Guideline Directed Medical Therapy Part II: 5 Pearls Segment

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Pearl 1: Quadruple-therapy in CKD

• There are four medications used in Guideline-Directed Medical Therapy (GDMT) for HFrEF:
  • 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 regardless of kidney function.
      • However, may have be limited by orthostasis 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 hyperkalemia in CKD)
  • 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, these medications slow the decline in kidney function even at advanced stages!
    • As long as the patient is not experiencing side effects, it is ok to continue these medications in CKD Stage 4 or even 5
    • Evidence supports the nephroprotective and beneficial cardiovascular effects of these medications independent of creatinine
• 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 → Lower blood pressure
• Outcomes and trial data:
  • V-HeFT trial (1986)
    • Trend towards improved survival among patients with systolic heart failure who were treated with hydralazine and isosorbide dinitrate
  • A-HeFT trial (2004)
    • Combination of hydralazine and isosorbide dinitrate improve survival and reduce hospitalization among black patients with HFrEF
  • V-HeFT II Trial
    • 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
  • Current guidelines 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:
  • Lowers HR
    • Selectively inhibits  cardiac pacemaker current called the “funny channel”
      • “Funny channel” controls the spontaneous diastolic depolarization in the SA node
• Outcomes and trial data:
  • SHIFT Trial
    • Addition of ivabradine to patients who had a resting HR >/ 70 bpm despite maximal beta blockade → 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: 
  • Lower the heart rate, the better the outcome!
  • 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
  • Many patients are still NOT on one or more evidence based, life-prolonging medications!
• CHAMP-HF registry (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 (STRONG-HF Trial):
  •  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 both observational and clinical trial datasets
• The HIGHEST rates of EF recovery in:
  • • Tachycardia induced cardiomyopathy those caused by
    • Hypo or hyperthyroidism 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, GDMT for HFrEF should be continued even when EF improves or fully recovers– a state now called Heart Failure with improved Ejection Fraction (HFimpEF)
• Data has shown that even among patients whose ejection fraction fully recovers, a large portion will develop recurrent LV dysfunction and heart failure events

Contributors

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

Reviewers

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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