Apr 29, 2022 This Week in Cardiology Podcast

John M. Mandrola, MD


April 29, 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 April 29, 2022, John Mandrola, MD comments on the following news and features stories.

Low-Dose Aspirin

This week, the US Preventive Services Task Force (USPSTF) updated their recommendations on the use of low-dose aspirin (ASA) for primary prevention of cardiovascular disease (CVD). Before I tell you about their ASA decision, here are three points of clarification on that leading sentence.

  • First, the USPSTF is one of my favorite guideline committees. They are independent experts trained in evaluation of evidence. They are as close to neutral-Martian evaluators of evidence as we have. They are the opposite of specialists who write guidelines of therapies they get paid to use.

  • Second, primary prevention means use to prevent a first cardiac event. Secondary prevention is therapy designed to prevent a second event after surviving a first event. Nothing I say here deals with people who have had a myocardial infarction (MI), a stent, bypass, or a stroke.

  • Third, low dose means 81 or 100 mg. Not 325 mg.

USPSTF made its recommendations by doing systematic review of ASA primary prevention studies. Their last update was in 2016, so this new review includes the three big trials from 2018: ARRIVE (moderate risk adults), ASCEND (diabetics), and ASPREE (elderly).

In 2016, before these largely null trials, the USPSTF recommended initiating ASA for the primary prevention of heart disease in adults ages 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, and are willing to take low-dose aspirin daily for at least 10 years. For those older than 60 years of age, their 2016 call was to leave the decision on ASA as an individual one.

For this update, USPSTF has changed the age ranges and grades of its recommendations.

  • The USPSTF now recommends that the decision to initiate low-dose aspirin use for the primary prevention of CVD in adults ages 40 to 59 years who have a 10% or greater 10-year CVD risk should be an individual one.

  • The USPSTF recommends against initiating low-dose aspirin use for the primary prevention of CVD in adults 60 years or older. Period. If you are 61, don’t take ASA to prevent a cardiac event.

The new review included 11 to 13 trials that enrolled 130,000 to 160,000 patients and tested ASA efficacy for reducing cardiac outcomes. The USPSTF also specifically considers harm. In the case of ASA, that is bleeding. The new review included hundreds of thousands of patients enrolled in numerous trials and found that ASA was associated a 58% increase in gastrointestinal (GI) bleeds and a 31% increase in intracranial hemorrhages.

For this new review, the USPSTF also commissioned a “microsimulation modeling study” to assess the net balance of benefit and harms from ASA. Truth be told, I have no expertise in how a microsimulation study works, but the modeling outcomes were stratified by age, decade of ASA initiation (40-49 years, 50-59 years, 60-69 years, and 70-79 years), sex, and baseline 10-year CVD risk level (5% to 20%).

  • Modeling data estimated that ASA use in men and women ages 40 to 59 years with 10% or greater 10-year CVD risk generally provides a modest net benefit in quality-adjusted life-years and life-years gained.

  • Initiation of ASA use in persons ages 60 to 69 years results in quality-adjusted life-years gained that range from slightly negative to slightly positive depending on CVD risk level, and life-years gained are generally negative.

  • In persons ages 70 to 79 years, initiation of ASA use results in a loss of both quality-adjusted life-years no matter the CVD risk levels.

  • The USPSTF thus determined that ASA use has a small net benefit (CVD risk reduction less than bleeding increase) in persons ages 40 to 59 years with 10% or greater 10-year CVD risk and that initiation of ASA has no net benefit in persons 60 years or older.

  • When looking at net lifetime benefit of continuous ASA use until stopping at age 65, 70, 75, 80, or 85 years, modeling data suggested that there is generally little incremental lifetime net benefit in continuing ASA beyond the age of 75 to 80 years.

One caveat that is relevant to the clinic is that there is a difference in net benefit between continuing ASA in persons ages 60 to 70 years and initiating ASA in that age group. That is because people who met ASA criteria at a younger age, who thus would be at higher risk, are at even higher risk at older ages. This assumes that major thought went into the previous recommendation to take ASA, which is rare, at least in my experience.

My basic summary hinges a lot on the three 2018 trials. ASA exerts a consistent effect on reduction of major adverse cardiac events (MACE) — in the range of 10% reduction (recall that statins are about 25% reduction). ASA clearly increases the risk for bleeding.

In older individuals, the ASPREE trial speaks volumes. Enrolled patients in ASPREE were about 74 years.

  • ASA reduced MACE by a nonsignificant 5%;

  • ASA increased bleeding by a significant 38%;

  • ASA was associated with a significant 14% higher rate of mortality.

