COMMENTARY

Sep 30, 2022 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

September 30, 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 September 30, 2022, John Mandrola, MD comments on the following news and features stories.

Pulmonary Embolism

At the TCT (Transcatheter Cardiovascular Therapeutics) conference, we learned results of a very novel way to treat patients with severe pulmonary embolism (PE). That’s good because acute pulmonary embolism is a deadly condition (upwards of 6% of inpatients die from PE) and the rate of death is not decreasing. I will talk about PE for a bit, but in the end, there is a message about evidence that all can appreciate—so hang in there.

Let’s leave aside the diagnostic problem of this condition, which is still tricky, and focus on PE treatment, which remains a real challenge. Currently, the guideline-directed options focus on standard anticoagulation (AC) for intermediate risk patients or thrombolytic (clot-busting) therapy for higher risk patients.

Thrombolysis can be given systemically or directly, via catheter. Systemic lytic therapy has the obvious limitation of a substantial risk of bleeding. Almost all lytic therapy for PE is now catheter delivered directly into the pulmonary arteries (PAs). But still, a lot of PE occurs after an operation. Even local lytic therapy can be dicey, after brain or spine surgery.

PE treatment — at least at our shop — has become a bit of a specialty, led by interventional cardiologists. One of these docs told me that millions of dollars are being spent treating PE aggressively on the basis of the surrogate marker right ventricular (RV)/left ventricular (LV) diameter ratios. We have no idea if any of this is reducing mortality.

With that intro, let’s get into the therapies:

For stable patients, the treatment is AC. But for sicker patients — those with soft BP, tachycardia, RV strain, hypoxia — two new options have emerged: mechanical thrombectomy and catheter-based delivery of lysis.

That is high-level jargon. Mechanical thrombectomy means putting a 24-French (very large) catheter through the fragile RV, into the PA, then taking the straw-like device and sucking the clot out. This can lead to rapid improvement in heart and lung function. It can also lead to ‘clot porn’, whereby docs can show and post pics of huge clots removed from patients.

If you think docs could be somewhat influenced by the things they do, nothing comes close to the effect of removing huge clots from a lung and seeing patients get better. The bias-inducing effects of stent placement and pulmonary vein isolation have no chance against clot removal from a mechanical thrombectomy device.

Another invasive, but far less dramatic way to treat clots in the pulmonary arteries going from the RV to the lungs is with a catheter that drips in thrombolytic drugs. This can be done with a $40 catheter with side holes or a far more expensive catheter that adds ultrasound waves to the drip of thrombolytics to help break up the clot.

At TCT, we heard results of a single-arm study of a mechanical thrombectomy device. It was called the FLASH study or FlowTriever All-Comer Registry for Patient Safety and Hemodynamics. And it was published in EuroIntervention; first author, Catalin Toma.

  • The study included 800 patients, mean body mass index of 34. More than three-quarters had intermediate risk PE, about 8% had high-risk PE, and a third had contraindications to lytics.

  • Major adverse events occurred in about 2% of patients. Only 1 patient had a cardiac injury from the huge sheath and stiff wire, which is pretty amazing to me.

  • All-cause mortality was only 0.3% at 2 days and 0.8% at 30 days and there were no device-related deaths.

  • The study reported clinically significant improvements in clinical parameters such as drops in PA pressure, increases in the cardiac index, and improved RV/LV ratios.

  • The number of patients with severe shortness of air plummeted.

  • The central illustration included clot porn — pics of huge clots and a PA full of clot before and patent after.

The mechanical thrombectomy device — called FlowTriever — gained US Food and Drug Administration (FDA) clearance and CE mark after the single-arm FLARE study of 100 patients with PE found success in removing clot from the PA’s of patients with PE.

In the TCT news coverage from Steve Stiles, it seems many of the experts spoke about systemic lysis, but that is weird, because we rarely use systemic lysis. And of course, either invasive strategy will have less bleeding than systemic lysis. That is not the question. The question in PE care is whether to use standard AC, catheter directed lytics, or mechanical thrombectomy.

