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In This Week’s Podcast
For the week ending July 15, 2022, John Mandrola, MD comments on the following news and features stories.
The LIFE Trial
I want to start with a discussion of a sub-study of the LIFE trial published in the Journal of the American College of Cardiology – Heart Failure (JACC-HF), first author, Justin Vader. It’s unusual for a substudy to lead #TWICPodcast, b/c here we focus most on main trial results, but this particular study deserves attention.
Recall that JAMA published the main LIFE results this year. LIFE compared sacubitril/valsartan to valsartan in patients with advanced, class 4, HF with reduced ejection fraction (HFrEF). Its main outcome measure was N-terminal B-type natriuretic peptide (NT-BNP) over 24 weeks. Clinical outcomes were secondary endpoints of this small trial.
The main finding was that there was no difference in NT-BNP in the two groups. Neither was there any improvement in clinical outcomes. What’s more, one in five patients were not able to tolerate the sacubitril/valsartan during the run in, and about a third of patients discontinued sacubitril/valsartan during the 24 weeks of the trial.
The Vader and colleagues substudy focused on the tolerability of sacubitril/valsartan during the run-in period. They found that the reasons for sacubitril/valsartan intolerance were:
When they did a correlation of multiple variables as predictors of intolerance, they found that low BP, low sodium, and implantable cardioverter-defibrillator or cardiac resynchronization therapy, mitral regurgitation, nonuse of ACE/ARB medications, or use of insulin at the initial visit predicted intolerance. And if a patient had four of these, there was a 50% chance of intolerance.
Comments. I lead the podcast with LIFE and this substudy because they speak to this anointed notion of guideline-directed medical therapy (GDMT). I’ve said it a gazillion times on this podcast, but I will say it again: most drug and device trials enroll ideal patients, with few multimorbid conditions and decent socioeconomic status. This is especially true for HF trials. LIFE is special because it took on the advanced HF patient who often has multimorbidity. It showed with obvious clarity that the anointed sacubitril/valsartan drug does not benefit these patients, and many — nearly most — cannot even tolerate it.
Once again, the important area of external validity or generalizability of trial results comes up. I don’t have data on this but I suspect that most sacubitril/valsartan gets started in vulnerable, advanced HF patients in the hospital. This is driven by GDMT. You know, the Get-With-the-Guidelines, near religious drive to practice evidence-based medicine. Yet this evidence comes from stable, ambulatory, mostly male outpatients.
LIFE and its run-in periods remind us that multimorbid patients with more advanced HF likely do not benefit from sacubitril/valsartan.
It reminds us with utter clarity that translation of evidence means going to Table 1, patient characteristics, and the paragraph on inclusion and exclusion criteria, and asking the question—who were these patients in the trial?
The notion that higher risk patients stand to benefit more from interventions is more often than not false.
LIFE shows perfectly that patients with multimorbidity or advanced organ failure do not garner the same benefit of those well enough to stroll into an outpatient HF clinic.
If you don’t believe me on the concept of higher-risk patient benefiting less from common therapies, go look up the GISSIHF and CORONA trials of statins in HF, or the AURORA and 4D trials of statins in patients with end-stage renal disease. All four trials studied super high-risk patients and all four trials showed no benefit from statins.
Resuscitation, Early Angiography, and Therapeutic Fashion
What is up with resuscitation science? This field seems to overflow with randomized controlled trials (RCTs). JAMA has published yet another RCT, called the Multicentric EMERGE trial, looking at the use of emergent vs delayed coronary angiography in patients who survive cardiac arrest and do not have ST segment elevation.
The whole notion got started from an uncontrolled case series of 84 patients published in the NEJM in 1997. This study found that half of survivors had a coronary occlusion, and about half had successful balloon angioplasty. Regression analysis correlation found that successful angioplasty predicted better survival. The confidence interval (CI) went from 1.1 (almost no benefit) to 24x.
Early angiography makes sense because cardiac arrest often stems from plaque rupture and total occlusion. But before the French EMERGE trial, which started in 2017, we have seen publication of not one but three trials testing early vs late angiography in survivors of cardiac arrest without ST elevation.
