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In This Week’s Podcast
For the week ending Jan 17, 2025, John Mandrola, MD, comments on the following news and features stories. Renal denervation (RDN), the obesity paradox crushed, JACC devotes an entire issue to the FINEARTS trial of finerenone in heart failure with preserved ejection fraction (HFpEF), disappointing kidney outcomes for finerenone, a setback for one pulsed field ablation (PFA) system and coffee.
RDN
The Centers for Medicare and Medicaid Services (CMS) has called for public comment regarding coverage of RDN for the treatment of uncontrolled hypertension (HTN).
Two systems for RDN have cleared US Food and Drug Administration (FDA) approval — the ultrasound device based on RADIANCE trials, and the Symplicity Spyral system based on SPYRAL trials.
Uptake of the device has been slow or nonexistent. The reason? Funding issues.
My take is that there should be funding issues. Recent sham-controlled data is not only not impressive (in the range of < 5 to 6 mmHg), but it there is no data on long-term effects beyond 6 months, and there are clear non-responders in the trials.
Proponents may say that there are open-label extension studies that confirm the benefit. To which I would say, open-label anything is essentially worthless for RDN, see SYMPLICITY HTN 1 and 2 vs the sham-controlled Symplicity 3.
Long-term efficacy is also worrisome because there is known re-innervation in animal models.
What’s more, we know that distal ablation is needed, but we have no measures of successful ablation.
Patient selection is also very difficult, but the trials had substantial numbers of non-responders.
Finally, there has been zero data on major adverse cardiac events (MACE).
In sum, I see RDN as a failure of proper regulatory oversight, and it is science that strove to clear a low bar. I will cite a controversies paper in the American Journal of Medicine, first author, Filippone, which lays out a proper RDN trial:
Sham-controlled;
Double blind;
Adherence assessed with blood and urine;
Maximal medical therapy in both arms;
Long duration (2 years) maintaining sham-blinding;
Target ambulatory blood pressure (BP) not office BP;
Second-generation device;
Assesses required number of meds and quality of life;
Assesses structural and functional target organ damage and relate to change in BP;
Assesses MACE;
Assesses cost-efficacy;
Finally, patients should be stratified by type of HTN and by co-morbidities.
I realize this sounds like a high bar, but I see at it as necessary because if not, imagine the costs and potential waste and harm if this procedure is let loose in the wild of private fee-for-service healthcare. You think GLP-1s are costly, HTN is as common or more common than obesity.
Professor Franz Messerli has a nice editorial out in JACC, “Renal Denervation: Antihypertensive Therapy or Gizmo Idolatry?” He urges us to balance the benefits of RDN against generic amlodipine, which easily reduces BP by > 10 mmHg in a day, weeks, or years. What’s more, if RDN works, it blocks sympathetic activity, the same mechanism as beta-blockers, which are consistently inferior for reducing outcomes when compared with other anti-HTN drugs.
I am glad CMS is moving slowly.
An Entire Issue of JACC Devoted to the FINEARTS Trial
I covered FINEARTS when it was published in the NEJM in the late summer during the European Society of Cardiology (ESC) meeting. Recall that finerenone is the first mineralocorticoid receptor antagonist (MRA) that is non-steroidal. Unlike spironolactone and eplerenone, there is no gynecomastia.
Here is an excerpt from my Sept 6 TWIC podcast, on the placebo-controlled finerenone vs placebo test in patients with HFpEF.
6000 patients with class 2-4 HF and an EF more than 40%. Patients were 72 years old with LVEF of 53%.
Primary endpoint: total worsening HF events (which could be unplanned hospitalization or urgent HF visit) and cardiovascular (CV) death.
Over 32 months, a primary endpoint of total HF events (first or recurrent hospitalization or urgent visit) and CV death, occurred in 14.9 per 100 patient years in the finerenone vs 17.7 per 100 patient years in the placebo arm. This was a 16% reduction with a hazard ratio (HR) of 0.84 (confidence interval [CI] 0.75-0.95).
The composite endpoint was driven by an 18% reduction (HR 0.82; CI 0.71-0.94) in HF events, but the rate of CV death was not significantly different, 8.1 vs 8.7. Not statistically significant.
The results for the primary outcome were consistent across all prespecified subgroups, including those defined according to baseline left ventricular (LV) ejection fraction (<60% or ≥60%) and baseline use of SGLT-2 inhibitors (yes or no).
