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; download the Medscape app, Apple Podcasts, Spotify, or your preferred podcast provider. This podcast is intended only for healthcare professionals.
In This Week’s Podcast
For the week ending December 13, 2024, John Mandrola, MD, comments on the following news and features stories: US doctor pay on the slide, the ticagrelor controversy is back, including new randomized controlled trial (RCT) data, clopidogrel beats aspirin (ASA) again, holding antiplatelets before non-cardiac surgery, and Professor Cleland questions another dogma.
Listener Feedback
I received a very nice note from a general cardiologist trained in heart failure (HF) who brought up an excellent point regarding my coverage of how bad palliative care penetration is in routine HF care. Namely, undertreatment.
She wrote that in her work she saw a lot of patients not being treated for their HF, even though they had clear HF with preserved ejection fraction (HFpEF).
She used the example of patients who go into atrial fibrillation (AF), elderly patients with a history of hypertension and chronic kidney disease who have been in HF for some time and later on present with AF, rapid ventricular rate, and HFpEF or even HF with reduced EF.
These patients, she believes, would benefit from an SGLT2 inhibitor and/or an MRA but do not get started earlier on during their course of illness because HF is unrecognized in the community.
Undertreatment, she wrote, is very frustrating. She reminded me that a lot of this care just takes a little bit of TLC and frequent follow up to get them compensated and it goes a long way with regard to quality of life in the long run.
I love this comment, especially the part about overcoming the inertia of treatment. The electronic health record (EHR) makes it harder. Just starting an MRA drug requires a lot of clicks, more testing, follow-up. In my discussion last week, I focused on overtreatment, but there is also clearly under-treatment of HF and this is often due to inertia.
US Physician Pay
A bunch happened this week regarding payment to US doctors. First was an online discussion about US healthcare, tragically sparked by the killing of the United Healthcare CEO in New York. The end result of the discussion was a conclusion about how badly US healthcare works for patients and clinicians alike. Insurance companies were the obvious focus but only soft thinking holds that the insurance companies are the only problem.
When US healthcare comes up in the general public, sure to follow is that US doctors make too much money—and our compensation should be cut.
Then, nearly simultaneous with this online discussion, came news that our major payer, the Centers for Medicare and Medicaid Services, proposed another pay cut for office-based work of up to 3%. However, good news for imaging cardiologist was that MD reimbursement for coronary computerized tomography angiography (CCTA) will double.
Comments. The first thing to say is how dumb it is to devalue face-to-face work in the office while increasing the value of a dubious imaging test like CCTA. I know this will make many of my colleagues mad. My problem with CCTA use in the United States is the matter of finding incidental coronary artery disease (CAD). One of the major wastes of healthcare dollars in the US comes from overuse of angiography and revascularization and underuse of medical therapy.
In fact, I made one of my Top Ten Stories for 2024 the many non-significant substudies of REVIVED BCIS 2. No trial casts more doubt on the use of ischemic revascularization than REVIVED. To review, percutaneous coronary intervention (PCI) + optimal medical therapy (OMT) vs OMT alone. Patients had multivessel CAD, amendable anatomy, left ventricular (LV) dysfunction and viable myocardium. In the real world, zero patients like this are taken off the cath lab table without revascularization. Yet, the trial found no differences in any outcome with PCI. CV death, death, or HF hospitalizations; even LV function was not different.
In the United States, patients with stable CAD get revascularization. They just do. Uptake of medical evidence — even strong trials like REVIVED BCIS 2 — is extremely weak. Herein is the problem with CCTA. The imaging test finds anatomical CAD, which is often incidental. But once seen, it can’t be unseen. Hospitals are in a hurry to deploy this technology because they know that seeing disease will start the lucrative cascade. Heck, coronary artery calcium (CAC) screening causes this stress-angio-stent cascade. CCTA is CAC on steroids.
Here is a scenario: a 70-year-old patient has atypical chest pain. Everything is negative: ECG is negative, troponin iz negative. The pain is clearly not cardiac. But the patientis sent to the chest pain center. A CCTA shows incidental CAD. The patient now gets sent to the cath lab. Boom. The incidental CAD is fixed. This doesn’t fall out of quality improvement measures because the patient had atypical chest pain. The pain is unrelated, but for the chart, it is called unstable angina.
It’s this sort of stuff — our collective and active ignoring of evidence — that makes me unsympathetic to pay cuts for cardiologists. We make a ton of money. Always have. If I were in a decision-making position in health policy, I would rack my brains trying to incentivize better evidence translation. I don’t have the answer but paying more for imaging and less for being with people seems backward.
Final comment on this, perhaps to the young listeners. We may see pay cuts and make slightly less money, but in terms of wealth, few jobs have more meaning than helping people with their heart disease.
