heart failure – The Early Career Voice

Key Takeaways From the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure

April 20, 2022April 13, 2022 Andi Shahu, MD, MHS

What’s new in the treatment of heart failure? The 2022 AHA/ACC/HFSA Guideline for the Management was just released in the beginning of April! While much of the ground it covers might not seem particularly groundbreaking to anyone who has been paying attention to discussions on #MedTwitter, #CardioTwitter or the latest clinical trials over the last 2-3 years, it codifies the guideline directed medical therapy (GDMT) that we have all come to know and love for the treatment of heart failure with a reduced ejection fraction (HFrEF). These new guidelines also provide the first-ever guideline recommendations for patients with (heart failure with a preserved ejection fraction) HFpEF and heart failure with mildly reduced ejection fraction (HFmrEF), though the strength of recommendation for these conditions is not as strong as those for HFrEF.

Here are some key takeaways from the new heart failure guideline!

Quadruple therapy GDMT for HFrEF

The latest guideline officially provides class IA recommendations for the use of the following medications in the treatment of HFrEF (defined as LVEF 40% or lower) in patients that have at least NYHA class II symptoms:

Angiotensin-converting enzyme (ACE) inhibitors (ACEi) [i.e. lisinopril] or angiotensin-receptor blockers (ARBs) [i.e. losartan] or angiotensin receptor blocker/neprolysin inhibitor combination (ARNi) [i.e. sacubitril-valsartan]
Beta blockers [i.e. metoprolol, carvedilol]
Mineralocorticoid antagonists [i.e. spironolactone]
SGLT2 inhibitors (SGLTi) [i.e. empagliflozin, dapagliflozin]

The first three classes were previously recommended for the treatment of HFrEF but prior American cardiovascular society guidelines did not include such a strong recommendation for the use of SGLT inhibitors.

We now have HFimpEF

HFimpEF now refers to heart failure in someone who previously had HFrEF but whose LVEF has improved to >40%. The guideline strongly recommends continuing GDMT for patients that fall into this category.

We now have HFmrEF recommendations

The guideline now provides a class 2A recommendation for the use of SGLT2i in the treatment of symptomatic HFmrEF (defined as LVEF 41-49%). It also provides class 2B recommendations for the use of ARNi/ACEi/ARB, beta blockers and MRAs in these patients. These recommendations confirm what some physicians/cardiologists have already begun doing in practice, though the level of evidence to support the use of these medications in HFmrEF as it is for patients with HFrEF.

We also have new HFpEF recommendations

For the first time ever, the guideline recommends medications for the treatment of symptomatic HFpEF (defined as LVEF 50% or greater). Similar to its recommendations for the treatment of HFmrEF, it provides a class IIA recommendation for the use of SGLT2i and class 2B recommendations for beta blockers, ARNi, ACEi, ARB and MRAs, especially if the patient has an LVEF that is closer to 50%. Again, as we know, the level of evidence to support these practices is not as strong as it is for HFrEF. Still, this represents a change from previous guidelines which provided limited options for treatment of HFpEF.

ICD or CRT is still recommended for primary prevention in certain cases

This guideline continues to recommend an implantable cardioverter-defibrillator (ICD) in a subset of patients, particularly those whose LVEF remains less than or equal to 35% despite being on maximally-tolerated GDMT (there are nuances to this that we will not get into here). Similarly, as before, the guideline also continues to recommend cardiac resynchronization therapy (CRT) for patients who have an LVEF less than or equal to 35%, sinus rhythm, left bundle branch block with a QRS duration of at least 150 ms, NYHA class II-III symptoms.

New recommendations for diagnosis and treatment of cardiac amyloidosis

The new guideline provides class I recommendations for checking serum and urine immunofixation electrophoresis and serum free light chains in patients (which would help diagnose AL amyloidosis) in patients for whom there is clinical suspicion for cardiac amyloidosis. Similarly, there is a class I recommendation for bone scintigraphy to evaluate for transthyretin (TTR) amyloidosis in patients for whom there is sufficient clinical suspicion for amyloidosis (left to the clinician’s judgment). Genetic testing is also recommended if a patient is diagnosed with TTR amyloidosis. For the first time, the guideline provides a class IB recommendation for the use of tafamadis in patients with transthyretin cardiac amyloidosis. And finally, the guideline gives a class IIA recommendation for use of anticoagulation in patients with concurrent atrial fibrillation and cardiac amyloidosis, regardless of CHA₂DS₂-VASc score.

“The views, opinions, and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness, and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions, or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your health matters. If you think you are having a heart attack, stroke, or another emergency, please call 911 immediately.”

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

April 15, 2022April 6, 2022 Reza Mohebi, MD

The 2022 American College of Cardiology (ACC) meeting was held in Washington DC. It was the first ACC meeting offering both in-person and virtual participation. After two years of uncertainty about the future of scientific meetings, hopefully, the COVID-19 pandemic was under control, and the cardiovascular community had the opportunity to meet colleagues, friends, and mentors/mentees once again. A day before the conference, the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure was released. A year ago, the 2021 Expert Decision Pathway for heart failure Treatment Optimization was released; however, the emerging new therapies available for heart failure necessitate the early update of heart failure (HF) guideline.

Guideline directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF: LVEF EF≤ 40%) and heart failure with mildly reduced ejection fraction (HFmrEF: LVEF 41%–49%) now includes four-pillar medications: sodium-glucose cotransporter 2 inhibitor (SGLT-2i), angiotensin receptor neprilysin inhibitor (ARNI)/ angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB), beta-blockers and mineralocorticoid receptor antagonist (MRA). New recommendations for patients with heart failure with preserved ejection fraction (HFpEF: LVEF ≥ 50%) were made for the first time. SGLT2i (Class of Recommendation 2a), MRAs (Class of Recommendation 2b), ARNIs (Class of Recommendation 2b), and ARB (Class of Recommendation 2b) are now the cornerstone of HF therapies in patients with HFpEF. Avoidance of routine use of nitrates or phosphodiesterase-5 inhibitors (Class of Recommendation 3: No Benefit) was endorsed in this patient population. Health care professionals also need to understand drugs that may worsen HF. In patients with HFrEF, non-dihydropyridine calcium channel-blocking, class IC antiarrhythmic medications and dronedarone, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors (Saxagliptin and Alogliptin) and Non-steroidal anti-inflammatory drugs should be avoided (Class of Recommendation 3: Harm). In patients with HFrEF without a specific indication, such as atrial fibrillation, or venous thromboembolism, anticoagulation is not indicated (Class of Recommendation 3: No Benefit).

