking a neprilysin inhibitor (P =.016) and by 1.71 ± 0.35 mL/min/1.73 m²/year in patients not taking a neprilysin inhibitor (P < .0001), interaction P = 0.81. Combined inhibition of SGLT2 and neprilysin was well tolerated.

Conclusion: The effects on empagliflozin to reduce the risk of heart failure and renal events are not diminished in intensively treated patients who are receiving sacubitril/valsartan. Combined treatment with both SGLT2 and neprilysin inhibitors can be expected to yield substantial additional benefits.

Comments: Just as dapagliflozin was demonstrated to provide benefits in addition to existing therapy including ARNI, this substudy from EMPEROR-Reduced has demonstrated that the benefits of empagliflozin are in addition to the benefits of sacubitril/valsartan. Consequently, we can confidently use empagliflozin in patients already on sacubitril/valsartan.

SGLT2 Inhibitors in Patients With Heart Failure With Reduced Ejection Fraction: A Meta-Analysis of the EMPEROR-Reduced and DAPA-HF Trials

Lancet. 2020 September 19;396(10254):819-829.

Faiez Zannad, João Pedro Ferreira, Stuart J Pocock, Stefan D Anker, Javed Butler, Gerasimos Filippatos, Martina Brueckmann, Anne Pernille Ofstad, Egon Pfarr, Waheed Jamal, Milton Packer

Background: Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose cotransporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterize effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and nonfatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials.

Methods: We did a prespecified meta-analysis of the 2 single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalization for heart failure. These subgroups were based on type 2 diabetes status, age, sex, and angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalization for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran’s Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model.

Findings: Among 8,474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0·87, 95% CI 0·77-0·98; P = .018) and 14% reduction in cardiovascular death (0·86, 0·76-0·98; P = .027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalization for heart failure (0·74, 0·68-0·82; P < .0001), and by a 25% decrease in the composite of recurrent hospitalizations for heart failure or cardiovascular death (0·75, 0·68-0·84; P < .0001). The risk of the composite renal endpoint was also reduced (0·62, 0·43-0·90; P = .013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI, and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race.

Interpretation: The effects of empagliflozin and dapagliflozin on hospitalizations for heart failure were consistent in the 2 independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF.

Funding: Boehringer Ingelheim.

Comments: Clearly, it was felt that there was adequate data available from the EMPEROR-Reduced and DAPA-HF trials to do a meaningful meta-analysis to assess effect of SGLT2i on all-cause death and overall cardiovascular death, two end points which the original trials were not powered to assess. The analysis has clearly demonstrated significant reduction in both these endpoints, in addition to improvement in renal outcomes.

While the data from EMPEROR-Reduced had generated a lot of interest, the show-stealer this year is clearly the EMPEROR-Preserved study, which is elaborated now.

Empagliflozin in Heart Failure With a Preserved Ejection Fraction

N Engl J Med. 2021 October 14;385(16):1451-1461.

Stefan D Anker, Javed Butler, Gerasimos Filippatos, João P Ferreira, Edimar Bocchi, Michael Böhm, Hans-Peter Brunner-La Rocca, Dong-Ju Choi, Vijay Chopra, Eduardo Chuquiure-Valenzuela, Nadia Giannetti, Juan Esteban Gomez-Mesa, Stefan Janssens, James L Januzzi, Jose R Gonzalez-Juanatey, Bela Merkely, Stephen J Nicholls, Sergio V Perrone, Ileana L Piña, Piotr Ponikowski, Michele Senni, David Sim, Jindrich Spinar, Iain Squire, Stefano Taddei, Hiroyuki Tsutsui, Subodh Verma, Dragos Vinereanu, Jian Zhang, Peter Carson, Carolyn Su Ping Lam, Nikolaus Marx, Cordula Zeller, Naveed Sattar, Waheed Jamal, Sven Schnaidt, Janet M Schnee, Martina Brueckmann, Stuart J Pocock, Faiez Zannad, Milton Packer, EMPEROR-Preserved Trial Investigators.

Background: Sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain.

Methods: In this double-blind trial, we randomly assigned 5,988 patients with class II to IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure.

Results: Over a median of 26.2 months, a primary outcome event occurred in 415 of 2,997 patients (13.8%) in the empagliflozin group and in 511 of 2,991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P < .001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P < .001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin.

Conclusions: Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951).

Comments: Finally, we have some good news regarding HFpEF. Ever since HFpEF was recognized as a separate clinical entity, no therapy has shown any real benefit. The only therapy available was rate control and low-dose diuresis along with BP control, if needed. While early results with ARNI are promising, the benefit seems to be much lower compared to HFrEF. Empagliflozin is the only drug so far which has shown a clear reduction in death or hospitalization of HFpEF patients, both diabetic and nondiabetic.

