After decades of futility we now have three drugs classes that benefit patients with HFrEF: non-steroidal mineral corticoid antagonists, #Flozins, and GLP1ra.

Milton Packer throws shade at the semaglutide HFrEF in the introduction:

"Two trials assessing the use of semaglutide in patients with heart failure with preserved ejection fraction and obesity showed that GLP-1 receptor agonism might not only reduce symptoms but might also lower the risk of major adverse outcomes of heart failure. The two trials noted a reduction of 8 to 9% in body weight, improvement in health status and exercise tolerance, and a potential decreased risk of worsening heart failure. However, the effect on worsening heart failure was observed in exploratory analyses with follow-up of only 52 weeks."

Before unveiling a 38% reduction in the composit of CV death or worsening heart failure over 2 years! Most of the end points came from a big reduction (46%!) in worsening heart failure.

Interesting mechanistic study looking at how tirzepatide was able to reduce cardiovascular death or worsening heart failure. The tirzepatide group had weight loss, decreased blood pressure, decreased blood volume, increased GFR, decreased albuminuria, and decreased pro-BNP. These GLP1ra are remarkable medications. 

"In post hoc exploratory analyses, decreased estimated blood volume with tirzepatide treatment was significantly correlated with decreased blood pressure, reduced microalbuminuria, improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and increased 6-min walk distance."

Since EPHESUS, we have known that blocking aldosterone reduces mortality in patients with heart failure after myocardial infarction. We also know that after an MI ACEi improves outcomes in unselected patients. Could spironolactone do the same in unselected patients following an MI? 

Apparently not.

The CLEAR study randomized patients to spiro or placebo after MI and looked at CV deaths and new or worsening heart failure. Spiro was unable to move the needle on either outcome. 

The ACCORD trial famously did not find a benefit from lowering blood pressure to less than 120 in patients with diabetes. This is why SPRINT did not randomize patients with diabetes.

However ACCORD was plagued by its 2x2 factorial design that failed to show a lack of intereaction between the two interventions, really low A1c as the other intervention. The possibility of interaction put the findings of ACCORD in doubt. Along comes the BPROAD trial which re-tested the hypothesis that a systolic BP < 120 would have benefits in a patient with diabetes. 

This was a 5-year study with a primary outcome of a composite of nonfatal stroke, nonfatal myocardial infarction, treatment or hospitalization for heart failure, or death from cardiovascular causes.

After a mean of 4.2 years they found a HR of 0.79 with the low blood pressure group without a difference in serious adverse events.

This along with ESPRIT is the second replication and expansion of SPRINT. Lower blood pressures for all!

The incidence of dialysis is falling. This is an under-reported story but dialysis in the US is slowly going away. From 2002 to 2022 the adjusted incidence of ESRD has fallen from 468 per million people to 381 per million. 

Maybe the problem with binders in dialysis is we have been focused on the wrong binder. This week's NephJC is on the ADAPT study, a trial that looked at the potassium binding drug sodium zirconium cyclosilicate (SZC) in dialysis patient. The hypothesis was to use the binder plus a 3K bath to decrease arrhythmias in dialysis patients. This was an Astra Zeneca sponsored trial.

This will be NephJC's first discussion on Bluesky. We will see how it goes. 

The DreamRCT was an online game that Jordan Weinstein and I cooked up in 2014. This was going to be the Yin to NephMadness' Yang that we ran for two years in the fall. The idea was to get a bunch of nephrology acaademics to come up with their dream study and write about it. Then we had the community vote which ones they wanted to support. 

Graham Abra came up with PhD, a study of potassium binders in dialysis patients which sounds surpringly similar to the ADAPT Trial that NephJC will be covering this week.