The new guideline also revised the definition for HF stages. Stage A (At risk for HF) was defined as patients with hypertension, cardiovascular disease, diabetes mellitus, obesity, exposure to cardiotoxic agents, or a family history of cardiomyopathy. Stage B (Pre-HF) was defined as patients without current or previous HF symptoms/signs but evidence of structural heart disease, increased filling pressures or elevated stress cardiac biomarker (persistent elevated cardiac troponin or natriuretic peptide). Stage C: patients with current or previous symptoms/signs of HF, and stage D (advanced HF): patients with marked HF symptoms that interfere with daily activity with recurrent hospitalization despite optimized GDMT. The guideline provides therapies for patients at each stage of HF to prevent the progression of HF.

Moreover, the 2022 HF guideline endorsed five additional therapies once GDMT has been optimized. Ivabradine (Class of Recommendation 2a) was recommended for patients with HFrEF, New York Heart Association (NYHA) I-III, in normal sinus rhythm, heart rate ≥70 beats per minute on a maximally tolerated beta-blocker. Vericiguat (Class of Recommendation 2a) for patients with LVEF <45%. Digoxin (Class of Recommendation 2b) for symptomatic HFrEF. Polyunsaturated fatty acids (Class of Recommendation 2b) for HF NYHA II-IV and potassium binders (Class of Recommendation 2b) for patients with HF with hyperkalemia while taking renin-angiotensin-aldosterone system inhibitors. Further recommendations were provided for select patients with HF and anemia, iron deficiency, hypertension, atrial fibrillation, malignancy, sleep disorder, and mitral regurgitation. I would highly recommend my blog readers to review this enlightening just-released HF guideline: https://www.ahajournals.org/doi/10.1161/CIR.0000000000001063

Taking the Guesswork out of HFpEF

March 21, 2022March 22, 2022 Devika Aggarwal, MBBS

With an aging population and a higher burden of comorbidities, the proportion of heart failure patients with a preserved ejection fraction, i.e. ejection fraction ≥ 50% is increasing.¹ Heart failure with preserved ejection fraction (HFpEF) now accounts for more than half of all heart failure hospitalizations. Despite the increasing prevalence, HFpEF remains a nebulous entity. HFpEF is often alluded to without a complete understanding of the underlying pathophysiology. Diagnosing HFpEF can be challenging as opposed to heart failure with reduced ejection fraction (HFrEF). With a normal ejection fraction, attributing dyspnea to cardiac congestion without performing invasive hemodynamic testing requires good clinical suspicion and judgment. Moreover, euvolemic patients with compensated HFpEF can have elevated filling pressures and dyspnea only with exertion. Non-invasive measurement of cardiac pressures can be inconclusive and invasive cardiopulmonary exercise testing (CPET) is considered the gold standard in this population.² However its routine use is not feasible as it is an invasive and technically complex procedure with limited availability. An algorithm incorporating clinical and non-invasive parameters can help stratify patients’ probability of having HFpEF. The utility of risk scores, such as the CHA₂DS₂-VASc, TIMI, and Wells’ scores, is well established in the field of cardiovascular disease. There has been research into developing similar algorithms/ prediction scores for the diagnosis of HFpEF. Here, we discuss 2 proposed scoring systems for HFpEF- H₂FPEF and HFA-PEFF.

H₂FPEF Score

Reddy and colleagues at Mayo Clinic, Rochester developed the H₂FPEF score to help physicians discriminate HFpEF from non-cardiac causes of dyspnea in symptomatic patients without obvious fluid overload.³ The score was developed from a cohort of 414 patients with an ejection fraction ≥ 50%, who underwent invasive hemodynamic exercise testing for definitive evaluation of unexplained dyspnea. Different clinical and echocardiographic markers were evaluated through logistic regression to identify variables associated with HFpEF. Ultimately 6 routinely available variables (BMI > 30 kg/m², atrial fibrillation, hypertension treated with ≥ 2 medications, pulmonary artery systolic pressure > 35 mmHg, age > 60 years, and E/e’ > 9) were used for the model. Each variable was assigned a point based on the strength of association observed with HFpEF diagnosed via invasive testing (Figure 1). The final score had good discriminatory power (area under the curve = 0.84) for differentiating HFpEF from other causes of dyspnea. As the score increased from 0 to 9, so did the probability of HFpEF. The robustness of the model was validated through sensitivity analyses and a test cohort of 100 patients. The authors proposed a Bayesian approach- using a low score (0-1) to rule out HFpEF, a high score (6-9) to make a diagnosis of HFpEF, and an intermediate score (2-5) to consider additional testing.

The major limitation of this important model is the setting of the study. It was conducted at a single institute serving as a referral center, which may not truly represent the general population. It is reassuring that the score has been validated in small external cohorts.^4,5 Moreover, an analysis from the TOPCAT trial population showed that patients with a higher H₂FPEF score had an increased risk of adverse outcomes, suggesting a prognostic value of the score.⁶

Figure 1. H2FPEF Score proposed by Reddy et al. https://doi.org/10.1161/CIRCULATIONAHA.118.034646

HFA-PEFF Score

In 2020, the Heart Failure Association (HFA) and the European Society of Cardiology (ESC) released a consensus recommendation for diagnosing HFpEF, proposing the stepwise HFA-PEFF algorithm.⁷ This recommendation centers around the use of the HFA-PEFF score. The proposed scoring system uses echocardiographic parameters and natriuretic peptide (BNP and NT-proBNP) levels. The variables are divided into major and minor criteria across 3 domains- functional, morphological, and biomarker (Figure 2). Parameters within a domain are not additive, hence the score can be used even when certain values are not available. Each domain can contribute a maximum of 2 points and the total score ranges from 0 to 6. A total score of 5-6 is considered diagnostic of HFpEF while a score of 0-1 makes HFpEF unlikely. An intermediate score of 2-4 warrants further testing with non-invasive or invasive functional testing.

