Nov 4, 2022 This Week in Cardiology Podcast

John M. Mandrola, MD


November 04, 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 November 4, 2022, John Mandrola, MD comments on the following news and features stories.

AF Conversion in the ED

JAMA Network Open has published a study looking at the conversion of atrial fibrillation (AF) in the emergency department (ED) using IV potassium and magnesium infusions. This study has received some attention, which isn’t surprising because AF is common; everyone loves it when AF converts; and potassium and magnesium are easily available and commonly used. If it were true that something so simple could convert AF, that would be something.

Regular listeners to #TWICPodcast are now waiting for me to tell you about how the authors randomly assigned one group to placebo and the others to the IV potassium and magnesium. That way we would know that all, both known and unknown, confounding factors were balanced. But that is not what the authors did. Instead, the investigators from the University of Vienna, Austria, used a registry that they kept in their very busy ED and looked back at two nonrandomized groups.

  • The authors considered all adult patients with AF who presented to the ED from 2009-2020.

  • The intervention was an infusion of potassium and magnesium. Some patients received it; some did not. A doctor decided whether to use them.

  • The primary outcome was the probability of spontaneous conversion to sinus rhythm (SCV) in the ED.

  • They used complicated statistics: Multivariable cluster-adjusted logistic regression was used to estimate the association between potassium and magnesium administration and the probability of SCV.

  • Over the time span they found about 2500 instances of AF and 570 episodes of atrial flutter.

  • Patients with AF who received potassium and magnesium had an odds ratio of SCV of 2; confidence interval (CI) 1.5 to 2.5. Essentially the odds of conversion were substantially higher in those who received the infusions.

  • The same relationship did not hold for atrial flutter episodes. Here there were no differences in SCV rates with or without the IV supplement.

Baseline potassium and magnesium levels did not influence the probability of conversion. There did seem to be an effect of time. Potassium and magnesium were only associated with SCV in short duration AF. The authors concluded that the higher conversion rate with potassium and magnesium infusions suggest an increased probability of SCV in AF.

Comments. This week, this was the third most-shared cardiology article on | Medscape Cardiology. It is plausible that the infusions may have conversion-like effects, especially magnesium.

I hope all of you recognize the problem, which the authors nicely laid out in the limitations section.

  • This was a non-randomized comparison, and despite the authors’ valiant effort to balance confounders, they can only balance those on the spreadsheets.

  • Clinicians seeing the patients had to decide whether or not to give the infusions. They use more than data to make these decisions.

  • I suspect that if this were repeated with randomization, it is highly likely to be null. I say that because there’s so much AF out there and I think we would have noticed a relationship already.

So, please don’t start willy-nilly giving potassium and magnesium infusions. Yes, you may see SCV afterwards, but also know that my number one treatment for acute AF is to distract the doctors, nurses, and patients so that time can convert the AF. If given enough time, short-duration AF converts on its own very often. #GivePeaceAChance

Hormone Replacement Therapy and the Heart

The story of hormone replacement therapy (HRT) for post-menopausal women comes up often in my lectures on medical evidence. This week the US Preventive Services Task Force (USPSTF) again issued an update on menopausal hormone therapy with the use of estrogen with or without progestin for the prevention of chronic conditions such as coronary artery disease (CAD).

Before I tell you about the USPSTF statement, which is largely unchanged from its previous documents, I want to say why HRT is so useful in lectures on evidence-based medicine (EBM).

In the early 1990s when I began training, it was typical to give post-menopausal women HRT to reduce heart disease. Why? Because it made sense, and oodles of observational studies had found an association — emphasis on the word association — with HRT and lower rates of cardiovascular (CV) events. I even have a slide of a huge meta-analysis of observational studies in the Annals of Internal Medicine, in which they use causal language urging doctors to prescribe HRT.

Then, 10 years later, the Women’s Health Initiative (WHI) randomized controlled trial (RCT) found that HRT not only did not prevent CAD, it worsened it. More myocardial infarctions (MI), more pulmonary emboli, more stroke, and more breast cancer. Thus, a therapeutic fashion, wrongly established, led the medical profession to harm millions of women.

The WHI may be as important a trial as the Cardiac Arrhythmia Suppression Trial (CAST) in the history of modern medicine. Every learner should read about these trials. I have an entire lecture based on these sorts of stories. What’s more, WHI has held up over time. Long-term follow-up, subgroup analyses, and other smaller trials have all found the same harm signal.

Now in 2022, the USPSTF has reiterated its guideline to not use menopausal hormone therapy for disease prevention such as heart disease, cancer, and osteoporosis. Drs Alison Huang and Deborah Grady have an excellent editorial in which they explore some of the controversies and misunderstandings surrounding HRT.

