Heart Failure (HF)

Biomarkers in HF

Assays for BNP (B-type natriuretic peptide) and NT-proBNP (N-terminal pro-B-type natriuretic peptide), which are both natriuretic peptide biomarkers, have been used increasingly to establish the presence and severity of HF.
In general, both natriuretic peptide biomarker values track similarly, and either can be used in patient care settings as long as their respective absolute values and cutpoints are not used interchangeably.
Notably, BNP, but not NT-proBNP, is a substrate for neprilysin. Therefore, ARNI (Angiotensin receptor-neprilysin inhibitor) increases BNP levels but not NT-proBNP levels.
Note that the type of natriuretic peptide assay that has been performed must be considered during interpretation of natriuretic peptide biomarker levels in patients on ARNI.
In 2 studies with ARNI, NT-proBNP levels were reduced, with the reduction in 1 study being associated with improved clinical outcomes.

A substantial evidence base exists that supports the use of natriuretic peptide biomarkers to assist in the diagnosis or exclusion of HF as a cause of symptoms (e.g., dyspnea, weight gain) in the setting of chronic ambulatory HF or in the setting of acute care with decompensated HF, especially when the cause of dyspnea is unclear.
The role of natriuretic peptide biomarkers in population screening to detect incident HF is emerging. Elevated plasma levels of natriuretic peptide biomarkers are associated with a wide variety of cardiac and noncardiac causes (Table 2). Obesity may be associated with lower natriuretic peptide concentrations, and this may modestly reduce diagnostic sensitivity in morbidly obese patients.

Because of the absence of clear and consistent evidence for improvement in mortality and cardiovascular outcomes, there are insufficient data to inform specific guideline recommendations related to natriuretic peptide–guided therapy or serial measurements of BNP or NT-proBNP levels for the purpose of reducing hospitalization or deaths in the present document.

Like natriuretic peptides, cardiac troponin levels may be elevated in the setting of chronic or acute decompensated HF, suggesting myocyte injury or necrosis. Troponins I and T respond similarly for acute coronary syndromes and acute decompensated HF. Elevations in either troponin I or T levels in the setting of acute HF are of prognostic significance and must be interpreted in the clinical context.

In addition to natriuretic peptides and troponins, multiple other biomarkers, including those of inflammation, oxidative stress, vascular dysfunction, and myocardial and matrix remodeling, have been implicated in HF.
Biomarkers of myocardial fibrosis, soluble ST2 receptor, and galectin-3 are predictive of hospitalization and death and may provide incremental prognostic value over natriuretic peptide levels in patients with HF.
Strategies that combine multiple biomarkers may ultimately prove beneficial in guiding HF therapy in the future, but multicenter studies with larger derivation and validation cohorts are needed.
Several emerging biomarkers await validation with well-defined outcome measures and prognostic accuracy before they can reach the clinical arena.

This section categorizes the role of biomarkers into prevention, diagnosis, prognosis, and added risk stratification to clarify evidence-based objectives of their use in clinical practice.

Table 2. Selected Potential Causes of Elevated Natriuretic Peptide Levelsxperience

Cardiac
HF, including RV syndromes
Acute coronary syndromes
Heart muscle disease, including LVH
Valvular heart disease
Pericardial disease
Atrial fibrillation
Myocarditis
Cardiac surgery
Cardioversion
Toxic-metabolic myocardial insults, including cancer chemotherapy

Noncardiac
Advancing age
Anemia
Renal failure
Pulmonary: obstructive sleep apnea, severe pneumonia
Pulmonary hypertension
Critical illness
Bacterial sepsis
Severe burns

HF indicates heart failure;
LVH, left ventricular hypertrophy;
RV, right ventricular.

