May 16 2025 This Week in Cardiology

Medscape

16-05-2025

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For the week ending May 16, 2025, John Mandrola, MD, comments on the following topics: The BedMed trial of nighttime BP meds, SURMOUNT-5, Troponin URL, gene tests in patients with no disease, and GDMT for heart failure.
JAMA has published what I hope is the last of the trials of timing of blood pressure (BP) meds. Here is a brief rundown of the history.
The MAPEC trial conducted between 2000-2009 found a 61% reduction of MACE favoring bedtime meds. This was published in a journal called Chronobiology International . I know. I had never heard of it either.
Then the same group from Spain conducted the Hygia trial of 19,000 patients with hypertension, and they reported a 45% reduction in major adverse cardiovascular events (MACE) with bedtime BP meds. EHJ published this trial in 2020, and it set off a storm of controversy. EHJ editors even issued a formal 'Expression of Concern' letter.
Ricky Turgeon and Canadian colleagues writing in the AHA journal Hypertension noted that the main concern (of many) with Hygia was that nighttime BP meds also reduced the risk of non-CV death. This, they argued, was a serious outlier as no BP trial had ever shown a reduction in nonCV death. Further, Turgeon noted that it was unclear whether or not Hygia was truly randomized, nor whether allocation was concealed.
Then came the TIME trial, which enrolled 21,000 patients with hypertension in the UK and found no difference in MACE depending on timing of meds. The Lancet published this study in 2022.
The BedMed trial, published this month, was a study of 3500 Canadian patients with hypertension, recruited from primary care clinics. Half got morning meds, and the other half took their meds at night.
There was absolutely no difference in MACE outcomes over a nearly 5-year follow-up. Comments
I believe the TIME and BedMed trials disprove the findings from the single group in SPAIN. My reasoning is simple: the findings of massive MACE reductions simply by changing the time of day of BP meds is implausible. I especially struggle with Hygia's reduction in non-CV-death.
Then, in two separate geographies, two independent groups find no benefit.
You go with the plausible two trials. Another lesson from this story is the matter of open data. Here, I don't single out the Hygia authors because I feel that all randomized controlled trials (RCTs) whose results could change practice ought to be submitted with source data so that it can be independently verified.
Think of the time and money that it took to disprove implausible findings. TIME enrolled 21,000 patients and BedMed enrolled 5000 and both trials followed patients for approximately 5 years. Trials with massive effect sizes deserve both attention and scrutiny. I hope the new leaders at NIH and FDA emphasize replication of studies.
For our patients, it is simple: it does not matter when you take your meds. Just take them todos los dias.
NEJM published the SURMOUNT-5 trial of tirzepatide vs semaglutide for weight loss. The manuscript is long. The statistical methods section is 3 paragraphs, the discussion is also many paragraphs. I don't understand why this is so.
Patients were nondiabetic, age 45 years, two-thirds female, and BMI of 39. One group gets tirzepatide, the other semaglutide, and the primary endpoint was change in weight from baseline.
Tirzepatide easily won. Over the 72 weeks of the trial, those in the tirzepatide group lost 20% of their body weight vs -13.7% in the semaglutide group. Those in the tirzepatide group were more likely than those in the semaglutide group to have reductions of at least 10%, 20%, and 25%.
Secondary endpoints, such as cardiometabolic risk factors (BP, glucose) were also lower in tirzepatide group. Systolic blood pressure (SBP) reduction was 10.2 mm Hg vs 7.7 mm Hg in the tirzepatide vs semaglutide groups.
Safety signals were similar.
As most know, tirzepatide is a dual GIP and GLP-1 agonist. Whatever is the mechanism, and the authors speculate a lot, tirzepatide induces more weight loss with a similar safety signal.
Semaglutide has been shown to reduce more than weight; in the SELECT trial of patients with established ASCVD, semaglutide reduced MACE outcomes by about 20% relative to placebo. SURMOUNT-5 authors tell us there is an ongoing CV outcomes trial with tirzepatide.
I would speculate that the CV-disease modifying effect is a class effect. Purists may say we need more data because weight loss is a surrogate measure. I don't know; the more weight loss we get, especially when starting at a BMI of 39, the better. SBP was lower with more weight loss.
One caveat was the trial was open label. Which is weird, because surely the sponsor, Eli Lilly, could afford proper blinding. I guess it's possible that if you know you are on the stronger drug, you might do more to lose weight, regarding diet and exercise.
As for clinical translation, I would reach for tirzepatide first. Why wouldn't you go for the more potent weight-loss inducer? Thing is, there will surely be more GLP-1s coming to market, and the tirzepatide lead now may soon be taken away.