First is something called the timing hypothesis: that is, one of the criticisms of WHI was that it enrolled older women who were largely past menopause. If you look at HRT in younger women very early in the menopausal change, there may be a heterogenous treatment effect where in the use of HRT in early in menopause may offer benefit.

  • USPSTF addresses this possibility and find little evidence for benefit:

  • For instance, women in the WHI trials who were aged 50 to 59 years did not have a statistically significant increased risk of CHD events (hazard ratio, 0.93 [95% CI, 0.65-1.33]) or stroke (hazard ratio, 1.13 [95% CI, 0.73-1.76]), but the numbers of these events in this subgroup of younger women were small, and no statistically significant differences in event rates by age were detected. The P for interaction was not significant.

  • My friend and mentor Andrew Foy has done meta-regression work in this space and agrees, saying that there may be an interaction but if it exists it is small and not clinically relevant.

  • USPSTF and the editorialists strongly urge clinicians not to use HRT early and then try to stop it before harm kicks in. In other words, don’t try to thread the needle with the timing hypothesis.

The problem with these recommendations is that they have spilled over into the treatment of people in whom HRT could relieve symptoms of menopause. The editorialists write that too many clinicians conflate the two indications — HRT for long term prevention of disease, which is not indicated, and HRT for the temporary relief of menopausal symptoms.

  • USPSTF urges clinicians to be wise about the two indications.

  • For younger severely symptomatic menopausal patients, a short course of HRT with plans to wean off at some point would be far better than unproven nonhormonal meds such as a selective serotonin reuptake inhibitor, gabapentin, or clonidine, which have no proven benefit but known harms.

The editorialists also note that new drugs for menopausal symptoms are under review by the US Food and Drug Administration and will be marketed to women concerned with risks related to HRT. But these new drugs will have nowhere near the heft of the safety studies of HRT.

The summary of this situation once again comes down to skillful doctoring.

When a young highly symptomatic woman seeks relief of menopausal symptoms, a course of HRT is a reasonable choice. Yes, it has been shown that long-term use for disease prevention increases risk of adverse effects, but medicine is replete with therapies that vanquish symptoms while conferring some risk of long-term use; nonsteroidal anti-inflammatory drugs, for example. Individuals and informed clinicians ought to be able to make well-aligned decisions that have a high values-choice concordance.

Post-Thrombectomy Blood Pressure Targets

Regular listeners to the #TWICPodcast know that I love the less-is-more concept. Well, Lancet has published a super-important RCT comparing intensive vs lenient control of blood pressure (BP) after stroke intervention.

Before I say anything about the ENCHANTED2/MT trial, I want to warn you that the specifics aren’t as important here as the general concept. Endovascular therapy of stroke is a new and pretty amazing therapy. Much like the opening of an occluded coronary artery to vanquish MI, stroke interventionalists can, with a combination of devices, reperfuse the brain and improve outcomes in selected patients. The optimal blood pressure after brain intervention is a matter of debate. There has been expert opinion (‘eminence’), observational studies (near worthless), and a small trial suggesting no difference in recovery with more intensive BP vs standard BP targets. The way to settle such a conundrum is...say it with me...randomization.

And this is what the authors of ENCHANTED2/MT trial did:

  • At 44 referral hospitals in China, 821 patients after stroke intervention were randomly assigned to a systolic BP target of less than 120 vs a less intensive target of 140-180.

  • The primary efficacy outcome was functional recovery assessed by the Modified Rankin Scale.

  • The trial was stopped early because of harm in the intensive BP target arm.

  • The likelihood of poor functional outcome was greater in the more intensive treatment group than the less intensive treatment group (common odds ratio 1.37 [95% CI 1·07–1·76]).

  • Compared with the less intensive treatment group, the more intensive treatment group had a 53% higher odds of earlier neurologic deterioration and two times the odds of major disability at 90 days.

  • There were no significant differences in symptomatic intracerebral hemorrhage.

Comments. I don’t treat post-stroke-intervention patients. You probably don’t either. But this is a shining example of how evidence-based practice should work. Beautiful, really. Medicine overflows with questions like this. The way forward is not more expert opinion and confounded observational non-randomized comparisons or industry-sponsored biased trials. It is randomization. These authors randomly assigned 400 patients in each arm. Now there is an answer for the hundreds of thousands, maybe millions of patients who will get this therapy going forward.

Imagine if we randomized this many patients in a study of left atrial appendage occlusion vs no treatment. Or another pragmatic mitral clipping trial in secondary mitral regurgitation. Or a rivaroxaban vs apixaban trial.

