COMMENTARY

Aug 5, 2022 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

August 05, 2022

Please note that the text below is not a full transcript and has not been copyedited. For more insight and commentary on these stories, subscribe to the This Week in Cardiology podcast on Apple Podcasts, Spotify, or your preferred podcast provider. This podcast is intended for healthcare professionals only.

In This Week’s Podcast

For the week ending August 5, 2022, John Mandrola, MD comments on the following news and features stories.

Hyperkalemia in Heart Failure

The European Heart Journal has published the DIAMOND trial, which studied the use of the potassium-binding powder patiromer vs placebo in patients with heart failure with reduced ejection fraction (HFrEF) and a current history of renin-angiotensin-aldosterone system-inhibitor(RAASi) related hyperkalemia.

The idea here is that patiromer, a drug designed to treat the side effects of another drug, aRAASi, may enable patients to take a RAASi or higher doses of a RAASi or mineralocorticoid receptor antagonists (MRAs). The issue in many cases of HF is that the MRAs — the ACE-ARB, ARNI class of drugs, which are clearly beneficial — can’t be given or titrated because they cause hyperkalemia. Enter patiromer, which is a powder you mix with water into a slurry and drink. The drug exchanges potassium for Calcium in the gut, and shazam it lowers potassium levels. Thing is, it also binds to other drugs and there is a US Food and drug Administration (FDA) warning telling patients to wait at least 3 hours between taking patiromer and certain other drugs. Think about that for a moment. A typical patients with HF takes oodles of cardiac meds, likely a bunch of other meds, and now they have to time the patiromer to certain hours. How would such a patient have a life outside of being a patient?

But DIAMOND investigators had the idea that if patiromer allowed for more RAASi use, that would lead to better outcomes. They set out to test that reasonable theory by counting up cardiovascular death (CVD) or hospitalization for CV reasons (HHF). I bet you wonder how such a trial would come out. Well, you aren’t going to know. Because they changed the endpoint to something else. Sit down for this: they changed the endpoint to change in potassium levels from baseline.

Insert pause. Lowering potassium levels is what the drug does. They already know this. The drug is labeled for the treatment of hyperkalemia. This would be like doing a study of furosemide and measuring urine output; a study of amlodipine and measuring blood pressure, a study of metoprolol and measuring heart rate.

So instead of asking whether the $1000 per month drug improves outcomes, they will tell us it reduces potassium levels. They write in the manuscript that the reason for this change was slow enrollment, changing hospitalization patterns, lower than expected event rates, and of course the uncertainty of the pandemic, so the sponsor, with recommendations from the steering committee, changed the study objectives.

There are some things to learn from this trial.

  • In the run-in phase patients got either 50 mg of spironolactone or eplerenone while taking RAASi at > 50% of target and patiromer.

  • 84% of the approximately 1000 patients were able to achieve > 50% of the target dose of RAASi and 50 mg of spironolactone. These patients were then randomly assigned to keep taking the patiromer or placebo.

  • Compared with placebo the change in potassium levels was a negative 0.1 mmol/L, which was highly statistically significant.

  • A drug whose purpose is to lower potassium lowered potassium by 0.1 mmol/L. Like going from a potassium of 4.8 to 4.7.

  • Secondary endpoints such as number of patients with hyperkalemia were lower in the patiromer arm, as were the number of patients with MRA reduction.

The conclusion in the abstract was a classic case of spin — language designed to detract from the primary endpoint. The authors wrote, “Concurrent use of patiromer and high dose MRAs reduced the risk of recurrent hyperkalemia.” This is a true statement, but it is a secondary endpoint. The proper spin free conclusion would be to emphasize the primary endpoint: use of patiromer reduced the potassium level by 0.1 mmol/l vs placebo.

My friend and virtual mentor of sorts Milton Packer wrote the editorial. As always, this man teaches us stuff.