Irish cardiologists Mark Coyle and John McEvoy have argued persuasively in the European Heart Journal that the coming fifth universal definition of myocardial infarction (MI) should include age-specific high-sensitivity troponin (hs-troponin) upper reference limits.
I did not know that another universal definition of MI was coming soon. Whenever I think of hs-troponin, the following sentence comes to mind…
It should not be so, but the increasingly sensitive troponin assays make life more complicated.
I say it should not be so because Andrew Foy and I have explained in JAMA Internal Medicine how to use troponins at the bedside. The teaser is that it's no different from creatine phosphokinase (CPK) and that you have to think first about whether the patient with an elevated troponin is having a plaque-rupture MI. If they are not, then you treat the underlying cause. Really, it's that simple.
The two writers make a compelling case for having age-specific reference values. I am sure you all have seen older patients with troponin levels just above the reference. This too should not be so, but the red values (for abnormal) infect our brains — it does mine at least. I hate seeing red numbers in the EHR.
Before I tell you their argument I want to ask a common-sense question:
Why should a 75-year-old have the same normal value as a 25-year-old? It makes no sense.
Coyle and McEvoy write an extremely compelling argument. It's structured, well written, and addresses both the pros and cons of having age-specific upper reference limits (URLs).
You will learn a lot reading this argument. I will give a brief summary:
They first tell us why we use troponin URLs are used to define myocardial injury.
First, you need URLs because troponin levels are not standardized across different manufacturers of troponin assays. Thus, there is a need for a common benchmark of 'abnormality' for all troponin assays.
They then explain how URL are derived. Basically, you measure troponins in a sample of normal adults. The reference population is 400 adults. Why 400? I don't know exactly; they say for 'statistical purposes.'
With this group of 400 troponins, you can calculate a value that is 99th percentile. This is the URL.
With that as background, the authors tell us of efforts to derive the 99th percentile troponin levels for the US population, using longitudinal data such as NHANES. Now they are getting close to making their case.
These efforts found significant differences in URL by sex. And indeed, there are sex-specific URL in the fourth universal definition of myocardial infarction (UDMI). But they also found substantial differences by age. For instance, adults aged ≥60 years had consistently higher URLs for high-sensitivity cardiac troponin than adults aged 40–59 or 18–39 years, with a clear age gradient.
There was little data on 70- and 80-year-olds so the age cutoff proposed is over 60. The authors write:
We believe that the use of age-specific high-sensitivity cardiac troponin URLs to define myocardial injury could have major clinical advantages.
Obviously, the No. 1 advantage is to avoid huge downstream workups for older adults with levels just above normal. They rightly argue that a good understanding of troponins would not lead to low-value workups for mildly abnormal lab values, but, since they are clinicians, they take a pragmatic approach and write:
We think it would be more impactful to implement age-specific URLs (as was done for sex-specific troponin URLs)
The next part of their argument is brilliant. They go through in a bullet-point type format — 7 con arguments against and rebut each.
I won't go through them all. Suffice to say, they persuaded me. Their case is strong. I wish such age-related normals weren't needed; I wish every doctor who uses troponins understood the test. But since that is not so, helping us with age-specific levels is a sound idea.
JACC EP has published a paper from the Michael Ackerman Mayo Clinic Genetic Heart Rhythm Clinic. The topic of gene +/phenotype – (G+/P–) people could not be more relevant.
More and more, cascade screening of family members of a patient with genetic heart disease is picking up people with the same gene but no disease. No disease as in no QT prolongation, no arrhythmogenic right ventricular cardiomyopathy (ARVC), no hypertrophic cardiomyopathy (HCM), etc.
Yet… these people (notice I am using the word 'people' not patients) are often disqualified from sport.
Mayo Clinic has one of the largest GHD clinics worldwide, and their retrospective chart reviews teach us a lot. There are few if any clinical trials in GHD.
Before I tell you the results of this report on 274 G+/P– people, let me first say that I consider disqualification from sports participation one of the severest restrictions we dole out. I love sports. And I owe some of my success as a doctor to my years of team sports. Had I had a funny gene and been disqualified, it would have been quite bad.
Patients were considered G+ if a genetic test identified a pathogenic variant or likely pathogenic variant in an established gene associated with long QT syndrome (LQTS), HCM, catecholaminergic polymorphic ventricular tachycardia (CPVT), or arrhythmogenic cardiomyopathy (ACM).
Phenotype testing was done with ECG, imaging, or exercise test.
Of the 274 total patients, most had LQTS (231 or 84%); 19 or 7% had CPVT, 15 or 5% had ACM, and a few percent had HCM. The age of diagnosis was 10 and 15 years. Mid 20s for ACM.
