COMMENTARY

Jul 22, 2022 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

July 22, 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 July 22, 2022, John Mandrola, MD comments on the following news and features stories.

Therapeutic Fashion and Conduction System Pacing

I want to thank Canadian cardiologist Dr. Vartan Mardigyan who perfectly enhanced my written discussion last week of therapeutic fashion. I was going on about how medical norms get established based on dubious data, or in the absence of data, and Vartan replies to me on Twitter, knowing full well that I am entranced by conduction system pacing.

“Do you think that LBBAP would qualify as a “therapeutic fashion” or do you think that the benefit can withstand critical appraisal? You have also adopted LBBAP prior to the results of the RCTs...”

I “Tweeted him back” that I love this . And I do. First of all, my friends, please, always, challenge me. I am a mere private practice electrophysiology (EP) doc whose hobby is reading, writing, and trying to communicate medical evidence. This podcast, all critical appraisal, is about content. Always judge the content. I am just John, the atrial fibrillation (AF) ablation doc from a little hospital in Louisville, Kentucky.

Second, as a practicing doc, I, too, am susceptible to therapeutic fashion. In the case of conduction system pacing, which produces the most gorgeous electrocardiograms (ECGs) ever, we have pragmatic challenges.

For one thing, we are unlikely to ever have large randomized controlled trials (RCTs) of conduction system pacing. This is because in cardiology and EP in particular, industry is the major funder of trials. Industry only funds stuff that has a confluence of interest — they fund trials that could increase market share of their product. This is totally not nefarious. It is how we got saline-irrigated ablation catheters, implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. Industry-funded trials can lead to benefits for both society and industry.

The problem with conduction system pacing is that it uses less expensive pacer-generators (simple dual chamber device, for example, vs a bi-ventricular [biV] device) and established pacing leads. If it were found noninferior to CRT in a trial or if it was shown to prevent pacing-induced cardiomyopathy in a trial of conduction system pacing vs right ventricular (RV) pacing, then industry would sell fewer CRT devices.

There is no confluence of interest. We will have to rely on government funding or self-funding. The HIS-SYNC trial for instance was self-funded. If you haven’t noticed, government has a lot of health problems to study, and I am being realistic that conduction system pacing may not be a top priority.

Second point here is that we do have pretty good data that when His-bundle pacing is successful, it provides excellent resynchronization and is quite similar to CRT. Yes, the clinical outcome data is lacking.

But CRT is simply electrical therapy of left ventricular (LV) delay. His bundle pacing seems equal to the task as an electrical therapy. But His bundle pacing has challenges — difficulty in placement, high thresholds, and low sensing. Left bundle branch (LBB) area pacing addresses those weakness. It is much easier and has great pacing parameters. And I love that the 3830-pacing lead has a proven track record. This means a lot to me. Newer pacing leads may be better, but they may be worse. We’ve been burned in EP so many times with “new” pacing leads. Finally, early data suggests the resynchronization one gets with true LB pacing is similar to His bundle pacing and CRT. Emphasis here on early.

While there remains much to learn about pacing in the LB area, these are the reasons I feel comfortable adapting it as a strategy. I admit that we need to stay humble, gather data, and try our best to promote trials.

Thanks again Vartan. And to everyone, always feel good about challenging me.

Early Rhythm Control

The Journal of the American College of Cardiology (JACC) has published a prespecified analysis of the EAST AFNET trial looking at whether the type or pattern of AF modifies the efficacy of early rhythm control (ERC). The authors distinguish three types of AF: first AF, paroxysmal AF (PAF), and persistent AF (persAF).

Before I tell you the results of this substudy, let’s briefly recap EAST AFNET, which The New England Journal of Medicine published in Oct 2020.

  • About 2800 patients with “early” AF, defined as less than a year in duration, were randomly assigned to two strategies: an early rhythm control (ERC) strategy that included mostly antiarrhythmic drugs (AAD).

  • After 2 years, less than 20% in the ERC group had undergone an ablation. So, this was not an early ablation trial. The usual care group used ERC only to treat symptoms. It was mostly rate control. The first primary outcome was vast and included cardiovascular disease (CVD), stroke, heart failure hospitalizations (HHF), or acute coronary syndrome (ACS). The second primary outcome was days in the hospital.

  • After 5 years of follow-up, the ERC group had a 21% lower rate of a primary outcome. This was statistically significant. Days in the hospital did not differ.

  • Safety outcomes were reported as similar, but the authors included primary outcome events like stroke and death in the safety outcomes. If you count only serious adverse events (AEs) of special interest in the ERC, it was more than three-fold higher.

AEs were one of my problems with EAST AFNET. The other problem was that the two groups had a difference in AF of only 20%. In the supplement, we learn that 80% of the ERC group were in sinus rhythm at 2 years vs 60% of the usual care group. My question is, how can a delta of 20% AF, in patients on oral anticoagulants (OAC), cause a major reduction in hard endpoints? And the answer to me is performance bias:

“Patients in early rhythm-control therapy were asked to transmit a patient-operated single-lead electrocardiogram (ECG) twice per week and when symptomatic.