Table 1. Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015)

CLASS (STRENGTH) OF RECOMMENDATION (COR)
CLASS I (STRONG)
CLASS IIa (MODERATE)
CLASS IIb (WEAK)
CLASS III: No Benefit (MODERATE)
CLASS III: Harm (STRONG)

LEVEL (QUALITY) OF EVIDENCE (LOE)
Level A High-quality evidence
Level B-R (Randomized)
Level B-NR (Nonrandomized)
Level C-LD (Limited Data)
Level C-EO (Expert Opinion)

Biomarkers for Prevention of HF

In a large-scale unblinded single-center study (STOP-HF [The St Vincent’s Screening to Prevent Heart Failure]), patients at risk of HF (identified by the presence of hypertension, diabetes mellitus, or known vascular disease [e.g., stage A HF]), but without established left ventricular systolic dysfunction or symptomatic HF at baseline, were randomly assigned to receive screening with BNP testing or usual primary care.

Intervention group participants with BNP levels of ≥50 pg/mL underwent echocardiography and were referred to a cardiovascular specialist who decided on further investigation and management.
All patients received further coaching by a specialist nurse who emphasized individual risk and the importance of adherence to medication and healthy lifestyle behaviors.

BNP-based screening reduced the composite endpoint of asymptomatic left ventricular dysfunction (systolic or diastolic) with or without newly diagnosed HF.
Similarly, in another small, single-center RCT, accelerated up-titration of renin-angiotensin-aldosterone system antagonists and beta blockers reduced cardiac events in patients with diabetes mellitus and elevated NT-proBNP levels but without cardiac disease at baseline.

Developing a standardized strategy to screen and intervene in patients at risk of HF can be difficult because of different definitions of HF risk, heterogeneity of prevalence in different populations, variable duration until clinical HF or left ventricular dysfunction develops, and variable interventions for risk factor modification or treatment.

Further studies are needed to determine cost-effectiveness and risk of such screening, as well as its impact on quality of life (QoL) and mortality rate.

Biomarkers for Diagnosis of HF

Natriuretic peptide biomarker testing in the setting of chronic ambulatory HF provides incremental diagnostic value to clinical judgment, especially when the etiology of dyspnea is unclear.

In emergency settings, natriuretic peptide biomarker levels usually have higher sensitivity than specificity and may be more useful for ruling out than ruling in HF. Although lower values of natriuretic peptide biomarkers exclude the presence of HF, and higher values have reasonably high positive predictive value to diagnose HF, clinicians should be aware that elevated plasma levels for both natriuretic peptides have been associated with a wide variety of cardiac and noncardiac causes (Table 2).

Biomarkers for Prognosis of HF

Higher levels of natriuretic peptide biomarkers on admission are usually associated with greater risk for clinical outcomes, including all-cause and cardiovascular mortality, morbidity, and composite outcomes, across different time intervals in patients with decompensated HF.

Similarly, abnormal levels of circulating cardiac troponin are commonly found in patients with acute decompensated HF, often without obvious myocardial ischemia or underlying coronary artery disease (CAD), and this is associated with worse clinical outcomes and higher risk of death.

Studies have demonstrated incremental prognostic value of these biomarkers to standard approaches of cardiovascular disease risk assessment. However, there were differences in the risk prediction models, assay cutpoints, and lengths of follow-up.
Furthermore, not all patients may need biomarker measurement for prognostication, especially if they already have advanced HF with established poor prognosis or persistently elevated levels of biomarkers in former settings.
Therefore, assays of natriuretic peptide biomarkers for incremental prognostication should not preclude good clinical judgment; an individualized approach to each patient is paramount.

Predischarge natriuretic peptide biomarker levels and the relative change in levels during hospital treatment are strong predictors of the risk of death or hospital readmission for HF.

Several studies have suggested that predischarge natriuretic peptide biomarker levels had higher reclassification and discrimination value than clinical variables in predicting outcomes.
Patients with higher predischarge levels and patients who do not have a decrease in natriuretic peptide biomarker levels during hospitalization have worse outcomes.