The problem is that one is very inexpensive and the others very costly and/or very invasive. The other problem is that PE patients can present in many different ways and worse, these patients become very sick and unstable very fast. So if you go with basic AC, the risk is rapid deterioration.

A number of trials are planned. Steve mentioned PEERLESS, a trial of mechanical thrombectomy vs catheter-delivered lytic therapy. At first I thought, great. I love trials. Then I thought, Wait, if the mechanical thrombectomy catheter is already approved, why would they study it? Why not just market and promote it to a rapturous audience of doctors, like the makers of left atrial appendage devices or LV support devices?

Then I thought, maybe they want to increase market share, because the rise in obesity is causing a lot of PEs to occur.

But there are two major problems with PEERLESS:

  • There is no standard AC arm. It’s one invasive device vs another. Having an AC only arm is scary from a sponsor point of view, because if AC was as good, it would crush business.

  • The other problem is in the choice of endpoint: The industry-sponsored trial of two PE treatments will use a composite of death, intracranial hemorrhage, major bleeding, and clinical deterioration, which are all fine, but then it also includes ICU length of stay.

  • The problem is that in our shop and probably others too you can only infuse lytics into the PA in an ICU. So even if there are no differences in outcomes, if there is shorter ICU length of stay, the trial could be spun as cost saving to hospitals.

Our hospital is involved with another trial in this space called the HI-PEIHO trial, A Randomized Trial of Ultrasound-facilitated, Catheter-directed, Thrombolysis Versus Anticoagulation for Acute Intermediate-high Risk Pulmonary Embolism: The Higher-risk Pulmonary Embolism Thrombolysis Study, which will have extremely selective entry criteria, and three primary outcome endpoints: PE-related mortality, PE recurrence, and cardiorespiratory decompensation or collapse. That is a bold trial because the comparator arm is AC alone.

The PE space is complicated because the assessment of which PE patients are stable enough to take AC alone is super hard; catheter-delivered lytic therapy comes with different doses of lytics, with lower doses approaching almost no increase in bleeding over AC alone, as well as the fact that catheter-delivered lytics can be done with a plastic perfusion catheter or a US catheter. Mechanical thrombectomy has potential advantages but has a significant learning curve.

I want to close with some deference to those working in this space, and here is why: when we treat people with PE, we are in the purest form of medicine. We are treating extremely ill people who absolutely need our help.

This is not like studying a reduction in a surrogate outcome of irregular beats on an ECG, or a tiny reduction in future nonfatal events or one kind of hospitalization. Treating PE is about saving life and preserving lung function.

Yet there is a lot of money at stake and consumers of this evidence will have to have their thinking hats on when more results come.

Another Coffee Study

There are so many coffee studies. There are so many media reports of coffee studies. I’ve written previously that we need to stop studying this topic as well as chocolate, blueberries, quinoa, and saunas with observational methods. I contended that it was wasteful and fatally confounded.

The eminent group of Melbourne arrhythmia researchers obviously felt differently. This is a group that has published some of the most important work in electrophysiology (EP). So. I will also extend them some deference. And one more thing: the current crisis we’ve all suffered through in the last 2.5 years has also infused me with a bit of deference for confounded observational studies on fun topics.

This particular study used the trove of data in the UK BioBank to study the association between different kinds of coffee intake and outcomes.

  • They found, as nearly all coffee studies have, that coffee is good for you.

  • Those who report drinking ground (espresso) and instant coffee seem to have less arrhythmia than those who drink decaf. I hope that finding alone gives you a hint to why this study is confounded.

  • Two to three cups/day of all coffee subtypes was consistently associated with the largest risk reduction in cardiovascular disease (CVD), coronary heart disease (CHD), and all-cause mortality.

Comments. I love coffee and I am resistant to evidence regarding its health benefits. Yet, no matter the eminence of the research group, these sorts of studies are confounded by the fact that coffee drinking surely associates with other activities and it these other activities that cause better outcomes. I know almost no competitive cyclist, for instance, that does not drink coffee. You can only adjust for confounders that are in spreadsheets. That’s why randomization works so much better for determining cause and effect. Why would decaf be associated with more arrhythmias, for example? Because those drinking decaf are abstaining from caffeine for a reason — because they are either having or are worried about having arrhythmia symptoms.