Notably, the HFA-PEFF score did not utilize demographic and clinical parameters and the power of the score was not assessed. However, an independent study later demonstrated its validity in two separate cohorts.⁸

Figure 2. HFA-PEFF Score proposed by HFA and ESC. https://doi.org/10.1002/ejhf.1741

Both of the above scoring systems have been received with enthusiasm, given the lack of a clear definition and diagnostic framework for HFpEF. Studies evaluating the 2 scores have also been published. Parcha and colleagues studied the generalizability of the H₂FPEF and HFA-PEFF scores in an analysis of participants with unexplained dyspnea from prior HFpEF trials and the Atherosclerosis Risk in Communities (ARIC) study.⁹ They found that both the scores could rule out HFpEF with a greater than 99% success rate but the H₂FPEF score had a higher specificity than the HFA-PEFF score. Amanai and colleagues calculated H₂FPEF and HFA-PEFF scores in patients with HFpEF referred for stress echocardiography.¹⁰ They found that both scores had similarly high positive and negative predictive values and a correlation with abnormal hemodynamics during exercise. Another study in the ARIC population also found that both high H₂PEFF and HFA-PEFF scores were associated with increased risk of heart failure hospitalizations or death, suggesting the prognostic value of both.¹¹

Both H₂FPEF and HFA-PEFF are validated and easy-to-use scores using readily available clinical, laboratory, and echocardiographic parameters. The use of these scores in the appropriate patient and context can aid in the timely and accurate diagnosis of HFpEF. Growing recognition and emergence of effective therapies such as SGLT2 inhibitors are important strides for improving outcomes for patients with HFpEF.

References:

Borlaug BA. Evaluation and management of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2020;17(9):559-573. doi:10.1038/s41569-020-0363-2
Sorajja P, Borlaug BA, Dimas VV, et al. SCAI/HFSA clinical expert consensus document on the use of invasive hemodynamics for the diagnosis and management of cardiovascular disease. Catheter Cardiovasc Interv. 2017;89(7):E233-E247. doi:10.1002/ccd.26888
Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A Simple, Evidence-Based Approach to Help Guide Diagnosis of Heart Failure With Preserved Ejection Fraction. Circulation. 2018;138(9):861-870. doi:10.1161/CIRCULATIONAHA.118.034646
Sepehrvand N, Alemayehu W, Dyck GJB, et al. External Validation of the H2F-PEF Model in Diagnosing Patients With Heart Failure and Preserved Ejection Fraction. Circulation. 2019;139(20):2377-2379. doi:10.1161/CIRCULATIONAHA.118.038594
Segar MW, Patel KV, Berry JD, Grodin JL, Pandey A. Generalizability and Implications of the H2FPEF Score in a Cohort of Patients With Heart Failure With Preserved Ejection Fraction. Circulation. 2019;139(15):1851-1853. doi:10.1161/CIRCULATIONAHA.118.039051
Myhre PL, Vaduganathan M, Claggett BL, et al. Application of the H2 FPEF score to a global clinical trial of patients with heart failure with preserved ejection fraction: the TOPCAT trial. Eur J Heart Fail. 2019;21(10):1288-1291. doi:10.1002/ejhf.1542
Pieske B, Tschöpe C, de Boer RA, et al. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur J Heart Fail. 2020;22(3):391-412. doi:10.1002/ejhf.1741
Barandiarán Aizpurua A, Sanders-van Wijk S, Brunner-La Rocca HP, et al. Validation of the HFA-PEFF score for the diagnosis of heart failure with preserved ejection fraction. Eur J Heart Fail. 2020;22(3):413-421. doi:10.1002/ejhf.1614
Parcha V, Malla G, Kalra R, et al. Diagnostic and prognostic implications of heart failure with preserved ejection fraction scoring systems. ESC Heart Fail. 2021;8(3):2089-2102. doi:10.1002/ehf2.13288
Amanai S, Harada T, Kagami K, et al. The H2FPEF and HFA-PEFF algorithms for predicting exercise intolerance and abnormal hemodynamics in heart failure with preserved ejection fraction. Sci Rep. 2022;12(1):13. doi:10.1038/s41598-021-03974-6
Selvaraj S, Myhre PL, Vaduganathan M, et al. Application of Diagnostic Algorithms for Heart Failure With Preserved Ejection Fraction to the Community. JACC Heart Fail. 2020;8(8):640-653. doi:10.1016/j.jchf.2020.03.013

Combining CAR-T and mRNA Therapeutics to Cure Heart Failure

February 23, 2022February 14, 2022 Khairunnisa Semesta, MA

Heart failure is the leading cause of death in the Western world, causing more than 300,000 deaths per year. Heart failure is also a source of significant economic burden, costing the American healthcare system more than 30 billion dollars in 2012.[i] Cardiac fibrosis is central to the pathology of heart failure. Cardiac fibroblasts are activated in response to injuries. However, when activated fibroblasts fail to quiesce and continue secreting extracellular matrix, cardiac fibrosis occurs, leading to scarring of heart tissues. Ultimately, cardiac fibrosis can lead to fatal heart failure. Fibrotic diseases, including lung and cardiac fibrosis, cause more than 800,000 deaths worldwide per year.[ii]

Researchers from the laboratory of Dr. Jonathan Epstein in the University of Pennsylvania recently showed that mRNA therapeutics can be used to address cardiac fibrosis.[iii] The researchers delivered a modified mRNA coated with T-cell targeting lipid nanoparticles. The mRNA encodes for a chimeric antigen receptor against FAP, a specific protein expressed by activated fibroblasts. This allows for the generation of transient chimeric antigen receptor T (CAR-T) cells that recognize fibrotic cardiac cells.

Successfully delivered, the mRNA was able to reprogram T cells to specifically recognize and eliminate activated fibroblasts. In a mouse model of heart failure, the engineered CAR T cells were able to resolve cardiac fibrosis, restructuring the heart and improving heart function after injury. Unlike ex vivo CAR-T cells generation, this method allowed the generation of CAR T cells entirely in the human body. In addition, these engineered CAR T cells are transient, therefore not compromising the heart’s ability to resolve future injuries through fibroblast activation.