This trial has generated a lot of interest and was extensively discussed in the ECC/EHA 2021 conference. A detailed analysis of the data showed an interesting point. This trial uses a cut-off of left ventricular ejection (LVEF) ≥40% to define HFpEF, since all therapy for HFrEF has shown clear benefits only when LVEF <40%. When the patients were subdivided into LVEF 40% to 60% (heart failure with mildly reduced EF or HFmrEF) and LVEF ≥60% (true HFpEF), the benefits of empagliflozin were found to be restricted to the HFmrEF group. The true HFpEF group did not show significant benefit. Incidentally, in the HFmrEF group, empagliflozin compared to placebo showed greater benefit than ARNI compared to placebo (though admittedly, this was an extrapolation from 2 different trials and not a head-to-head comparison).

Indirectly, this trial has suggested that the creation of the HFmrEF category is justified and is different from HFpEF with LVEF >60%.

We have started getting data about dapagliflozin in HFpEF as well, though it was released a couple of months after EMPEROR-Preserved.

The SGLT2 Inhibitor Dapagliflozin in Heart Failure With Preserved Ejection Fraction: A Multicenter Randomized Trial (PRESERVED-HF)

Nat Med. 2021 November;27(11):1954-1960.

Michael E Nassif, Sheryl L Windsor, Barry A Borlaug, Dalane W Kitzman, Sanjiv J Shah, Fengming Tang, Yevgeniy Khariton, Ali O Malik, Taiyeb Khumri, Guillermo Umpierrez, Sumant Lamba, Kavita Sharma, Sadiya S Khan, Lokesh Chandra, Robert A Gordon, John J Ryan, Sunit-Preet Chaudhry, Susan M Joseph, Chen H Chow, Manreet K Kanwar, Michael Pursley, Elias S Siraj, Gregory D Lewis, Barry S Clemson, Michael Fong, Mikhail N Kosiborod

Patients with heart failure and preserved ejection fraction (HFpEF) have a high burden of symptoms and functional limitations, and have a poor quality of life. By targeting cardiometabolic abnormalities, sodium glucose cotransporter 2 (SGLT2) inhibitors may improve these impairments. In this multicenter, randomized trial of patients with HFpEF (NCT03030235), we evaluated whether the SGLT2 inhibitor dapagliflozin improves the primary endpoint of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CS), a measure of heart failure-related health status, at 12 weeks after treatment initiation. Secondary endpoints included the 6-minute walk test (6MWT), KCCQ Overall Summary Score (KCCQ-OS), clinically meaningful changes in KCCQ-CS and -OS, and changes in weight, natriuretic peptides, glycated hemoglobin, and systolic blood pressure. In total, 324 patients were randomized to dapagliflozin or placebo. Dapagliflozin improved KCCQ-CS (effect size, 5.8 points (95% confidence interval [CI] 2.3-9.2, P = .001), meeting the predefined primary endpoint, due to improvements in both KCCQ total symptom score (KCCQ-TS) (5.8 points [95% CI 2.0-9.6, P = .003]) and physical limitations scores (5.3 points [95% CI 0.7-10.0, P = 0.026]). Dapagliflozin also improved 6MWT (mean effect size of 20.1 m [95% CI 5.6-34.7, P = .007]), KCCQ-OS (4.5 points [95% CI 1.1-7.8, P = .009]), proportion of participants with 5-point or greater improvements in KCCQ-OS (odds ratio [OR] = 1.73 [95% CI 1.05-2.85, P = .03]), and reduced weight (mean effect size, 0.72 kg [95% CI 0.01-1.42, P = 0.046]). There were no significant differences in other secondary endpoints. Adverse events were similar between dapagliflozin and placebo (44 [27.2%] vs 38 [23.5%] patients, respectively). These results indicate that 12 weeks of dapagliflozin treatment significantly improved patient-reported symptoms, physical limitations, and exercise function and was well tolerated in chronic HFpEF.

Comments: This trial has demonstrated that dapagliflozin provides significant symptomatic improvement in patients with HFpEF. We hope that the ongoing DELIVER trial will provide information about mortality reduction, but this study is a decent start.

We also have some more information about ARNI.

Reverse Cardiac Remodeling and ARNI Therapy

Curr Heart Fail Rep. 2021 April;18(2):71-83.

Andrew Abboud, James L Januzzi

Purpose of Review: To review reverse cardiac remodeling and guideline-directed medical and device therapy (GDMT) within the context of recent data on combined angiotensin receptor/neprilysin inhibitor (ARNI) therapy.

