Comparative cohort study of post-acute COVID-19 infection with a nested, randomized controlled trial of ivabradine for those with POTS(COVIVA study)

[Mij]

Full Title: Comparative cohort study of post-acute COVID-19 infection with a nested, randomized controlled trial of ivabradine for those with POTS(the COVIVA study), 2025, David Saunders et al

Background: Significant clinical similarities have been observed between the recently described “Long-Haul” COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, “brain-fog,” and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms.

Methods/design: A detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction. A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction. Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights.

Discussion: Optimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade.
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[Utsikt]

The primary aim is to identify the proportion of volunteers with relevant symptoms diagnosed with postural orthostatic tachycardia syndrome (POTS) or inappropriate sinus tachycardia (IST). We will first attempt to address the frequency of clinically confirmed POTS in those with persistent COVID-19 symptoms suggestive of autonomic dysfunction.

We can already put this objective down as a fail. The study design is not suitable for determining the prevalence of anything.

The second aim is to determine the potential benefits of ivabradine treatment for those with LHC-associated POTS or IST. A nested clinical trial for ivabradine responsiveness on reduction of tachycardia. Ivabradine is a drug approved to treat tachycardia in severe heart failure with some demonstrated improvement in POTS outcomes. Those with confirmed POTS or IST will be randomized to ivabradine or placebo to determine efficacy in reducing heart rate and POTS symptoms.

Interventional methods​

Treatment intervention​

Ivabradine (Procoralan) at a starting dose of 5 mg twice per day will be compared to placebo in addition to otherwise appropriate medical care. The dose will be adjusted based on individual heart rate response in accordance with the approved product label.

Randomization, allocation, and blinding​

Study drug will be allocated to treatment groups by an unblinded research pharmacist. Treatment allocation and randomization will be determined in advance using time-blocked randomization with blocks of three. Allocation will be concealed from the volunteers and study team with treatment assignments predetermined by unblinded personnel not otherwise engaged in study procedures. Test article will be concealed from both subjects and investigators by placing medications at predetermined doses in gel capsules. For active treatment, 2.5 mg dose units will be encapsulated with a pharmaceutically inactive compound (e.g., microcrystalline cellulose), while the placebo group will receive capsules with only the inactive compound.

How easy is it to tell if you’re on Ivabradine? My very low dose beta blocker was night and day when I started it.

The third aim is to characterize potential differences in hematologic, metabolic, immunologic, and genetic variants among volunteers with and without LHC. Cellular and molecular characterization of LHC and non-LHC participants will be performed. This aim will identify risk factors and provide mechanistic insights into the pathophysiology of LHC and POTS for those with and without LHC. The biopsychosocial mechanisms of LHC and POTS will also be explored.

Enrolled volunteers will undergo whole genome sequence analysis to look for biomarkers of LHC risk, along with multi-omic analysis. Volunteers will have orthostatic vital signs, an interval medical history, EKG, immunologic assays, psychosocial, quality of life, and cognitive surveys; complete cognitive performance tasks; undergo metabolic testing, and have concomitant medications reviewed.

WGS is interesting, but isn’t it a small number of participants? Do we have established genetic biomarkers for LHC?

 

[Hoopoe]

How easy is it to tell if you’re on Ivabradine? My very low dose beta blocker was night and day when I started it.

Depends on the severity of the symptoms and the dose. I took a low dose and it didn't have a dramatic effect but it was noticable. I felt calmer, the heart felt less irritated, there was less chest pain.

Ivabradine also felt like it was fast acting with an effect that declined after a few hours and that makes it easier to distinguish between placebo and ivabradine.