Allopurinol, a drug commonly used to treat gout, provided no benefit in reducing cardiovascular (CV) events in patients with ischemic heart disease, new randomized trial results show.
Treatment of these non-gout patients with allopurinol 600 mg daily had no effect on composite primary outcomes, including nonfatal myocardial infarction (MI), nonfatal stroke, or CV death .
“ALL-HEART is the first large, prospective, randomized trial of the effect of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease and provides strong evidence for the role of allopurinol in these patients” , said lead researcher Isla Shelagh Mackenzie, MBChB. Honours), PhD, University of Dundee, Scotland, concluded at a press conference here.
Their results suggest that allopurinol should not be recommended for secondary prevention of events in this group, Mackenzie said. While it remains an important treatment for gout, he added, “other avenues for the treatment of ischemic heart disease should be explored in the future.”
The results of the ALL-HEART (Allopurinol and Cardiovascular Outcomes in Ischemic Heart Disease) trial were presented on August 27 at the European Society of Cardiology (ESC) 2022 Congress.
Treatment of gout
Allopurinol is a xanthine oxidase inhibitor and works by reducing serum uric acid levels and oxidative stress. The treatment is generally well tolerated, Mackenzie noted in his presentation, but some patients develop a rash, which in some cases can be severe or even fatal, progressing to Stevens-Johnson syndrome or toxic epidermal necrolysis. “especially in certain ethnicities.” If a rash develops, the advice is to stop treatment immediately.
“The importance of serum uric acid levels in cardiovascular disease is controversial, and there have been different reports over the years about how important they may be,” explained Mackenzie.
Observational studies have shown variable results, while intervention trials, most with fewer than 100 participants, have suggested potential improvements in factors such as blood pressure, endothelial function, left ventricular hypertrophy or intima- middle carotid Some have reported benefits in acute coronary syndrome and coronary artery bypass grafting, but others have not, he said. A previous study by his own group suggested an improvement in chest pain and exercise time in patients with stable chronic angina and documented coronary artery disease (CAD).
“Therefore, to date, there have been no large prospective randomized trials of the effects of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease,” Mackenzie said, and that was the goal of ALL-HEART.
ALL-HEART was a prospective, randomized, open-label, blinded endpoint multicenter trial. Patients with ischemic heart disease but no history of gout were recruited from 424 general practices across the UK, starting in February 2014 and with follow-up ending in September 2021. Participants were randomized 1:1 to receive 600 mg of allopurinol daily or usual care.
“This was a decentralized trial, so monitoring was largely remote after the first 6 weeks, and this included the use of record linkage data collected from the centralized NHS. [National Health Service] databases of hospitalizations and deaths in Scotland and England,” he said. The median follow-up was 4.8 years.
During this time, 258 (9.0%) participants in the allopurinol group and 76 (2.6%) in the usual care group withdrew from follow-up. At the end of the trial, 57.4% of patients in the allopurinol arm withdrew from randomized treatment.
Mean serum uric acid levels dropped from 0.34 mmol/L at baseline to 0.18 mmol/L at 6 weeks of treatment, “so we can see that the treatment was effective in reducing uric acid,” he noted.
In total, there were 5,721 patients in the final intention-to-treat analysis and 639 patients had a first primary event.
For the primary outcome of nonfatal MI, nonfatal stroke, and cardiovascular death, there was no difference between the groups, the researchers reported, with a hazard ratio of 1.04. Similarly, in secondary analyses, there were no differences in any of the components that make up the primary outcome, or in all-cause mortality, between the two groups, Mackenzie noted, “so a trial definitely neutral”.
table ALL-HEART: primary endpoints and components for allopurinol vs placebo
Hazard ratio (95% CI) P-value Non-fatal MI, non-fatal stroke, CV death 1.04 (0.89 – 1.21) 0.65 Non-fatal MI 0.97 (0.78 – 1.21 ) 0.81 Non-fatal stroke 1.20 (0.89 – 1.20 CV) 1.20 (death) 0.85 – 1.43) .48 All-cause mortality 1.02 (0.87 – 1 .20) .77
In addition, no differences were observed in prespecified subgroups, including age, sex, estimated glomerular filtration rate or diabetes, MI, heart failure, peripheral arterial disease, stroke, and stroke or transient ischemic attack at baseline.