Death from any cause was not different.
The original paper included the difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score. It was significantly better on finerenone, but the absolute difference in mean was only 1.6 points.
Total adverse events were similar but… in the F arm. 3% vs 1.4% of patients had K > 6,. Though no episodes of high K led to death.
I also mentioned in September that finerenone has been shown to reduce the risk of kidney disease progression and CV events in two large trials in patients with chronic kidney disease (CKD), see FIGARO-DKD and FIDELIO-DKD.
My main criticisms at the time were that a) FINEARTS basically replicated the Americas part of TOPCAT, which studied spironolactone vs placebo in HFpEF. Recall that TOPCAT overall was negative, but if you excluded Russia and Georgia which had serious irregularities, the trial was positive.
Second criticism: finerenone should have been compared with generic spironolactone. With FINEARTS being positive we now have two drugs better than placebo. A comparison study would have been the proper scientific question.
Third criticism: the differences were modest. In a 6000 patient trial, there were 200 fewer events in the finerenone arm. No difference was seen in CV death.
Finally, neither the main paper nor many of the other FINEARTS-related publications broke down the HF events. We don’t know how total hospitalizations were affected.
Back to this week, Editor-in-chief Harlan Krumholz writes in his intro piece that this themed issue underscores JACC’s commitment to advancing cardiovascular science by curating key findings and analyses around transformative trials.
By bringing together complementary papers, this issue provides a comprehensive view of the trial's implications for clinical care and future research, he says.
He included a nice figure that you might have seen in an advertisment that company reps hand out with free burritos in doctor’s offices.
Now to the papers.
Subanalysis Number 1: Finerenone in Patients with a Recent Worsening HF Event
In the main paper, there was a subgroup based on when patients were enrolled since an HF event: Less than a week, a week to 3 months, and more than 3 months. The patients in the first two groups — within a week or within 3 months — had HR less than 0.80 whereas patients with distant HF event before entering the trial did not benefit.
Well, now we get a whole paper on one subgroup in JACC. This showed, basically, what the main paper showed in one sentence.
First, there was a 2-fold higher rate of a primary outcome event (CV death or worsening HF [WHF]) in those enrolled early after a qualifying HF event.
Compared with placebo, finerenone appeared to lower the risk of the primary composite to a greater extent in those enrolled within 7 days of WHF (relative risk [RR]: 0.74; 95% CI: 0.57-0.95) or between 7 days and 3 months of WHF (RR: 0.79; 95% CI: 0.64-0.97) than in those >3 months from WHF or without prior WHF (RR: 0.99; 95% CI: 0.81-1.21).
But the P for the interaction did not reach statistical significance at 0.07.
They then did something I don’t understand. They calculated the ARR for the three subgroups (7.8 for the 1 week group, 4.6 for the 1 week to 3 month group, and 0.1 for the >3 month group). They say this is “statistically significant for the a trend across ordinal categories”
JACC let the authors conclude that there was a “possible signal of enhanced absolute treatment benefit with finerenone in those with a recent WHF.
However, in the limitations, they essentially nullify all this by saying:
Although treatment effects appeared to be greater among those enrolled proximate to a WHF in the primary analysis of total WHF events and CV death, there was no definitive treatment-by-time interaction and secondary analysis of time-to-first occurrence of CV death or WHF event analysis did not suggest the same pattern of diminishing treatment efficacy over time from WHF.
They do say this hypothesis-generating trend will be studied in the REDEFINE HF: A Study to Determine the Efficacy and Safety of Finerenone on Morbidity and Mortality Among Hospitalized Heart Failure Patients.
This subanalysis also included a favorable editorial.
Subanalysis Number 2: Effect of Finerenone on the KCCQ in Patients With HFmrEF/HFpEF:
Change from baseline KCCQ in the two group, finerenone vs placebo was a secondary endpoint of the main trial. It was in favor of finerenone but the difference was small at less than 2 points. Recall that the scale goes from zero to100.
This paper looked at the effect of finerenone in patients with differing KCCQ baseline scores. First, the baseline KCCQ was quite high at 70.
The authors made three groups or tertiles based on KCCQ: < 57, 57 to 81, and > 81. Finerenone reduced the primary endpoint nearly as well in all three categories, 0.82, 0.88 and 0.88 respectively. “However, compared with placebo, treatment with finerenone did not reduce mortality (caused by CV or all-causes), and did not improve New York Heart Association functional class across the tertiles of KCCQ.”