Recent Findings: Preliminary data suggested that ARNI therapy led to significant reversal of deleterious cardiac remodeling. More definitive data regarding impact of ARNI therapy on remodeling parameters are now available from 2 prospective trials, PROVE-HF (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure) and EVALUATE-HF (Study of Effects of Sacubitril/Valsartan vs Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction). Both studies demonstrated marked improvements in biomarker and echocardiographic parameters of reverse cardiac remodeling in patients with heart failure with reduced ejection fraction (HFrEF). Much of the observed clinical benefit of sacubitril/valsartan therapy in patients with HFrEF is likely related to significant reverse cardiac remodeling. Ongoing trials will assess the role for ARNI therapy in patients with heart failure with preserved ejection fraction (HFpEF) and in the postmyocardial infarction setting. Future studies should comprehensively assess predictors of response to ARNI therapy.

Comments: The PROVE-HF and EVALUATE-HF trials both demonstrate that ARNI can bring about significant reversal of adverse cardiac remodeling. This seems to be a major mechanism for the long-term benefit of this combination.

The last abstract on heart failure deals with nonpharmacological therapy.

MitraClip Plus Medical Therapy vs Medical Therapy Alone for Functional Mitral Regurgitation: A Meta-Analysis

Cardiol Ther. 2020 June;9(1):5-17.

Sunny Goel, Ravi Teja Pasam, Karan Wats, Srilekha Chava, Joseph Gotesman, Abhishek Sharma, Bilal Ahmad Malik, Sergey Ayzenberg, Robert Frankel, Jacob Shani, Umesh Gidwani

Introduction: The purpose of this meta-analysis is to compare the efficacy of MitraClip plus medical therapy vs medical therapy alone in patients with functional mitral regurgitation (FMR). FMR caused by left ventricular dysfunction is associated with poor prognosis. Whether MitraClip improves clinical outcomes in this patient population remains controversial.

Methods: We conducted an electronic database search of PubMed, CINAHL, Cochrane Central, Scopus, Google Scholar, and Web of Science databases for randomized control trials (RCTs) and observational studies with propensity score matching (PSM) that compared MitraClip plus medical therapy with medical therapy alone for patients with FMR and reported on subsequent mortality, heart failure rehospitalization, and other outcomes of interest. Event rates were compared using a random-effects model with odds ratio as the effect size.

Results: Five studies (n = 1513; MitraClip = 796, medical therapy = 717) were included in the final analysis. MitraClip plus medical therapy compared to medical therapy alone was associated with a significant reduction in overall mortality (odds ratio [OR] = 0.66, 95% confidence interval [CI] = 0.44-0.99, P = .04) and heart failure (HF) rehospitalization rates (OR = 0.57, 95% CI = 0.36-0.91, P = .02). There was a reduced need for heart transplantation or mechanical support requirement (OR = 0.48, 95% CI = 0.25-0.91, P =.02) and unplanned mitral valve surgery (OR = 0.21, 95% CI = 0.07-0.61, P = .004) in the MitraClip group. No effect was observed on cardiac mortality (P = .42) between the 2 groups.

Conclusions: MitraClip plus medical therapy improves overall mortality and reduces HF rehospitalization rates compared to medical therapy alone in patients with FMR.

Comments: While the benefit of MitraClip in functional mitral regurgitation has been demonstrated, this meta-analysis combines 5 studies to get a much higher-powered sample. The results clearly show consistent reduction in need for heart transplant, left ventricular assist device, and unplanned mitral surgery. Unfortunately, mortality benefit remained lacking.

After heart failure, we look at coronary artery disease.

Fractional Flow Reserve-Guided PCI as Compared With Coronary Bypass Surgery

N Engl J Med. 2022 Jan 13;386(2):128-137.

William F Fearon, Frederik M Zimmermann, Bernard De Bruyne, Zsolt Piroth, Albert HM van Straten, Laszlo Szekely, Giedrius Davidavičius, Gintaras Kalinauskas, Samer Mansour, Rajesh Kharbanda, Nikolaos Östlund-Papadogeorgos, Adel Aminian, Keith G Oldroyd, Nawwar Al-Attar, Nikola Jagic, Jan-Henk E Dambrink, Petr Kala, Oskar Angerås, Philip MacCarthy, Olaf Wendler, Filip Casselman, Nils Witt, Kreton Mavromatis, Steven ES Miner, Jaydeep Sarma, Thomas Engstrøm, Evald H Christiansen, Pim AL Tonino, Michael J Reardon, Di Lu, Victoria Y Ding, Yuhei Kobayashi, Mark A Hlatky, Kenneth W Mahaffey, Manisha Desai, Y Joseph Woo, Alan C Yeung, Nico HJ Pijls, FAME 3 Investigators.