Comments. First, any ongoing trials in this space should stop. For patients with cardiac arrest and no ST elevation, the strategy of immediate angiography should stop. We have enough data.
My question, and this is a real question as I don’t know, is why do we have four trials testing a strategy for this condition, and often have one or often none in other strategies? Why has the therapeutic fashion of coronary angiography become so ensconced that it takes four trials to de-adopt it for this condition? By contrast, think of the anointed therapies that we accept with one or no trials:
Sacubitril/valsartan in HFrEF, for instance, has one trial, PARADAGM-HF, in which the drug beat a medium dose of enalapril. All other sacubitril/valsartan vs stronger ACE-I or valsartan alone have yielded nonsignificant primary endpoints. Four trials for immediate angiography in cardiac arrest vs one for a drug we spend billions of dollars on.
WATCHMAN for stroke prevention. We know WATCHMAN did not meet noninferiority vs warfarin for the primary endpoint of stroke and systemic embolism in PREVAIL. So we extrapolate that unimpressive data to patients who cannot or do not want to take oral anticoagulants (OAC). Yet these patients were excluded from the trials. An utterly preventive procedure, done every day, with significant risks of major complications, and yet we have not a shred of data to support its use. (And don’t cite PRAGUE-17 because that trial does nothing to change my pessimistic priors).
Atrial fibrillation (AF) ablation. One of the main financial engines of electrophysiology (EP). We don’t know the cause of AF, we don’t have convincing evidence the procedure reduces hard clinical outcomes (CABANA was nonsignificant), and there are zero published sham-control studies looking at quality of life.
Stents in stable coronary artery disease. Here, the case is different. Here, we have oodles of data showing that revascularization added to optimal medical therapy does not reduce myocardial infarction (MI) or death, and even does not improve exercise time against a sham, and we, for the most part, ignore the results.
Don’t worry I am going to make a point. But first I want to point you to a shocking paper published in April, a paper you won’t see covered in media. The Journal of Clinical Epidemiology published a systematic review of 1500 interventions in biomedicine. The authors, Howick and colleagues, used this large random sample of interventions that had Cochrane reviews — if there is a Cochrane review of something, it’s likely to be a common intervention.
The authors wanted to know what proportion of interventions tested by Cochrane have high quality evidence of benefit. They characterized high quality as follows:
Using GRADE, the primary endpoint had to have high-quality or low-bias;
The primary had to be statistically significant; and
The Cochrane authors had to conclude the therapy was effective.
With this high bar, guess how many interventions have the highest quality evidence: 5%. Less than 10% of the things we do in healthcare have such robust backing. Howick and colleagues also looked at harms reporting and found:
My question is, how can therapeutic fashion become so firmly established? And is this not dangerous? Recall how strong the therapeutic fashion was for treating premature ventricular contractions after MI. Did you know that a doctor tried to warn us 10 years before CAST? Cast found that the number needed to kill was 29. Imagine how many lives would have been saved had we been less cocksure of our interventions!
I’ve got a column coming on this topic Monday. In it, I ask you to consider the idea of therapeutic fashion, why and how it occurs, and how to prevent it. Four RCTs to unwind the fashion of immediate angio after cardiac arrest. Yet so much of what we do has minimal evidence.
Please read the Howick paper. It’s open access.
Diabetes and Cardiology
I had a very busy few weeks in the lab. I’ve done Vein of Marshal ablation for mitral isthmus flutter, multiple left bundle branch area pacers, ICDs, ablations for supraventricular tachycardia (SVT), ventricular tachycardia, AF, and atrial flutter. But the thing I was bragging most about was changing a patient’s diabetes meds. I was seeing him for an arrhythmia, but he had type 2 diabetes (DM) and chronic kidney disease (CKD), and was on an oral sulfonylurea, not an SGLT2 inhibitor.