When DOACs Do Not Work

In 2013, when the New England Journal of Medicine published the RE-ALIGN trial of dabigatran vs warfarin in patients with mechanical valves, which was terminated early because of an excess of stroke events in the dabigatran arm, I was surprised. After enrolling only 252 patients, there were nine strokes in the dabigatran arm and none in the warfarin arm.

This data was in stark contrast to the atrial fibrillation (AF) and venous thromboembolism (VTE) data showing equivalence of direct oral ACs (DOACs).

The PROACT Xa trial tested what most of us now feel is the better DOAC (apixaban) in a specific mechanical valve — the On-X valve in the aortic position. On-X has some data showing that it can be used with reduced INR requirements, so the company felt it was studying a DOAC.

It would have been a huge finding because, obviously, the main drawback of these valves is the warfarin requirement. Remember that clickers, as I call them, last much longer than bioprosthetic valves. While there is great excitement for transcatheter aortic valve implantation (TAVI), remember, this is a tissue valve. It won’t come close to lasting as long as a mechanical valve. But it was not to be. As announced in a company press release, the trial data safety monitoring board recommended stopping the trial because the interim analysis found a low likelihood that apixaban would even reach non-inferiority with warfarin. Stroke rates were higher in the apixiban arm.

It's possible that someday, perhaps the Factor XI inhibitors may prove non-inferior to warfarin, as they are higher up the coagulation cascade then Factor X, but the Factor XI inhibitors still have to pass muster in much less thrombotic conditions, such as AF.

I guess the two messages here are that

  • Vitamin K antagonists are the only drugs to be used with mechanical valves. What’s weird is that two docs have reached out to tell me that some docs still use DOACs in mechanical valves. This seems incredibly wrong to me.

  • Second, it is good thing that trials have data-safety monitoring boards to insure the least number of patients are exposed to inferior therapies.

Lp(a) and ASA

This week on Twitter I had a small conversation about not overselling trial results. My friend Dr. Saurabh Jha, a radiologist who knows philosophy and history, wrote back:

“Remember, for the initial adoption of penicillin there was neither any marketing team nor a team of academics conducting a meta-analysis. We’re now in the zone of extremely marginal, marginal benefits.”

Well, the Journal of the American College of Cardiology has published a paper that perfectly encapsulates the notion of extremely marginal, marginal benefits. This was a sub-analysis of one of the most important trials of this decade: the ASPREE trial of low-dose aspirin (ASA) vs placebo in elderly individuals who were free of CVD.

  • 19,000 individuals.

  • Primary endpoint was death, dementia, or physical disability.

  • ASA did not prolong disability free survival over 5 years.

  • It also did not reduce CV events.

  • ASA did increase bleeding.

  • After 4.7 years of follow-up, the risk of death from any cause was 14% higher in the ASA group, a result that reached statistical significance.

Now, to the ASPREE substudy:

  • Authors analyzed about 12,000 of the 19,000 individuals in the trial who had genotyped blood samples. They were interested in lipoprotein(a) (Lp[a]) effects.

  • They did not have Lp(a) levels, so they used two surrogates of Lp(a), carrier status of one gene variant and quintiles of a Lp(a) genomic risk score.

  • They analyzed interactions between genotypes and ASA in models for the incidence of major adverse cardiac events (MACE) and bleeding.

  • They also analyzed these associations in the ASA and placebo arms separately.

Before I tell you the results, let’s briefly go over Lp(a).This is a cholesterol particle that is genetically determined and likely and independent risk factor for CVD. Mendelian randomization studies (nature’s RCT), in which individuals who have genetic variants leading to low and high Lp(a), find strong protective associations of being born with genes that lead to low Lp(a) and higher CV risks in people who have genes that lead to higher Lp(a).

Elevated Lp(a) confers up to a 4-fold increased CV risk. And nearly one in three individuals in the general population may be affected. There are no drugs that target Lp(a), though there is a short-interfering RNA drug which, in a phase 1 study of 32 patients with high Lp(a) found dose dependent reduction in Lp(a) and no AE.