Most patients were discovered via family or cascade screening. Nearly 1 in 5 sought RTP after disqualification at another institution.
All but 4 (270 of 274) were allowed RTP after an evaluation or guideline-directed treatment and shared decision-making.
For LQTS, patients who were truly disease nonpenetrant were treated mostly with pharmacologic therapy (80, 72%) or an intentional nontherapy (INT) strategy (28, 25%), which consisted of avoiding QT-prolonging drugs, advice for proper hydration, acquisition of a personal automated external defibrillator, and routine follow-up visits.
The small remainder of patients were treated with more invasive therapies, such as left cardiac sympathetic denervation (LCSD; 2, 1%) or an implantable cardioverter-defibrillator (3, 2%). Two of the patients (1%) with an ICD had the device placed before being seen at our clinic.
For CPVT (N =19), after evaluation, most patients were treated pharmacologically (11, 58%) or with an INT strategy (8, 43%).
For ACM (N =15), all patients were put on a plan of active surveillance to monitor for any evidence of phenotypic conversion or disease emergence. All cardiac imaging was normal, including cardiac MRI, and patients had no structural evidence of disease. On follow-up, 2 patients showed late gadolinium enhancement on cardiac MRI 4 and 5 years after the initial Mayo Clinic visits and were considered P+ at that point.
For HCM (N=9), all patients (9, 100%) were managed with INT. They were all referred for evaluation because of a positive family history for disease.
Overall, in total, 68% of G+/P– people received pharmacologic therapy and 27% received INT or intentional non-therapy. And no patients had any disease-related cardiac events or deaths in more than 1,300 years of combined follow up. No patients. None. Nada.
About 60 patients had their gene variant downgraded from pathogenic, likely pathogenic or VUS to likely benign. These patients were not included in the 274 in this report, but this is an important data point because they were disqualified at the same rate as the patients with true pathogenic gene variants.
This is a really important paper. Really important. I get gene reports, and they are scary. Why? For two reasons: First, because no one wants to have a young person have cardiac arrest. Second, because almost no one knows much about genetic heart disease.
Indeed, gene testing is about as opposite from troponin testing as it gets. Cardiologists deal with troponin levels about every day. We have a feel for troponins, often the wrong feel, but there is familiarity. Gene reports come with a bold-faced phrase 'pathogenic variant.' Our tendency is to pull the trigger and say 'no sports.'
What this report tells us is that if you do a proper evaluation (history, exam, ECG, image, and stress test) you can identify phenotype negative people. That is, they don't have the disease. And then set forth a treatment and follow-up plan, often with no treatment, these people (not patients) can live normal lives and participate in sports.
The authors write with caution:
In fact, the purpose of this study is not to encourage physicians to disregard a positive genetic test, but to use it as a tool to further risk-stratify and guide management and treatment of the patient, and to not automatically disqualify from exercise.
For instance, for the INT strategy the authors write that 'even though no prescription is given or intervention performed, avoidance of QT-prolonging drugs, being proactive with electrolyte replenishment and hydration, monitoring other variables that could lead to an event (ie, lack of sleep, excess caffeine, postpartum period), and attending frequent follow-ups are still expected.
I realize you (and I) will not become experts in genetic heart disease from reading this paper. But reading this paper should infuse us with perspective. That is, genes are not fate. Genotype is not phenotype. Disqualification is severe. And when we find gene positive people the answer is not to scare people and disqualify them. The answer is to read, research the problem and as I often do — phone a friend.
Then, once you have done that have a discussion with the person and their family.
I want to say thank you to Michael Ackerman and his team. They have taught me, and the entire field of cardiology, tons about genetic heart disease.
STRONG HF: More Beats Less After Discharge for Heart Failure
Here we go again with rushing guideline-directed medical therapy (GDMT). JACC-HF has published a research letter in which numerous authors performed a post-hoc analysis of the STRONG HF trial. The main study question was to quantify how many days free of death or heart failure hospitalization (HHF) over 6 months is gained with rapid uptitration of GDMT after an admission for HF.
The secondary aim of the study was to promote the endpoint of RMST — restricted mean survival time — and RMSTD, or restricted mean survival time difference, which they authors say provides a direct measure of clinical benefit and can complement the hazard ratio (HR).
It's interesting because in years past, trial reports often included such a measure. For instance, in the AVID trial of ICD vs AAD for VT, the average unadjusted length of additional life associated with ICD therapy over AAD was 2.7 months at 3 years. (I don't know why authors stopped including such data points, but one theory is that it seriously minimized the differences.)
Back to the STRONG HF substudy and the matter of 'rapid uptitration of GDMT.' STRONG HF was published in 2022.
