Nuances in Medical Therapy in Heart Failure


Nuances in Medical Therapy in Heart Failure

The American College of Cardiology’s newest consensus decision pathway for patients hospitalized for heart failure (Hollenbery Warner Stevenson, Ahmad et al; JACC, September 2019 DOI: 10.1016) underscores, among many factors, the key role that comprehensive assessment of comorbid conditions plays as part of the initial assessment for these patients. Due to the contributory effect of comorbidities to heart failure decompensation, and highly individualized individual risk factors, early assessment and intervention to mitigate these effects is key. 

Challenge yourself on what you would do for different clinical trajectories of heart failure through case study presentations in CurrentMD’s  Nuances in Medical Therapy in Heart Failure, a series of five unique case scenarios addressing the complexities of heart failure.

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Case Presentation

So our case is a 76-year-old man who presents to the outpatient clinic with fatigue, shortness of breath with minimal exertion, increasing edema. He is known to have history of ischemic cardiomyopathy with a left ventricular ejection fraction of 15%, history of NYHA class III heart failure symptoms, and he is status post CRTD. He states that his symptoms have not changed much over the last three months, but edema is slightly worse. He is comfortable at rest but has marked limitation of physical activity and can only walk one block, and he then gets short of breath. On physical exam, his blood pressure is 102/70. Heart rate is 78. He has marked jugular venous distention with bibasilar rales and 2+ edema. His past clinical physical exams were similar. He is on furosemide 40 mg twice daily, lisinopril 5 mg once daily, metoprolol succinate 25 mg once daily. ACE inhibitors have been intermittently discontinued due to his kidney function, and he was just restarted on lisinopril. His BNP is 2100. Three months ago, it was 1800. His creatinine is 1.6. Three months ago, it was 1.8. The eGFR is 28, and potassium is 4.9. EKG reveals A-V sequentially paced rhythm at a rate of 75, which is unchanged from baseline.

What is the best next step in his management?

A: Consider switching lisinopril to sacubitril/valsartan.

B: Add ivabradine.

C: Add spironolactone.

D: Increase furosemide.

E: Do not change the current management.

Our correct answer is, "Increase furosemide." The rationale for increased furosemide is that the patient is congested and has been inadequately treated to relieve congestion symptoms. This may have been due to the concerns for chronic kidney disease and/or chronicity of his symptoms. It's important to recognize that residual congestion and increase in elevated LV filling pressures are associated with adverse outcomes.

Congestion and HF Hospitalization

Also, keep in mind that for hospitalized heart failure patients with signs of improving congestion during hospitalization, such as improvement in physical exam signs of JVD, rales, and edema, or invasively measured filling pressures, or evidence of hemoconcentration and reduction of natriuretic peptides have all been associated with better outcomes.

The association of elevated filling pressures with adverse outcomes. The data is from COMPASS trial, demonstrating that estimated resting PA diastolic pressures are associated with a heart failure-related event, as can be seen as the filling pressures rise either in heart failure with reduced EF patients or presented by the green line, or heart failure with preserved ejection fraction represented by the red line. As you can see, there is an escalation or rise in the PA pressures, which eventually result in a heart failure-related event, such as admission to the hospital or an urgent care visit. So the rise in Pa pressures usually precede an event that culminates in a hospitalization.

Decongestion & Outcomes

The association with death or readmission rates when the filling pressures, represented by the BNP levels, remain elevated in hospitalized heart failure patients, as can be seen if the BNP levels are high at the time of the discharge, represented by the red line. The combined end point of death or readmission rates are quite high. Whereas if the BNP levels are less than 350, compared to the elevated levels, the event rates are much lower. So if a patient achieves the decongestion state, the association is usually better.

Keep in mind though, targeted therapies, meaning BNP targeted or NT-proBNP targeted approaches, have not been proven to be better than guideline-directed medical therapies either for acute or chronic heart failure patients. Thus, we do not advocate trying to achieve a certain number of BNP or NT-proBNP during hospitalization, but keep in mind: try to decongest the patient during hospitalization or even as an outpatient, and decongestion strategies. Achieving appropriate decongestion is associated with better outcome.


