Roxadustat after a heart attack did not shrink the damaged area

Giving the oral drug roxadustat after emergency stenting for a major heart attack did not reduce the size of the damaged heart muscle, according to the phase 2 ROXAMI trial [s1]. The result is a negative one on the measure that mattered most: the amount of heart tissue lost was no smaller with the drug than with standard care [s1].

Roxadustat stabilises hypoxia-inducible factor (HIF), a protein that cells switch on when starved of oxygen, and laboratory work had suggested that boosting it might blunt the injury that occurs when blood flow is suddenly restored to oxygen-starved tissue [s1]. ROXAMI set out to see whether that idea held up in people having the most severe kind of heart attack [s1]. Roxadustat is already used in some countries to treat the anaemia of chronic kidney disease, so its short-term safety in people is reasonably well characterised; the trial repurposed it to ask a different question about protecting heart muscle [s1].

What the trial did

ROXAMI was a phase 2, open-label, randomised trial at a single tertiary medical centre, enrolling adults with ST-segment-elevation myocardial infarction (STEMI) who were undergoing primary percutaneous coronary intervention — emergency stenting — between 1 April 2021 and 31 March 2024, with follow-up through one year [s1]. Patients were assigned either to oral roxadustat (100 mg three times a week for two weeks), started within two hours after the stenting procedure, or to standard care alone [s1][s2].

The primary endpoint was infarct size, expressed as a percentage of the left ventricle, measured at 30 days by late gadolinium enhancement on positron-emission-tomography and magnetic-resonance imaging [s1]. Prespecified secondary endpoints included major adverse cardiovascular events, markers of heart injury, and echocardiographic and fibroblast-activation measures [s1].

What it found

Among 158 randomised patients — mean age 63.6 years, 133 (84.2%) men, 79 assigned to each group — 148 (93.7%; 72 on roxadustat and 76 on control) had imaging that could be evaluated for the primary outcome [s1]. Mean infarct size did not differ significantly between the groups: 23.3% of the left ventricle with roxadustat versus 22.0% with control, a difference of 1.3 percentage points (95% confidence interval −2.7 to 5.3; P=.51) [s1]. On the trial's main question, the drug made no measurable difference [s1].

Major adverse cardiovascular events occurred in 3 of 79 patients (3.8%) on roxadustat and 7 of 79 (8.9%) on control (hazard ratio 0.42; 95% confidence interval 0.11 to 1.63; P=.21) — a numerically lower rate that did not reach statistical significance and involved small numbers [s1]. In secondary analyses that were not adjusted for multiple comparisons, the roxadustat group showed a larger 12-month gain in left-ventricular ejection fraction (a between-group difference of 2.9 percentage points; 95% confidence interval 0.4 to 5.3; P=.02) and a smaller left-ventricular end-diastolic volume index (a difference of −4.5 mL/m²; 95% confidence interval −8.9 to −0.1; P=.045) [s1]. The incidence of prespecified safety endpoints did not differ between the groups [s1].

How to read it

The primary result is clear and should anchor interpretation: roxadustat did not shrink the infarct [s1]. The later remodelling signals — better ejection fraction and less ventricular enlargement at a year — are the kind of finding that is easy to over-read. They came from secondary endpoints that were not corrected for the many comparisons made, which inflates the chance that one or more crosses the significance line by chance, and the trial's own authors call them exploratory and in need of confirmation [s1].

Design features reinforce caution. ROXAMI was open-label, so patients and clinicians knew who got the drug, which can colour softer measures more than a hard imaging endpoint; it was run at a single centre; and with 79 patients per arm it was small, as the wide confidence interval around the event-rate comparison shows [s1]. Imaging for the primary outcome was available for 148 of the 158 randomised patients, so the main comparison rested on most of the enrolled group rather than a depleted subset [s1]. A negative phase 2 trial on its primary endpoint is not a reason to pursue the drug for this use on the strength of secondary signals alone [s1].

What to watch

Whether any of the remodelling findings survive a larger, blinded, multi-centre trial with those outcomes prespecified as primary is the question a future study would need to answer [s1][s2]. For now, the evidence does not support roxadustat as a way to limit heart-attack damage [s1]. This article describes research and is not medical advice; decisions about heart-attack care belong with treating clinicians.