Guideline Directed Medical Therapy Part II: 5 Pearls Segment

Core IM

This episode on Heart Failure with Reduced Ejection Fraction (HFrEF) GDMT (Guideline-directed medical therapy) further expands on the considerations and guidelines for medical management of HFrEF. With the new results from clinical trials and major guideline updates, a detailed explanation is needed to address medications recommended only in specific subsets of patients such as ivabradine or hydralazine and in diverse and commonly encountered circumstances such as heart failure treatment in the setting of chronic kidney disease, inpatient vs. outpatient setting. Additionally, the team will discuss the expected recovery of the ejection fraction with appropriate GDMT along with many practical pearls for practicing internists.

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Pearl 1: Quadruple-therapy in CKD

  • There are four medications used in :
    • Beta-blocker
    • ACE, ARB, ARNI
    • MRA
    • SGLT-2 Inhibitor

What additional considerations are warranted when using these medications for patients with CKD?  for patients with CKD?

    • Beta blockers:
      • Should be considered in all patients with HFrEF .
        • However, may have be limited by and other side effects (e.g dizziness)
    • ACE inhibitors, ARBs, and ARNIs:
      • May cause a temporary increase in creatinine (~30%)
        • Long-term nephroprotective effects
      • There is no absolute creatinine-based contraindication to initiation
      • Subsequent dose-adjustment may be required based on follow-up:
        • Blood pressure
        • Potassium levels
      • Consider potassium binders if necessary (check out our episode on )
    • Mineralocorticoid antagonists (MRAs):
      • If Creatinine > 2.5 mg/dl, avoid initiating an MRA, but do not discontinue if they patient is already on it as CKD progresses
    • SGLT2 inhibitors:
      • If GFR < 20, don not initiate SGLT2i therapy, but may be ok to continue
      • PRACTICAL TIP! Starting SGLT2 inhibitors and MRAs together may provide a buffer against hyperkalemia.
  • As CKD progresses to stage 3, using these medications becomes increasingly challenging!
    • However, !
      • As long as the patient is not experiencing side effects,
      • Evidence
  • Consider the difference between initiating and continuing a medication:
    • Initiating:
      • Uncertainty about how a patient will respond to a new drug and whether it will be well-tolerated.
    • Continuing:
      • Patient already demonstrated they can tolerate that agent in the long-term and doses can be adjusted if adverse effects occur
    • Always keep therapeutic inertia in mind, which can manifest in both continuing effective medications and hesitating to initiate new ones

Pearl 2: Hydralazine/Isosorbide Dinitrate

  • Pathophysiology:
    • Vasodilators
      • Reduce peripheral resistance 鈫 Lower blood pressure
  • Outcomes and trial data:
    • (1986)
      • Trend towards improved survival among patients with systolic heart failure who were treated with hydralazine and isosorbide dinitrate
    • (2004)
      • Combination of hydralazine and isosorbide dinitrate improve survival and reduce hospitalization among black patients with HFrEF
      • Enalapril had a more favorable effect on 2-year survival than a combination of hydralazine plus isosorbide dinitrate.
    • Hydralazine and isosorbide dinitrate can be considered if:
      • Initiation of first-line therapy (ACE-I, ARB, or ARNI) is contraindicated
        • Drug intolerance Renal insufficiency)
      • Blood pressure goals are not met on first-line therapy alone
    • recommend initiation for self-identified African American patients who are otherwise receiving optimal medical therapy to:
      • Improve symptoms
      • Reduce morbidity and mortality.
  • Patient Counseling:
    • Vasodilatory effects  can lead to headaches
    • Require 3 times daily dosing
      • Short half-lives
    • Lab monitoring is NOT required
      • Do not affect renal function
  • Pro tips:
    • If caring for a patient on hydralazine/isosorbide dinitrate, always look back at the chart to investigate the reason they are not on preferred first line agents and continually re-evaluate!  

Pearl 3: Ivabradine

  • Pathophysiology:
      • Selectively inhibits  cardiac pacemaker current called the 鈥渇unny channel鈥
        • 鈥淔unny channel鈥 controls the spontaneous diastolic depolarization in the SA node
  • Outcomes and trial data:
      • Addition of ivabradine to patients who had a resting HR >/ 70 bpm despite maximal beta blockade 鈫 reduced rates of hospitalization
  • Patient Counseling:
    • Start only if the patient is on maximally tolerated doses of beta blockers
    • Does not affect blood pressure or kidney function
  • Pro tips: 
    • !
    • Patients must be in sinus rhythm for this med!
      • Can't be in afib, flutter, and should not have pre-existing conduction abnormalities

Pearl 4: Inpatient vs Outpatient Considerations

  • 1 in 4 annual cardiovascular deaths are due to heart failure
    • !
  • (2016-2018):
    • ONLY 1% of eligible patients were simultaneously on target doses of ACEi/ARB/ARNI, BB, and MRA therapy
  • Safety, Tolerability and efficacy of Rapid Optimization
    • Simultaneous initiation of all 4 GDMT agents is:
      • Safe
      • Well tolerated
      • Rapidly effective
      • Overcomes inertia
    • Specifically, the protocol aimed for optimal dosing at 2 weeks after discharge, and 4 outpatient visits over 6 weeks to monitor clinical status
  • There is no substantial overlap in effect of the GDMT meds, thus it is important to utilize each in combination!

Pearl 5: Patient Expectations on EF Recovery

  • Patients with heart failure with improved ejection fraction may have:
    • Complete recovery of LVEF (EF >/50%)
    • Partial recovery of LVEF (EF 40-50%)
    • No recovery of LVEF (EF <40%)
  • Estimates of the proportion of patients with improved LVEF range widely (e.g., 10% to 40%)
    • This is due to:
      • Variable definitions
      • Use of
      • induced cardiomyopathy
    • Make sure to fully investigate the underlying cause of the cardiomyopathy in order to improve chances of recovery of EF!
  • The SECOND HIGHEST rates of EF recovery:
    • Dilated cardiomyopathies that are associated with immune responses
      • Peripartum cardiomyopathy
      • Viral myocarditis
      • Systemic inflammatory response syndrome
  • According to the 2022 ACC/AHA guidelines, even when EF 鈥 a state now called Heart Failure with improved Ejection Fraction (HFimpEF)
  • Data has shown that




Shreya Trivedi, MD, ACP Member - Host / Editor
Aaron Troy, MD - Editor
Viktoria Mladenovik, MD - Editor, Host
Santiago Callegari, MD - Editor
Sweta Motiwala, MD* - Guest Discussant
Greg Katz, MD - Guest Discussant


Randal Goldberg, MD
Susan McIlvaine, MD

*Sweta Motiwala, MD

End Point Review Committee - Abbott Labs

Those named above, unless otherwise indicated, have no relevant financial relationships to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.  All relevant relationships have been mitigated.

Release Date:  September 20, 2023

Expiration Date: September 19, 2026

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