So, no heterogeneity based on functional capacity.
They then restated the 1.62 point mean improvement from the main trial. But this paper added something called a “responder analysis” to sort out quality of life signals.
This is a complicated type of analysis. In fact, the JACC issue included two papers explaining how it works, and its limitations. This is what AI generates when I ask for an explanation.
A responder analysis in a clinical trial measuring KCCQ (Kansas City Cardiomyopathy Questionnaire) is a method used to identify the proportion of patients who achieve a predefined level of improvement in their health status or quality of life (QOL).
This approach involves setting a threshold for what constitutes a meaningful change in the KCCQ score, and then categorizing patients as either "responders" or "non-responders" based on whether they meet or exceed this threshold.
In the context of KCCQ, which measures various aspects of heart failure symptoms and their impact on daily life, a responder analysis typically involves:
Defining a threshold: Researchers determine what change in KCCQ score represents a clinically meaningful improvement. For example, a change of 5 points or more in the KCCQ Overall Summary Score (OSS) might be considered significant.
Categorizing patients: After the intervention or treatment period, patients whose KCCQ scores improve by at least the predetermined threshold are classified as "responders," while those who do not meet this criteria are "non-responders."
Comparing groups: The proportion of responders in the treatment group is compared to the proportion in the control or placebo group to assess the effectiveness of the intervention.
Responder analyses can provide clinically relevant information by showing the percentage of patients who experience substantial symptom relief or quality of life improvement. However, it's important to note that this method has limitations, including potential loss of statistical power due to dichotomization of continuous data and the risk of misclassification of individual patient responses.
In the paper, the results are not impressive. The authors simplify by saying “numerically more patients in the finerenone group had “clinically meaningful” responses compared with placebo, but they actually write:
“Therefore, in a sensitivity analysis using categories of change in KCCQ that were bound by ranges — ie, worsening (≤−5-point decrease), no change (>−5 to <5-point change), small improvement (≥5 to <10-point increase), moderate improvement (≥10 to <15-point increase), large improvement (≥15 to <20-point increase), and very large improvement (≥20-point increase) — there was no evidence of a benefit with finerenone.”
They include a highly favorable discussion saying this data supports the conclusion that finerenone is an effective therapy for improving health status in pts with HFpEF, and it was consistent across subgroups.
This isn’t a false statement, but it also isn’t very clear that the improvements were tiny, and hardly clinically significant, regardless of the statistical method used to present the data.
Subanalysis Number 3: Finerenone, Obesity, and Heart Failure With Mildly Reduced/Preserved Ejection Fraction
In the main NEJM paper, the authors tell us results based on body mass index (BMI) < 30 or > 30. In the non obese category, the HR was 0.80 and in the > 30 category it was 0.79. So, effective in both from the September paper.
Well, now we get a whole new paper where the authors break down categories:
Underweight to normal; overweight, obese class 1 (30-35); obese class 2 (35-39) and obese class 3 (> 40).
The median BMI in FINEARTS was 29.2.
The main finding: The effect of finerenone on the primary outcome did not vary by baseline BMI (underweight/normal weight, rate ratio: 0.80 [95% CI: 0.62-1.04]; overweight: 0.91 [95% CI: 0.72-1.15]; obesity class 1: 0.92 [95% CI: 0.72-1.19]; obesity class 2 to 3: 0.67 [95% CI: 0.50-0.89];
When BMI was examined as a continuous variable, the beneficial effect of finerenone seemed to be greater in those with a higher BMI (P interaction = 0.005). A similar pattern was observed for total worsening HF events.
But when the authors used waist to hip ratio as a measure for obesity, they found no such trend.
Obesity paradox: The best part about this paper is how it crushes the obesity paradox. There are probably hundreds of papers in the literature describing the observation that in observational studies there seems to be a protective effect of obesity in heart failure. Patients with low or normal BMI seem to do worse than those with obesity. Hence, the paradox.
The paradox is totally 100% fake news. Every single one of these paradox papers is marred by collider bias, a type of selection bias wherein if you only look at say hospitalized patients, the patients with normal BMI tend to have disease worse than obesity and do worse. Hence the appearance that obesity is protective or even “healthy.”
