This week in Cardiology

This AudioScholar briefing is generated by artificial intelligence for healthcare professionals and trainees. It is not medical advice.

Welcome to This Week in Cardiology. This week we're covering 10 notable papers spanning two high-profile failures and two successes in preventive targets, new mechanistic and long-term data in heart failure with preserved ejection fraction and amyloid cardiomyopathy, and how we pace, revascularize and resuscitate. Let's dive in.

We start with prevention, where this week brought two large negative outcome trials, both in the New England Journal of Medicine. Cho and colleagues report the Lp(a) HORIZON trial, which randomized more than eight thousand patients with established cardiovascular disease and lipoprotein(a) of at least 70 milligrams per deciliter to monthly pelacarsen or placebo [1]. The antisense drug did what it was designed to do biochemically, cutting lipoprotein(a) by roughly three quarters at one year. Yet over a median of almost five years, major adverse cardiovascular events occurred in about 12 percent of patients in each arm, with no difference at all, and the result was equally flat in patients with the highest baseline levels. Serious adverse events were, if anything, slightly less frequent on pelacarsen. This is a single trial of a single agent, but it substantially weakens the assumption that lowering lipoprotein(a) by this degree translates into fewer events over this time frame. A similar story comes from ZEUS, led by Ridker, testing the interleukin-6 antibody ziltivekimab in about six thousand four hundred patients with atherosclerotic disease, chronic kidney disease and a high-sensitivity C-reactive protein of at least 2 milligrams per liter [2]. Free interleukin-6 and C-reactive protein fell sharply, but major cardiovascular events occurred in just under 18 percent of patients in both groups, and serious infections were modestly more common with the antibody. Taken together, these two trials show that hitting a biomarker hard is not the same as preventing events, and they reopen questions about which patients, if any, benefit from targeting these pathways.

Against that backdrop, a more conventional target delivered. The OPTIMAL-STROKE trial, also in the New England Journal and led by Sampaio Silva, randomized about forty-four hundred Brazilian patients with prior ischemic stroke or transient ischemic attack to a systolic target below 120 or below 140 millimeters of mercury [3]. The groups separated by about 13 millimeters, and the intensive arm saw roughly a fifth fewer major cardiovascular events over about four years. The composite kidney outcome was more common with intensive treatment, although overall serious adverse events were similar. This is an open-label trial in one country, but it adds randomized evidence that a lower target benefits survivors of cerebrovascular events, with renal function a trade-off to monitor. Then, at the other end of preventive intensity, the STREAM trial by Rodondi and colleagues, again in the New England Journal, randomized about nineteen hundred adults aged 70 or older with multiple chronic conditions and no known cardiovascular disease to stop or continue their statins [4]. Discontinuation met the prespecified noninferiority margin, with a difference of about two weeks of event-free time over two years. But the raw numbers deserve attention: primary events occurred in about 13 percent of patients who stopped versus about 9 percent of those who continued, and serious adverse events were slightly more frequent after stopping. The trial supports discontinuation as a reasonable option within its noninferiority framework, but the direction of the event counts means the debate over deprescribing in older adults is far from closed.

Our second theme is heart failure with preserved ejection fraction and infiltrative cardiomyopathy, where mechanism and longer-term data dominated. In Nature Medicine, Borlaug and colleagues randomized 81 patients with obesity-related preserved ejection fraction heart failure to semaglutide 2.4 milligrams weekly or placebo for a year, measuring filling pressures invasively [5]. Pulmonary artery wedge pressure during exercise fell by about 10 millimeters of mercury more with semaglutide, resting pressures also dropped, and just over half of treated patients reached normal filling pressures at rest and exercise, compared with about one in fourteen on placebo. It is a small mechanistic trial, but it gives a hemodynamic explanation for the symptom benefits seen previously. In Circulation, Lewis and colleagues report IRONMET-HFpEF, randomizing 65 iron-deficient patients to a single 1000 milligram dose of intravenous ferric derisomaltose or placebo [6]. Peak oxygen uptake improved by about one milliliter per kilogram per minute relative to placebo, with gains in six-minute walk and functional class, though the Kansas City quality-of-life score did not differ significantly. This is the largest iron trial in this population but still small and short, so it supports a functional signal rather than outcome benefit. Also in Circulation, Garcia-Pavia and colleagues present four-year data from the HELIOS-B open-label extension of vutrisiran in transthyretin amyloid cardiomyopathy [7]. Patients who received vutrisiran from the start had about a third lower risk of death and of the composite of death or cardiovascular events than those who switched from placebo, with better quality of life and biomarkers. Open-label extensions carry selection bias, but the persistent gap argues that delayed treatment is not fully recovered, reinforcing the case for early diagnosis.

Our final theme covers procedures and strategies, from the pacing lead to the helicopter. The OptimPacing trial by Qian and colleagues in the New England Journal randomized about seven hundred patients with atrioventricular block to left bundle-branch pacing or conventional right ventricular pacing [8]. The trial was stopped early at interim analysis, and at about three years the composite of death, heart failure hospitalization or pacing-induced cardiomyopathy was cut by more than half, with four-year incidence around 9 percent versus 19 percent. Serious adverse events unrelated to implantation were similar. Early stopping can exaggerate effect sizes and the trial was open-label, but this is the first randomized outcome evidence favouring conduction system pacing in this group. In JAMA, Hochman and colleagues report ISCHEMIA-EXTEND, now with a median of nine years and over a thousand deaths among about fifty-two hundred patients with chronic coronary disease and moderate or severe ischemia [9]. Eleven-year all-cause mortality was about 26 percent with an initial invasive strategy and 27 percent with conservative management, not significantly different, with a difference in average survival of about two weeks. A small, nonsignificant trend toward lower cardiovascular death was offset by a nonsignificant trend toward more noncardiovascular death. For stable patients like those enrolled, this firmly suggests routine invasive management does not extend life. Finally, the Dutch OnScene study by Reis Miranda and colleagues, in the New England Journal, compared helicopter teams equipped for prehospital extracorporeal resuscitation with teams without that capability in patients aged 50 or younger with refractory out-of-hospital arrest [10]. Survival to discharge was about 40 percent versus 20 percent, and favourable neurologic outcome at six months was about 36 percent versus 13 percent, with more adverse events in the intervention group. This was nonrandomized and modest in size, so the comparison is associational, but it makes a strong case for further evaluation of bringing extracorporeal support to the patient.

If you only have time for one paper this week, make it the OptimPacing trial of left bundle-branch pacing [8]. It provides the first randomized hard-outcome evidence that the pacing site matters in atrioventricular block, a question that touches a very large number of patients receiving pacemakers.

That's your roundup for This Week in Cardiology. The full transcript and references are available on the episode page. See you next week.

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