“Documentation of recurrent atrial fibrillation triggered an in-person visit from the site team to escalate rhythm-control therapy as clinically indicated”

Patients in the ERC group got much more interaction with docs. Again, this is not nefarious. It is no knock on the German investigators, for whom I have the utmost respect. This is a hurdle for all pragmatic trials that test strategies.

In sum, while EAST AFNET produced “positive” results, I feel like the small delta in AF, the likely performance bias, and the much higher rate of AE related to ERC render the results hard to translate to the average patient. In Bayesian terms, the results did not change my prior practice, which was to treat risk factors, use OAC, give time a chance to heal, and use ERC selectively.

Now to the sub-analysis looking at AF types.

  • It was about one-third first AF, one-third PAF, and one-third persAF. Not exactly but close.

  • The authors report that ERC reduced the primary endpoints in each of the three AF types but the degree of reduction was least in patients with first AF, although the P for the interaction was nonsignificant.

They then did something curious, they delved into the components of the primary endpoints in each AF type. I say curious, because trials are powered for the overall population; they have already separated three groups by AF type. Now, they delve further into individual endpoints which, to me, seems very likely to get into noise more than signal.

  • In the abstract, they reported as the main finding that ACS events were higher in the ERC arm in the first AF group. They report it as a relative risk.

  • The rate ratio of ACS was 1.5 in the ERC vs usual care in the first AF group. In the PAF and persAF groups, the rate ratio for ACS was favorable for ERC.

  • They also report that first AF spent more nights in the hospital than those in the other groups.

They concluded:

“ERC reduces the first primary composite outcome in all AF patterns. Patients with FDAF are at high risk for hospitalization and acute coronary syndrome, particularly on ERC.”

Comments. This paper is problematic on many levels.

  • First, let’s take ACS as an endpoint. I’ve treated AF for decades, and I have not ever thought that treating it in any way prevents an ACS. ACS as I see it is plaque rupture. This is unrelated to AF treatment. Sure, you could get into demand-type myocardial infarction (MI), but I don’t think we call that ACS. When you treat AF, you try to prevent HF and stroke and relieve symptoms.

  • Just having ACS in the main EAST trial adds noise. Focusing on one part of a four-part composite end point in a sub-analysis seems strange, especially since it’s the one least connected to AF care.

  • Second, even if you allow looking at one component of the endpoint, there were only 27 ACS events in the ERC vs 19 in the usual care arm—a delta of 8 ACS events in a trial with nearly 3000 patients. How is that noise?

  • Third, as for the higher number of hospital days in the first AF group, this is explained by Table 1 which tells us that first AF patients were far more likely to be enrolled as inpatients whereas PAF and persAF patients were more likely to be enrolled as outpatients.

The one thing I would say, and I agree here with editorialist, Dr. Emma Svennberg, is that first- AF patients, especially those in the hospital, should trigger us to look for upstream causes. Recall that AF is almost always driven by stuff that aggravates the left atrium. In the outpatient clinic, this may be cardiometabolic risk factors, such as obesity, hypertension, sleep disordered breathing, or alcohol.

In the hospital, it could also be pneumonia, pulmonary embolism, thyroid storm, or other medical illnesses. So the higher hospital days with first AF is easily explained by the fact that more patients in this category had AF associated with medical conditions requiring a hospital stay.

In sum, this sub-analysis does nothing to change my approach to rate vs rhythm control.

Rosuvastatin and Kidney Effects

I have a confession: I did not know there was controversy over rosuvastatin at the time of its approval. I did not know it had risks of causing blood and protein to spill into the urine, and that it may be associated with an increased risk of kidney failure requiring replacement therapy (renal dialysis or transplantation).

Journalist Marlene Busko has written an excellent recap of an observational study published in the Journal of the American Society of Nephrology looking at the association of rosuvastatin with hematuria and proteinuria. It turns out that these effects were likely dose-related and the US Food and Drug Administration (FDA) approved rosuvastatin at doses less than 40 mg. But the label includes a comment that the starting dose of rosuvastatin in patients with a creatinine clearance (CrCl) below 30, ought to be 5 mg with a maximum dose of 10mg.

The authors of the study collected data from an Optum labs data warehouse that involved 40 healthcare organizations. They emulated a target trial, which is recommended by the causal inference group of Miguel Hernan (more on that in future podcasts). The goal was to assess the association of rosuvastatin vs atorvastatin use with the risk of hematuria or proteinuria and to study dosing patterns in patients with chronic kidney disease (CKD).

The methods section is beyond the scope of my abilities, but the idea behind target trial emulation is to get as close to randomization as possible. The technique here was something called inverse probability of treatment weighting (IPTW). Someday I hope to understand this as well as I do arrhythmia.

This was a large cohort of patients — 150,000 on rosuvastatin, nearly 800,000 on atorvastatin. Mean age 60 yrs and half were women.

Even before applying the IPTW, most of the baseline characteristics were similar between the groups.

