Patrick Campbell is the managing editor of HCPLive. Formerly the editorial lead of Endocrinology Network, Practical Cardiology, and Rheumatology Network, Patrick has spent years spearheading coverage surrounding cardiometabolic health and rheumatic disease for MJH Life Sciences. He now helps to lead coverage in each of these respective areas for HCPLive. Before joining MJH Life Sciences in 2019, he spent time as a beat reporter with the Pocono Record in Stroudsburg, PA, and Star News Group in Manasquan, NJ. He also touts experience in multimedia, having spent time as a multimedia specialist with NJ Advance Media and multimedia coordinator at the Pocono Record. Follow him on Twitter @RealPatCampbell or reach him via email at PCampbell@mjhlifesciences.com.

Patrick Campbell

Natalie McCormick, PhD
Credit: American College of Rheumatology

An analysis of data from the National Health and Nutrition Examination Survey (NHANES) suggests the risk of mortality associated with 

 has persisted across the last 3 decades in the US.

European Congress of Rheumatology (EULAR) 2023

 annual meeting, results of the study indicate the adjusted risk of all-cause mortality among people with gout in the US has remained consistent dating back to the 1980s despite advances in technology and pharmacological treatment options.

“We looked at risk of mortality among people with and without gout in a representative sample of the US population, and found that there was an increased mortality risk, and it has not improved over time,” said lead investigator Natalie McCormick, PhD, an epidemiologist at Harvard Medical School, in an interview with HCPLive.

According to an analysis of NHANES data presented at EULAR 2023, the overall prevalence of gout among US adults had increased from 3.6% in 2011-2012 to 5.1% in 2017-2018.

 In the current study, McCormick and fellow investigators leveraged data from NHANES with the intent of comparing the risk of all-cause and cardiovascular mortality among patients with gout using historic and contemporary data.

For the purpose of analysis, the early cohort included data recorded within NHANES survey cycles occurring from 1988-1994 and the late cohort included data from NAHNES survey cycles occurring from 2007-2016. The primary outcome of interest for the study was the 10-year risk of all-cause mortality relative to their counterparts without gout. Investigators pointed out models used to estimate hazard ratios for mortality were adjusted for atherosclerotic cardiovascular disease risk factors, cardiometabolic comorbidities, kidney function, and relevant medication use.

Upon analysis, results suggested the risk of all-cause mortality was 19% greater for those with gout relative to their counterparts without gout among the entire study cohort (aHR, 1.19 [95% Confidence interval [CI], 1.08-1.32]). Further analysis revealed there was little difference in risk observed for those in the early (aHR, 1.19 [95% CI, 1.02-1.38]) and late (aHR, 1.19 [95% CI, 1.03-1.37]) cohorts.

Results of subgroup analysis suggested the risk of all-cause mortality was greater among women (aHR, 1.33 [95% CI, 1.11-1.60]; 

 = .03), Black individuals (aHR, 1.40 [95% CI, 1.12-1.74]), and older individuals, with those aged greater than 60 years of age having a 62% greater relative risk of mortality compared to those aged 60 years or less ( aHR, 1.62 [95% CI, 1.19-2.19]; 

 < .001). Investigators noted the risk of cardiovascular mortality was 39% greater among those with gout relative to their counterparts among those in the late cohort.

McCormick underlined the importance of precision medicine and taking an individualized approach to patient care.

“What potentially could help is maybe more supplementary medications,” McCormick explained. “There has been evidence of daily low dose colchicine use helping with cardiovascular risk in gout populations and others. This might be a call for that because urate-lowering therapy can be great at reducing flare risk, but evidence does not suggest that it has much of an impact on the cardiovascular risk that people with gout face.”

McCormick N, Yokose C, Lin K, Lu L, Joshi A, Choi H. Persistent Premature Mortality in Gout: Nationwide Prospective Cohort Study. Paper presented at: European Congress of Rheumatology (EULAR) 2023. Milan, Italy. May 31 – June 3, 2023.

Campbell P. Report: For US patients, gout burden greatest among Asian Americans. HCP Live. May 31, 2023. Accessed June 8, 2023. https://www.hcplive.com/view/report-for-us-patients-gout-burden-greatest-among-asian-americans.

Articles

NHANES data presented at EULAR 2023 offer insight into trends in the risk of mortality over a time period beginning in 1988 and lasting through 2016. 