Background: Patients with 3-vessel coronary artery disease have been found to have better outcomes with coronary-artery bypass grafting (CABG) than with percutaneous coronary intervention (PCI), but studies in which PCI guided by measurement of fractional flow reserve (FFR) have been lacking.

Methods: In this multicenter, international, noninferiority trial, patients with 3-vessel coronary artery disease were randomly assigned to undergo CABG or FFR-guided PCI with current-generation zotarolimus-eluting stents. The primary end point was the occurrence within 1 year of a major adverse cardiac or cerebrovascular event, defined as death from any cause, myocardial infarction, stroke, or repeat revascularization. Noninferiority of FFR-guided PCI to CABG was prespecified as an upper boundary of less than 1.65 for the 95% confidence interval of the hazard ratio. Secondary end points included a composite of death, myocardial infarction, or stroke; safety was also assessed.

Results: A total of 1,500 patients underwent randomization at 48 centers. Patients assigned to undergo PCI received a mean (±SD) of 3.7 ± 1.9 stents, and those assigned to undergo CABG received 3.4 ± 1.0 distal anastomoses. The 1-year incidence of the composite primary end point was 10.6% among patients randomly assigned to undergo FFR-guided PCI and 6.9% among those assigned to undergo CABG (hazard ratio, 1.5; 95% confidence interval [CI], 1.1 to 2.2), findings that were not consistent with noninferiority of FFR-guided PCI (P = .35 for noninferiority). The incidence of death, myocardial infarction, or stroke was 7.3% in the FFR-guided PCI group and 5.2% in the CABG group (hazard ratio, 1.4; 95% CI, 0.9 to 2.1). The incidences of major bleeding, arrhythmia, and acute kidney injury were higher in the CABG group than in the FFR-guided PCI group.

Conclusions: In patients with 3-vessel coronary artery disease, FFR-guided PCI was not found to be noninferior to CABG with respect to the incidence of a composite of death, myocardial infarction, stroke, or repeat revascularization at 1 year. (Funded by Medtronic and Abbott Vascular; FAME 3 ClinicalTrials.gov number, NCT02100722).

Comment: The FAME 3 trial results are unambiguous. In multivessel coronary artery disease, FFR-guided PCI does not provide comparable results vs CABG. CABG remains the superior option. Multivessel PCI should remain restricted to patients who refuse CABG even after proper counselling by a heart-care team and to patients refused by the surgical team.

Initial Invasive vs Conservative Management of Stable Ischemic Heart Disease in Patients With a History of Heart Failure or Left Ventricular Dysfunction: Insights From the ISCHEMIA Trial

Circulation. 2020 November 3;142(18):1725-1735.

Renato D Lopes, Karen P Alexander, Susanna R Stevens, Harmony R Reynolds, Gregg W Stone, Ileana L Piña, Frank W Rockhold, Ahmed Elghamaz, Jose Luis Lopez-Sendon, Pedro S Farsky, Alexander M Chernyavskiy, Ariel Diaz, Denis Phaneuf, Mark A De Belder, Yi-Tong Ma, Luis A Guzman, Michel Khouri, Alessandro Sionis, Derek J Hausenloy, Rolf Doerr, Joseph B Selvanayagam, Aldo Pietro Maggioni, Judith S Hochman, David J Maron

Background: Whether an initial invasive strategy in patients with stable ischemic heart disease and at least moderate ischemia improves outcomes in the setting of a history of heart failure (HF) or left ventricular dysfunction (LVD) when ejection fraction is ≥35% but <45% is unknown.

Methods: Among 5,179 participants randomized into ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches), all of whom had left ventricular ejection fraction (LVEF) ≥35%, we compared cardiovascular outcomes by treatment strategy in participants with a history of HF/LVD at baseline vs those without HF/LVD. Median follow-up was 3.2 years.