Ticagrelor Controversy
On December 11, the British Medical Journal published a review by senior editor, Peter Doshi, a highly referenced argument of doubts over ticagrelor in the PLATO trial, published in 2011 in NEJM.
This came as a shocker to me, though it stirred two memories.
One memory was that many years ago, I was in Scotland for a talk and a doctor there expressed frustration that NICE (the National Institute for Health and Care Excellence) had approved ticagrelor over clopidogrel based on the PLATO trial and it was costing the National Health Service significant amounts of money. I faintly remember him saying how weak the PLATO data were and how no trials had convincingly confirmed ticagrelor benefit.
I also recall being surprised at the lukewarm reception of ISAR-REACT 5, which was a non-industry sponsored head-to-head comparison of prasugrel vs ticagrelor. Prasugrel clearly beat ticagrelor (by a statistically significant 36%) for the primary endpoint of death, myocardial infarction (MI), and stroke and trended toward lower bleeding as well. ISAR wasn’t a perfect trial as there were different loading dose strategies, poor adherence to therapy, and event ascertainment was by phone. But still. The trial did not seem to get much play.
I just discovered the controversy this morning, so I need more time to get into it. I encourage you to read the PLATO trial, and read the BMJ piece as it’s open access. Here is the teaser:
PLATO randomly assigned 18,624 patients in an RCT conducted across 43 countries.
The main result was that at 12 months, patients assigned to ticagrelor compared with clopidogrel saw a reduction in risk of the primary endpoint — cardiovascular (CV) death, MI, or stroke — from 11.7% to 9.8%, a 16% decrease in relative risk.
This met statistical significance. A win for sure. The primary outcome was driven mostly by a reduction in CV deaths; 21% risk reduction (RR) in CV death vs only 16% reduction in acute MI. No reduction in stroke.
Despite this clear win, the drug failed at its first review at the US Food and Drug Administration (FDA), mainly because a subgroup analysis found that, in the United States, ticagrelor patients had poorer outcomes than those assigned to clopidogrel — a 27% higher risk of the primary endpoint in the US.
Thomas Marciniak, who was an FDA medical officer, wrote a scathing review saying he had worries about the PLATO data quality. Marciniak called AstraZeneca’s application “the worst in my experience regarding completeness of the submissions and the sponsor responding completely and accurately to requests.”
However, FDA leadership did not endorse these reservations. One explanation put forth by the authors was that US patients fared better with clopidogrel because US patients had higher doses of ASA.
Another chapter in this controversy came with an analysis based on sponsor data monitoring vs clinical research organization monitoring. In the four countries exclusively monitored by non-sponsor personnel — Georgia, Israel, Russia, and the United States — ticagrelor fared worse.
And another chapter: Eric Bates, a professor of medicine at the University of Michigan, recently wrote a concise but readable narrative review in Journal of the American Heart Association, and the striking finding is how scant few other observational or RCTs align with PLATO.
One more chapter: Victor Serebuany and Dan Atar wrote an editorial in the European Heart Journal in 2010 titled. “PLATO Trial, Do You Believe in Magic?”
Their major point was the massive overall and CV death reduction. There were 107 more lives saved with ticagrelor than after conventional clopidogrel (399 vs. 506), representing a highly significant absolute mortality reduction (hazard ratio [HR] = 0.78; confidence interval [CI] = 0.69 to 0.89; P <0.001). This, they believed, was highly surprising because it was three times more than in COMMITT where clopidogrel beat placebo. What’s more, the mortality reduction (107 deaths) numerically exceeds the MI prevention benefit (89 events), making it a hitherto unmatchable achievement.
Finally, in support of the PLATO authors, who have published numerous rebuttals, a Department of Justice (DOJ) investigation was started but then terminated 11 months later. DOJ said: “After an extensive investigation…we determined that the allegations lacked sufficient merit such that it was not in the best interests of the United States to intervene in the suit.”
Comments. I need to read more about this. I am also interested in your opinion. Let me know. Perhaps also why did ISAR-REACT-5 come out so strongly in favor of prasugrel. I am a Neutral Martian here but it’s an interesting story.
More Regarding Ticagrelor vs Clopidogrel
Infectious disease doctor Todd Lee sent me a preprint of a recent single-center clinical trial from McGill in Montreal. Senior author was James Brophy, first author was Stephen Kutchner
This was a cluster RCT where all patients with acute coronary syndrome (ACS) during a 2-month cluster would receive the scheduled dual antiplatelet therapy (DAPT) for that period. The primary endpoint was death, MI, or ischemic stroke. Safety endpoint was bleeding.
Statistics were Bayesian. Clinically significant benefits and harms were defined as risk reductions exceeding a 10% difference.
Results:
1,005 patients with ACS were randomly assigned to ticagrelor (n = 450) or clopidogrel (n = 555).