He first told about RALES and EMPHASIS, which established the substantial benefit of spironolactone and eplerenone in HF. He then wrote that in clinical practice, there is great fear of high potassium and widespread inappropriate use of MRAs, including:

  • not checking potassium levels;

  • not stopping potassium supplements; and

  • not reducing the dose of MRAs.

This is true and it’s one of the reasons that make HF trials harder to translate to the real world, because in trials, there are research nurses and pharmacists to help do this, and in the real world, where clinicians are overworked, there are not those failsafe mechanisms.

Packer then tells us that in the PEARL HF trial, patients with HFrEF were randomly assigned to patiromer vs placebo to determine whether patiromer might enhance the tolerability of spironolactone 50 mg/ day. After 4 weeks, the patiromer group was more likely to receive the high dose of spironolactone, but it was only 91% vs 74%,

But Packer had just told us that in RALES, the mean dose of spironolactone was only 26 mg and that is enough to deliver huge benefits. It is clear that he believes there is little need to push high doses of MRAs.

Packer noted the endpoints in DIAMOND, but then pivoted quickly to the fact that 80% of historically hyperkalemic patients did not report a potassium level > 5.5 mmol/L during double blind follow-up, even in the absence of patiromer and even though they were getting high doses of an MRA.

He noted that in table S4, patiromer did not enhance the dosing of RAASi and the proportion of patients taking comparable doses of MRA were nearly identical in the placebo and treatment groups.

  • The most important finding from DIAMOND, Packer writes, is that MRAs were stopped in 7% of patients in the placebo arm and 5% of the patiromer arms.

  • The investigators treated more than 400 previously hyperkalemic patients with patiromer for 6 months to achieve an eleven-patient difference. And actually, that is the number needed to treat to prevent one HHF with MRA over 3 years.

  • Given the expense of patiromer over 3 years, it is unlikely to be cost-effective to prevent one HHF.

  • His conclusion: By salvaging the DIAMOND trial, the investigators delivered real enlightenment.

  • Specifically, they found that the vast majority (≈ 80%) of patients with HFrEF and a history of hyperkalemia will not experience recurrent hyperkalemia in the absence of patiromer even when challenged with doses of MRAs that are likely higher than those needed to reduce mortality.

  • Of importance, the proportion of patients who tolerate MRAs without hyperkalemia and without potassium binders will only increase in the future, since two foundational drugs — sacubitril/valsartan and sodium-glucose cotransporter 2 (SGLT2) inhibitors — mitigate the risk of hyperkalemia while having direct benefits on HF outcomes.

These immensely reassuring findings mean that, if we truly seek to improve outcomes in clinical practice, we must assuage physicians’ exaggerated fears about the dangers of hyperkalemia, since trial-based MRA dosing strategies currently represent an exceptionally cost-effective and well-tolerated (but regrettably scorned) way to slow the progression of HFrEF.

Comments. Dr. Packer is right about good doctoring. If we could create a trial-like atmosphere, more patients with HF could gain the benefit of MRAs. The trouble is that what is possible in a drug sponsored trial is not so easy to do in practice. Everyday docs in the real world, are faced with this choice: the risk of death from hyperkalemia vs the missing out on a potential relative risk reduction in the future.

Given that dilemma, many docs choose to hold MRAs. What is clear from this trial, and from Packer’s commentary is a $1000 per month drug with drug-drug interactions requiring spacing from taking multiple other drugs, will not change that calculus.

The Future of CVD

The Journal of the American College of Cardiology (JACC) has published a paper from a Harvard group, first author, Reza Mohebi, that attempts to project the number of people with CV risk factors and heart disease into the coming decades. They use National Health and Nutrition Examination Survey (NHANES) data. NHANES is one of those longitudinal health studies that follow people over the years. It includes diverse communities.

They then conducted logistic regression and combined the findings with census reports. It’s sort of complicated.

Healthcare journalist Marlene Busko called the findings “staggering” in the title of her excellent news coverage. Indeed, the findings are staggering.