Although observational or retrospective studies have suggested that patients with natriuretic peptide biomarker reduction had better outcomes than those without any changes or with a biomarker rise, targeting a certain threshold, value, or relative change in these biomarker levels during hospitalization may not be practical or safe for every patient and has not been tested in a prospective large-scale trial.

Clinical assessment and adherence to GDMT should be the emphasis, and the prognostic value of a predischarge value or relative changes does not imply the necessity for serial and repeated biomarker measurements during hospitalization.

Biomarkers of myocardial fibrosis (e.g., soluble ST2 receptor, galectin-3, high-sensitivity cardiac troponin, and others) are predictive of hospitalization and death in patients with HF and also are additive to natriuretic peptide biomarker levels in their prognostic value.

A combination of biomarkers may ultimately prove to be more informative than single biomarkers.

Biomarkers for Indications for Use in HF

Colors correspond to COR in Table 1.

*Other biomarkers of injury or fibrosis include soluble ST2 receptor, galectin-3, and high-sensitivity troponin.

ACC indicates American College of Cardiology;
AHA, American Heart Association;
ADHF, acute decompensated heart failure;
BNP, B-type natriuretic peptide;
COR, Class of Recommendation;
ED, emergency department;
HF, heart failure;
NT-proBNP, N-terminal pro-B-type natriuretic peptide;
NYHA, New York Heart Association;
pts, patients.

Renin‐Angiotensin System Inhibition

Angiotensin-converting enzyme (ACE) inhibitors reduce morbidity and mortality in heart failure with reduced ejection fraction (HFrEF).
Randomized controlled trials (RCTs) clearly establish the benefits of ACE inhibition in patients with mild, moderate, or severe symptoms of HF and in patients with or without coronary artery disease.

ACE inhibitors can produce angioedema and should be given with caution to patients with low systemic blood pressures, renal insufficiency, or elevated serum potassium.

ACE inhibitors also inhibit kininase and increase levels of bradykinin, which can induce cough but also may contribute to their beneficial effect through vasodilation.

Angiotensin receptor blockers (ARBs) were developed with the rationale that angiotensin II production continues in the presence of ACE inhibition, driven through alternative enzyme pathways.

ARBs do not inhibit kininase and are associated with a much lower incidence of cough and angioedema than ACE inhibitors; but like ACE inhibitors, ARBs should be given with caution to patients with low systemic blood pressure, renal insufficiency, or elevated serum potassium.
Long-term therapy with ARBs produces hemodynamic, neurohormonal, and clinical effects consistent with those expected after interference with the renin-angiotensin system and have been shown in RCTs to reduce morbidity and mortality, especially in ACE inhibitor– intolerant patients.

In ARNI (Angiotensin receptor neprilysin inhibitor), an ARB is combined with an inhibitor of neprilysin, an enzyme that degrades natriuretic peptides, bradykinin, adrenomedullin, and other vasoactive peptides.

In an RCT that compared the first approved ARNI, valsartan/sacubitril, with enalapril in symptomatic patients with HFrEF tolerating an adequate dose of either ACE inhibitor or ARB, the ARNI reduced the composite endpoint of cardiovascular death or HF hospitalization significantly, by 20%.
The benefit was seen to a similar extent for both death and HF hospitalization and was consistent across subgroups.

The use of ARNI is associated with the risk of hypotension and renal insufficiency and may lead to angioedema, as well.

ACE inhibitors

ACE inhibitors have been shown in large RCTs to reduce morbidity and mortality in patients with HFrEF with mild, moderate, or severe symptoms of HF, with or without coronary artery disease.

Data suggest that there are no differences among available ACE inhibitors in their effects on symptoms or survival. ACE inhibitors should be started at low doses and titrated upward to doses shown to reduce the risk of cardiovascular events in clinical trials.

ACE inhibitors can produce angioedema and should be given with caution to patients with low systemic blood pressures, renal insufficiency, or elevated serum potassium (>5.0 mEq/L). Angioedema occurs in <1% of patients who take an ACE inhibitor, but it occurs more frequently in blacks and women.

