COMMENTARY

Sep 11, 2020 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

September 11, 2020

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.

In This Week’s Podcast

For the week ending September 11, 2020, John Mandrola, MD comments on the following news and features stories.

COVID Vaccines

This week we heard news that the Oxford group had to pause a trial of its vaccine due to an adverse effect in a patient. Reading the news stories and reactions on this, I could almost feel the disappointment. The heretofore good news on vaccines had created a sense of optimism.

Most progress we make is marginal and slow. COVID is a bad virus but 99+% of people with it survive. This is a seriously high bar for safe vaccine development.

Icosapent Ethyl (Vascepa)

At the virtual European Society of Cardiology (ESC), Dr. Mathew Budoff from Harbor UCLA presented results of a study called EVAPORATE, an 80 patient RCT of icosapent ethyl (IPE) vs placebo. Patients had to have some degree of coronary artery disease and the placebo here was same as in REDUCE-ITmineral oil. The authors used multidetector CT to measure change in plaque volume in either arm. The purpose of this experiment was to help explain the massive effect size in the REDUCE-IT trial.

Recall that REDUCE-IT was a large RCT of IPE added to a statin and was shown to reduce total CV events by 32%. But REDUCE-IT was controversial primarily because the placebo included mineral oil and the placebo group had substantial increases in non-HDL cholesterol and C-reactive protein. This raised the question of whether IPE was great or the placebo was harmful. (Proponents of IPE say its benefits stem from the higher dose and pure EPA formula.)

The topline results in EVAPORATE were positive for the IPE. Low attenuation plaque (LAP) volume declined by 17%, while in the placebo group LAP volume more than doubled. The authors concluded that IPE caused regression of LAP and this may be why IPE crushed it the REDUCE-IT trial.

But on Twitter, Dr Tanboga, a cardiologist and statistician from Turkey, questioned how the change in LAP was possible clinically. Then Professor Darrel Francis commented that there were in fact large differences in baseline characteristics, and worried that there not blinded assessment of the data. Francis also noted highly statistically significant plaque progression in the placebo group.

Steve Nissen from Cleveland Clinic also commented: "I've published more than a dozen regression/progression trials, and we have never seen anything like this in a placebo group, ever. "If this was a clean placebo, why would this happen in a short amount of time?”

Principal investigator Budoff rejected these concerns and cited previous work his group has done that shows that mineral oil placebo does not affect plaque any differently than a cellulose placebo.

My take home is to again revert to the medically conservative view: REDUCE-iT had compelling but surprising results. The question of harm from the placebo mineral oil is legitimate. EVAPORATE data actually strengthens the argument that mineral oil placebo may be problematic.

How Sudden Is Sudden Death?

One of the “rules” of cardiology we were taught decades ago is that about 1 in 5 (20%) of people learn they have heart disease when they have sudden death. This teaching had it that people who present with heart failure, angina, or MI were the lucky ones. But my editor and theheart.org | Medscape Cardiology site director Tricia Ward has always pushed back and said studies show that many of these patients who have sudden cardiac death (SCD) actually had warning signs.

A paper presented at ESC from Danish researchers support this view. The authors examined contacts with the healthcare system in the two weeks and one year before out-of-hospital cardiac arrest OHCA. The team used the Danish Cardiac Arrest Registry from 2001-2014.

About 28,000 patients had OHCA over the time period. Nearly 17,000 or 58% contacted their GP or hospital within 2 weeks before OHCA. This compared with only 14% of the general population during this time period. The reasons for hospital contact were heterogeneous; ischemic heart disease and heart failure were most common.

In her news story on this study, Marlene Busko cites a paper from researchers in Ontario Canada who found that more than one in four patients were assessed in the emergency department prior within 90 days of their cardiac arrest.

My take of this data is, a) be more humble about our rules; b) have these observations in the back of your mind when seeing high risk people with vague symptoms; c) but don’t go overboard with overzealous workups.

Caring for the Elderly Who Have PCI for MI

Before I tell you about a nifty ESC presentation (and simultaneous publication in Circulation) from the SWEDEHEART investigators, we should briefly go over the landmark PLATO trial.

Published in 2009, the PLATO trial compared ticagrelor and clopidogrel in roughly 20,000 patients who had percutaneous coronary intervention (PCI) and stent after acute coronary syndrome (ACS). Ticagrelor reduced a composite endpoint of CVD, MI, stroke by 1.9%. Overall death was also 1.4% lower with ticagrelor, and no significant differences were noted in the rates of major bleeding.

But the median age of the guideline-changing trial was a mere 61 years and only 15% of patients were ≥ 75 years old; RCTs enroll patients who are, in general, motivated, and likely to be adherent to twice daily meds (ticagrelor); and RCTs have research nurses who arrange for follow-up, and the patients get medications at no cost.

Now to the SWEDEHEART study. Patients older than 80 years were recruited after ACS between 2010-2017; 8400 were discharged on clopidogrel; 5500 discharged on ticagrelor. Note this was a nonrandomized observational study.

Patients who were on ticagrelor were sicker, older, had more heart failure, more prior CV events, etc. In an unadjusted analysis, patients on ticagrelor also had higher rates of death, MI, and stroke, but less bleeding compared with those on clopidogrel. After adjustment, there were no significant differences in a composite MACE endpoint. But ticagrelor was associated with a 17% higher rate of death, a 48% higher risk of bleeding, but a lower risk of MI and stroke.

We have to be careful here as this was a nonrandomized comparison. And even though the authors perform statistical adjustments, the decision to use ticagrelor over clopidogrel was a clinician’s. It’s possible, likely even, that inherently higher risk patients got ticagrelor and that confounder accounts for the higher rates of death.

But I think this is a stronger than usual signal for an observational study. Consider a recently published RCT from the Netherlands, called POPular AGE, compared ticagrelor and clopidogrel in patients older than 70 who had non-STEMI. The Dutch authors found that in this population, clopidogrel led to fewer bleeding events without an increase in the combined endpoint of all-cause death, myocardial infarction, stroke, and bleeding.

Another finding that is hard to counter is that the twice daily dosing of ticagrelor will likely perform better in trials than in the real world. The authors of the SWEDEHEART study write a terrific concluding sentence: “There is a need for an adequately powered randomized study examining the effects of potent anti-platelets in the elderly population.”

And the editorialists also do well: “The optimal selection of platelet inhibitors in elderly patients post-MI should account for a multitude of factors that need to be weighed-up, as this choice can make the difference.”

Speaking of Evidence Translation...

I wrote a column on the biggest trial from the Heart Rhythm Society meeting this Spring. The PRAETORIAN trial compared the subcutaneous implantable cardioverter defibrillator (ICD) to traditional transvenous ICDs. I shared the column with one of my electrophysiologist groups and received both positive and negative feedback.

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