With the recent advances of the COVID-19 vaccines, the use of mRNA therapeutics in other diseases is gaining traction. The possibility of eliminating the disease burden of cardiac fibrosis using mRNA therapeutics is extremely attractive, as it has the potential to reverse cardiac fibrosis and restore heart function. This presents a significant addition to existing antifibrotic agents that only limit or slow down fibrosis progression. This first proof-of-concept study opens a new avenue to optimize the strategy of combining mRNA therapeutics and CAR-T technology to address cardiac fibrosis and fibrotic diseases in general.

References:

[i] Virani, S. S. et al. (2021) Circulation 143: e254–e743

[ii] Hinderer, S. and Schenke-Layland, K. (2019) Advanced Drug Delivery Reviews 146: 77-82

[iii] Rurik, J. et al. (2022) Science 375.6576: 91-96

Medications to Avoid in patients with Heart Failure

July 30, 2021July 29, 2021 Lina Ya'qoub, MD

The number of patients being diagnosed with heart failure (HF) is increasing worldwide, and thus we need to know which medications to avoid or be cautious with prescribing that may cause or exacerbate this medical condition. So, we decided to talk about these medications, how they cause these adverse events in these patients, and their mechanism of action.

How these medications cause adverse events in HF patients?

Overall, these medications might cause these adverse effects by one of the following mechanisms: 1) causing direct myocardial toxicity; 2) by negative inotropic effect; 3) chronotropic effects; 4) by exacerbating hypertension; 5) by delivering a high sodium load; or 6) by drug-drug interactions that limit the beneficial effects of HF medications.

Here, we will talk briefly about the common medication classes that should be avoided in heart failure and their mechanism of causing these adverse events.

1. Non-dihydro Calcium Channel Blockers (CCB):

Including (diltiazem and verapamil) è have a negative inotropic effect, thus might increase adverse outcomes [1].

2. Nonsteroidal Anti-Inflammatory Drugs (NSAID) : Diclofenac , indomethacin , ketorolac ..etc AND COX-2 selective inhibitors (Celecoxib) :

Commonly Dispensed as over the counter drugs or as anti-inflammatory prescribed drugs è these medications are associated with increased risk of HF exacerbation, causing decline in renal function, and peripheral vasoconstriction; as such they can attenuate the efficacy and enhance the toxicity of diuretics and angiotensin converting enzyme inhibitors [2].

US Boxed Warning regarding Serious cardiovascular risk: (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use. Celecoxib is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [2].

3. Some Oral Hypoglycemic Agents:

Thiazolidinediones such as Pioglitazone è are associated with fluid retention

US Boxed Warning: Thiazolidinediones may cause or exacerbate heart failure è closely monitor for signs and symptoms of HF particularly after initiation or dose increases. If HF develops, treat and consider dose reduction or discontinuation of pioglitazone. Initiation of therapy is contraindicated in patients with NYHA class III or IV HF [3].

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors: Sitagliptin, saxagliptin, and linagliptin

In a scientific statement from American Heart Association (AHA) , saxagliptin has been determined to be an agent that may exacerbate underlying myocardial dysfunction , 2016 . The ADA recommends avoiding the use of saxagliptin in patients with HF, 2020) [4].

Bies ( Metformin ) is associated withguanid lactic acidosis, which can be fatal in patients with CHF

US Boxed Warning regarding Lactic acidosis: Risk factors include renal impairment, ≥65 years and hypoxic states, e.g: acute congestive heart failure. Metformin may be used in patients with stable heart failure, ADA 2020 [5].

4. Tumor Necrosis Factor alpha inhibitors (Anti-TNF-alpha):

Including infliximab, etanercept, and adalimumab.

Use with caution in patients with mild HF (NYHA class I, II) or decreased left ventricular function. Infliximab doses >5 mg/kg are contraindicated with moderate to severe HF (NYHA class III/IV). In a scientific statement from AHA, TNF blockers have been determined to cause either direct myocardial toxicity or exacerbate underlying myocardial dysfunction, 2016 [6,7].

5. Antiarrhythmic medications:

Class I: Flecainide, disopyramide [8]

Class III: Dronedarone, Sotalol [8]

6. Anti- Cancer medications:

Anthracyclines: doxorubicin, Daunorubicin, Mitoxantrone

US Boxed Warning: Myocardial damage (including acute left ventricular failure) can occur with doxorubicin with incidences from 1% to 20% for cumulative doses from 300 mg/m² to 500 mg/m² when administered every 3 weeks è monitor LVEF before, during and after treatment [9]

Targeted therapy: Bevacizumab, Lapatinib, Trastuzumab

US Boxed Warning: Trastuzumab is associated reductions in left ventricular ejection fraction (LVEF) and heart failure; the incidence is highest in patients receiving trastuzumab with an anthracycline-containing chemotherapy regimen è Evaluate LVEF in all patients prior to and during treatment; discontinue for cardiomyopathy [10]

7. Cilostazol

This is a selective inhibitor of phosphodiesterase type 3, antiplatelet and vasodilatory agent used primarily in patients with intermittent claudication and peripheral arterial disease [11].

US Boxed Warning: Cilostazol is contraindicated in patients with heart failure of any severity è causing decreased survival in patients with class III to IV heart failure [11].

8. Anti-depressant drugs:

Citalopram, Tricyclic antidepressants (TCA) such as amitriptyline, Imipramine … etc.

TCAuse with extreme caution in patients with a history of CVD or family history of sudden death, dysrhythmias, or conduction abnormalities. In a scientific statement from AHA, TCA has been determined to exacerbate underlying myocardial dysfunction,2016 è monitor EKG [12]

Citalopram risk of dose-dependent QT prolongation ECG and torsade de pointes (TdP) . Risk factors include Structural heart disease, e.g: MI or HF [12]

9. α1 -Blockers:

Such as prazosin and doxazosin

In a scientific statement from the AHA, -Zosin has been determined to exacerbate underlying myocardial dysfunction , 2016 [13].