So, I agree that in younger patients with high CVD risk and minimal bleeding risk (eg – no NASIDs, minimal alcohol consumption, not on anticoagulants) and who don’t mind taking a daily ASA and are more concerned with reduction of MACE than GI bleeding, they might garner some slight benefit. Recall though that a 10% relative risk reduction is no more than a 1% reduction in nonfatal events over more than 5 years. That is tiny. As an electrophysiologist (EP), most of my patients have high bleeding risk, so I spend a lot of time stopping ASA.

But perhaps the greatest lesson from this topic transcends the specific decision on ASA and centers on why the results with ASA have changed. Older studies have largely favored ASA for a net benefit in primary prevention. The reason for the change is relevant for tons of other CVD therapies.

  • One reason ASA no longer provides a net benefit in most primary prevention scenarios is that there has been a temporal decline in CVD event rates. This is likely because of things like smoking bans and removal trans-fats from prepared foods.

  • The second reason ASA no longer provides a bigger bang for its buck is that background therapies are better. If statins reduce events by 25%, a drug like ASA is going to have less absolute effect.

  • The third reason ASA looks less beneficial is competing causes of CV and overall mortality. I hope regular listeners of this podcast understand why older individuals get less net benefit: because they have many more ways to die and have higher risks of bleeding. Always remember the point of preventive therapies is to become elderly.

Time-Restricted Feeding

As an atrial fibrillation (AF) doc, I spend oodles of time talking with patients about weight loss. Weight loss is crucial for long-term management of AF.

In clinic, I show the evidence, mostly from Adelaide, Australia, and then the next question comes up: Okay doc, I hear you. What do you suggest for getting it done? Of course, as an EP, not an obesity expert, I am cautious in my specific advice. My main job is to make sure patients understand the vital role of weight loss, so they are motivated.

Recently, the strategy of time restricted feeding (TRF) has gained interest. this is sort of like a daily fast in which you go many hours without eating and only eat during a window of 4, 6, 8, or 10 hours daily. Different studies use different time windows. Restricting the window of time for eating may sustain circadian rhythms and may improve metabolism by prolonging the daily fast, which in turn activates cellular pathways that are implicated in mediating the benefits of calorie restriction.

One of the more obvious and pragmatic potential advantages is that if your time window is short enough, you may not have to count or restrict calories. You eat less because there is less time to eat. Several pilot clinical studies have shown that time-restricted eating resulted in reduction in the body weight and fat mass in patients with obesity.

Last week, the New England Journal of Medicine (NEJM), published a small randomized controlled trial (RCT) from investigators in China looking at TRF.

  • They enrolled 139 patients with obesity.

  • Control and TRF groups were instructed on calorie restriction that represented a 25% calorie reduction from baseline.

  • Follow-up was 12 months

  • The TRF groups ate between 800 and 1600 calories. The control group was not calorie restricted.

  • The results: both groups lost lots of weight. But there was no statistically significant difference between the groups.

    • TRF lost 8 kg over one year.

    • Controls lost 6.3 kg.

Waist size, body mass index, body fat, blood pressure, and metabolic risk factors were not significantly different. These nonsignificant differences were quite similar to a UCSF-led TREAT trial published in 2020, which also found that both groups lost weight and there was no significant difference between groups.

Caveats of the Chinese study: Both groups restricted calories. In other words, the control group was quite good at restricting calories. This was the same problem in SODIUM HF, a trial of strict sodium restriction vs standard care. In this case, the control arm took in a really low salt diet, making it hard for the intervention to do well by comparison.

This makes me think of two opposing tensions: One is the science question of whether there is something special about TRF over and above calorie restriction. This trial and the UCSF study suggest there is not anything special about TRF. The other tension is whether TRF may be more easily accepted as a weight loss strategy. These trials do not answer that question.

Part of me thinks TRF could be useful because so many of my patients report grazing in front of the TV or computer at night. Restricting the time when eating may be an effective calorie restricting strategy.

Another caveat with the Chinese study was the small numbers which leads to a wide confidence interval (CI). The difference in weight loss was only 1.8 kg, but the 95% CI included a loss of 4 kg. That is a lot.

In sum, I love trials like this, imperfections and all. No trial is perfect. In the Western world, obesity will be the main driver of poor CV outcomes, and empirical studies of how best to deal with food excess are super-important.

My main advice remains to make a food diary. Look at what you eat and drink; come up with a strategy to reduce the baddies — sugary drinks, beer, Cheeze-its, huge helpings. So, it is calorie restriction.