And if we were to look at why the sacubitril/valsartan was not an appropriate choice, sacubitril/valsartan is an angiotensin receptor blocker with neprilysin inhibition. According to the 2017 Focused Update of Heart Failure Guidelines, patients with chronic symptomatic heart failure with reduced EF NYHA class II or III, who tolerate an ACE inhibitor or ARB, then replacing by an ARNI is recommended to further reduce morbidity and mortality. Keep in mind, this patient has not been able to tolerate ACE inhibitors consistently. And if we were to look at our recommendations, represented by the first row in the table, again, ARNI is recommended in patients who tolerate an ACE inhibitor or ARB which our patient is unfortunately unable to tolerate.

If we are to further examine the reasons for not being able to administer sacubitril/valsartan, as we had stated, he has not been ultimately treated with ACE inhibitors, and also he's not been appropriately decongested, and it's usually expected for the patient to achieve a certain stability before initiation of ARNI, and we would like to see optimal decongestion prior to consideration for ARNI initiation, and in addition to stability on ACE inhibitors.

Renal Function and ARNI

Therefore, initiation of ARNI at present time would not be appropriate. And if we were to examine whether the ARNI would be appropriate according to patient's renal function, keep in mind sacubitril/valsartan was tested among patients with chronic heart failure with reduced EF in a randomized controlled trial named "Paradigm Heart Failure Trial," which enrolled patients with class two to four, predominantly class two to three heart failure patients with EF of less than 40%, on stable doses of ACE inhibitors or ARBs], and on other background guideline-directed medical therapy.

Keep in mind that patients with history of angioedema, eGFR less than 30, symptomatic hypotension, or current decompensated heart failure were excluded. Subjects like our patient, who has an eGFR of less than 30...Remember our patient had an eGFR of 28...were not included in the Paradigm HF trial. The FDA package insert, however, does not exclude patients with eGFR less than 30, but rather recommends a lower initiation dose, and we'll go over the reasons as to why.


If we look at the Paradigm HF adverse events, the symptomatic hypotension rates were higher with the sacubitril/valsartan arm compared to enalapril arm, but hyperkalemia or elevation in creatinine levels were lower in the sacubitril/valsartan compared to enalapril arm. So if we are to examine the package insert according to FDA, as can be seen by the bolded statement, for patients with eGFR less than 30 or patients with moderate hepatic impairment, the starting dosage of ARNI is recommended to be 24/26 mg twice daily. So there is not an exclusion against eGFR less than 30, according to the package insert.

Package Insert Recommendations

Let's keep in mind that patients with eGFR less than 30 were not included in the PARADIGM-HF trial, but due to a more favorable profile for worsening renal function, hyperkalemia with ARNI compared to ACE inhibitors, FDA did not exclude eGFR less than 30 in the package insert.

Procedures for up-titrating medications was covered in the 2017 ACC Expert Consensus Decision Pathway for optimization of heart failure treatment, and this pathway aims to complement the clinical practice guidelines, providing guidance to the practitioners for transforming guideline recommendations into clinically actionable information.

Why is Answer "A" (sacubitril/valsartan) Incorrect?

Now let's try to review the pathway, just to see how our patient may fit into the guideline-directed therapy. So if we are to re-examine the pathway and look at why the sacubitril/valsartan is incorrect, our patient is in heart failure with a reduced EF, and he is stage C. He is with symptoms, and he is intermittently on ACE inhibitors and ARBs, and he is on beta-blockers. He's still congested with residual congestion symptoms.

As you can see, according to the pathway, we would expect stability on ACE inhibitors or ARB for us to be able to consider the ARNI. Since our patient does not have stability, we would not be able to initiate or consider ARNI. If the patient was stable on ACE inhibitors and if he demonstrated stability in terms of his symptoms and overall state on background medical therapy, then this is the recommendation for ARNI titration.

It is recognized that abnormal renal function and hyperkalemia are common barriers for initiation and titration of guideline-directed medical therapy. For patients with established renal disease, the pathway recommends caution. Caution is made necessary when starting guideline-directed medical therapy, and it is also recognizing that ACE and ARB are usually considered in stable patients with creatinine less than three. In patients with mild to moderate renal impairment, such as with eGFR over 30 and less than 60, usually no adjustment is needed in the ARNI dose. But in patients with severe renal impairment, very similar to the package insert, the pathway suggests the starting dose of sacubitril/valsartan should be reduced to 24/26 mg twice daily. So there is definitely harmonization between the FDA package insert and the ACC consensus decision pathway.

Why Not Ivabradine?

Let's look at the question of why not ivabradine as a choice, though this patient is NYHA class III and has a heart rate over 70 and may eventually be appropriate for consideration of ivabradine. He has not been on optimal background doses of beta-blockers. Therefore, initiation of ivabradine at present time would not be appropriate. Let's look at the guidelines.