10. Pregabalin

Peripheral edema may occur in patients with or without a prior history of heart failure, which may result in acute decompensated heart failure. Risk factors: Pre-existing heart failure (NYHA Class III or IV) (cautious use recommended due to limited data in this patient population [14]

11. Beta-blockers (except those approved for HF treatment: Metoprolol, Bisoprolol, Carvedilol) [15]

12. Selected Intravenous and Oral Medications High in Sodium content:

Oral meds: Alendronate effervescent tablet, Sodium polystyrene sulfonate suspension, Polyethylene glycol powder for solution, erythromycin
Injection meds: Piperacillin/tazobactam, Metronidazole, Ticarcillin/clavulanate, azithromycin

13. Trimethoprim-sulfamethoxazole (TMP/SMX)

==> by increasing the risk of Hyperkalemia which can be life-threatening [16].

Figure 1: Summary of medications to avoid in heart failure patients.
AAA: anti-arrhythmic agents

A special thank you to my sister, Pharm.D Rawan Ya’acoub, Clinical pharmacist and Research assistant at Jordan university .

References:

[1] Kostis JB, Lacy CR, Cosgrove NM, Wilson AC. Association of calcium channel blocker use with increased rate of acute myocardial infarction in patients with left ventricular dysfunction. Am Heart J. 1997 May;133(5):550-7. doi: 10.1016/s0002-8703(97)70150-9. PMID: 9141377.

[2] Ungprasert P, Srivali N, Kittanamongkolchai W. Non-steroidal anti-inflammatory drugs and risk of heart failure exacerbation: A systematic review and meta-analysis. Eur J Intern Med. 2015 Nov;26(9):685-90. doi: 10.1016/j.ejim.2015.09.012. Epub 2015 Oct 1. PMID: 26427540.

[3] Singh S, Loke YK, Furberg CD. Thiazolidinediones and heart failure: a teleo-analysis. Diabetes Care. 2007 Aug;30(8):2148-53. doi: 10.2337/dc07-0141. Epub 2007 May 29. PMID: 17536074.

[4] Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, Udell JA, Mosenzon O, Im K, Umez-Eronini AA, Pollack PS, Hirshberg B, Frederich R, Lewis BS, McGuire DK, Davidson J, Steg PG, Bhatt DL; SAVOR-TIMI 53 Steering Committee and Investigators*. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014 Oct 28;130(18):1579-88. doi: 10.1161/CIRCULATIONAHA.114.010389. Epub 2014 Sep 4. Erratum in: Circulation. 2015 Oct 13;132(15):e198. PMID: 25189213.

[5] Kinsara AJ, Ismail YM. Metformin in heart failure patients. Indian Heart J. 2018 Jan-Feb;70(1):175-176. doi: 10.1016/j.ihj.2017.05.009. Epub 2017 May 15. PMID: 29455774; PMCID: PMC5902828.

[6] Behnam SM, Behnam SE, Koo JY. TNF-alpha inhibitors and congestive heart failure. Skinmed. 2005 Nov-Dec;4(6):363-8. doi: 10.1111/j.1540-9740.2005.04502.x. PMID: 16276152.

[7] Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT; Anti-TNF Therapy Against Congestive Heart Failure Investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation. 2003 Jul 1;107(25):3133-40. doi: 10.1161/01.CIR.0000077913.60364.D2. Epub 2003 Jun 9. PMID: 12796126.

[8] Køber L, Torp-Pedersen C, McMurray JJ, Gøtzsche O, Lévy S, Crijns H, Amlie J, Carlsen J; Dronedarone Study Group. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008 Jun 19;358(25):2678-87. doi: 10.1056/NEJMoa0800456. Erratum in: N Engl J Med. 2010 Sep 30;363(14):1384. PMID: 18565860.

[9] Songbo M, Lang H, Xinyong C, Bin X, Ping Z, Liang S. Oxidative stress injury in doxorubicin-induced cardiotoxicity. Toxicol Lett. 2019 Jun 1;307:41-48. doi: 10.1016/j.toxlet.2019.02.013. Epub 2019 Feb 25. PMID: 30817977.

[10] Nemeth BT, Varga ZV, Wu WJ, Pacher P. Trastuzumab cardiotoxicity: from clinical trials to experimental studies. Br J Pharmacol. 2017 Nov;174(21):3727-3748. doi: 10.1111/bph.13643. Epub 2016 Nov 25. PMID: 27714776; PMCID: PMC5647179.

[11] Wu CK, Lin JW, Wu LC, Chang CH. Risk of Heart Failure Hospitalization Associated With Cilostazol in Diabetes: A Nationwide Case-Crossover Study. Front Pharmacol. 2019 Jan 7;9:1467. doi: 10.3389/fphar.2018.01467. PMID: 30666197; PMCID: PMC6330376

[12] Teply RM, Packard KA, White ND, Hilleman DE, DiNicolantonio JJ. Treatment of Depression in Patients with Concomitant Cardiac Disease. Prog Cardiovasc Dis. 2016 Mar-Apr;58(5):514-28. doi: 10.1016/j.pcad.2015.11.003. Epub 2015 Nov 10. PMID: 26562328.

[13] Hundemer GL, Knoll GA, Petrcich W, Hiremath S, Ruzicka M, Burns KD, Edwards C, Bugeja A, Rhodes E, Sood MM. Kidney, Cardiac, and Safety Outcomes Associated With α-Blockers in Patients With CKD: A Population-Based Cohort Study. Am J Kidney Dis. 2021 Feb;77(2):178-189.e1. doi: 10.1053/j.ajkd.2020.07.018. Epub 2020 Sep 11. PMID: 32920153.

[14] Lund M, Poulsen G, Pasternak B, Worm Andersson N, Melbye M, Svanström H. Use of Pregabalin and Worsening Heart Failure: A Nationwide Cohort Study. Drug Saf. 2020 Oct;43(10):1035-1044. doi: 10.1007/s40264-020-00969-6. PMID: 32651945

[15] Kotecha D, Flather MD, Altman DG, Holmes J, Rosano G, Wikstrand J, Packer M, Coats AJS, Manzano L, Böhm M, van Veldhuisen DJ, Andersson B, Wedel H, von Lueder TG, Rigby AS, Hjalmarson Å, Kjekshus J, Cleland JGF; Beta-Blockers in Heart Failure Collaborative Group. Heart Rate and Rhythm and the Benefit of Beta-Blockers in Patients With Heart Failure. J Am Coll Cardiol. 2017 Jun 20;69(24):2885-2896. doi: 10.1016/j.jacc.2017.04.001. Epub 2017 Apr 30. PMID: 28467883.