Patients should not be given ACE inhibitors if they are pregnant or plan to become pregnant.

ACE inhibitors also inhibit kininase and increase levels of bradykinin, which can induce cough in up to 20% of patients but also may contribute to beneficial vasodilation.

If maximal doses are not tolerated, intermediate doses should be tried; abrupt withdrawal of ACE inhibition can lead to clinical deterioration and should be avoided.

Although the use of an ARNI in lieu of an ACE inhibitor for HFrEF has been found to be superior, for those patients for whom ARNI is not appropriate, continued use of an ACE inhibitor for all classes of HFrEF remains strongly advised.

Angiotensin receptor blockers (ARBs)

ARBs have been shown to reduce mortality and HF hospitalizations in patients with HFrEF in large RCTs.

Long-term therapy with ARBs in patients with HFrEF produces hemodynamic, neurohormonal, and clinical effects consistent with those expected after interference with the renin-angiotensin system.

Unlike ACE inhibitors, ARBs do not inhibit kininase and are associated with a much lower incidence of cough and angioedema, although kininase inhibition by ACE inhibitors may produce beneficial vasodilatory effects.

Patients intolerant to ACE inhibitors because of cough or angioedema should be started on ARBs; patients already tolerating ARBs for other indications may be continued on ARBs if they subsequently develop HF.

ARBs should be started at low doses and titrated upward, with an attempt to use doses shown to reduce the risk of cardiovascular events in clinical trials.

ARBs should be given with caution to patients with low systemic blood pressure, renal insufficiency, or elevated serum potassium (>5.0 mEq/L). Although ARBs are alternatives for patients with ACE inhibitor–induced angioedema, caution is advised because some patients have also developed angioedema with ARBs.

Head-to-head comparisons of an ARB versus ARNI for HF do not exist.
For those patients for whom an ACE inhibitor or ARNI is inappropriate, use of an ARB remains advised.

Angiotensin receptor neprilysin inhibitor (ARNI)

Benefits of ACE inhibitors with regard to decreasing HF progression, hospitalizations, and mortality rate have been shown consistently for patients across the clinical spectrum, from asymptomatic to severely symptomatic HF.

Similar benefits have been shown for ARBs in populations with mild-tomoderate HF who are unable to tolerate ACE inhibitors.

In patients with mildto-moderate HF (characterized by either 1) mildly elevated natriuretic peptide levels, BNP [B-type natriuretic peptide] >150 pg/mL or NT-proBNP [Nterminal pro-B-type natriuretic peptide] ≥600 pg/mL; or 2) BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL with a prior hospitalization in the preceding 12 months) who were able to tolerate both a target dose of enalapril (10 mg twice daily) and then subsequently an ARNI (valsartan/sacubitril; 200 mg twice daily, with the ARB component equivalent to valsartan 160 mg), hospitalizations and mortality were significantly decreased with the valsartan/sacubitril compound compared with enalapril.

The target dose of the ACE inhibitor was consistent with that known to improve outcomes in previous landmark clinical trials.
This ARNI has been approved for patients with symptomatic HFrEF and is intended to be substituted for ACE inhibitors or ARBs.

HF effects and potential off-target effects may be complex with inhibition of the neprilysin enzyme, which has multiple biological targets.

Use of an ARNI is associated with hypotension and a low-frequency incidence of angioedema.

To facilitate initiation and titration, the approved ARNI is available in 3 doses that include a dose that was not tested in the HF trial; the target dose used in the trial was 97/103 mg twice daily. Clinical experience will provide further information about the optimal titration and tolerability of ARNI, particularly with regard to blood pressure, adjustment of concomitant HF medications, and the rare complication of angioedema.

Oral neprilysin inhibitors, used in combination with ACE inhibitors can lead to angioedema and concomitant use is contraindicated and should be avoided.