Well, in FINEARTS, as in DANISH and PARADIGM-HF, the rates of bad events increased with increasing BMI. No paradox. HFpEF patients, as with HF with reduced EF patients, should be counseled to lose weight.
Comments. I am not sure what this paper adds. The drug works in all weight categories, just as what was shown in the NEJM paper subgroup. Maybe it is a little more effective in heavier patients. Maybe. The association was not strong and not seen when using other measures of obesity.
The subanalysis also includes a favorable editorial. So there is even more attention to finerenone.
Subanalysis Number 3: Finerenone and Kidney Outcomes in Patients With Heart Failure: The FINEARTS-HF Trial
In the main paper, in September, the authors reported on a secondary kidney outcome. It was a composite of a sustained decrease in the estimated glomerular filtration rate (eGFR) of ≥50%, a sustained decline in the eGFR to < 15 mL per minute per 1.73 m2 of body-surface area, or the initiation of long-term dialysis or kidney transplantation.
This was not significantly different; 2.5% with finerenone vs 1.8% with placebo (HR 1.33; CI 0.94-1.89).
You know the drill. Now we get a whole paper looking at kidney outcomes even though we are told there was no difference.
The first finding in this paper is exactly what was written in the first paper: 33% higher rates of bad kidney outcomes in the finerenone group but not significantly higher.
They also looked at greater than 57% eGFR decline or kidney failure, eGFR slope, and changes in urine albumin/creatinine ratio (UACR).
The more than 57% decline was essentially the same in both groups. Higher in finerenone group but not significantly. As for slope of eGFR, finerenone led to an acute decline early, but did not alter chromic eGFR slope. Finerenone did reduce UACR — an effect that persisted throughout follow up.
Some other notable findings:
Treatment effect did not significantly differ according to categories of baseline eGFR (≥ 60 vs 45 mL/min/1.73 m2 to < 60 vs < 45 mL/min/1.73 m2) or albuminuria, or history of diabetes.
However, despite lower event rates, eGFR decline to < 15 mL/min/1.73 m2 (a more robust component of the composite) was increased 2-fold with finerenone (0.8% vs 0.4%; relative risk: 2.1; 95% CI: 1.1-4.1).
Serious adverse events including serum creatinine elevation > 3 mg/dL, acute kidney injury, systolic blood pressure < 100 mm Hg, and hyperkalemia (including events that led to hospitalization), were more frequent with finerenone, especially in patients with eGFR < 60 mL/min/1.73 m2.
The authors concluded something similar to what they would say in the main paper:
In FINEARTS-HF, a population at low risk of adverse kidney outcomes, finerenone did not significantly modify the kidney composite outcomes. Finerenone led to a greater reduction in initial eGFR, but did not result in a significant difference in chronic eGFR slope vs placebo. Finerenone led to early and sustained reductions in albuminuria and reduced the risk of new-onset micro- and macroalbuminuria.
Comments. Taken together, the kidney results for finerenone in patients with HFpEF were not that spectacular and certainly not as good as that was seen in FIDELIO-DKD, a cohort with diabetes and CKD.
Why didn’t a 30% reduction in UACR not improve the other outcomes of GFR decline and slope?
Sanjay Kaul and Swapnil Hiramath explain in the editorial that the baseline UACR in FINEARTS was very low. So 30% decline of a low number is low; The CKD trials FIDELIO had much higher urine albumin numbers.
Yet they agree that there is a discordance between HF outcomes and kidney outcomes.
They raise important questions:
How will the guidelines respond to the discordant effects on heart and kidney outcomes? Are the adverse kidney effects concerning enough to offset the favorable HF outcomes? Given similar efficacy and safety profile among steroidal and nonsteroidal MRAs, will cost and affordability drive the decision to initiate an MRA in HFmrEF/HFpEF?
Subanalysis Number 3a Initial Decline in Glomerular Filtration Rate With Finerenone in HFmrEF/HFpEF
Matsumoto and colleagues examined the association between initial decline in eGFR (≥15%) from randomization to 1 month and subsequent outcomes in patients assigned to finerenone or placebo. The primary outcome was the composite of total HF events and CV death.
Among ≈ 5500 patients with an eGFR measurement at both baseline and 1 month, 18.2% experienced a ≥ 15% decline in eGFR. And it was nearly 2 times more in the finerenone group (OR: 1.95; 95% CI: 1.69-2.24; P < 0.001).