But he had two indications for an SGLT2 inhibitor: DM and CKD. So, boom, I switched him. I don’t understand why we wouldn’t use drugs that have been shown in trials to reduce important hard endpoints. But here’s the problem, in the United States, and maybe in your country as well, there are barriers to using these drugs. Which brings me to a very nice study from a young researcher from University of Pittsburgh, named Utibe Essien, who, with many co-authors, decided to look at the care of patients with DM who select Medicare Advantage as their health plan.
More Americans choose Medicare Advantage. These are offered by private insurance companies contracted with Medicare and provide at least the same level of coverage that Medicare Part A and Part B provide. They often cost less but there are tradeoffs. There may be less freedom of choice.
By looking at a diabetes database, Essien and his co-authors found that
About one-third of nearly 350,000 patients chose Medicare Advantage.
Those in Medicare Advantage were significantly less likely to receive glucagon-like peptide 1 (GLP-1) receptor agonists and sodium–glucose cotransporter 2 (SGLT-2) inhibitors.
Journalist, Dr. Mitchel Zoler, has a nice recap of the paper. He notes that diabetic patients in Medicare Advantage did have some upside — they were more likely to be screened for nephropathy or eye disorders and more likely to have foot exams.
To me, this is a terrible trade-off: you can have screening for disease that may be prevented by taking an SGLT2 inhibitor, or have your foot examined, or you could simply get your effective medicine covered.
I like this study, it’s nice work. The main limitation is that drug A or drug B use, or the number screened, or blood glucose or BP levels are surrogate markers. What we would really want to know is whether patients with Medicare Advantage vs regular Medicare have better or worse outcomes. To answer this, you’d need randomization. Not a week goes by that the profit-driven US healthcare system doesn’t frustrate me. If we could figure out a way to reward insurers for better outcomes, perhaps they would be more apt to cover drugs and interventions shown beneficial in trials.
And speaking of therapeutic fashion, how about the power of treating to the surrogate of HbA1c rather than using drugs that reduce outcomes?
Re-imbursement Cuts Coming to EP
I want to close with a plea to think of us American EP doctors, because we have recently endured a 30% cut to our AF ablation fees. My field is experiencing a spasm of palpitations.
Payers decided that all that add-on stuff we do during ablation — use of 3D mapping, intracardiac ultrasound, etc, should now be considered normal and they bundled lucrative add-on codes into one lesser fee.
Now, we learn that payers are considering even more cuts to other sorts of ablation, and perhaps even the goldmine that was remote monitoring.
I have mixed feelings about this. Of course, it’s normal to feel great about what we do in the lab. It’s pretty amazing how far EP has come.
We actually cure patients with focal arrhythmias.
And remote monitoring can often uncover important problems with a device before, say, a shock.
We pick up AF and start OACs and likely prevent stroke. You get to feel that these are valuable things worthy of a big salary.
But the payers have a point too. We’ve been using codes for ablation that stem from the days when ablations took many hours.
Now it’s normal for an SVT ablation to be over in less than 90 minutes. Same for AF ablation.
Pulmonary vein isolation is not nothing, but it is rote, well-practiced, and about 10 times easier than seeing patients in clinic.
I am not sure there is a more low-value medical intervention than an implantable loop recorder for AF detection. The devices are expensive, and we can bill patients super-frequently for remote monitoring. There is way too much fat in the remote monitoring space.
Finally, and this is crucial: if you are going into EP for the money, you are making a huge mistake.
This is a glorious field because your knowledge of basic physiology translates directly to the care of patients. Knowing the action potential of cardiac tissue explains many things at the bedside.
You use amazing curative procedures. I used to consider the pacemaker banal, and now appreciate it as exceedingly elegant. It transforms patients’ lives for the better. Sometimes Lazarus-like.
In EP, you also get to have a relationship with people for decades. Through health and illness. Your patients come to trust you. You are also part life coach and psychologist. You have the power to remove their fear simply with your expertise. This is meaningful. Priceless. So, for me, my ‘relative value units’ hardly matter. They never really mattered. Even with these cuts, we will do fine. We will be ok.
Some will rebut my comments with the fact that EP docs have to train longer. My response is that training may be the best years of your life. You should never want to shorten them.