A medication that represented both a neprilysin inhibitor and an ACE inhibitor, omapatrilat, was studied in both hypertension and HF, but its development was terminated because of an unacceptable incidence of angioedema and associated significant morbidity. This adverse effect was thought to occur because both ACE and neprilysin break down bradykinin, which directly or indirectly can cause angioedema. An ARNI should not be administered within 36 hours of switching from or to an ACE inhibitor.

Omapatrilat, a neprilysin inhibitor (as well as an ACE inhibitor and aminopeptidase P inhibitor), was associated with a higher frequency of angioedema than that seen with enalapril in an RCT of patients with HFrEF.

In a very large RCT of hypertensive patients, omapatrilat was associated with a 3-fold increased risk of angioedema as compared with enalapril.
Blacks and smokers were particularly at risk.
The high incidence of angioedema ultimately led to cessation of the clinical development of omapatrilat.
In light of these observations, angioedema was an exclusion criterion in the first large trial assessing ARNI therapy in patients with hypertension and then in the large trial that demonstrated clinical benefit of ARNI therapy in HFrEF.

ARNI therapy should not be administered in patients with a history of angioedema because of the concern that it will increase the risk of a recurrence of angioedema.

Ivabradine

*In other parts of the document, the term “GDMT” has been used to denote guideline-directed management and therapy. In this recommendation, however, the term “GDEM” has been used to denote this same concept in order to reflect the original wording of the recommendation that initially appeared in the “2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure”.

Ivabradine is a new therapeutic agent that selectively inhibits the I_f current in the sinoatrial node, providing heart rate reduction.

One RCT demonstrated the efficacy of ivabradine in reducing the composite endpoint of cardiovascular death or HF hospitalization.
The benefit of ivabradine was driven by a reduction in HF hospitalization.
The study included patients with HFrEF (NYHA class II-IV, albeit with only a modest representation of NYHA class IV HF) and left ventricular ejection fraction (LVEF) ≤35%, in sinus rhythm with a resting heart rate of ≥70 beats per minute.
Patients enrolled included a small number with paroxysmal atrial fibrillation (<40% of the time) but otherwise in sinus rhythm and a small number experiencing ventricular pacing but with a predominant sinus rhythm.
Those with a myocardial infarction within the preceding 2 months were excluded.
Patients enrolled had been hospitalized for HF in the preceding 12 months and were on stable GDEM* for 4 weeks before initiation of ivabradine therapy.
The target of ivabradine is heart rate slowing (the presumed benefit of action), but only 25% of patients studied were on optimal doses of beta-blocker therapy.
Given the well-proven mortality benefits of beta-blocker therapy, it is important to initiate and up titrate these agents to target doses, as tolerated, before assessing the resting heart rate for consideration of ivabradine initiation.

Treatment of HFrEF Stage C and D

Colors correspond to COR in Table 1. For all medical therapies, dosing should be optimized and serial assessment exercised.
*See text for important treatment directions.
†Hydral-Nitrates green box: The combination of ISDN/HYD with ARNI has not been robustly tested. BP response should be carefully monitored.
‡See 2013 HF guideline.
§Participation in investigational studies is also appropriate for stage C, NYHA class II and III HF.
ACEI indicates angiotensin-converting enzyme
ARB, angiotensin receptor-blocker;
ARNI, angiotensin receptor-neprilysin inhibitor;
BP, blood pressure;
bpm, beats per minute;
C/I, contraindication;
COR, Class of Recommendation;
CrCl, creatinine clearance; CRT-D, cardiac resynchronization therapy–device; Dx, diagnosis; GDMT, guideline-directed management and therapy;
HF, heart failure;
HFrEF, heart failure with reduced ejection fraction;
ICD, implantable cardioverter-defibrillator;
ISDN/HYD, isosorbide dinitrate hydral-nitrates; K+, potassium;
LBBB, left bundle-branch block;
LVAD, left ventricular assist device;
LVEF, left ventricular ejection fraction;
MI, myocardial infarction;
NSR, normal sinus rhythm;
NYHA, New York Heart Association.