Mortality Risk in Gout Has Persisted for Decades Despite Advances in Care

Carolyn Bramante, MD, MPH
Credit: University of Minnesota 

New research from a phase 3 trial of people with 

 with COVID-19 suggests use of metformin could reduce risk of long COVID by up to 67% percent.

Results of the study, which compared use of metformin, ivermectin, and fluvoxamine against placebo therapy, indicate use of metformin was associated with a reduced cumulative incidence of long COVID, with earlier initiation associated with a greater effect and no benefit observed with ivermectin or fluvoxamine compared with placebo.

“Long COVID is a significant public health emergency that may have lasting physical health, mental health, and economic impacts, especially in socioeconomically marginalized groups. There is an urgent need to find potential treatments and ways to prevent this disease,” said lead investigator Carolyn Bramante, MD, MPH, assistant professor of Medicine at the University of Minnesota Medical School.

 “Our study showed that metformin, a medication that is safe, low-cost, and widely available, substantially reduces the risk of being diagnosed with long COVID if taken when first infected with the coronavirus. This trial does not indicate whether metformin would be effective as a treatment for those who already have long COVID.”

Named the COVID-OUT trial, the study was designed as a decentralized, randomized, quadruple-blind, parallel-group, phase 3 trial and conducted at 6 sites in the US. The trial enrolled adults aged 30-85 years of age with overweight or obesity who a documented SARS-CoV-2 positive PCR or antigen test within the prior 3 days and were experiencing symptoms for fewer than 7 days. After enrollment, these patients were randomized in a 1:1:1:1:1:1 to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo.

The primary outcome of interest for the trial was severe COVID-19 by day 14. Investigators pointed out the a priori primary sample was a modified intention-to-treat sample. The secondary outcome of interest for the trial was long COVID diagnosis by a medical provider.

Overall, 6602 patients were assessed for eligibility. A total of 1431 were enrolled and randomly assigned between December 30, 2020-January 28, 2022. Of these, 1323 participants received a dose of study treatment and were included in the ITT population. A cohort of 1126 consented for long-term follow-up and completed a survey after the assessment for long COVID at day 180.

A diagnosis of long COVID was observed in 8.3% (n=93) of the 1126 patients who consented to long-term follow-up. Results of the investigators’ analysis suggested the cumulative incidence of long COVID by day 300 was 6.3% (95% confidence interval [CI], 4.2-8.2) in those who received metformin and 10.4% (95% CI, 7.8-12.9) in those who received placebo (Hazard ratio [HR],0.59 [95% CI, 0.39-0.89]; 

 = .012). Investigators pointed out this effect was consistent across prespecified subgroups and earlier administration of metformin appeared to increase the benefit, with initiation within 3 days of symptom onset associated with a 63% relative risk reduction (HR, 0.37 [95% CI, 0.15-0.95]; 

When examining the effects of other treatments, results indicated there was no effect on cumulative incidence of long COVID with either ivermectin (HR, 0.99 [95% CI, 0.59-1.64]) or fluvoxamine (HR, 1.36 [95% CI, 0-.78-2.34]) relative to placebo therapy.

In a Linked Comment, Jeremy Faust, MD, of Harvard Medical School and Brigham and Women’s Hospital, noted more research is necessary to confirm the findings of the current study, but commended investigators for their novel and “potentially landmark” findings.

“If confirmed, the findings from the study by Bramante and colleagues are profound and potentially landmark on two distinct counts,” wrote Faust.

 “First, to our knowledge, this is the first high-quality evidence from a randomized controlled trial to show that the incidence of long COVID can be reduced by a medical intervention, metformin—an inexpensive treatment with which clinicians have ample experience. Second, the authors have, perhaps inadvertently, made an important contribution to medical epistemology. If a new disease has been sufficiently well characterized by clinicians so that it can be successfully modified by a therapy compared with placebo, then the entity must, from a practical standpoint, truly exist.”

Data from the COVID-OUT trial suggests use of metformin could reduce a person's risk of developing long COVID by more than 50% relative to placebo therapy, with results also providing insight into the apparent lack of benefit with ivermectin and fluvoxamine.

Metformin Could Reduce Long COVID Risk in People with Overweight or Obesity

George Karpouzas, MD
Credit: Lundquist Institute

A new analysis of data from the ORAL Surveillance trial provides further insight into patient profiles most likely to benefit from use of tofacitinib.

