Can Vitamin K1 Replace Heart Valve Surgery? PASSPORT Trial Investigates Revolutionary Treatment

Can Vitamin K1 Transform Aortic Valve Stenosis Treatment?

Royal Perth Hospital has completed enrollment in a groundbreaking clinical trial investigating whether high-dose vitamin K1 supplementation can halt or slow the progression of calcific aortic valve stenosis (CAS), a common and deadly heart valve disease. The Prevention of Aortic Stenosis Progression Phylloquinone Ossification Reduction Trial (PASSPORT) has randomized 108 participants with mild to moderate CAS to receive either 10mg daily vitamin K1 or placebo for an average of 16 months.

The trial addresses a critical unmet need in cardiovascular medicine, as CAS affects approximately 10% of adults over 80 years of age, with no effective pharmacological treatments currently available. Despite its high prevalence and mortality risk, the only effective intervention for severe CAS remains valve replacement – either surgically or via transcatheter approach – which carries significant procedural risks and high healthcare costs. The PASSPORT trial represents a potential paradigm shift in treatment approach by targeting the calcification process that drives disease progression. Dr. William A. Courtney, the lead investigator, explains that vitamin K1 works by activating proteins that inhibit vascular calcification, potentially preserving valve function without invasive intervention. "If successful, this could be the first proven pharmacotherapy for CAS, dramatically altering the treatment landscape for this condition," Dr. Courtney noted.

What Scientific Evidence Supports the PASSPORT Trial?

The trial builds upon promising preliminary research, including a smaller open-label study that showed vitamin K1 supplementation (2mg daily) reduced aortic valve calcification progression by 57% compared to controls. PASSPORT employs a more rigorous double-blind design with a higher vitamin K1 dose (10mg daily) and focuses exclusively on patients with established mild or moderate stenosis rather than including those with aortic sclerosis. The primary outcome measure is progression of aortic valve calcification volume as measured by non-contrast cardiac computed tomography, with secondary endpoints including changes in echocardiographic measures of stenosis severity and safety assessments. The trial team has implemented comprehensive follow-up procedures with participants reviewed every three months to monitor adherence and safety. As of March 2025, 104 participants continue in the trial, with only four dropouts reported and no adverse effects related to the investigational product identified.

The scientific rationale for the PASSPORT trial stems from vitamin K's crucial role in activating matrix gamma-carboxyglutamic acid (GLA) protein and GLA-rich proteins, which are present in aortic valve leaflets and inhibit calcification. Research has shown that vitamin K-dependent carboxylation of matrix GLA protein stabilizes extracellular vesicles produced by valvular interstitial cells, thereby reducing calcification. Previous studies have demonstrated that low dietary vitamin K is associated with increased cardiovascular disease risk, while vitamin K antagonism by warfarin accelerates CAS progression. The trial specifically focuses on vitamin K1 (phylloquinone) rather than vitamin K2 (menaquinone), as recent research suggests the former may be more effective in reducing aortic valve calcification progression.

Is This the Disruptive Therapy the Market Needs?

The PASSPORT trial positions vitamin K1 as a potentially disruptive therapy in a field dominated by device-based interventions from companies like Edwards Lifesciences and Medtronic, which manufacture surgical and transcatheter heart valves. While pharmaceutical giants like Novartis and Bristol Myers Squibb have investigated various compounds for CAS, including PCSK9 inhibitors and anti-inflammatory agents, none have demonstrated significant clinical benefit. The potential market for an effective CAS pharmacotherapy is substantial, with the global heart valve devices market valued at approximately $8.9 billion in 2022 and projected to grow at a CAGR of 11.4% through 2030. A successful vitamin K1 intervention could capture a significant portion of this market while substantially reducing healthcare costs associated with valve replacement procedures, which typically range from $50,000 to over $200,000 per patient.

The trial's statistical design provides 90% power to detect a 57% difference in aortic valve calcification progression between treatment groups, assuming a common standard deviation of 165 μL. Even with potential dropouts of up to 25%, the trial would retain 80% power to detect the primary effect. To ensure accurate assessment of outcomes, all CT-derived aortic valve calcification volume scores will be analyzed centrally by two independent imaging specialists blinded to treatment allocation, using vendor-independent software (OsiriX, Version 5.8.5). The trial has also implemented rigorous measures to assess adherence, including the Brooks Medication Adherence Scale at each follow-up visit and measurement of the ratio of undercarboxylated osteocalcin to total osteocalcin, a validated biomarker of vitamin K status.

What Does the Future Hold for Vitamin K1 Therapy?

If the PASSPORT trial demonstrates positive results, the investigators anticipate that vitamin K1 supplementation could be rapidly incorporated into clinical practice guidelines for non-severe CAS, potentially benefiting millions of patients globally. The trial results could also inform future research exploring vitamin K's role in other calcific vascular conditions, including coronary artery and peripheral vascular disease. The trial team plans to complete follow-up by late 2025, with final results expected in early 2026. "Even if the trial does not meet its primary endpoint, it will provide crucial information to guide future research into alternative therapeutic targets for this disease," Dr. Courtney emphasized. The trial has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN12622000447752) and received ethical approval from the Royal Perth Hospital and East Metropolitan Health Service human research ethics committees.

Industry Context: The PASSPORT trial represents a growing trend toward repurposing established nutritional supplements and vitamins for targeted therapeutic applications in cardiovascular disease. This approach offers potentially lower development costs and favorable safety profiles compared to novel molecular entities. The vitamin K1 strategy aligns with increasing investor interest in preventive cardiovascular therapies that could reduce the need for expensive interventional procedures, particularly as healthcare systems worldwide grapple with aging populations and rising cardiovascular disease burden. The trial also highlights Australia's emerging role as a hub for innovative cardiovascular clinical research, with implications for future industry partnerships and investment in the region's biomedical sector.

Summary

Royal Perth Hospital has completed enrollment in the PASSPORT clinical trial, investigating whether high-dose vitamin K1 supplementation can slow or halt the progression of calcific aortic valve stenosis, a common and deadly heart valve disease affecting approximately 10% of adults over 80. The trial has randomized 108 participants with mild to moderate stenosis to receive either 10mg daily vitamin K1 or placebo for an average of 16 months. Currently, no effective pharmacological treatments exist for this condition, and the only intervention for severe cases is valve replacement, which carries significant risks and costs. The trial builds on preliminary research showing that vitamin K1 reduced aortic valve calcification progression by 57% in a smaller study. Vitamin K1 works by activating proteins that inhibit vascular calcification, potentially preserving valve function without invasive procedures. The primary outcome measure is progression of aortic valve calcification volume measured by cardiac computed tomography, with secondary endpoints including echocardiographic measures of stenosis severity. As of March 2025, 104 participants continue in the trial with only four dropouts and no adverse effects reported. The potential market for an effective pharmacotherapy is substantial, with the global heart valve devices market valued at approximately $8.9 billion in 2022. If successful, this could be the first proven pharmacotherapy for calcific aortic valve stenosis, dramatically altering the treatment landscape and potentially benefiting millions of patients globally. Final results are expected in early 2026.