  • The number of people the authors predict will develop diabetes (DM) , hypertension, abnormal lipids, and obesity will increase by millions. Same with actual disease — atheroscerotic cardiovascular disease, HF, myocardial infarction (MI), and stroke — are going up by millions.

  • Their model predicts that minority populations will fare the worst. Particularly striking was a steep rise in DM in Black and Hispanic populations.

Comments. The #TWICpodcast has touched on this topic many times. This study is especially stark because they put absolute numbers to the projections.

In my talks on the humility of Medicine, I always show some slides of the vital statistics on lifespan over the past 50 years. And despite the huge gains in imaging, pharmaceuticals, procedures, the cath labs, the electrophysiology (EP) labs, the Watchmans, the MitraClips, and transcatheter aortic valve implantations, and of course, digital health like smartwatches, the average lifespan of all groups is essentially flat.

The Mandrola theory is that while modern medicine can extend life, this is counterbalanced by the increasing poor health of the population we treat. In their paper, the authors project to 2060. As for the accuracy of their predictions, all one needs to do is get out of the wealthy part of cities, or visit middle America, or come see me here in Kentucky and open your eyes.

Physically, the “general appearance” of American health is scary bad. In my clinic, in the grocery store, at kids’ sports events, and especially in airports, you see that obesity and limited mobility has been normalized. It is truly shocking. Add to these observations the many papers I have covered on the atrocious state of kids’ cardiometabolic health. So, I think the authors of this paper may be underestimating the coming calamity in noncommunicable disease.

As for solutions, here is where I differ from the narrative in many parts of the medical establishment. I feel that doctors and healthcare per se have very little effect on this.

Yes, we can stop normalizing ill health by ignoring someone’s obesity or sedentary lifestyle. For instance, I frequently see patients with atrial fibrillation (AF) who are obese and when I discuss the relationship of weight and AF, they look surprised, as no clinician has discussed this with them. “My doctor said I had great numbers!”

But still, doctors treat individuals. The problem that the Harvard group – and others — have identified is way upstream from individuals.

I’ve also covered the extremely strong evidence base that shows that more easily available healthcare does not improve outcomes on average. Many studies show this. The CV health problem is cultural and societal and can only come from changing norms. I don’t have an answer for that, but I am sure it is not more medical centers that give out more pills and do more stents. It’s much broader than that. Some examples:

  • I ride my bike to work. I live in a city of about a million people. I typically see zero people riding or walking to work. Zero. One reason is that there is no infrastructure. It’s not really that safe. And there are few places to shower at work.

  • I always ask patients what they do for exercise, some tell me they go the gym 3 times per week. But what about the other 4 days?

  • When I volunteer in my colleague’s clinic for disadvantaged people, I realize how little these people need a cardiac specialist. What most of these people need is far more basic than a cardiologist.

I am pretty sure no one knows the best way to change these norms. America is not Denmark. We are a sprawling diverse country born of rebelliousness. That makes it hard for any one policy to work.

There is a great debate as to the best policy to improve our health. I have no idea which one will be best. I can say this: the most recent approaches don’t seem to be working. Like burning in the wrong area and not terminating the tachycardia. When that happens, it may be worth considering different approaches.

Primary Prevention ICDs in the Modern Era

The journal JACC-EP, of which I am a social-media editor along with Janet Han, has published a provocative paper from the University of Pittsburgh group, first author, Mehak Dhande. This group wanted to assess the impact of the number of guideline-directed medical therapy (GDMT) meds prescribed for HFrEF on all-cause mortality in patients who get an implantable defibrillator (ICD). They used their own database of patients who received an ICD from 2010 to 2021. This was nearly 6400 patients. Most were for primary prevention.

Their primary endpoint was the rate of all-cause death at 2 years after implant in those who had either a primary prevention or cardiac resynchronization therapy defibrillator (CRT-D) device.

They then correlated the 2-year mortality rate with the number of GDMT meds—either 1,2,3, or 4. Recall that there are four classes of GDMT for HFrEF: beta blocker, RAS, MRA, and SGLT2 inhibitor.