Presented at the European Congress of Rheumatology (EULAR) 2023 annual meeting, the analysis of ORAL Surveillance data indicates the efficacy of tofacitinib is “at least as good” as TNF inhibition with comparable risk of MACE in patients with no history of cardiovascular disease.

“In patients who do not have ASCVD risk, the use of tofacitinib is much more likely to produce clinical remission compared to TNF inhibition. There is a Blackbox Warning that's in place now stating that patients at high risk should not be taking this, but it's not as monolithic as that,” said study investigator George Karpouzas, MD, professor of Medicine at the David Geffen School of Medicine at UCLA and chief of the Division of Rheumatology at Harbor-UCLA Medical Center, in an interview with HCPLive at EULAR 2023. “If you exclude actual patients who suffered a cardiovascular event, as opposed to the rest of the patients with high to moderate risk, the patients at high to moderate risk actually had better clinical responses to tofacitinib versus TNF inhibitors and, more importantly, did not have a safety signal.”

A randomized, open-label, noninferiority, postauthorization, safety end-point trial, the ORAL Surveillance trial enrolled patients 4362 patients and randomized them in a 1:1:1 ratio to 5 mg tofacitinib twice daily,10 mg tofacitinib twice daily, and 1451 received a TNF inhibitor. Initial results published in the 

suggested use of tofacitinib was associated with increased incidence of major adverse cardiovascular events (MACE) and cancers.

At the American College of Rheumatology 2022 annual meeting, an analysis of the trial using an 8-point MACE endpoint suggested there did not appear to be a difference in incidence between the tofacitinib and TNF inhibitor groups. This analysis also indicated risk was numerically higher in patients with a history of atherosclerotic cardiovascular disease (ASCVD).

In the EULAR 2023 study, Karpouzas and investigators sought to further explore the benefit-risk profile of tofacitinib based on history of ASCVD. Of the 4362 patients included in the trial, 640 had a history of ASCVD and 3722 had no history of ASCVD. Investigators pointed out 3672 of the 3722 had baseline cardiovascular risk score data available.

Upon analysis, results suggested the odds ratios (ORs) for achieving remission or low disease activity were greater for those receiving tofacitinib relative to their counterparts receiving TNF inhibitors among the overall study populations. Investigators pointed a similar trend was observed for those with no history of ASCVD while the ORs for achieving remission with tofacitinib among those with a history of ASCVD were comparable to those seen with TNF inhibitor use.

“In the United States, it can be a bit jarring for the physician to sort of forego this massive block of a Blackbox Warning, but I think it's really important to understand that this Blackbox Warning is a highly nonselective block and we need to really redefine what is the actual population that incurred the risk,” Karpouzas explained. “There could still be people that you've inadvertently, and platform, put into this box that could benefit much more from this modality without presenting a danger signal.”

Buch MH, Mortezavi M, Giles J, et al. IMPACT OF CARDIOVASCULAR COMORBIDITIES ON EFFICACY OF TOFACITINIB VS TNFI IN RHEUMATOID ARTHRITIS. Paper presented at: European Congress of Rheumatology (EULAR) 2023. Milan, Italy. May 31 – June 3, 2023.

Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. 

. 2022;386(4):316-326. doi:10.1056/NEJMoa2109927

Campbell P. Examining drivers of cardiovascular risk with tofacitinib, with Deepak Bhatt, MD, MPH. HCP Live. November 15, 2022. Accessed June 8, 2023. https://www.hcplive.com/view/examining-drivers-of-cardiovascular-risk-with-tofacitinib-with-deepak-bhatt-md-mph.

An analysis of the ORAL Surveillance trial details the efficacy of tofacitinib relative to TNF inhibition based on history of ASCVD and baseline cardiovascular risk.

Analysis Offers Insight into Patients Most Likely to Derive Benefit from Tofacitinib

A new study from investigators in Europe warns patients who experienced heart attacks during the first COVID-19 lockdowns in the UK and Spain could expect to live 1.5-2 years less than their pre-COVID counterparts.

Results of the study, which used a Markov decision-analytic model to assess the probability of outcomes, suggest hospitalization with ST-elevated myocardial infarction (STEMI) during a lockdown period was associated with a reduction in survival and quality-adjusted life-years (QALYs) compared to hospitalization for STEMI during pre-pandemic periods.

