#459 DIGEST: Finerenone for Heart Failure, PCV21 and the latest Pneumonia Vaccine Recs, 24-hour vs 15-hour Oxygen Therapy, and PREVENT vs PCE for Cardiovascular Risk Estimation

October 28, 2024 | By Nora Taranto

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Join us as we review recent articles and news featured in The DIGEST issues #56 and #57, including finerenone for heart failure, the skinny on pneumonia vaccines and the latest, PCV21, long-term oxygen therapy (the REDOX trial), and the PREVENT vs PCE cardiovascular risk equations.  Fill your brain hole with a fully digestible meal! Featuring Alex Chaitoff (@alexchaitoff), Rahul Ganatra (@rbganatra), Nora Taranto (@norataranto), and Matt Watto (@doctorwatto). 

Note: **Update on Pneumonia Vaccine from ACIP: After we recorded and just before we published this episode, the CDC updated its vaccine guidance to include pneumonia vaccination for all adults aged 50 years and older to receive either PCV20, PCV21, or the combination of PCV15 followed by PPSV23 one year later (CDC site accessed 24 Oct 2024).**

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Show Segments

• Introduction + Pun 
• Exploring Finerenone in Heart Failure
• Pneumonia Vaccines: The PCV21 Trial
• Long-Term Oxygen Therapy: The REDOX Trial
• Cardiovascular Risk Calculators: The PREVENT Equation

Hot take #1 Finerenone for HFpEF (Watto)

Covered by Jen DeSalvo in DIGEST #57

Solomon SD et al FINEARTS-HF Committees and Investigators. Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2024 Sep 1. doi: 10.1056/NEJMoa2407107. Epub ahead of print. PMID: 39225278. 

Summary: The FINEARTS-HF trial compared finerenone (a non-steroidal mineralocorticoid antagonist) to placebo in over 6,000 patients with symptomatic heart failure and an ejection fraction of 40% or greater. After a median follow-up of 32 months, the primary composite outcome of new heart failure events or cardiovascular death was observed less often with finerenone than placebo, 1083 events vs 1283 events, respectively (rate ratio, 0.84; 95% confidence interval, 0.74 to 0.95; P=0.007). Hyperkalemia (K above 5.5 in 13.3% vs 6.9%) and the composite renal outcome (decrease in GFR, initiation of dialysis, or kidney transplant) was seen more often with finerenone. 

Bottom line (Is this practice changing?): This will be adopted into practice since some experts have already interpreted the TOPCAT trial (Pitt, 2014; de Denus, 2017) as evidence to support using mineralocorticoid receptor antagonists in heart failure with preserved ejection fraction (HFpEF). Is the effect size worth the cost of finerenone (about $800 for 30 tabs as of October 2024)? Will the benefits be extrapolated to spironolactone, which is much less expensive? We believe the answer (whether to extrapolate to spironolactone) is likely yes, after talking with friends of the show who are experts in heart failure.  

Hot take #2 PCV21 Vaccine (Nora)

Covered by Molly Heublein DIGEST #57

Platt HL, et al; STRIDE-3 Study Group. Safety, tolerability, and immunogenicity of an adult pneumococcal conjugate vaccine, V116 (STRIDE-3): a randomised, double-blind, active comparator controlled, international phase 3 trial. Lancet Infect Dis. 2024 Jul 

Recommended Reading:

• PneumoRecs App
• CDC Guidance on the use of 21-valent Pneumococcal Vaccine 
• MMWR guidance on PCV21

**Update on Pneumonia Vaccine from ACIP: After we recorded and just before we published this episode, the CDC updated its vaccine guidance to include pneumonia vaccination for all adults aged 50 years and older to receive either PCV20, PCV21, or the combination of PCV15 followed by PPSV23 one year later (CDC site accessed 24 Oct 2024).**

Summary: Streptococcus pneumoniae causes both community-acquired pneumonia and invasive pneumococcal disease (IPD) such as meningitis and bacteremia. Pneumococcal vaccination dramatically decreased the incidence of invasive disease in children such that now rates of IPD are higher in adults.  Just as a reminder about vaccine types – there are the polysaccharide vaccines (a.k.a. PPSV23) which don’t activate T-cells, and then conjugate vaccines (a.k.a. PCVs) which display a polysaccharide-protein complex and trigger a more robust immune response involving T and memory B cells. Over the years, new PCVs have been developed, covering more serotypes, up to PCV20.  V116, or PCV21, was created to target 21 serotypes, including new ones associated with invasive adult disease.  STRIDE-3 was a randomized, double-blind, active comparator controlled,  international phase III trial comparing PCV21 to PCV20 vaccination in > 2500 adults naive to pneumococcal vaccination. Outcomes were primarily immunogenicity related (as is the case for many vaccine trials in diseases that have vaccines already approved based on clinical endpoints). This was a positive trial, with PCV21 meeting its non-inferiority outcome, comparing PCV21-to-PCV20 immune response for all 10 serotypes shared by both vaccines, and meeting superiority for 10/11 serotypes unique to PCV21.  There weren’t any serious vaccine-related adverse events.  Based on this data, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended that PCV21 be added as a vaccination option among adults eligible for pneumococcal conjugate vaccination. 

Bottom line (Is this practice changing?): The pendulum is likely swinging towards PCV21 as the stock vaccine for a majority of adults who qualify, given its breadth of coverage.  It covers the serotypes causing ~85% of IPD cases in adults, including 8 serotypes not in any other vaccine. These were major gaps with PCV20 and other licensed pneumococcal vaccines.  One possible downside is that it does not cover serotype 4, which is an emerging cause of invasive disease in certain populations in the Western US and in individuals experiencing homelessness.  Use the CDC’s PneumoRecs app to help guide you about what vaccine options are right for your patient, with the incorporation of this new data.