Drugs Commonly Used for HFrEF (Stage C HF)

ACE indicates angiotensin-converting enzyme;
ARB, angiotensin receptor blocker;
ARNI, angiotensin receptorneprilysin inhibitor;
CR, controlled release;
CR/XL, controlled release/extended release;
HF, heart failure; HFrEF, heart failure with reduced ejection fraction;
QD, once daily; BID, twice daily; and TID, 3 times daily.

Angiotensin-Converting Enzyme (ACE) Inhibitors
Commonly prescribed include:
•Captopril (Capoten)
•Enalapril (Vasotec)
•Fosinopril (Monopril)
•Lisinopril (Prinivil, Zestril)
•Perindopril (Aceon)
•Quinapril (Accupril)
•Ramipril (Altace)
•Trandolapril (Mavik)

Angiotensin II Receptor Blockers (or Inhibitors)
(Also known as ARBs or Angiotensin-2 Receptor Antagonists)
Commonly prescribed include:
•Candesartan (Atacand)
•Losartan (Cozaar)
•Valsartan (Diovan)

Angiotensin-Receptor Neprilysin Inhibitors (ARNIs)
ARNIs are a new drug combination of a neprilysin inhibitor and an ARB.
•Sacubitril/valsartan

I_f Channel Blocker (or inhibitor)
This drug class reduces the heart rate, similar to another class of drugs called beta blockers.
•Ivabradine (Corlanor)

Beta Blockers
(Also known as Beta-Adrenergic Blocking Agents)
Commonly prescribed include:
•Bisoprolol (Zebeta)
•Metoprolol succinate (Toprol XL)
•Carvedilol (Coreg)
•Carvedilol CR (Coreg CR)Toprol XL

Aldosterone Antagonists
Commonly prescribed include:
•Spironolactone (Aldactone)
•Eplerenone (Inspra)

Hydralazine and isosorbide dinitrate (specifically benefits African Americans with heart failure)
Commonly prescribed:
•Hydralazine and isosorbide dinitrate (combination drug) - (Bidil)

Diuretics
(Also known as Water Pills)
Commonly prescribed include:
•Furosemide (Lasix)
•Bumetanide (Bumex)
•Torsemide (Demadex)
•Chlorothiazide (Diuril)
•Amiloride (Midamor Chlorthalidone (Hygroton)
•Hydrochlorothiazide or HCTZ (Esidrix, Hydrodiuril)
•Indapamide (Lozol)
•Metolazone (Zaroxolyn)
•Triamterene (Dyrenium)
What this type of medication does:
Causes the body to rid itself of excess fluids and sodium through urination. Helps to relieve the heart's workload. Also decreases the buildup of fluid in the lungs and other parts of the body, such as the ankles and legs. Different diuretics remove fluid at varied rates and through different methods.

Other possible medications that might be prescribed
Your doctor may also prescribe other less commonly used drugs depending on your additional health problems. These drugs include:
•Anticoagulants (blood thinners)
These drugs may be prescribed if you are a heart failure patient with atrial fibrillation, or have another problem with your heart where adding this drug is indicated. Anticoagulants are not used to treat heart failure without the presence of atrial fibrillation.
•Cholesterol lowering drugs (statins)
Your doctor may prescribe this class of medication if you have high cholesterol or have had a heart attack in the past. This class of drugs is not used to treat heart failure, but other conditions as indicated.
•Digoxin
There are some heart failure patients who might be prescribed this drug as the doctor feels indicated.

Additional medication information:
Find further descriptions of how these medications also affect cardiovascular diseases other than heart failure.

Pharmacological Treatment for Stage C HFpEF: Recommendations

Mechanistic studies have suggested that mineralocorticoid receptor antagonists can improve measures of diastolic function in patients with HFpEF, possibly by a similar effect on remodeling.

