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

Table of contents for the PARAGON-HF Trial summary:

October 24 2019

Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction

The Paragon-HF Trial

Scott D. Solomon, M.D., John J.V. McMurray, M.D., Inder S. Anand, M.D., D.Phil., Junbo Ge, M.D., Carolyn S.P. Lam, M.B., B.S., Ph.D., Aldo P. Maggioni, M.D., Felipe Martinez, M.D., Milton Packer, M.D., Marc A. Pfeffer, M.D., Ph.D., Burkert Pieske, M.D., Margaret M. Redfield, M.D., Jean L. Rouleau, M.D., Dirk J. van Veldhuisen, M.D., Faiez Zannad, M.D., Michael R. Zile, M.D., Akshay S. Desai, M.D., M.P.H., Brian Claggett, Ph.D., Pardeep S. Jhund, M.B., Ch.B., Ph.D., Sergey A. Boytsov, M.D., Josep Comin-Colet, M.D., John Cleland, M.D., Hans-Dirk Düngen, M.D., Eva Goncalvesova, M.D., Tzvetana Katova, M.D., Jose F. Kerr Saraiva, M.D., Małgorzata Lelonek, M.D., Bela Merkely, M.D., Michele Senni, M.D., Sanjiv J. Shah, M.D., Jingmin Zhou, M.D., Adel R. Rizkala, Pharm.D., Jianjian Gong, Ph.D., Victor C. Shi, M.D., and Martin P. Lefkowitz, M.D. for the PARAGON-HF Investigators and Committee

  • To date, there are no proven treatments to reduce the morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF), with therapies mainly focused on symptomatic relief and treatment of co-existing conditions.
  • PARADIGM-HF, which evaluated sacubitril-valsartan vs enalapril in patients with heart failure with reduced ejection fraction (HFrEF), reported a decrease in mortality, risk of hospitalization for heart failure, symptoms and physical limitations in such patients.
  • The positive results of PARADIGM-HF, along with evidence of improved cardiac biomarkers and remodeling with sacubitril-valsartan use in HFpEF patients, led to the PARAGON-HF trial

Relevant Guidelines for PARAGON-HF11

  • Mineralocorticoid antagonists can be considered to decrease hospitalizations for heart failure exacerbations in patients with HFpEF if the following criteria are met: EF ≥ 45%, elevated BNP or heart failure admission within 1 year, eGFR >30 and creatinine <2.5 mg/dl, and potassium <5.0 mEq/L. (COR IIb, LOE B-R)
  • The use of ARBs can be considered in HFpEF patients to decrease hospitalizations (COR IIb, LOE B)
  • In patients with NYHA Stage II-III HFrEF tolerating ACE-inhibitor or ARB, replacement with ARNI is recommended to improved morbidity and mortality (COR I, LOE B-R)

Study Rational

Given the known mortality benefit of sacubitril-valsartan in HFrEF, and the improvement in cardiac biomarkers and remodeling seen in HFpEF, a randomized clinical trial was initiated to investigate the effect of sacubitril-valsartan, when compared to valsartan alone, on cardiovascular mortality and heart failure hospitalization in patients with HFpEF.  


The Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction (PARAGON-HF) trial was designed to test if the use of sacubitril/valsartan in patients with HFpEF will lead to improved cardiovascular mortality and decreased rates of heart failure hospitalizations.

Paragon-HF Trial:
Randomized, double-blind, active-comparator trial, international (43 countries)

Patients were randomly assigned to receive sacubitril-valsartan (target dose 97-103 mg twice daily) or valsartan (target dose, 160 mg twice daily)

Enrollment criteria 


Statistical Analysis
Intention-to-treat analysis, with a hierarchical, sequentially rejective procedure for secondary outcomes if the primary outcome was positive

Notable Baseline Characteristics

  • Average age: 72.7 (sacubitril-valsartan) and 72.8 (valsartan) years old
  • Female sex: 51.6% (sacubitril-valsartan) vs. 51.8% (valsartan)
  • Average ejection fraction: 57% in both treatment arms
  • ~34-37% with ischemic heart failure in both treatment arms
  • Medications (sacubitril-valsartan group): diuretics 95%, ACEI or ARB 86%, mineralocorticoid antagonist 25%, beta-blocker 80%
  • PMHx (sacubitril-valsartan group): HTN 96%, DM 44%, AF/Aflutter 32%, stroke 11%, prior HF hospitalization 47%, prior MI 23%

Primary Outcome (Sacubitril-Valsartan vs Valsartan)