[16] Michel A, Martín-Pérez M, Ruigómez A, García Rodríguez LA. Risk factors for hyperkalaemia in a cohort of patients with newly diagnosed heart failure: a nested case-control study in UK general practice. Eur J Heart Fail. 2015 Feb;17(2):205-13. doi: 10.1002/ejhf.226. Epub 2015 Jan 10. PMID: 25581138.

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Stage D Heart Failure – Who and When to Refer (#ACC21)

May 28, 2021May 21, 2021 Baljash Cheema, MD, MSCI

#ACC21 came and went, bringing the usual flurry of practice-changing clinical trials, new scientific theories and inquiries, and a wealth of creative ideas showcased through poster presentations. While the virtual format is quite the departure from the in-person atmosphere, it allows flexibility in viewing sessions on-demand and allows individuals that may have an otherwise challenging time traveling to join the discussion. Aside from the trials and presentations that got the most headlines, I wanted to highlight a talk within the advanced heart failure space that expanded on a challenging clinical scenario we encounter routinely. This blog contains screenshots that are directly from the talk Moving Beyond NYHA Class: Risk Stratification and Prognosis in Advanced Heart Failure (within Session 603 The Advanced Heart Failure Therapies of LVAD and Transplant: Who, What, When, Where, Why, and How?) by Dr. Garrick Stewart from Brigham and Women’s Hospital.

Dr. Stewart starts with an overview of how we think about and classifies patients who have heart failure, starting with the history of the New York Heart Association Class grading schema. While it is simple to use and universally known, its limited in its ability to discriminate how sick those with heart failure truly are. Specifically, it cannot tell you who is at the highest risk for morbidity and mortality. To try and address those specifically with advanced heart failure, the INTERMACS Profiles were created. He outlines in his talk how these schemes are related

While this helps us think more critically about this patient population, there remains the issue of knowing who to refer for advanced heart failure therapies. Timing is anything from trivial, as those that are referred too late have worse outcomes, and those that are referred too early are placed at the risks associated with the therapies before they may actually need them. A commonly used mnemonic to remind clinicians of red flags for patients with advanced heart failure is “I NEED HELP.” If your patients has any of these criteria, and certainly if they have several, it may be time to refer.

Despite this, improvements in the referral process are still needed. Thankfully this is an area of active investigation! Congrats to Dr. Stewart on creating this excellent review.

Reference:

Stewart, Garrick. Moving Beyond NYHA Class: Risk Stratification and Prognosis in Advanced Heart Failure. Session 603 The Advanced Heart Failure Therapies of LVAD and Transplant: Who, What, When, Where, Why, and How? ACC 2021 Scientific Session. May 15, 2021.

Coronary Allograft Vasculopathy – The Achilles’ Heel of Heart Transplant

March 31, 2021March 29, 2021 Baljash Cheema, MD, MSCI

As a 3^rd year medical student in the coronary care unit (CCU), I helped care for a patient whose story I will never forget. She had developed advanced heart failure due to peripartum cardiomyopathy in her 20s giving birth to her only child and required a heart transplant. She did well for a number of years, but I met her in her 30s when she was admitted post-MI in cardiogenic shock. Her coronary atherosclerosis was due to severe coronary allograft vasculopathy (CAV), an aggressive form of CAD transplant patients may develop. She got a LAD stent and was supported with a balloon pump but was tenuous at best. Some days after her PCI, in a moment seared into my memory, she let out an ear-piercing yell and suddenly arrested and died, her daughter at the bedside. I’ll always remember the pain on her child’s face when she passed, and I will always have a sincere appreciation for the misery CAV can cause. This blog is meant to provide some historical context to heart transplantation and the issue of CAV, as well as to discuss ways we can prevent it.

Since the first heart transplant in Cape Town, South Africa, there have been tremendous advances in cardiac transplantation with median survival now around 12 years. It didn’t always appear that this would be the case, with mortality so high in the early days that many felt heart transplant wasn’t worth it. The advent of calcineurin inhibitors with cyclosporine in the 1980s and tacrolimus in the 1990s were key (Figure 1). Steady improvements in infection prophylaxis, screening for and treating rejection, and surgical technique and expertise further helped the cause.

But as we addressed one set of problems, we found another. CAV is an aggressive form of coronary artery disease (CAD) present in 30% of heart transplant recipients at 5 years and 50% at 10 years. Those with it have worse survival. It shares some risk factors with classic CAD but has several of its own, and there are key pathophysiologic differences (Figures 2 and 3). Our patient was unique in that she had a true plaque rupture MI, typically occurring less often with CAV relative to classic CAD, but this may have been related to a donor transmitted lesion acting more as typical CAD would.

Figure 2. Pathophysiologic Differences

Figure 3. Risk Factors

So how do we prevent CAV? Our best data comes from statin trials in the 1990s-2000s (pravastatin, simvastatin, and atorvastatin studied), showing lower rates of rejection and CAV with improved survival in transplant patients treated with statins. This makes intuitive sense, as dyslipidemia is a rock-solid risk factor for classic CAD and nearly universally seen post solid organ transplantation due to the metabolic consequences of common immunosuppressives. These immunosuppressives, while life-saving in their own right, also lead to worsening glucose control, hypertension, obesity, and kidney disease. Addressing each of these while encouraging a heart-healthy diet and routine exercise is of paramount importance in keeping our transplant patients healthy. Finally, a reminder that there are many drug-drug interactions with transplant medications. Figure 4 is adapted from Warden et al and shows the relative degree of interactions between immunosuppressives and common lipid-lowering drugs.

Figure 4. Drug-Drug Interactions

While this story was tragic for the patient and her family, it’s given me a profound respect for CAV that I will carry forward when I eventually care for heart transplant patients in my career. Below are the references for this article from which parts of the figures were taken. Each of these is a fantastic resource for further learning.