  • Users of rosuvastatin had an 8% higher risk for hematuria, a 17% higher risk for proteinuria, and a 15% higher risk for kidney failure with replacement therapy compared with those on atorvastatin, though that risk barely met significance.

  • They noted a rosuvastatin dose-dependent risk of hematuria and proteinuria in patients with CKD.

  • The two groups avoided myocardial infarction and stroke to similar extents.

  • 44% of patients with severe CKD G4+ (eGFR < 30 mL/min/1.73 m2) were prescribed a higher rosuvastatin dosage than the maximum 10 mg/day recommended for such patients by the US FDA.

The authors speculated on the mechanism of increased blood and protein in the urine with rosuvastatin. It may simply be a class effect, in that rosuvastatin is renally excreted to a greater degree, and exposure is more than 3 times that of atorvastatin in those who have CrCl < 30.

They then write that an initial study suggested similar signals but was small. Other observational studies have not shown this association but were limited by small numbers of events.

They discuss a trial called PLANET 1 that looked at renoprotection in patients with diabetes and proteinuria. It was atorvastatin 80 mg vs rosuvastatin 10 mg vs rosuvastatin 40 mg and the primary endpoint was change in urine protein: creatinine ratio. This and other substudies found that atorvastatin reduced proteinuria whereas rosuvastatin did not.

They were also quite clear and comprehensive regarding their limitations. Obviously, despite the IPWT, without randomization, there still can be unmeasured confounders. For example, sicker patients get rosuvastatin over atorvastatin.

The sample size was large, but the number with CrCl < 30 was tiny — about 1% of the study population — so like the previous study, there is the chance for noise.

Comments. I learned something here. Most obviously, way too many patients are receiving high doses of rosuvastatin that go against the recommendations.

  • Rosuvastatin compared with atorvastatin surely seems to predispose to kidney toxicity—especially in patients with advanced CKD. The hematuria and proteinuria signals are stronger than in kidney failure with replacement therapy.

  • I agree with Canadian nephrologist, Dr. Swapnil Hiremath, who commented in the story that we needed more awareness of this phenomenon. He’s probably right in that we see patients on high dose rosuvastatin, develops CKD, and the dose isn’t adjusted. This is a place where clinical pharmacists could have a great role.

  • Finally, let’s always remember that statins may not have the same cardiovascular protection in patients with CKD or end stage KD.

The AURORA trial, enrolled nearly 3000 patients on hemodialysis to rosuvastatin 10 mg vs placebo and found that rosuvastatin lowered LDL cholesterol but had no effect on major adverse cardiac events (MACE). The 4d Trial looked at atorvastatin vs placebo in patients with diabetes who were on hemodialysis and found no benefits in MACE.

Salt and HFpEF

Journalist Patrice Wendling has a keen eye for good topics. Salt restriction in heart failure (HF) is indeed a relevant everyday thing.

The journal Heart has published a secondary analysis of the TOPCAT trial of spironolactone vs placebo in patients with HF with preserved ejection fraction (HFpEF). In 2014, the original TOPCAT trial found that spironolactone did not reduce outcomes but the study was marred by huge geographic variations in results. Patients enrolled in Russia and Georgia had shockingly low outcomes. Re-analyses of the trial excluding those groups finds that spironolactone indeed has benefits. Recall also that the recently published pragmatic SODIUM HF trial published in the Lancet found that strict sodium restriction produced no reduction in clinical events.

  • A research group from China wanted to further explore the notion of salt restriction. They used data from TOPCAT — which is available because it is an NIH sponsored study — unlike many industry trials.

  • They excluded the contested patients from Russia and Georgia and studied the association of sodium intake via a self-reported cooking score, which was available on the patient data forms, and outcomes. The primary outcome of TOPCAT was CVD, cardiac arrest, or HHF.

  • A cooking score of 0 was the control arm so to speak which meant no added salt. Cooking scores of 1,2, and 3 were given for increasing amounts of added salt.

  • Main result: Compared with patients with a cooking salt score of 0, patients with cooking salt score higher than 0 had statistically significant, 24% lower risks of the primary endpoint and 27% lower risks of HHF.

Comments.

  • You don’t want to go crazy over a post-hoc observational study of an old trial, especially one using a self-reported salt cooking score.

  • Plus, the authors dichotomized the results — meaning they compared score 0 or > 0. That always raises a red flag. I wonder if it would be better to just display the continuous results. (I learned this from following statistician Frank Harrell on Twitter.)

  • But here is another signal — similar to SODIUM HF — that suggests that we not be overly restrictive in our salt intake recommendations.

  • I agree with commenter Dr. Minnow Walsh who emphasized that many of these patients with HFpEF are volume overloaded, and for sure, we should counsel them on not taking in high-salt diets.

Finally, and I will close on this comment, a lot of post-hoc studies are misleading spin, but not all of them are. Some are valuable. Papers like this one are possible because there is open data. I believe all trials used for regulatory purposes ought to be open for such analyses.

Comments

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