  • Composite outcome of HF hospitalization and CV mortality: 894 vs 1009  (RR 0.87; 95% CI 0.75-1.01, p=0.06)
    • HF hospitalizations: 690 vs 797 (RR 0.85, CI 0.72-1.00)
    • CV Deaths: 204 vs 212 (HR 0.95, CI 0.79-1.16)
Paragon-HF Primary Outcomes

Secondary Outcomes (Sacubitril-Valsartan vs Valsartan)

  • Change in NYHA class at 8 months
    • OR 1.45 (95% CI 1.13-1.86)
  • Change in KCCQ clinical summary score at 8 months
    • -1.6 vs -2.6 (Difference 1.0; 95% CI 0.0-2.1)
  • Renal composite – Renal failure mortality, ESRD or decrease in EGFR >50% from baseline
    • 1.4% vs 2.7% (HR 0.50; 95% CI 0.33-0.77)
  • All-cause Mortality
    • 14.2% vs 14.6% (HR 0.97; 95% CI 0.84-1.13)

Adverse events

Adverse Events (Sacubitril-Valsartan vs Valsartan)

  • Hypotension with SBP <100mmHg: 15.8% vs. 10.8% (p<0.001)
  • Elevated serum creatinine >2.0 mg/dl: 10.8% vs. 13.7% (p=0.002)
  • Elevated serum potassium:
    • >5.5mmol/liter: 13.2% vs. 15.3% (p=0.048)
    • >6.0mmol/liter 3.1% vs. 4.3% (p=0.04)
  • Angioedema: 0.6% vs 0.2% (p=0.02)

PARAGON-HF Trial Conclusions

In patients with clinically overt HFpEF (LVEF ≥45%), there was no significant difference in heart failure hospitalization and cardiovascular-related death between patients on sacubitril-valsartan compared to valsartan alone.

Limitations & Considerations

  • In an exploratory analysis of secondary outcomes, sacubitril-valsartan was associated with improved NYHA class at month 8 compared to baseline and decreased incidence of renal function decline.
  • Trial included patients with HF mid-range EF (EF 45-50%) who may derive benefits from sacubitril-valsartan. Furthermore, a third of patients had ischemic heart disease which may also derive benefits from sacubitril-valsartan.
  • Given the extensive exclusion criteria, only 4822 patients, out of 10,359 that were screened, underwent randomization. 
  • Strict criteria for adjudication of HF hospitalizations by the steering committee, compared to investigator-reported, resulted in enough adjustments in the outcomes that the trial changed from positive (p < 0.05) to negative (p > 0.05)12
  • Post-hoc analyses identified women and EF < 57% as two categories with a significant response to sacubitril-valsartan, though these are both considered hypothesis-generating13

1. Redfield MM. Heart failure with preserved ejection fraction. New England Journal of Medicine. 2016;375(19):1868-1877.

2. McMurray JJV, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.

3. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. The Lancet. 2003;362(9386):777-781.

4. Cleland JGF, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (Pep-chf) study. Eur Heart J. 2006;27(19):2338-2345.

5. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. New England Journal of Medicine. 2008;359(23):2456-2467.

6. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309(12):1268.

7. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383-1392.

8. Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation. 2015;131(1):34-42. doi:10.1161/CIRCULATIONAHA.114.013255

9. Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide mononitrate in heart failure with preserved ejection fraction. New England Journal of Medicine. 2015;373(24):2314-2324.

10. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. The Lancet. 2012;380(9851):1387-1395.

11.. Yancy Clyde W., Jessup Mariell, Bozkurt Biykem, et al. 2017 acc/aha/hfsa focused update of the 2013 accf/aha guideline for the management of heart failure. Journal of the American College of Cardiology. 2017;70(6):776-803.

12. O’Connor CM, deFilippi C. Paragon-hf — why we do randomized, controlled clinical trials. New England Journal of Medicine. 2019;381(17):1675-1676

13. McMurray John J.V., Jackson Alice M., Lam Carolyn S.P., et al. Effects of sacubitril-valsartan versus valsartan in women compared with men with heart failure and preserved ejection fraction. Circulation. 2020;141(5):338-351.


Dr. Omid Amidi, @OAmidiMD, Cardiology Fellow at UCLA, Los Angeles, CA. 


Dr. Najah Khan, @najahakhan, Internal Medicine Resident at Houston Methodist Hospital, Houston, TX. 


Dr. Dinu Balanescu, @dinubalanescu, Internal Medicine Resident at Beaumont Health, Royal Oak, MI. 


Gurleen Kaur, Gurleen_Kaur96, Medical Student at Albany Medical College, Albany, NY


Dr. Evelyn Song, @EvelynSongMD, Internal Medicine Resident at the Johns Hopkins Hospital, Baltimore, MD. 