Basically, this was a two group observational comparison. About 4500 patients with no decline in eGFR vs 1000 patients with a decline in eGFR in first month.
After adjustment, an eGFR decline was associated with a higher risk of the primary outcome (HF and CV death) in patients assigned to placebo (adjusted rate ratio: 1.50; 95% CI: 1.20-1.89) but not in those assigned to finerenone (adjusted rate ratio: 1.07; 95% CI: 0.84-1.35; P interaction = 0.04)
By contrast, the efficacy of finerenone was consistent across the range of change in eGFR from baseline to 1 month (P interaction = 0.50 for percent change in eGFR), and safety, including hyperkalemia, was similar regardless of an early eGFR decline.
Comments. As with all HF therapies, ACE, ARNI, SGLT2 inhibitors, and MRA, there may be an initial decline in kidney function. Watch it. Check labs but continue the medicine as it appears to provide similar benefits.
Overall Comments. None of these papers overcome my overall worries about finerenone evidence in HF. Namely, that it should have been compared to spironolactone, and the effects are modest, and we don’t know the proportion of hospitaiizations related to HF to total hospitalizations.
The obesity paper added a little. The KCCQ paper confirmed the very modest effect on QOL. The kidney papers make you think there may be some discordance between HF and kidney outcomes. Maybe. The subanalysis on timing seemed most like marketing, as it stands to reason a drug will be more effective when used in acutely sicker patients.
I guess most trialists publish oodles of subanalysis, but the fact that JACC put them in one issue, each with an editorial, tempts me to think…well this aligns with the business model of journals, which is supported by industry money.
That said, three of the editorials, Kaul and Hiremath, and the two on the limits of KCCQ analyses were quite robust in their criticism. Good.
In a proper evidence-based landscape, one not dominated by industry, one dominated by evidence-based clinicians, we would have a spironolactone vs finerenone trial. Until then, I see no reason not to start with spironolactone first for HF.
Bad News for PFA
This week, Johnson & Johnson got terrible news. It had to halt a post-approval regulatory study of its pulsed field ablation (PFA) system for atrial fibrillation (AF) ablation due to four strokes. It’s really bad news. J&J with its CARTO BioSENSE systems has been a leader in the ablation field, with its mapping system and ablation catheters.
But it’s trailed Boston Scientific and Medtronic in the PFA system.
PFA as an energy source looks quite promising. I now have about a 6 month experience with PFA, and I already can’t imagine doing AF ablation with radiofrequency. PFA is fast. You likely avoid esophageal injury. Efficacy data looks similar. The two initial systems from Boston Scientific and Medtronic, have not had a stroke signal.
The strokes with the J&J device may be explainable. But four out of a 140 cases is a lot. This will surely set the company back. And it speaks to the need for proper regulatory studies of new devices. Good on J&J for halting the study and looking hard for root causes.
Things like this re-enforce my conservative approach to new tech. The PFA system I use had been in use in Europe for 2 years. In the United States, I waited 6 months. Then I looked at the data. New devices worry me. I will never forget that low-profile thin blue Sprint Fidelis lead. What a disaster.
Coffee
I want someone to let me know if everything is okay over at the European Heart Journal (EHJ) editorial office. I am worried about them.
I got a message from an ABC journalist Monday morning about this new coffee study. According to this observational study of 40,000 adults in the NHANES study, if you compare morning coffee drinkers to all-day drinkers, it turns out that morning drinkers have 16% lower rate of death.
Nearly 8 years ago I wrote a ranting column in which I called for an end to observational coffee and blueberry and quinoa studies, because these studies are flawed and biased and equally ridiculous and embarrassing.
Nothing has stopped. Nutritional research comparing outcomes with different macronutrient exposure continues in earnest.
It’s surprising that the lofty EHJ got involved. That’s why I am worried. I hope there is nothing in the food or water there. You know, like red dye. Or heavy metals. Someone check on them.
Seriously though, the paper’s altmetric score if off the charts. And herein lies one of the main lessons of this paper: that medical publishing has a business model. And it is attention. So, OK, we still love you EHJ. We get it. Next time, maybe give us an editorial saying something like, this one is red meat for the BBC and ABC and NBC.
The second lesson from these studies is that their main value is to show how foolish it is to even attempt such a study. The authors themselves say all the right things: it’s observational, there are baseline differences in the groups. Plus there is recall bias.
I am beginning to think complaining about these studies is like being mad when it rains.
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