References:

Stehlik, J., et al. (2018). “Honoring 50 Years of Clinical Heart Transplantation in Circulation: In-Depth State-of-the-Art Review.” Circulation 137(1): 71-87.
Warden, B. A. and P. B. Duell (2019). “Management of dyslipidemia in adult solid organ transplant recipients.” J Clin Lipidol 13(2): 231-245.
Costanzo, M. R., et al. (2010). “The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients.” J Heart Lung Transplant 29(8): 914-956.

Entresto Use in Heart Failure w Preserved Function

March 11, 2021March 12, 2021 Aubrey J. Grant, MD

Heart failure is a pervasive diagnosis and unfortunately about 6.2 million adults in the United States suffer from this disease.¹ Furthermore, heart failure represents a significant proportion of total healthcare expenditures including the cost of healthcare services, medicines to treat heart failure, and missed days of work. While we often focus on the management of heart failure with reduced ejection fraction, epidemiological studies report about 50% of all heart failure patients have preserved function.² Heart failure patients with preserved function have similar rates of hospitalization and death when compared to heart failure patients with reduced function.²

While there are several treatment options that have proven mortality benefit in chronic heart failure patients with reduced function, the treatment options for patients with preserved function are limited.

Following the results of the PARADIGM-HF trial, PARAGON-HF was an industry funded, multi-national, double blinded trial that attempted to determine whether entresto was more effective than valsartan at lowering the rate of total hospitalizations for heart failure and death from cardiovascular causes. The investigators of this trial randomly assigned 4822 patients with symptomatic heart failure with preserved function (left ventricular ejection fraction [LVEF] ≥ 45%) to entresto or valsartan alone. The primary endpoint was total hospitalizations for heart failure and death due to cardiovascular causes.

Regarding the patient group studied; the mean age of the patients was 73 years, 52% were female, only 2% were black, and the average ejection fraction was approximately 57%. The investigators found that entresto did reduce the rate of the primary endpoint by 13% (rate ratio, 0.87; P = .06). The data shows that the lower event rate was mostly driven by fewer hospitalizations for heart failure. Notably, death due to cardiovascular causes was essentially the same with 204 deaths in the Entresto group and 212 deaths in the valsartan group.³

Following the PARAGON-HF trial, the FDA has now granted an expanded indication to Entresto that would allow for use of the therapy in at least some patients with heart failure and preserved ejection fraction (HFpEF). The manufacturer Novartis touts that this is the first time that there is a heart failure treatment with an indication that includes patients with preserved function. While it is truly an amazing feat to now have an FDA indicated drug for this patient population, the effect on hard cardiovascular outcomes as suggested by PARAGON-HF are marginal. Further studies should be conducted to determine whether the drug is more effective in certain patient populations in order to truly understand the potential benefits of entresto in heart failure with preserved function.

Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics—2020 update: a report from the American Heart Association external icon Circulation. 2020;141(9):e139-596.
1.Gladden JD, Linke WA, Redfield MM. Heart failure with preserved ejection fraction. Pflugers Arch 2014;466:1037-1053
Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Claggett B, Jhund PS, Boytsov SA, Comin-Colet J, Cleland J, Düngen HD, Goncalvesova E, Katova T, Kerr Saraiva JF, Lelonek M, Merkely B, Senni M, Shah SJ, Zhou J, Rizkala AR, Gong J, Shi VC, Lefkowitz MP; PARAGON-HF Investigators and Committees. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019 Oct 24;381(17):1609-1620. doi: 10.1056/NEJMoa1908655. Epub 2019 Sep 1. PMID: 31475794.

AHA2020 – The Next Steps in Treating Heart Failure

December 29, 2020December 28, 2020 Baljash Cheema, MD, MSCI

AHA 2020 came and went, and now is the time to put into context the scientific advances presented. While all areas of cardiology saw therapeutic innovations, the ever-evolving landscape for heart failure (HF) therapies stood out in particular.

These were among the key discoveries shared at AHA20 in the HF space:

GALACTIC-HF: In patients with chronic heart failure with a reduced ejection fraction (HFrEF), the cardiac-specific myosin activator omecamtiv mecarbil reduced the primary composite endpoint of time to HF event or cardiovascular death, driven by a reduction in hospitalizations and ED visits. Importantly, the therapy appeared to be hemodynamically neutral, and subgroup analysis showed those with lowest ejection fraction (EF) may benefit in particular.

AFFIRM-AHF: In patients with HFrEF and iron deficiency stabilized from an acute HF event, IV iron repletion reduced the risk of subsequent hospitalization for HF but not death.

SOLOIST-WHF: In patients with worsening HF, the SGLT1/2 inhibitor sotagliflozin significantly reduced the risk of death and hospitalization for HF subgroup analysis showed the results persisted regardless of EF.

SCORED: In patients with diabetes and chronic kidney disease, sotagliflozin reduced the risk of cardiovascular death and subsequent hospitalization and/or urgent visits for HF. Similarly, the effect was seen regardless of EF.

These results not only add to the proven therapies for HFrEF including the cornerstones of ARNI, MRA, BB, and SGLT2 inhibitors, they add therapies for worsening heart failure and strongly suggest therapy for heart failure with a preserved ejection fraction. They may even hint at therapy for those with very low EF. With the VICTORIA trial showing benefit for vericiguat at ACC 2020, and additional therapies already indicated for subsets of patients including ivabradine and fixed-dose isosorbide dinitrate and hydralazine, we now find ourselves with a number of medications our patients should be receiving.

The path forward will be deciphering how best to implement these therapies at doses with proven benefit. Dealing with the issue of cost will be key. Sequencing trials, collating datasets with prescription fill data, machine learning tools to support clinical decision making, and personalized medicine through “omics” technologies may all play a role, as recently discussed by the HF Collaboratory (1).

While there is much to be seen, it’s certainly a very exciting time for heart failure!

Reference

Bhatt AS, Abraham WT, Lindenfeld J et al. Treatment of HF in an Era of Multiple Therapies: Statement From the HF Collaboratory. JACC: Heart Failure 2020.

