PCORI Biweekly COVID-19 Scan: Treating Postural Orthostatic Tachycardia Syndrome (POTS) and Systemic Inflammation (August 4-17, 2022)

ECRI Horizon Scanning has selected the topics below as those with potential for impact relative to COVID-19 in the United States within the next 12 months. All views presented are preliminary and based on readily available information at the time of writing.

Because these topics are rapidly developing, we cannot guarantee the accuracy of this information after the date listed on this publication. In addition, all views expressed in the commentary section are solely those of ECRI Horizon Scanning and have not been vetted by other stakeholders. Topics are listed in alphabetical order.

Description

Ivabradine is a heart rate–lowering medication previously approved by the FDA to treat heart failure. It is currently being investigated as a treatment for post-COVID-19 POTS.

POTS is a debilitating condition with orthostatic intolerance in which autonomic dysfunction leads to inadequate vasoconstriction when standing, resulting in an excessively high heart rate to compensate for the reduced blood supply to the heart and brain. POTS is increasingly reported as a symptom of post-COVID conditions and might contribute or be linked to other common symptoms of long COVID, including fatigue, headache, and brain fog. There are no FDA-approved treatments for post-COVID conditions or POTS; therefore, there is an unmet need for effective therapies.

Ivabradine is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that lowers heart rate by selectively blocking the channel responsible for the cardiac pacemaker current (If). Based on findings from a phase 3 clinical trial in patients with hyperadrenergic POTS, researchers suggest that ivabradine might also help relieve symptoms of post-COVID POTS. A phase 4 clinical trial will begin enrolling 250 people with prior COVID-19 with and without post-COVID conditions in September 2022, with primary completion expected in September 2024. About 40 of the participants will be eligible to evaluate whether ivabradine, given at an unspecified dose for three months, effectively lowers standing heart rate in adults with post-COVID-19 POTS.

We were unable to determine the cost of a course of ivabradine for treating post-COVID-19 POTS. However, the wholesale acquisition cost for treating heart failure is estimated at $4,500 per year.

Commentary

Effective therapies are needed to treat post-COVID conditions, including post-COVID-19 POTS.

Early feedback from ECRI stakeholders suggested that preliminary results from the study of ivabradine to treat POTS are encouraging because the drug might regulate heart rate, potentially alleviating several debilitating symptoms associated with post-COVID conditions and accelerating patients’ return to regular daily activities.

Ivabradine carries a small risk of atrial fibrillation or low heart rate (bradycardia). Therefore, it might not be appropriate for all patients, and treatment with ivabradine for post-COVID-19 POTS requires appropriate patient selection and close monitoring during treatment.

Research on ivabradine might improve clinician understanding and provide evidence for its use as a standard-of-care treatment for post-COVID-19 POTS. However, varied access to the treatment and cost might hinder its diffusion.

Additional data and longer-term studies are needed to identify patients who would benefit most from this treatment and to assess its impact on patient health outcomes.

• Category: Treatment
• Areas of potential impact: Patient outcomes, health care costs, health care disparities

Description

OP-101 is an investigational treatment for systemic inflammation caused by severe COVID-19 in adult patients. It is being developed by Ashvattha Therapeutics (Redwood City, California).

A hallmark of severe COVID-19 is dysregulated proinflammatory cytokine release by immune cells (e.g., macrophages and microglia). This hyperinflammation can cause lung injury, acute respiratory distress syndrome, multiorgan dysfunction, CNS dysfunction, and death. Standard-of-care dexamethasone can be effective in suppressing inflammation, but the strong systemic impact of the treatment has serious potential side effects, including secondary infections. Therefore, novel targeted therapies are needed to improve patient outcomes.

Hydroxyl dendrimer therapeutics (HDTs) are specialized “carrier” molecules that are capable of crossing the blood-brain barrier. NAC is an amino acid derivative with antioxidant, anti-inflammatory, and immune-modulating characteristics. OP-101 is an HDT designed to carry NAC through the blood and deliver it specifically to sites of inflammation, where it is selectively absorbed by reactive inflammatory macrophages and microglia. The developer suggests that NAC might help relieve hyperinflammation in these cells caused by SARS-CoV-2 infection.