A primary endpoint occurred in 11.1% ticagrelor vs 11.5% clopidogrel patients (relative risk, 0.95; 95% credible interval [95% CrI]: 0.67, 1.35 with a vague prior).
For the safety endpoint, there was no consistent signal of benefit or harm with ticagrelor. Sensitivity analyses with a range of prior beliefs gave generally consistent results.
The probability that ticagrelor offered a more than 10% benefit was only 2%. The probability of ticagrelor harm was 57%.
Authors conclusions: Whether this trial was analyzed with a vague, or a range of reasonable informed priors, no strong evidence for the superiority of ticagrelor over clopidogrel was found.
Comment. I love this approach. It resulted in excellent balancing of baseline characteristics and is quite feasible. I wonder why we don’t do more of these trials. I also love the Bayesian analysis. Again, it’s a modern trial that fails to align with PLATO.
Clopidogrel Better Than ASA Even in Patients with High Bleeding Risk
JAMA-Cardiology has published a post-hoc study of the HOST-EXAM-Extended trial looking at two relevant clinical factors — patients with high bleeding risk and patients with high PCI complexity.
First, we need to review HOST-EXAM trials, which were conducted in 37 sites in South Korea.
The main trial enrolled about 5500 patients who had taken DAPT after a PCI with a drug eluting stent (DES) and who had not a clinical event in 6- to18 months. One group was randomly assigned to ASA 100mg the other to clopidogrel.
During 24-month follow-up, the primary outcome of death, MI, stroke, ACS, or bleeding occurred in 5.7% patients in the clopidogrel group and 7.7% in the aspirin group (HR 0.73 [95% CI 0.59 to 0.90]; P=0·0035.
Then came the HOST-EXAM-Extended study which was carried out for nearly 6 years. Prescription of the antiplatelet was at the discretion of the doctor.
The results were reported as per-protocol but obviously were non-randomized.
Here clopidogrel also won: the same primary end point occurred in 12.8% and 16.9% in the clopidogrel and ASA groups, respectively (HR, 0.74 [95% CI, 0.63 to 0.86]; P<0.001). Interesting that the results were nearly identical.
The current study was a post-hoc analysis of the extended study. Recall that 5500 patients were originally in the study. This analysis included about 4000 after excluding people with missing data on high-bleeding risk or PCI.
Patients were designated as high bleeding risk if they met at least one major or two minor criteria from the High Bleeding Risk–Academic Research Consortium definition.
Complex PCI was defined by the presence of at least one of the following features: three or more stents implanted, three or more lesions treated, bifurcation with two stents implanted, total stent length more than 60 mm, or chronic total occlusion.
Coprimary end points were thrombotic composite end point (CV death, MI, stroke, ACS, and definite/probable stent thrombosis) and any bleeding (BARC type 2 to 5).
Results:
Bottom line, clopidogrel wins over ASA in both subgroups
Thrombotic:
For those with high bleeding risk, clopidogrel reduced the thrombotic endpoint 0.75 vs 0.62 (95% CI, 0.48 to 0.80) among patients without high bleeding risk (P for interaction = 0.38).
For complex PCI it was 0.49 (95% CI, 0.32 to 0.77) among patients with complex PCI vs 0.74 (95% CI, 0.59 to 0.92) among patients with noncomplex PCI (P for interaction = 0.12).
Bleeding:
For those with high bleeding risk: the clopidogrel HR, 0.82; 95% CI, 0.56 to 1.21 vs HR, 0.58; 95% CI, 0.40 to 0.85; for those without high bleeding risk. P for interaction = 0.20)
For complex PCI, the clopidogrel HR, 0.79; 95% CI, 0.47 to 1.33 and for noncomplex PCI, HR, 0.68; 95% CI, 0.50 to 0.93; P for interaction = 0.62.
The conclusion is for an obvious preference for clopidogrel no matter the bleeding risk or complexity of PCI. This upholds the main RCT and the extended open label trial.
And that is the main limitation — namely that, as it is in all nonrandom studies, other factors could have played into the clopidogrel advantage.
Final comment regarding ASA: Here is yet more data that we overestimate the benefits of ASA and underestimate its harms.
A Bit More on ASA During Non-Cardiac Surgery
JACC published, first online in August and now in print, an RCT on perhaps the most common question I receive in the EHR: Can my patient discontinue anti-thrombotic drugs for non-cardiac surgery. As an AF doc, it’s often about oral anticoagulants (OAC), but since most adults in Louisville have had a stent or diagnosis of CAD, the question also comes up regarding antiplatelets. This latter question makes me nervous, especially in patients who have had a DES.
ASSURE-DES randomly assigned 1000 patients who had a DES more than a year before their non-cardiac surgery. One group maintained their ASA while the other group had antiplatelet drugs held for 5 days before and resumed within 48 hours.