From evidence to practice: Insights from the GWTG-HF Registry on the Applicability of FDA Labeling for Dapagliflozin in Heart Failure with Reduced Ejection Fraction

December 16, 2020December 15, 2020 Aaysha Cader, MD, MRCP

Sodium-glucose co-transporter-2 (SGLT-2) inhibitors continue to amaze the world of cardiovascular pharmacotherapeutics. Initially developed as anti-diabetic agents, SGLT-2 inhibitors have demonstrated a wide range of benefits across various patient subsets, most notably those with heart failure.

The landmark Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial, a phase 3, placebo-controlled trial the results of which were published in November 2019, demonstrated that the SGLT-2 inhibitor dapagliflozin reduced mortality and worsening heart failure events, and improved health-related quality of life among patients with heart failure with reduced ejection fraction (HFrEF), regardless of the presence or absence of diabetes.¹

Based on these DAPA-HF trial results, in May 2020, dapagliflozin was the first SGLT-2 inhibitor approved by the US Food and Drug Administration (FDA) for HFrEF.² However, as previous registries have shown, many novel evidence-based therapies are either delayed or not optimally utilized in practice. ^3,4 Thus, in order to determine the proportion of eligible candidates for the initiation of dapagliflozin and define potential barriers to therapeutic optimization, an analysis of the American Heart Association (AHA)’s The Get With The Guidelines®–Heart Failure (GWTG-HF) registry was undertaken by Vaduganathan and colleagues. This blog is a summary of the results of this analysis, part of TRANSLATE-HF research platform, the results of which were presented at AHA Scientific Sessions 2020, with simultaneous publication in JAMA Cardiology.⁵

The GWTG-HF registry: This a large contemporary hospital-based quality improvement registry including a total of 586,580 patients from 529 sites across the United States.

Population of interest: After exclusion criteria were applied, the primary study cohort for this analysis included 154,714 patients hospitalized with HFrEF at 406 sites between January 2014 – September 2019. As with DAPA-HF, the focus was on chronic HFrEF (≤40%) and treatment eligibility of patients based on discharge parameters during the transition to ambulatory care.

Treatment candidates for Dapagligflozin: The FDA label excluded patients with type 1 diabetes and chronic kidney disease (i.e. estimated glomerular filtration rate [eGFR]<30 mL/min/1.73 m² and dialysis). When this FDA label was applied to patients in the above cohort, 81.1% would be candidates for dapagliflozin, with similar proportions across all study years (range 80.4-81.7%). When analyzed for 355 sites with ≥10 hospitalizations (enrolling 154,522 patients), the median proportion of FDA label candidates was similar, at 81.1%.

Eligibility according to diabetic status: Notably, the proportion of eligible patients for dapagliflozin was higher among those withOUT a history of or new diagnosis of diabetes, as compared with those with type 2 diabetes (85.5% vs. 75.6%).

Reasons for not meeting FDA label: The predominant reason for ineligibility for dapagliflozin in this cohort was an eGFR<30 mL/min/1.73 m² at discharge; this was more frequent among diabetics (23.9%) than non-diabetics (14.3%). Other reasons were far less frequent: 3.2% were ineligible due to chronic dialysis and only 0.02% due to type 1 diabetes.

Especially in terms of ineligibility for Dapagliflozin reported in this publication, it is important to note that this data analysis was undertaken between April 1^st to June 30^th, 2020. More compelling data from two other pivotal SGLT-2 trials reported after DAPA-HF are likely to further extend SGLT-2 inhibitor treatment indications to patients with more severe CKD. DAPA CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease⁶ evaluated patients with albuminuric chronic kidney disease with eGFR down to as low as 25mL/min/1.73 m²and EMPEROR-Reduced⁷ evaluated patients with HFrEF with eGFR as low as 20mL/min/1.73 m^2.

Differences between DAPA-HF Trial Participants vs. FDA Label Candidates in GWTG-HF: Participants in DAPA-HF were younger, less often women, and less often Black compared with participants in GWTG-HF, underscoring the need for greater representation of older adults, women, racial/ethnic minority groups, and those with multiple comorbidities in clinical trials relative to reference usual care (i.e. registry) populations. GWTG-HF registry participants had lower left ventricular EF and eGFR; however, a history of myocardial infarction and percutaneous coronary intervention) were more prevalent among DAPA-HF participants. The overall prevalence of diabetes was similar between both cohorts (44.1% in GWTG-HF registry vs 45% in DAPA-HF population). There was a lower use of evidence-based HF medical therapies among GWTG-HF participants, but higher use of implantable-cardioverter defibrillators. Most other clinical characteristics were qualitatively similar between the two groups

Conclusions & implications: A lag from clinical trial to clinical practice is not uncommon for most novel pharmacotherapeutics. However, data from this large, contemporary US hospitalized HF registry show that 4 out of 5 patients with HFrEF, irrespective of type 2 diabetes status are candidates for initiation of dapagliflozin at hospital discharge, supporting broad generalizability to practice. This represents a potential opportunity for in-hospital implementation of evidence-based medical therapies and treatment optimization of stable chronic HFrEF, pending data on safety and efficacy of SGLT2 inhibitors in acute HF (NCT04363697, NCT04298229, NCT04157751).

References

McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008.
US Food and Drug Administration. FDA approves new treatment for a type of heart failure. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-type-heart-failure. Accessed on December 1, 2020.
Greene SJ, Fonarow GC, DeVore AD, et al. Titration of Medical Therapy for Heart Failure With Reduced Ejection Fraction. J Am Coll Cardiol. 2019;73(19):2365-83.
Greene SJ, Butler J, Albert NM, et al. Medical Therapy for Heart Failure With Reduced Ejection Fraction: The CHAMP-HF Registry. J Am Coll Cardiol. 2018;72(4):351-66.
Vaduganathan M, Greene SJ, Zhang S, et al. Applicability of US Food and Drug Administration Labeling for Dapagliflozin to Patients With Heart Failure With Reduced Ejection Fraction in US Clinical Practice: The Get With the Guidelines-Heart Failure (GWTG-HF) Registry. JAMA Cardiol. 2020 Nov 13:e205864. doi: 10.1001/jamacardio.2020.5864
Heerspink HJL, Stefánsson BV, Correa-Rotter R. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24. PMID: 32970396.
Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413-24. 32865377.