There were also no significant effects on quality of life outcomes. Cost-effectiveness analyzes are ongoing, although no differences are expected there, Mackenzie noted.
In terms of safety, incident cancers and all-cause mortality did not differ between groups. Serious adverse events were also similar between the groups, Mackenzie said, “and there were no treatment-related fatal SAEs. [serious adverse events] in the studio.”
Another negative antioxidant trial
Guest speaker for the presentation, Leslie Cho, MD, Cleveland Clinic, Ohio, said that ALL-HEART, while an excellent trial with a pragmatic design, is another negative antioxidant trial.
He pointed out three problems with this study and antioxidant trials in general. “First, the problem is with the antioxidant,” a xanthine oxidase inhibitor. “Xanthine oxidase is not a major trigger of oxidative stress. In a field of major players,” including nitric oxide, uncoupled endothelial nitric oxide synthase and mitochondrial myeloperoxidase, Cho said, “xanthine oxidase is a minor player.”
“In addition, 57% of patients stopped taking allopurinol, and rightly so,” he said. Patients were receiving optimal medical therapies, many of which are also antioxidants, including statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and β-blockers.
Second, the patient population was older, with a mean age of 72 years. “That makes the ALL-HEART study a chronic angina study, a chronic CAD study, one of the oldest modern CAD trials. If you look at the LoDoCo or ISCHEMIA trials, the median age is 63.” Patients also had established disease, many with prior revascularization.
The final problem seen with this trial, and all antioxidant trials, is that patient selection is not based on oxidative stress or antioxidant level. “Antioxidant trials have been disappointing at best. There is clear and compelling evidence that oxidative stress is involved in the pathogenesis of atherosclerosis, and yet study after study of antioxidant trials has been negative,” he said. to say.
“Currently, there is no reliable measure of the overall level of oxidative stress,” Cho noted. “Furthermore, dose response was not tested, and if we cannot test patients’ baseline level of antioxidant stress, we also cannot measure the effect of treatment on overall oxidative stress.”
So, “no hope for antioxidant testing?” she asked. Three factors will be required for future success, he said. “Number one, selecting the right patient at the right time. Number two, a reliable biomarker to measure oxidative stress to guide who should receive therapy and whether the therapy works. And finally, targeted therapies that work on the main triggers of oxidative stress.”
Also commenting on the findings, B. Hadley Wilson, MD, executive vice president of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at the University of North Carolina School of Medicine, and vice president of the American College of Cardiology, he called. ALL-HEART “an important and interesting study”.
“For years, cardiologists and others have been interested in allopurinol as an anti-inflammatory, xanthine oxidase inhibitor … to prevent coronary ischemic events,” he told theheart.org | Cardiology Medscape.
But this was a well-designed and well-conducted study and “unfortunately there was no improvement in the primary outcome, no reduction in major cardiovascular events such as myocardial infarction or stroke or cardiovascular death,” he said. said Wilson. “So it’s a bit of a disappointment that there isn’t an important drug to help us with these patients with ischemic heart disease, but it also answers an important question: that we need to look at treatments for ischemic heart disease other than l “allopurinol.”
The trial was supported by the Health Technology Assessment (HTA) Program of the National Institute for Health and Care Research (NIHR) in the UK. Mackenzie reports research contracts to his institution of NIHR HTA for this work and other disclosures related to other work. Cho and Wilson report no relevant disclosures.
European Society of Cardiology (ESC) Congress 2022. Hotline 3. Presented on 27 August 2022.
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