Results: There were 398 (7.7%) participants with HF/LVD at baseline, of whom 177 had HF/LVEF >45%, 28 HF/LVEF 35% to 45%, and 193 LVEF 35% to 45% but no history of HF. HF/LVD was associated with more comorbidities at baseline, particularly previous myocardial infarction, stroke, and hypertension. Compared with patients without HF/LVD, participants with HF/LVD were more likely to experience a primary outcome composite of cardiovascular death, nonfatal myocardial infarction, or hospitalization for unstable angina, HF, or resuscitated cardiac arrest (4-year cumulative incidence rate, 22.7% vs 13.8%; cardiovascular death or myocardial infarction, 19.7% vs 12.3%; and all-cause death or HF, 15.0% vs 6.9%). Participants with HF/LVD randomized to the invasive vs conservative strategy had a lower rate of the primary outcome (17.2% vs 29.3%; difference in 4-year event rate, −12.1% [95% CI, −22.6 to −1.6%]), whereas those without HF/LVD did not (13.0% vs 14.6%; difference in 4-year event rate, −1.6% [95% CI, −3.8% to 0.7%]; P interaction = .055). A similar differential effect was seen for the primary outcome, all-cause mortality, and cardiovascular mortality when invasive versus conservative strategy-associated outcomes were analyzed with LVEF as a continuous variable for patients with and without previous HF.

Conclusions: ISCHEMIA participants with stable ischemic heart disease and at least moderate ischemia with a history of HF or LVD were at increased risk for the primary outcome. In the small, high-risk subgroup with HF and LVEF 35% to 45%, an initial invasive approach was associated with better event-free survival. This result should be considered hypothesis generating. Registration: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

Comments: The COURAGE and BARI-2 trials demonstrated the equivalence of medical management to intervention in terms of survival in stable, low-risk coronary artery disease. However, defining “low-risk” and “stable” has remained mired in controversy as newer and newer data suggest that even so-called stable disease is not innocuous. The ISCHEMIA trial further muddies the water by concluding that high-risk subgroups (patients with HF or LVEF 35% to 45%) of stable coronary artery disease have increased survival with early intervention. While the results appear logical, the actual number of high-risk patients is small (398), due to which, the investigators have described their result as “hypothesis-generating”. I guess we need to continue waiting for more data!

No Journal Scan will be complete without the latest COVID-19 controversy, so we conclude with the latest controversy to hit mRNA COVID vaccines.

Abstract 10712: mRNA COVID Vaccines Dramatically Increase Endothelial Inflammatory Markers and ACS Risk as Measured by the PULS Cardiac Test: A Warning

Circulation. 2021, November 8;144:A10712

Steven R Gundry

Our group has been using the PLUS Cardiac Test (GD Biosciences, Inc, Irvine, CA), a clinically validated measurement of multiple protein biomarkers which generates a score predicting the 5-year risk (percentage chance) of a new Acute Coronary Syndrome (ACS). The score is based on changes from the norm of multiple protein biomarkers including IL-16, a proinflammatory cytokine, soluble Fas, an inducer of apoptosis, and Hepatocyte Growth Factor (HGF) which serves as a marker for chemotaxis of T-cells into epithelium and cardiac tissue, among other markers. Elevation above the norm increases the PULS score, while decreases below the norm lowers the PULS score. The score has been measured every 3 to 6 months in our patient population for 8 years. Recently, with the advent of the mRNA COVID 19 vaccines (vac) by Moderna and Pfizer, dramatic changes in the PULS score became apparent in most patients. This report summarizes those results. A total of 566 pts, aged 28 to 97, M:F ratio 1:1 seen in a preventive cardiology practice had a new PULS test drawn from 2 to 10 weeks following the second COVID shot and was compared to the previous PULS score drawn 3 to 5 months previously preshot. Baseline IL-16 increased from 35=/−20 above the norm to 82=/−75 above the norm post-vac; sFas increased from 22+/−15 above the norm to 46=/−24 above the norm post-vac; HGF increased from 42+/−12 above the norm to 86+/−31 above the norm post-vac. These changes resulted in an increase of the PULS score from 11% 5-year ACS risk to 25% 5-year ACS risk. At the time of this report, these changes persist for at least 2.5 months post second dose of vac. We conclude that the mRNA vacs dramatically increase inflammation on the endothelium and T cell infiltration of cardiac muscle and may account for the observations of increased thrombosis, cardiomyopathy, and other vascular events following vaccination.

Commentary: This abstract casts doubt on the initial presumption that only the AstraZeneca/Oxford/Serum Institute of India vaccine (Vaxzevria/Covishield) causes dangerous coagulation related events in recipients, especially the young. The hype around this rare though significant adverse event rose to such a level that many countries which had started vaccination with Vaxzevria switched to mRNA vaccines for the second dose for recipients who had received a single dose of Vaxzevria. Now, it seems that mRNA vaccines too have a similar adverse event profile. This data clearly shows the problems caused by the political hype around COVID vaccination. Regardless, as of today, we are still far better off taking a complete course of whichever vaccine is available rather than risking severe COVID infection by the still prevalent delta variant while waiting for a “perfect” vaccine.