The primary endpoint was death, MI, stent thrombosis, or stroke between 5 days before and 30 days after surgery.
Before I tell you the results, I should say that there was really very little existing RCT data on this important question.
The results were clear:
The primary composite outcome occurred in three patients (0.6%) in the ASA monotherapy group and four patients (0.9%) in the no antiplatelet group (P > 0.99). There was no stent thrombosis in either group.
The incidence of major bleeding did not differ significantly between groups (6.5% vs 5.2%; P = 0.39), whereas minor bleeding was significantly more frequent in the ASA group (14.9% vs 10.1%; P = 0.027).
The conclusion: Among patients undergoing low-to-intermediate risk noncardiac surgery more than 1 year after stent implantation primarily with a DES, in the setting of lower-than-expected event rates, we failed to identify a significant difference between perioperative aspirin monotherapy and no antiplatelet therapy with respect to ischemic outcomes or major bleeding.
Notable was that the event rates were a lot lower than expected. This could be because DES are better than non-DES, or East Asian patients have lower rates of thrombotic events, or the noncardiac surgery was very low risk. While low event rates make for wider CIs, I think low event rates tell an important story.
Professor Cleland on ASA for Secondary Prevention
The inimitable Professor John Cleland has written yet another beautiful editorial in JAMA Cardiology., The title: “Aspirin for Secondary Prevention of Atherosclerosis—Evidence or Dogma?”
Here I think you should slow the treadmill or stop the bike because it is a shocker. Questioning the value of ASA in secondary prevention? That is in chronic secondary prevention well after an event.
Well, let me tell you what I learned.
We all used to think ASA was great for primary prevention. But that went away with three trials in 2018. No benefit. Maybe harm in the elderly.
Cleland then wrote “No single trial provides conclusive evidence that long-term administration of aspirin improves outcomes for chronic atherosclerotic cardiovascular disease (ASCVD).”
You might wonder how the recommendation got established. Indeed it was a meta-analysis that he calls flawed, mainly because the original trials that were included were not conclusive. And, he adds, combining inconclusive trials does not always equal strong conclusions.
Next point: why would ASA fail? Here he argues that the pathophysiology of chronic plaque is different than in the acute setting. Namely, that once an ulcerated plaque is healed it is less likely to benefit from a reduction in platelet aggregration. ASA’s propensity to cause hemorrhage may be important.
Get this:
“Moreover, long after most placebo-controlled trials of aspirin were conducted, the widespread introduction of lipid-lowering agents will have reduced the lipid content of the plaque, reducing the risk of rupture of lipid gruel through a thin fibrous cap and increasing the proportion of ruptures due to plaque hemorrhage. Plaque hemorrhage might also increase the proportion of coronary occlusions presenting as sudden death, thereby reducing the rate of nonfatal MI without reducing mortality.”
Cleland notes there are only two RCTs of ASA in chronic ASCVD.
The AMIS study in 1980; 4500 patients received ASA 1000 mg per day vs placebo 2 years after MI. CV events were not reduced and there was a signal for higher death.
SAPAT, the Swedish Angina Pectoris Aspirin Trial; 2000 patients received 75 mg of ASA vs placebo. They were followd for 4 years; there was only an absolute risk reduction of 0.5% in MI with no difference in stroke, CV death, or mortality.
I thought about ISIS 2. So did Cleland. It was his next paragraph, where he argues that ASA is highly beneficial during the acute phase. I had forgotten that in ISIS 2, ASA was only given for 28 days, then stopped, but the benefit was long-lasting.
Best Quote: “The edifice of antiplatelet trials for chronic ASCVD has no solid foundations but is built on shifting sands.”
Cleland knows that most readers won’t be convinced, so he adds a few sentences on CAST and the new data on beta-blockers after MI.
He recommends that RCTs withdrawing all antiplatelet therapy 3 to 6 months after a vascular event or procedure should be done, writing that, “there is no randomized trial comparing antiplatelet therapy with placebo in patients who have received a coronary stent…”
Perhaps a trial comparing 75 mg of ASA once daily to a less intense antithrombotic intervention, such as ASA or clopidogrel 75 mg once or twice per week, might not be too heretical. If this showed no substantial difference in disability or mortality, it could pave the way to placebo-controlled trials of complete withdrawal of long-term antiplatelet therapy for ASCVD.
I hope you all read this shining example of thinking well. This is how science is supposed to go. We need to question our dogmas. I remember treating PVCs back in the 1980s, because it was the dogma. I remember using beta-blockers routinely. And soon the implanted defibrillator for primary prevention may be reversed.
© 2024 WebMD, LLC
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: Dec 13, 2024 This Week in Cardiology Podcast - Medscape - Dec 13, 2024.
Comments