But TRF is also a viable strategy to reduce calories, especially if one of your meals includes, say, a donut for breakfast. If you restrict calories to 1200 to 2000, you skip the morning donut.

Renal Denervation

At the American College of Cardiology (ACC) meeting, we learned results of the extension of the SPYRAL HTN-ON MED trial. This trial used the Medtronic version of renal denervation (RDN) with radio frequency energy. The trial was designed as a 6-month sham-controlled trial of patients with hypertension (HTN) who were on antihypertensives.

That trial, reported in the Lancet in 2018, found that the change in systolic blood pressure (BP) as measured by 24-hour ambulatory blood pressure monitoring (ABPM) was about 7 mmHg. This was statistically significant

The trial presented at ACC involved a 3-year extension, and the topline was positive: ambulatory systolic BP was about 10 mmHg less at 3 years in the RDN arm. The authors also tell us that, although the number of meds in the two groups were similar, an index that accounts for dose and drug class found that the sham arm had more intense medical management.

The graphs presented show separation of the systolic BP at 6 months — that was in the original study — then they come together at 1 year, but then, after 1 year, the curves start separating in favor of the RDN arm. If you read the topline, you’d think we all should be going to RDN ablation training programs. HTN is serious. It leads to huge amounts of CV mortality and morbidity. Adherence to meds is less than ideal; RD is always on. No brainer, right? No, not so fast. There are tons of limitations here. Most important is that patients and trialists were unmasked at 6 months.

Patients could cross-over to RD at 1 year, in an unblinded fashion. And that is exactly when BPs start separating—at 1 year.

I may be wrong here, but the lesson of the first chapter of RD was that you absolutely had to have blinding to tell anything. I say this because the early RD trials were hailed as a major breakthrough. Then SYMPLICITY HTN 3, which had proper blinding and a sham, showed no difference.

So, in this extension trial, you basically have an unblinded comparison — like there was in the irrational exuberance phase of RD before SYMPLICITY 3. I am shocked that none of the trial discussants mentioned this in their review of the trial at ACC. This is not nefarious. Without a sham, there is a huge opportunity for performance bias on both the investigators’ and patients’ parts.

Blinding is the biggest issue, but there are others: the original trial screened more than 460 patients and randomly assigned only 80. So, generalizability is weak. Another problem: there were more missing BP readings in the sham-controlled arm.

Summary: I see the potential for RD; always being ‘on’ is huge. It takes away medical adherence issues.

  • The short-term data with the new techniques look like they reduce BP a little. But does it sustain? From 6 months to 12 months in this trial, the BPs come together, and then separate again only after the unblinded crossovers from sham to RD happened.

  • Whether these 5 to 7 mm Hg reductions in systolic BP are enough to move outcomes will require more trials.

  • The main issue is that we need longer-term data, and it has to be sham controlled because the early chapters of RDN clearly show us that looking at unblinded results may be worse than useless.

  • I could be wrong, but this extension study does not provide us useful information. RDN could expand into a huge area of over-treatment. I also wonder whether we can achieve the same BP reductions with mineralocorticoid receptor antagonists like spironolactone, or the new kid on the block, finerenone.

Let me know if you disagree.

Big News in Obesity Management:

Eli Lilly, the makers of the tirzepatide, a novel investigational once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist, announced in a press release the topline results of the SURMOUNT-1 trial.

This was a big RCT of 2500 patients with obesity and type 2 diabetes that tested the injectable at doses of 5, 10, and 15 mg weekly. The primary endpoint was percent change in body weight. And gosh did it hit the mark.

  • Participants taking tirzepatide achieved average weight reductions of 16.0% (35 lb) on 5 mg, 21.4% (49 lb) on 10 mg and 22.5% (52 lb) on 15 mg, compared with 2.4% (5 lb) for those on placebo.

  • 89% (5 mg) and 96% (10 mg and 15 mg) of people taking tirzepatide achieved at least 5% body weight reductions compared with 28% of those taking placebo.

  • The overall safety and tolerability profile of tirzepatide was similar to other incretin-based therapies approved for the treatment of obesity.

  • The most commonly reported adverse events were GI-related and generally mild to moderate in severity, usually occurring during the dose escalation period

After review of, notably absent from the endpoints of this trial were clinical outcomes. The press release said the full results will be presented at an upcoming medical meeting, and we need to see the paper, but this is extremely promising news for perhaps our biggest CV risk factor.


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