Dr. Alexandra Pipilas, @apipilasMD, Cardiology Fellow at Boston University, Boston, MA

Dr. Maria Pabon, @mapabonp, Cardiology Fellow at Brigham and Women’s, Boston, MA

CardioNerds Correspondent

Dr. Mark Belkin, @MarkBelkinMD, Cardiology Fellow at University of Chicago, Chicago, IL


Dr. Carine Hamo, @CarineHamo, cardiology fellow at the Johns Hopkins Hospital, Baltimore, MD

The published archive features curated twitter highlights from the journal club event featuring the PARAGON-HF trial.

Phenotypes of HFpEF

Richard Ferraro (@RichardAFerraro)

Lots of #CardsJC discussion on varying HFpEF phenotypes. Where should the internist in clinic start with work up for etiology?

Kavita Sharma (@KSharmaMD)

First evaluate for co-morbidities associated with #HFpEF. Suspect amyloid when: BMI is low, BNP is high, trop elevated, echo signs of infiltrative disease. We get serum light chains, nuclear scan for ATTR disease in select patients @hopkinsheart HFpEF Clinic.

TcPYP scan not always conclusive in #HFpEF. Apical sparing strain on echo does not always distinguish HFpEF from #amyloidosis. If extra-cardiac symptoms, above features, keep looking. Tissue is the issue – go for biopsy of clinical suspicion is high.

Devesh Rai (@DeveshRaiMD)

Evaluating for red flag signs of amyloid is good. I wish there was the predictive model on the basis of amyloid risk factors. Biceps rupture, Spinal stenosis, Carpal tunnel syndrome, Chronic trop, and BNP elevation

Ronald Witteles (@Ron_Witteles)

Great question @RichardAFerraro. At the very least screening for ATTR amyloid in the right population (particularly older men with significantly increased wall thickness) makes sense – as testing is simple & we have Rx.…

Mark Belkin (@MarkBelkinMD)

Definitely! Learned from @SarswatNitasha to do a careful history (carpal tunnel, spinal stenosis, GI issues, family history, etc) and always review echo images, not just the report. Low threshold to test. Similarly consider other etiologies, like sarcoid

Dinu Balanescu (@dinubalanescu)

Amyloid is a recurrent topic on our PARAGON-HF discussion on HFpEF. Should our first question when diagnosing HFpEF be “ok is this amyloid?” Are we underscreening? Are we screening at all?

Amit Goyal (@AmitGoyalMD)

Would it make sense for future HFpEF trials to have a “run-in” period where underlying etiologies like amyloid are actively evaluated?

Chony Albert (@ChonyAlbertMD)

Keeping a healthy index of suspicion for infiltrative heart disease is step one! This is a nice summary. I probably “over screen” my HFpEF patients for amyloid. However better to over than under screen I think.

HFpEF Treatment


You just diagnosed your patient with HFpEF. What is your go-to initial treatment and why?

Gregg Fonarow (@gcfmd)

Protect patient with AS from cardioembolic stroke with NOAC. Consider underlying etiologies, including amyloid.


What do you think are the most promising novel therapies that are being studied for HFpEF?

Ryan J Tedford (@RyanTedfordMD)

Hard not to say SGLT-2 (or combined 1/2) right now. Don’t count out splanchnic nerve modulation.

Dinu Balanescu (@dinubalanescu)

As a resident I read TOPCAT and would’ve said spironolactone, but when I brought that up on my Cards consult month, I always got shut down. Is there a role for aldactone yet? Or are we all about ARNI/SGLT2i?

Mark Belkin (@MarkBelkinMD)

With the secondary analyses of TOPCAT it’s hard to think it doesn’t help. I tend to try to start it, if just for HTN, where it can be very powerful, especially in the obese phenotype patients.

Ed Kasper (@EdKasper3)

To Dinu. Topcat is a complicated study with lots of problems. I think there is something there. It could be a topic for another night.

Devesh Rai (@DeveshRaiMD)

Where does this diuretics stand on these, although no mortality benefits.

Ronald Witteles (@Ron_Witteles)

Diuretics remain a critical part of HF care. Always a bit of an oversimplification to say they don’t lower mortality in HF; it’s a trial you couldn’t practically do for diuretic-dependent patients (i.e. most patients). But no substitute for GDMT – at least in HFrEF.


Gregg Fonarow (@gcfmd)    

All cause mortality reductions in RCTs in HFrEF and HFpEF

Wei Ni (@niwei78)

Thanks for sharing. Great to see the improvements in rEF management. Let’s not to forget the mortality rate and HF hospitalization in rEF patients are still comparable to pEF patients even when rEF patients are on optimal therapies. There are work still need to be done for both.