Here’s another nice feature of their study:

“Individual, deidentified participant data used in these analyses will be shared on request from any qualified investigator following approval of a protocol and signed data access agreement.”

The authors tell us there are other ongoing trials in this space. Good. These will further define the best blood pressure target.


In the past I’ve been critical of professional societies, but this week I laud the American College of Cardiology (ACC) for releasing an expert consensus document on treating and managing patients with heart disease who have chronic comorbidities. In my practice, that’s about 90% of patients.

On Twitter, in journals, at meetings, doctors are bombarded with messages about getting with the guidelines. Get your patients on guideline directed medical therapy; all of them; and on max doses and right quick.

And I agree with them, if the patient is like those in the clinical trials, or if regular practicing docs had the support that clinical trials offer — like research nurses coordinating things.

I recently saw a youngish man with heart failure with reduced ejection fraction (HFrEF). He still rides bikes; he’s wealthy; he’s got good insurance. Well, we threw the kitchen sink at him. He’s on maximum doses of every HF medication. He’s able to come in for follow-ups. He has no other medical conditions and needs no other medications.

Then there’s the other 90% of patients I see, who have oodles of conditions, take oodles of meds, do not have the best insurance, and have spotty transportation to clinic. Treating these patients with increasing doses and numbers of tablets illustrates the Icarus story: you feel as if one more medicine will be enough to cause a trip to the ED — for hyperkalemia, or hypotension, or something else.

Good on the ACC for even mentioning multimorbidity. To the authors — Kim Birtcher and Larry Allen as chairs — I say thank you.

A few highlights:

  • The authors underscore the notion that a patient with heart disease might fall under multiple guidelines. A 75-year-old patient who has CAD may also have diabetes (with its guideline), hypertension (with its guideline), HFrEF (with its guideline), AF (more guidelines), chronic kidney disease (even more guidelines).

  • Pretty soon, the typical patient we see is facing a stack of guidelines all recommending numerous meds.

  • The writing committee recommends considering the whole patient, not just CV conditions.

  • We should put that on tee-shirts. The advocates of considering the whole patient should have a booth in the EXPO next to the one with the Xarelto stock car.

  • Another highlight: “Priority should be given to treatments that address multiple conditions at once.” This is exactly what regular doctors do every day. We know that older patients with co-morbid conditions or limited insurance can’t take everything that the quality police would have us give, so after we learn about the patient’s situation, we put them on the best regimen they can tolerate or afford or take safely.

  • The authors note that deprescribing might be the best option in some patients. This, too, should have tee-shirts, and booths in the EXPO. As I’ve said many times, the purpose of preventive medicines is to get to be 88 years old. At that age, preventive meds often cause more harm than good. No matter what the guidelines say. If your 88-year-old, 50-kilogram patient is barely mobile, prescribe food, not pills.

  • Optimal care should reflect the patient’s goals, priorities, and preferences. This is another source of tension between the get-with-the-guidelines proponents and doctors seeing regular patients.

I dare you to discuss the results of the ARNI and SGLT2 inhibitor drugs in HF with preserved EF. Show patients the data showing that these drugs reduce hospitalizations for HF — only a fraction of total hospitalizations — and then ask them if they want to spend hundreds of dollars per month.

Many patients don’t want to take 15 tablets per day and visit a clinic every other week. Some patients look at the stroke risk reduction and major bleeding increase with oral anticoagulants and say no thanks. That’s their priority, but it clashes with guidelines. That’s why I don’t like the boxes of algorithmic recommendations in guidelines.

I say we are advisors to patients. We advocate for the best health. But that might mean not using the best life-prolonging therapy—because some patients value quality and freedom from being a patient as a goal.

Read and save the document. It’s one of year’s best from the ACC.

AHA Preview

The annual American Heart Association meeting starts tomorrow, November 5. Look for presentations on:

  • Torsemide vs furosemide;

  • Chlorthalidone vs hydrochlorothiazide;

  • CRISPR for hATTR cardiomyopathy;

  • Pemafibrate, a novel triglyceride-lowering drug;

  • Non-pharmacologic interventions for HF;

  • Small-interfering RNA meds to reduce lipoprotein(a);

  • Surgery or endovascular therapy for severe peripheral artery disease. Boy, this is a big one.

  • And don’t forget EMPA Kidney, from the American Society of Nephrology meeting. This trial reported positive results in a press release in March of this year. We will learn results of that trial. Recall that DAPA-CKD significantly reduced renal outcomes and you’d expect similar results from EMPA Kidney.

I will be in Chicago. Please do say hello. And follow our team at | Medscape Cardiology for great news and features’ coverage: Patrice Wendling, Steve Stiles, Mitchell Zoler, and my boss, features editor Tricia Ward, will all be there.


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