The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial investigated the effects of spironolactone on a combined endpoint of death, aborted cardiac death, and HF hospitalization in patients with HFpEF.
A small reduction (HR=0.89) in this composite endpoint did not reach statistical significance, although HF hospitalization was reduced (HR=0.83);
known side effects of hyperkalemia and rising creatinine were seen more commonly in the treatment group.
An unusual amount of regional variation was seen in this trial, prompting a post-hoc analysis that showed that rates of the primary endpoint were 4-fold lower in Russia/Georgia than in North America and South America (the Americas).
Rates in the Americas were comparable to those in other HFpEF trials. The post-hoc analysis showed efficacy in the Americas (HR=0.83) but not in Russia/Georgia (HR=1.10). Moreover, a sample of the Russia/Georgia population, despite having been in the active treatment arm, had nondetectable levels of the metabolite of spironolactone.
These post-hoc analyses have significant limitations, but they suggest that in appropriately selected patients with symptomatic HFpEF (with ejection fraction [EF] ≥45%, elevated BNP level or HF admission within 1 year, estimated glomerular filtration rate >30 mL/min creatinine <2.5 mg/dL, and potassium <5.0 mEq/L), particularly in those with elevated BNP levels, use of spironolactone might be considered with close monitoring of potassium and renal function.
Confirmatory studies are required.
With regard to the use of mineralocorticoid receptor antagonists, creatinine should be <2.5 mg/dL in men or <2.0 mg/dL in women (or estimated glomerular filtration rate >30 mL/min) and potassium should be <5.0 mEq/L. Careful monitoring of potassium, renal function, and diuretic dosing represents best practices at initiation and during follow-up thereafter to minimize risk of hyperkalemia and worsening renal function.

Nitrate therapy can reduce pulmonary congestion and improve exercise tolerance in patients with HFrEF.
However, the NEAT-HFpEF (Nitrate’s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction) trial randomized 110 patients with EF ≥50% on stable HF therapy, not including nitrates, and with activity limited by dyspnea, fatigue, or chest pain, to either isosorbide mononitrate or placebo and found no beneficial effects on activity levels, QoL, exercise tolerance, or NT-proBNP levels.
On the basis of this trial, routine use of nitrates in patients with HFpEF is not recommended.
This recommendation does not apply to patients with HFpEF and symptomatic CAD for whom nitrates may provide symptomatic relief.

Phosphodiesterase-5 inhibition augments the nitric oxide system by upregulating cGMP activity.
The RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) trial randomized 216 patients with EF ≥50% on stable HF therapy and with reduced exercise tolerance (peak observed VO2 <60% of predicted) to phosphodiesterase-5 inhibition with sildenafil or placebo.
This study did not show improvement in oxygen consumption or exercise tolerance.

9.5.1. Treating Hypertension to Reduce the Incidence of HF: Recommendation

A large RCT demonstrated that in those with increased cardiovascular risk (defined as age >75 years, established vascular disease, chronic renal disease, or a Framingham Risk Score >15%), control of blood pressure to a goal systolic pressure of <120 mm Hg, as determined by blood pressure assessment as per research protocol, was associated with a significant reduction in the incidence of HF and an overall decrease in cardiovascular death.

Blood pressure measurements as generally taken in the office setting are typically 5 to 10 mm Hg higher than research measurements; thus, the goal of <130/80 mm Hg is an approximation of the target blood pressure in conventional practice.

Targeting a significant reduction in systolic blood pressure in those at increased risk for cardiovascular disease is a novel strategy to prevent HF.

Clinical trials evaluating goal blood pressure reduction and optimal blood pressure–lowering agents in the setting of HFrEF and concomitant hypertension have not been done.
However, it is apparent that in those patients at higher risk, blood pressure lowering is associated with fewer adverse cardiovascular events.
GDMT for HFrEF with agents known to lower blood pressure should consider a goal blood pressure reduction consistent with a threshold now associated with improved clinical outcomes but not yet proven by RCTs in a population with HF