Daniel Pipilas (@DPipilasMD)

Is there a HFpEF patient that hasn’t yet had “HF” who may benefit? A phenotype with a cardiomyopathy like in HFrEF? @apipilasMD

Dinu Balanescu (@dinubalanescu)

What about HF with recovered EF (HFrecEF)? Do we address as HFrEF or HFpEF?

Carine Hamo (@CarineHamo)

Excellent Question! We know that these patients have better outcomes than HfpEF and HFrEF but still have persistent risk.

Vanessa Blumer (@vmbluml)

Being able to define #HeartFunctionNotFailure is so important!! This is very helpful to see new definitions:…

Alexandra Pipilas (@apipilasMD)

I think it may be hard to get a positive HFpEF trial until we get better at stratifying by underlying mechanism (amyloid, HCM, hemochromatosis, HTN ect.)

Ed Kasper (@EdKasper3)

Trajectory is important. Is EF improving or declining? These are likely different subsets.Not all HFpEF.

Daniel Pipilas (@DPipilasMD)

Yes, true! Or even patients with a stable EF and more frequent exacerbations. EF doesn’t equal outcomes (and HFpEF patients often have worse outcomes)

Approach to HTN in HFpEF & Use of Valsartan

Ed Kasper (@EdKasper3)

You can make an argument for ARNI, ARB, MRA to treat HTN

Gregg Fonarow (@gcfmd)

Choice of ARB as control driven by findings in CHARM-PRESERVED and Class IIB recommendation in HF guidelines for ARB. If it had been Sac/Val vs placebo question would have remained could the same results be obtained with ARB alone.

Amit Goyal (@AmitGoyalMD)

I don’t quite understand the use of valsartan as an active comparator — not my standard of care for HFpEF, especially in those without HTN…?

Michael Felker (@DukeHFDoc)

The data showed that the vast majority of eligible patients would be treated with a RAAS inhibitor. That meant either excluding them (impractical) or stopping RAASi to enroll (which could be harmful). Active control was the best compromise.

Matthew Sparks (@Nephro_Sparks)

IMO this is strength to have valsartan only. Cleaner result without confounder of apples and oranges with ACEi or varied doses of other ARBs.

Vanessa Blumer (@vmbluml)

Active comparator (valsartan) because 87% of HFpEF patients on ACEi/ARB at baseline.

BNP as a Surrogate Endpoint

Ryan M. Heer (@DrRyanHeer)

high bnp can be due to lung/ki dz plus may be different b/w males vs females. not a great endpoint.

Carine Hamo (@CarineHamo)

Not to mention differences observed in those with obesity…which compose a large portion of those with HFpEF

Keith Andrew Chan (@keithachanmd)

Given the pharmacologic effects and pathways acted on by ARNIs, I dont think it’s entirely a good measure

Gregg Fonarow (@gcfmd)

NT-BNP tracked benefit in HFrEF. However in HFpEF, where there is more AF, frequent high BMI, and less well understood pathophysiology, has been less predictive/useful.

BNP Cutoff for Inclusion Criteria

Maria A. Pabon (@mapabonp)

Unfortunately some patients with HFpEF (up to 1/3) may have low levels of BNP which makes HFpEF trial design difficult

Chony Albert (@ChonyAlbertMD)

I think it is essential for any well-run HFpEF to be stringent with its inclusion criteria given the heterogeneity of “HFpEF.” This BNP cutoff necessary. I only wonder if the cutoff should have even been higher. #ParagonHF

Daniel Ambinder (@Dr_DanMD)

Would there be a way to use BNP in relationship to #BMI – like a BNP/BMI index

Vibhu Parcha (@Vibhuparcha)

Absolutely correct. We noted this recently in HFrEF and have established this several times even in healthy young adults. See:…

Devesh Rai (@DeveshRaiMD)

NT-pro BNP changes with obesity…

Ronald Witteles (@Ron_Witteles)

The problem with NOT including BNP cutoffs is enrolling pts who don’t have HF at all in the trials. Lots of things (venous insufficiency, renal failure, lung disease to name a few) get incorrectly labeled “HFpEF” and you clearly want to avoid those pts in a trial.

Keith Andrew Chan (@keithachanmd)

Inclusion of BNP appropriate – currently adheres to our understanding of HFpEF. Also “standardizes” enrollment with the large degree of heterogeneity. Was probably wondering if cath criteria would be overkill

Kevin shah (@KevinShahMD)

Adding inclusion of natriuretic peptides and structural abnormalities on echo improved refinement of #HFpEF trials- but there’s still room to go

Does a 95% CI ending in 1.00 mean we should clinically dismiss this result?