It turns out that Lp(a) has biochemical similarities, so called homology, to plasminogen and some data suggest that Lp(a) prevents plasminogen activation to plasmin. This led to the idea that elevated Lp(a) may have antifibrinolytic effects, thereby tilting the coagulation cascade towards clotting. Lp(a) may also be a platelet aggregator — another means to increase CV risk.

This led to the idea that ASA use may be especially helpful in patients with high Lp(a). A previous analysis of the Women’s Heart Study — an RCT of low-dose aspirin and vitamin E supplementation for the primary prevention of CVD in initially healthy women found that women carrying the Lp(a) gene variant benefited from 100 mg ASA every other day compared with noncarrier women.

So, in this recent sub-analysis, they looked at that gene variant plus a gene-risk score for Lp(a). The main findings:

  • In all participants, ASA reduced MACE by 1.7 events per 1,000 person-years and increased clinically significant bleeding by 1.7 events per 1,000 person-years.

  • However, the gene-variant group had a net beneficial effect (MACE reduction + bleeding increase) of 8 events per 1000 person years.

Authors’ Conclusion:

Aspirin may benefit older individuals with elevated lipoprotein(a) genotypes in primary prevention.

Authors comment in the second paragraph of the discussion:

“Our results provide new evidence to support the potential use of aspirin to target individuals with elevated Lp(a) for the primary prevention of CVD events.”

Another comment from the authors in the paper:

Nonetheless, given the lack of any currently approved therapies for targeting elevated Lp(a), our findings may have widespread clinical implications, adding evidence to the rationale that aspirin may be a viable option for reducing Lp(a)-mediated cardiovascular risk."

The title and lead of the news article:

“Aspirin Primary Prevention Benefit in Those With Raised Lp(a)?”

Comments. While I appreciate the work it took to do this study, write it up, and get it through peer review, and then talk to the media, I think the messages here are problematic. The message is maybe we should use ASA in those who have Lp(a) elevations. Or worse, maybe we should measure Lp(a).

Let’s start with the two main limitations of this analysis then go to the problem of outsized conclusions of medical papers:

  • First, this was a sub-analysis of a non-significant trial, ASPREE. ASPREE no found benefits for ASA in physical functioning or CV events and a higher risk of bleeding and death.

  • Nothing could be clearer: don’t use ASA in the healthy elderly. Now you want to analyze a trial with highly negative results to find a potentially positive heterogeneous effect based on genetics.

  • Second, this analysis did not use elevated Lp(a) levels. It used a fraction of people with gene variants.

  • Only 3.2% of the 12,000 individuals in this analysis had the gene variant. Thus, the vast majority of people with elevated Lp(a) don’t have this gene variant.

Now to the conclusions. First, close your eyes, and imagine a scientific world without the introduction and discussion sections of papers. If not for the many words spent on persuasion regarding biologic mechanisms of Lp(a) and then the authors oversized conclusions in the discussion section, medical readers would look at the methods and results and think, my gosh, they are looking at a tiny fraction of people in a non-significant trial, who have gene variants that we could never measure in clinical practice, and they find a borderline significant association of a tiny absolute risk reduction (less than 1% net benefit).

A regular reader would think: this paper might be ok in a basic science journal, this paper might inform a future trial in which individuals with high Lp(a) are randomized to ASA or placebo, but they would never think to start measuring Lp(a) or worse, using ASA in these patients based on this data.

  • The main results of the ASPREE trial are clear: ASA is a bad idea in older patients. Period.

  • The problem gets back to what Dr. Jha said about marginal value. Major developments don’t need sub-analyses such as these. Sub-analyses like this don’t deserve this much attention.

  • If we want to help patients who do not have heart disease avoid heart disease, discuss with them the benefits of exercise, a healthy diet, having fun, going to sleep.

  • Perhaps at most measure their cholesterol so as to estimate a 10-year risk. If it is high enough for them to accept a pill every day that reduces nonfatal events by about 25%, then they can take a statin. Otherwise leave them to live their life free from medical interference.

Comments

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