After risk adjustment for age, sex, ejection fraction, body mass index, a comorbidity score, the type of cardiomyopathy, and the year of device implantation, each additional GDMT conferred a reduction in the risk of death of 36% in recipients of ICD (hazard ratio [HR]: 0.64; P < 0.001) and 30% in recipients of CRT-D (HR: 0.70; P < 0.001).

Picture KM survival curves that look increasingly less steep with the number of meds.

They then take these associations and make two conclusions:

  • Initiation of maximum number of tolerated GDMT medications should therefore be the goal for all patients with HFrEF.

  • In the setting of robust GDMT, the risk vs benefit of a primary prevention ICD warrants re-examination in future studies.

Comments. First, a small critique of the study. It’s an association study. Sure, patients who took the four classes of meds did better. And while we have strong data that these drugs provide incremental benefit over placebo, I also think the ability to take these four meds may also be a marker for a healthier patient, and that is why they may have better survival.

I assume the University of Pittsburgh gives pretty high-level care, and if a person with HFrEF could be on 3 or 4 classes of drugs, the doctors would have prescribed them. So it’s possible that their finding is at least partially association rather than all causal.

Now to the other side. I agree that sudden death rates in HF are dropping. In 2017, a group of HF trialists published in the New England Journal of Medicine a very important but not too highly cited paper, showing a steep decline in sudden death over the years in HF trials.

Here is a quote: “There was a 44% decline in the rate of sudden death across the trials (P=0.03). The cumulative incidence of sudden death at 90 days after randomization was 2.4% in the earliest trial and 1.0% in the most recent trial.”

  • Think about that—if the sudden death rate is only 1%, how much benefit can you get from an ICD? The UPitt authors therefore confirm the HF trialists’ observation, and it is everything, right?

  • It’s everything because ICDs are dumb — they only prevent one kind of death, from arrhythmia. That was a huge deal 20 or 30 years ago when sudden death represented such a huge proportion of total death. But now, with better medical therapy and also temporal trends, better treatment of MIs, the proportion of sudden death is greatly decreased. Yet the risks of the ICD remain pretty stable.

  • So the authors are totally correct. If we did another SCD-HeFT trial, there is a very good chance there would be little benefit on average to the ICD.

Look no further than DANISH. Patients with non-ischemic cardiomyopathy, bad left ventricular EF, 6-year follow-up. ICD had no benefit over medical therapy. It boggles my mind how the EP establishment has essentially ignored the null finding of that extremely well-done trial. Upton Sinclair comes to mind.

I would love to see another ICD trial. I don’t think it will happen. Therapeutic fashion is still pretty strong.

Digital Posters

I will close with a fun topic. When we started going back to in-person medical meetings this year, the poster sessions had changed. Gone were the rows of paper posters attended by impossibly young and earnest people anxiously awaiting any questions.

Now we had little pods of people listening to one person discuss their poster on a digital screen. The listeners had to tune their headphones to hear the speaker. And the digital screen was super small. It was detached, sterile, almost dystopian.

Well, via social media, a number of influencers spoke out that we needed to bring back the paper posters. theHeart.org | Medscape Cardiology has great coverage of the paper vs digital poster “controversy.” I agree totally. The paper posters may be a pain for someone to travel with, they may not be as green as a digital poster, but they were better for several reasons:

  • They allow a casual perusal. You could stroll lines of posters, and there would always be a few that sparks an interest. Even changes a practice. I first learned about micropuncture and US access on posters.

  • Perusal is not the same digitally. It’s just not.

  • Paper posters led to human-human interactions often with big groups. My friendship with Piotr Futyma in Poland stems from a meeting at a poster. Connections are highly under-rated.

Paper posters won’t solve the crisis in CV health, but it was one of the biggest draws of actually attending a medical meeting in person. Sometimes what is new is not better than what is old.

Comments

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