Stephen Greene, MD Duke University

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. 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. “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. 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. #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. 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. #2 - Therapies Enable Tolerance of Each Other
Greene SJ, Khan MS. JACC 2021

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. #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. #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. 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. 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