According to the 2017 ACC/AHA/HFSA Focus Update for Heart Failure Guidelines, ivabradine can be beneficial as a class 2A recommendation, can be beneficial to reduce heart failure hospitalization for patients with symptomatic class 2 or 3 stable, chronic heart failure with reduced EF, who are receiving guideline-directed medical therapy including a beta-blocker at maximum tolerated dose and who are in sinus rhythm with a heart rate of 70 beats per minute or greater at rest. Our patient was not on optimal doses of beta-blockade, and for that reason, ivabradine would not be the appropriate choice as a next step. If he had been on optimal doses of beta-blockade and he was clinically stable, ivabradine then could be a choice.

Let's look at the pathway, the heart failure consensus decision pathway, which states that, "Determine whether the beta-blockers are adjusted maximally tolerated dose, and if not, do try to achieve the maximum doses of beta-blockers." Or beyond optimal beta-blocker titration, if the heart rate is still over 70, for younger patients than age 75, the initiation dose is 5 mg twice daily. For older patients over age 75, the initiation dose is 2.5 mg twice daily. And again, ivabradine should only be considered after optimal doses of beta-blockers, which this patient was not on.

Why Not Spironolactone?

Why not spironolactone? Though this patient is NYHA class III and has a creatinine of less than 2.5, his eGFR is less than 30, and his potassium level is borderline high. Aldosterone antagonism is contraindicated in the following patients: in patients with eGFR less than 30, creatinine greater than 2.5 in men, creatinine greater than 2 in women, and/or potassium levels exceeding that of 5.

According to the focused update in heart failure guidelines in 2017, aldosterone antagonism is a class 1 recommendation for symptomatic heart failure patients with NYHA class II to IV as long as their creatinine clearance is over 30 and potassium levels are less than 5. And of course, they are expected to be on optimal background medical therapy with ACE inhibitors and beta-blockers.

And if we are to examine the details in the recommendations, aldosterone-receptor antagonists are recommended in patients who are class 2 to 4 who have an EF of 35 or less, unless contraindicated, to reduce morbidity and mortality. Patients with NYHA class II should have a history of prior hospitalization or elevated plasma natriuretic peptide levels, and creatinine should be less than 2.5 for men, less than 2 for women, and the eGFR should be greater than 30, and the potassium should be less than 5.

It's very important that, in the event ALDO antagonism is considered, careful monitoring of potassium, renal function, and diuretic dosing should be performed both at initiation and after initiation closely to monitor and minimize risk of hyperkalemia and renal insufficiency. It should also be recognized that inappropriate use of aldosterone-receptor antagonist is potentially harmful because life-threatening hyperkalemia or renal insufficiency when serum creatinine is greater than 2.5 in men and greater than 2 in women and potassium over 5 is associated with increased mortality.

So we do have a class 3 level of evidence B with implication for harm recommendation in the guidelines, stating that inappropriate use of aldosterone antagonism is associated with adverse outcomes. It's also important to recognize that patients such as ours, who are complex and with advanced heart failure, should be referred to a specialist program. This is recognized as a recommendation, and this table goes over the types of patients which we recommend for a referral to a specialist program. These are chronic heart failure patients with high risk features, such as those who require chronic IV inotropes, those who have persistent class 3 to 4 heart failure symptoms of congestion or profound fatigue, which our patient needs to fit into the categorization of, or patients with systolic blood pressure less than 90 mmHg or symptomatic hypotension, patients with persistent elevation in creatinine or BUN, patients with atrial arrhythmia, atrial fibrillation, or ventricular arrhythmias or repeated ICD shock, patients with recurrent emergency room visits or hospitalizations in the last 12 months, patients who are unable to tolerate optimally dosed beta-blockers, ACE inhibitors, ARBs, or other RAS antagonism with ARNI or aldosterone antagonist. Our patient would fit this phenotype because he's unable to tolerate ACE inhibitors. Or patients with clinical deterioration as indicated by worsening edema, rising biomarkers, or worsened exercise test, decompensated hemodynamics, or evidence of progressive remodeling on imaging or high mortality risk features by validated risk models. Those definitely may be triggers for referral to a specialist program.

As a review of our learning objectives, you should now be able to:

Prescribe appropriate drug treatment strategies based on patients' individual risk

Thank you for attending our lecture.