Ed Kasper (@EdKasper3)

Look carefully. The trial did not find the number of events they expected. They then went looking for events – hence the Investigator vs adjudication committee difference.

Daniel Ambinder (@Dr_DanMD)

Fascinating! Is this something common in trials – and is there a way to address this in trial design @EdKasper3

Ed Kasper (@EdKasper3)

Yes. You can do an interim analysis at say 70% enrollment. Extend the trial if the # of expected events is within reach.

Subgroup Analysis in Women

Maria A. Pabon (@mapabonp)

PARAGON-HF shows again how all of the HFpEF patients are not the same, women and those with EF in the lower range may be benefit from sacubitril-valsartan

GurleenKaur (@Gurleen_Kaur96)

Article poses many hypotheses: normal LVEF range higher inwomen (sex-related differences in cardiac remodeling), age-related arterial stiffening higher in women, neprilysin also degrades other peptides (sex-related diff in alternative actions)…

Ashish Correa (@AshishCorrea)

Could it be because there was a lot of undiagnosed amyloid? And ATTRwt amyloid is more common in men.

Andrew J. Sauer (@AndrewJSauer)

Seems likely related to differences in remodeling already described/observed in males vs females and we know patients with more “HFrEF-like” remodeling benefited more from ARNI.

Ed Kasper (@EdKasper3)

Raises an interesting hypothesis. Needs further study.

Muthu Vaduganathan (mvaduganathan)       

Interestingly similar sex-LVEF interactions observed in pooled analyses of trials of ARB (#CHARM program) and MRA (#RALES#EMPHASIS#TOPCAT). The benefit of each Rx seemed to extend to a higher LVEF in women, compared with men.…

Adi Sabarwal (@Suberwall)

I think PARAGON and vast preceding trials tell us we need to execute HFpEF trials differently; disease state with vast heterogeneity where ‘HFpEF’ is just the common denominator. Why did the female arm show improvement relative to males? Need to dig into comorbidities.

Amit Goyal (@AmitGoyalMD)

Historic HFpEF trials had relatively fewer women so these differences may have been overshadowed…should we stratify randomization by sex in future trials?

Quentin Youmans (@QuentinYoumans)

Future HFpEF trials should definitely plan to stratify by sex. The underrepresentation is striking and we’re only beginning to understand the sex differences that exist.

Vanessa Blumer (@vmbluml)

This supports something we already know: We need to enroll more women in clinical trials and more research focused on women!!! Stratifying by sex is not enough

Vibhu Parcha (@VibhuParcha)

Absolutely!! This is true for most of the CV trials(~65% is White Male pts.) and especially true for HFpEF. We have a massive under representation of racial subgroups where more HTN and more HFpEF.

FDA Approval of ARNI for HFpEF

Robert Mentz (@robmentz)

Would clarify that the label expansion notes an indication for “chronic HF” – with benefits most clearly evident in those with “LVEF below normal”. Also notes “LVEF is a variable measure, so use clinical judgment in deciding whom to treat”

Ed Kasper (@EdKasper3)

I thought so when we debated it. It is carefully worded to NOT say HFpEF but “less than normal” EF.

Changes to Clinical Practice

Robert Mentz (@robmentz)

Nice to have a new tool in our toolkit to help pts with HF regardless of EF (aka, also in mildly reduced or preserved EF) – have started to prescribe and thankful for a fantastic partner in my clinic nurse who is helping make it possible

Roberta Florido (@FloridoRoberta)

I have started prescribing it for some patients with EF 40-50%, however, have had issues with insurance approval

Ed Kasper (@EdKasper3)

Remember, FDA approval was only in December. It will take time for insurance to catch up

Future of HFpEF Trials

Robert Mentz (@robmentz)

Lots of excitement about SGLT2i. Also, must highlight the ongoing PARAGLIDE-HF trial investigating ARNI vs. val in patients stabilized with acute HF (EF>40%) – inhospital or within 30 days of d/c. Recruitment ongoing!…

Gregg Fonarow (@gcfmd)

SGLT2 inhibitors may be the therapy that finally shows clear benefit. We will find out soon.

Ed Kasper (@EdKasper3)

I think what’s next is better phenotyping. EF isn’t enough. See Dr Sharma’s work.

Roberta Florido (@FloridoRoberta)

Agree. Trial defined on sub-groups/phenotypes, not just broad HFpEF.

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