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Simultaneous or Rapid Sequence Initiation of Quadruple Therapy for HFrEF

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Simultaneous or Rapid Sequence Initiation of Quadruple Therapy for HFrEF

  1. 1. Simultaneous or Rapid Sequence Initiation of Quadruple Therapy for HFrEF Stephen J. Greene, MD Assistant Professor Duke University School of Medicine Duke Clinical Research Institute @SJGreene_md October 8, 2021
  2. 2. Disclosures  Research support from Duke Department of Medicine Chair’s Award  Research support from American Heart Association, NHLBI, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, and Pfizer.  Advisory boards for Amgen, AstraZeneca, Bristol Myer Squibb, Cytokinetics, Sanofi  Consulting for Amgen, Bayer, Bristol Myers Squibb, Merck, Vifor
  3. 3. “Status Quo” Serial & Selective Approach to Optimizing GDMT MS Khan, Butler J, Greene SJ. Eur J Heart Fail 2021; Courtesy of Dr. Gregg Fonarow
  4. 4. Start all 4 mortality reducing drugs without delay, or in rapid sequence Greene SJ, Butler J, Fonarow GC. JAMA Cardiol 2021 GDMT Day 1 Days 7-14 Days 14-28 Days 21-42 ARNI Initiate, low dose Continue Titrate, as tolerated Titrate, as tolerated Beta-blocker Initiate, low dose Titrate, as tolerated Titrate, as tolerated Titrate, as tolerated MRA Initiate, low dose Continue Titrate, as tolerated Continue SGLT2i Initiate Continue Continue Continue
  5. 5. #1 - Clinical Benefits Appear Within Days to Weeks Following GDMT Initiation Beta- blocker ARNI MRA SGLT2i Delayed initiation of any of these 4 drugs in eligible patient = needless exposure to excess clinical risk
  6. 6. Risk of Death, HF Hospitalization, or Urgent HF Visit HR 0.42 (95% CI 0.19, 0.92) P=0.029 HR 0.67 (95% CI 0.44, 1.00) P=0.048 Empagliflozin Placebo Empagliflozin Placebo Day 12 Statistical significance reached first time Day 34 Statistical significance sustained Days after randomization Consider that 1 in 4 patients hospitalized for HFrEF is dead or rehospitalized within 30 days.
  7. 7. #2 - Therapies Enable Tolerance of Each Other Greene SJ, Khan MS. JACC 2021
  8. 8. Initiating SGLT2i or Switching to ARNI Reduces MRA Discontinuation MRA Discontinuation Delaying initiation of SGLT2i or delaying switch from ACEI to ARNI needlessly exposes patients to excess risk of hyperkalemia and MRA discontinuation Ferreira JP et al. JACC 2021 Bhatt AS et al. Eur J Heart Fail 2021
  9. 9. #3 - Addressing Hesitation – Won’t starting multiple meds at once increase risk of intolerance? There is no objective evidence that simultaneous or rapid sequence initiation increases risk of medication intolerance. Key Comments:  Tolerability enhanced by initiating low doses  SGLT2i and MRA rarely cause symptomatic side effects  Worsening HFrEF disease-state may be mis- attributed to medication-related adverse event… …..disease-state worsening more likely if initiation of any of 4 meds is delayed. Empagliflozin Placebo Packer M et al. Circultion 2021
  10. 10. #4 - Addressing Hesitation – But there is no dedicated RCT of simultaneous/ rapid sequence initiation That is correct. Yet…  There is no evidence that delaying initiation of any pillar of quadruple therapy accomplishes anything beneficial or improves medication tolerance.  Instead, there is evidence that delaying initiation of any pillar of quadruple therapy needlessly exposes patients to excess risk of 1. clinical worsening and death 2. possibility of never having the medication prescribed.
  11. 11. Deferring Initiation = Never Initiation (or Substantial Delay) Granger B et al. HFSA Sessions 2021; Greene SJ et al. JACC 2019 A culture of clinical inertia towards GDMT In CONNECT-HF RCT, median change in HFrEF therapy quality score from hospital discharge to 12 months? ZERO
  12. 12. Take-Home Points – Simultaneous or Rapid Sequence Initiation of Quadruple Therapy  Optimal approach is to initiate each of the 4 medications proven to reduce all-cause mortality in all patients who are eligible, and to start all without significant delay.  A serial or selective approach will result in needless and prolonged delays in GDMT optimization….and will lead to excess HF hospitalizations and deaths that could have been prevented with earlier comprehensive quadruple therapy.  Simultaneous or rapid sequence initiation seeks to: – Break clinical inertia – Leverage the early benefits of each of the 4 therapies – Treat HFrEF with the sense of urgency it deserves

Editor's Notes

  • This is the normal traditional approach to GDMT
  • Most patients never receive medications proven to extend their survival or receive them with significant delay.

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