“Restrictions to treatment of life-threatening conditions have immediate and long-term negative consequences for individuals and society as a whole,” said study investigator William Wijns, MD, PhD of the Lambe Institute for Translational Medicine, University of Galway, Ireland.

“Back-up plans must be in place so that emergency services can be retained even during natural or health catastrophes.”

Now, more than 3 years after the start of the COVID-19 pandemic, investigators are just beginning to uncover and unravel years of data. An example of this is a data release from the American Heart Association in January 2023. In the organization’s 2023 Statistical Update, the American Heart Association released data detailing an increased rate of cardiovascular disease-related deaths during the first year of the COVID-19 pandemic in the US. According to the AHA, cardiovascular disease-related deaths surged for 874,612 in 2019 to 928,741 in 2020, which is the largest single-year increase since 2015 and the greatest total recorded since 910,000 deaths in 2003.

Among the chief concerns cited by cardiologists and cardiology care professionals in the early portions of the pandemic was ante reduction in patients presenting to the hospital and emergency departments with myocardial infarction. A study in England found the admission rates for acute coronary syndromes in England were approximately 40% lower than prepandemic periods.

In the current study, Wijns and a team of investigators sought to examine the consequences of untimely or missed revascularization of STEMI patients during the COVID-19 pandemic, with a specific interest in predicting the long-term health outcomes and cost of reduced treatment of STEMIs during the COVID-19 lockdowns in the UK and Spain.

Investigators used a Markov decision-analytic model to calculate survival and QALYs as well costs of reduced treatment. Investigators pointed out these models included data related to probability of hospitalization, and timeliness of percutaneous coronary intervention in calculations. For the purpose of analysis, the UK model compared STEMIs occurring from March 23-April 22, 2020 to those occurring during the equivalent time in 2019. The Spanish model compared March 2020 to March 2019. Investigators pointed out their survival projections considered age, hospitalization status, and time to treatment using published data for each country.

Upon analysis, results indicated STEMI patients from the first UK lockdown were expected to lose a mean of 1.55 life-years and 1.17 QALYs compared to their counterparts who presented with STEMI during a prepandemic period. Investigators pointed out this correlated to an increase of €41.3 million ($44.3 million) in total additional lifetime costs. Results indicated STEMI patients from the first SPANISH lockdown were expected to lose 2.03 life-years and 1.63 QALYs compared to their counterparts who presented during the prepandemic period. Investigators pointed out this correlated to an increase of €88.6 million ($95.12 million) in total additional lifetime costs. Investigators pointed out work absenteeism was the main contributor to costs among, but also noted part of this cost was offset by lower costs of heart failure hospitalizations as more STEMI patients died during lockdown.

“The findings illustrate the repercussions of delayed or missed care. Patients and societies will pay the price of reduced heart attack treatment during just one month of lockdown for years to come,” Wijns added.

“Health services need a list of lifesaving therapies that should always be delivered, and resilient healthcare systems must be established that can switch to emergency plans without delay. Public awareness campaigns should emphasize the benefits of timely care, even during a pandemic or other crisis.”

Lunardi M, Mamas MA, Mauri J, et al. Predicted clinical and economic burden associated with reduction in access to acute coronary interventional care during the COVID-19 lockdown in two European countries [published online ahead of print, 2023 Jun 7]. 

. 2023;qcad025. doi:10.1093/ehjqcco/qcad025

One-month of COVID-19 lockdown cost heart attack patients up to two years of life. European Society of Cardiology. June 7, 2023. Accessed June 8, 2023. https://www.escardio.org/The-ESC/Press-Office/Press-releases/One-month-of-COVID-19-lockdown-cost-heart-attack-patients-up-to-two-years-of-life.

Iapoce C. CVD-related deaths surged during first year of COVID-19 pandemic. HCP Live. January 30, 2023. Accessed June 8, 2023. https://www.hcplive.com/view/cvd-related-deaths-surged-during-first-year-covid-19-pandemic.

Mafham MM, Spata E, Goldacre R, et al. COVID-19 pandemic and admission rates for and management of acute coronary syndromes in England. 

. 2020;396(10248):381-389. doi:10.1016/S0140-6736(20)31356-8

A decision-analytic model leveraging data from the UK and Spain suggests people who experienced STEMI during COVID-19 lockdown periods could have a reduced life expectancy relative to their counterparts who experienced similar events in prepandemic periods.