STRONG HF enrolled about 1600 patients with acute heart failure who were not treated with optimal medications from 87 hospitals in 14 countries. Nearly 90% were recruited from Africa and Russia. Patients were randomly assigned to a high-intensity treatment arm or usual care.
The high-intensity arm was aptly named. Patients first were given half the optimal dose of heart failure meds while still hospitalized. These included all the usuals (renin-angiotensin blockers, β-blockers, mineralocorticoid receptor antagonists). At week 1 after discharge, patients were checked for tolerance of these meds. At week 2, meds were uptitrated to full dose. The week 3 visit was used to check tolerance of full-dose meds, and then patients were checked again after 6 weeks. Notably, cardiologists performed these "safety" visits, using only a history, exam, and measurement of basic labs. The usual care arm was according to the local practice—in Africa or Russia.
Obviously, the high-intensity arm did better. They had 5-fold more frequent in-person visits and far more patients taking optimal HF meds.
The primary endpoint of death or HHF at 6 months was 34% lower. Readmission for heart failure drove the benefit, but all-cause death was 16% lower and cardiovascular death was 26% lower in the high-intensity arm. The trial was terminated early for benefit. Adverse events, actually, were higher in the high-intensity arm, 46% vs 29%, most commonly related to low BP or hyperkalemia and renal issues.
I wrote about the STRONG-HF trial in 2022 and wondered if it would change hospital systems. That is, if you found a way for a cardiologist to see the patient 4 times in the 6 weeks after hospital discharge you could improve outcomes. Well, since STRONG has come out, I have heard little about hospital systems changing their systems.
But perhaps I was naïve back in 2022. GDMT enthusiasts used the STRONG HF study to promote the value of rapid titration of meds. While that happened, I now have come to recognize STRONG-HF as one of the classic examples of performance bias—which infects so many strategy trials. That is, patients randomized to high-intensity care got a lot more than just rapid titration of meds. They had 5-fold more interactions with doctors and HF teams. They had more education, more follow-up and, simply stated, more care.
There is no way to tell if it was all the extra care of the meds. I can think of few examples of situations where you give one group of sick patients 5x more healthcare interactions than the other group and it doesn't matter. In fact, this is the reason EAST AF found benefit for early rhythm control. In EAST, there was little difference in sinus rhythm between the early rhythm control (ERC) and rate control arms, so rhythm control can't explain the better outcomes. Instead, the ERC had tons more healthcare encounters.
That was a long introduction to the research letter looking at days free of the primary composite of death or HHF.
In STRONG-HF, it was nearly 9 days longer without an event in the high-intensity arm compared with the usual care. The HR was 0.61 or 39% reduction. Most of the benefit was driven by a reduction of HHF, but the difference in death was 3.5 days but this did not reach statistical significance.
The authors than do a similar analysis, looking at extra days free of the primary endpoint based on the percentage of optimal dose of HF meds. And, of course, patients on optimal doses of HF meds did better.
Each 10% increase in percentage optimal dose of GDMT was associated with an RMSTD of +1.7 days (95% CI: +0.8 to +2.5 days; P < 0.001).
The authors are impressed. They write:
Our post hoc analysis of the STRONG-HF trial highlights the magnitude of benefit from rapid GDMT uptitration in HF patients beyond reduced risk.
RMST complements HR and risk differences (RDs) and can enhance the physician's ability to convey the real-world impact of interventions to patients and families.
The authors write:
Therefore, we believe RMST should be considered for routine inclusion among clinical trial result reporting.
This can potentially bridge the knowledge gap between clinical trial results and bedside decision-making with patients and family. Unlike HRs and RDs, which address the critical question of whether a treatment works, RMST provides a tangible and intuitive answer to the question, 'How many extra days does this treatment offer?
I like the idea of using the RMST but for 100% opposite reasons. I am not sure where the authors practice, or what their patients are like. But here in Kentucky, if I tell a farmer from Grayson County, Kentucky, that if he spends 4 extra days of his life in the next 6 weeks driving to Louisville to see a cardiologist, running through the paperwork gauntlet each time, then taking extra meds (many of which are costly), that he may have an extra 8 days before having another HHF, I am not sure they would be interested.
Same with AVID trial. Would the ICD have gained their lofty status if we emphasized the extra 2.7 months of life over 3 years? What do you all think? I think we should use something like RMST. I'm afraid it would make a lot of our highly valued recent 'breakthroughs' look relatively modest.
This is why I love basic old pacemakers. The RMST for a pacemaker for heart block is likely infinity. The patient dies without the pacemaker, and lives perhaps two decades with it.
I guess the value of using RMST is an empirical question—one that could be evaluated in qualitative studies of what patients think.