Preliminary published results from an ongoing phase 2 clinical trial found that a single intravenous infusion of OP-101 was well tolerated, reduced the risk of death or mechanical ventilation, and decreased inflammatory biomarkers. OP-101 is also the first therapeutic agent shown to reduce biomarkers of COVID-19-associated brain injury. Regulatory meetings between the developer and FDA are planned for the fourth quarter of 2022.

We were unable to find information regarding the potential cost of a course of OP-101 treatment.

Commentary

OP-101’s targeted approach might effectively deliver anti-inflammatory NAC to activated macrophages and microglia. This approach might reduce hyperinflammatory responses during severe COVID-19, reducing the risk of death and long-term complications such as lung and neurological damage, while reducing the risk of systemic immune suppression and adverse side effects associated with dexamethasone treatment.

Feedback from ECRI stakeholders suggested that if OP-101 proves safer and more effective at addressing COVID-19 neurological symptoms, it would be a welcome clinical tool. Current evidence suggests the burden of these symptoms increases costs to both the health care system and patients. The potential to mitigate long-term neurological disability might decrease overall treatment costs and increase the quality of life for patients recovering from severe COVID-19. More long-term, clinical data are needed to assess the effectiveness of treatment.

The unknown cost of OP-101 might create health care disparities in affordability and availability of treatment.

• Category: Treatment
• Areas of potential impact: Patient management, patient outcomes, health care costs, health care disparities

Horizon scanning is a systematic process that serves as an early warning system to inform decision makers about possible future opportunities and threats. Health care horizon scanning identifies technologies, innovations, and trends with potential to cause future shifts or disruptions—positive or negative—in areas such as access to care, care delivery processes, care setting, costs of care, current treatment models or paradigms, health disparities, health care infrastructure, public health, and patient health outcomes.

The PCORI Health Care Horizon Scanning System (HCHSS) conducts horizon scanning to better inform its patient-centered outcomes research investments. Initially, PCORI defined the HCHSS project scope to focus on interventions with high potential for disruption in the United States in 5 priority areas: Alzheimer’s disease and other dementias, cancer, cardiovascular diseases, mental and behavioral health conditions, and rare diseases. In addition, the system captures high-level disruptive trends across all clinical areas, which may lead PCORI to expand the project scope to include other priority areas in the future.

In early 2020, the COVID-19 pandemic created a fast-moving, widespread public health crisis. In May 2020, PCORI expanded its HCHSS to elucidate the landscape of potentially impactful applications for COVID-19. The HCHSS COVID-19 supplement scans for, identifies, monitors, and reports on emerging and available COVID-19-related treatments, diagnostics, preventive measures, management strategies, and systems changes with potential for high impact to patient outcomes—for individuals and populations—in the United States in the next 12 months.

The HCHSS COVID-19 supplement produces 3 main outputs:

• Biweekly COVID-19 Scans (eg, this document) provide ECRI Horizon Scanning with a vehicle to inform PCORI and the public in a timely manner of important topics of interest identified during ongoing scanning and topic identification or through the ECRI stakeholder survey process.
• Status Reports (quarterly) briefly list and describe all COVID-19-related topics identified, monitored, and recently archived.
• High Impact Reports (every 4 months) highlight those topics that ECRI internal stakeholders (eg, physicians, nurses, allied health professionals, public health professionals, first responders, health systems experts, clinical engineers, researchers, business and finance professionals, and information technology professionals) have identified as having potential for high impact relative to COVID-19 in the United States.

In May 2021, the COVID-19 supplement was modified and merged with the HCHSS. The Biweekly COVID-19 Scans continue, while the Status Reports and High Impact Reports were folded into the PCORI Horizon Scanning Database and High Potential Disruption Reports.