Hot take #3 Long-term Oxygen Therapy (Rahul)

Covered by Laura Glick in DIGEST #57

Ekström M, et al; REDOX Collaborative Research Group. Long-Term Oxygen Therapy for 24 or 15 Hours per Day in Severe Hypoxemia. N Engl J Med. 2024 Sep 19;391(11):977-988. doi: 10.1056/NEJMoa2402638. Epub 2024 Sep 10. PMID: 39254466. 

Recommended Reading:

• Background on different durations of LTOT 
• British guidelines on LTOT

Summary: The REDOX trial tested whether long-term O2 therapy (LTOT) administered for 24 hours/day was “non-superior” to LTOT for 15 hours/day with respect to all-cause mortality and hospitalizations at 12 months. The authors used a registry of patients receiving LTOT in Sweden to compare outcomes among 241 patients in their mid-70s with severe hypoxemia (meaning SpO2 <88% at rest, or <90% with evidence of CHF or polycythemia). Most patients had COPD (and a minority had pulmonary fibrosis); these patients were randomized to LTOT 24 h/day or 15 h/day. The top-line results are that this was a “positive” trial for “nonsuperiority.”  At 1 year, the rate of all-cause death or hospitalizations was identical in both groups: 124.7 vs 124.5 events / 100 person-years in the 24h group and 15h group, respectively. Put another way, the hazard ratio was 0.99, with a 95% confidence interval of 0.72 to 1.36.

Bottom line (Is this practice changing?): There are at least three problems that should affect our interpretation of the results: First, it is hard to know who to generalize these results to, since more than half of the ~1,600 patients who were screened were excluded for unspecified reasons. Second, the primary outcome and the nonsuperiority margin were both changed after the trial began, and the choice of the original margin would NOT have shown nonsuperiority (see figure below).  Third, the initial sample size listed on clinicaltrials.gov was 2,126, but after the primary outcome and nonsuperiority margin were changed due to slow accrual, the study was completed with only about 10% of that, which would bias towards nonsuperiority.  Finally, the confidence interval does not preclude the existence of a smaller benefit of LTOT for 24h than what the study was powered for (a 6% absolute risk reduction or greater).  In light of how the study was designed, this doesn’t help me decide which patients might benefit from LTOT for 24h/day, and which patients might be fine with 15h/day.  

Dr. Ganatra’s Visual Explanation of the Non-superiority Margin Change  

Hot take #4 CV Risk Equation Update (Alex)

Covered by Jen DeSalvo in DIGEST #56

Anderson TS, et al. Atherosclerotic Cardiovascular Disease Risk Estimates Using the Predicting Risk of Cardiovascular Disease Events Equations. JAMA Intern Med. 2024 Aug 1;184(8):963-970. doi: 10.1001/jamainternmed.2024.1302. PMID: 38856978; PMCID: PMC11165411. 

Recommended Reading:

• Background on issues with the Pooled Cohort Equations

Summary: Currently, we use the Pooled Cohort Equations (PCE) to calculate patients’ atherosclerotic cardiovascular disease (ASCVD) risk.  Concerns arose about the initial cohorts on which the PCEs were based not reflecting our modern-day population as they were composed primarily of White individuals and some began recruiting patients in the 1950s, with a 2018 study finding that the PCE overestimated 10-year risk by an average of 20% (especially among Black individuals).  Thus, the PREVENT equations were developed in 2023, using data from over 6.6 million patients from various cohorts, including more contemporary ones recruiting in the 2000s.  But this begs the question – how does risk predicted by PREVENT differ from risk predicted by PCE, and would it change who is recommended for a statin?  In their 2024 study, Anderson et al. asked this question and used a nationally representative survey to find out the answer.  The authors calculated the PREVENT risk of having a cardiovascular event and compared it with PCE-calculated risk for adults between 40 to 75. The average ASCVD risk was 8.0% when using the PCE and only 4.3% using the PREVENT equations. Across every single age, sex, and race subgroups, the average ASCVD risk was lower using the PREVENT equation. The authors concluded that using the PREVENT equation instead of the PCE would result in 17.3 million fewer adults being recommended for a statin. 

Bottom line (Is this practice changing?):  Not yet, but likely in the future.  If you go and read the “comments” on the JAMA site, you’ll see people say things like they aren’t going to act on this until it’s in the guidelines–and that’s reasonable.  But this is the kind of observational study–based on more modern populations for its derivation–that will likely eventually be cited in guidelines.  So for now, it could be reasonable to pull out this calculator for patients who are borderline by the pooled cohort equation (PCE) to determine how hard you want to push starting a statin. 

Goals

Listeners will review recent practice-changing articles and medical news.

Learning objectives

After listening to this episode listeners will…

1. Decide when to consider finerenone or spironolactone for heart failure with preserved ejection fraction
2. Identify the differences between PCV-21 and PCV-20 vaccination for pneumococcal pneumonia
3. Consider the benefits of 24 versus 15 hour Oxygen for severe hypoxemia
4. Understand the differences between the PREVENT and PCE cardiovascular risk equations 

Disclosures

The Curbsiders report no relevant financial disclosures. 

Citation

Taranto N, Chaitoff A, Ganatra RB, Watto MF. “#459 DIGEST: Finerenone for Heart Failiure, PCV-21 and the latest Pneumonia Vaccine Recs, 24-hour vs 15-hour Oxygen Therapy, and PREVENT vs PCE for Cardiovascular Risk Estimation.” The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list October 28, 2024.