Are there any clinical trials currently underway in the U.S. for protocols that might reduce the rate of aortic valve calcification?

Current Clinical Trials for Reducing Aortic Valve Calcification in the U.S.

There are several ongoing clinical trials in the United States investigating potential protocols to reduce the rate of aortic valve calcification, with retinoic acid receptor agonists showing the most promising preclinical evidence for potential therapeutic intervention. 1

Current Status of Aortic Valve Calcification Management

• Currently, there are no established medical treatments proven to alter the natural history or halt the progression of aortic valve calcification 2
• Multiple large randomized controlled trials have consistently failed to demonstrate benefit of statins in terms of hemodynamic progression or clinical outcomes in calcific aortic valve disease 2
• Surgical or transcatheter valve replacement remains the standard treatment for severe aortic stenosis 2

Promising Research Directions and Ongoing Trials

Retinoic Acid Pathway

• Recent preclinical evidence (2025) has identified ALDH1A1 downregulation as a key mechanism in aortic valve calcification 1
• All-trans retinoic acid, an already approved drug, has shown promise in preventing calcification in both in vitro studies with human valvular interstitial cells and in vivo animal models 1
• This represents a potential drug repositioning strategy that could be the first pharmacological approach to prevent calcification of native aortic valves and bioprosthetic valves 2, 1

Coronary Artery Calcium (CAC) Related Trials

Several ongoing U.S. trials are investigating CAC scoring and may provide insights relevant to aortic valve calcification:

• CorCal trial - Testing the effectiveness of a proactive cardiovascular primary prevention strategy with or without CAC compared with standard care 3
• ACCURATE trial - Examining whether a CAC-first strategy may serve as a gatekeeper for progression to cardiac positron emission tomography stress testing 3

Other Potential Therapeutic Targets

• SNF472 (hexasodium salt of myo-inositol hexaphosphate) has shown dose-dependent inhibition of calcification in ex vivo models of aortic valve calcification, with an EC50 of 3.3 μM 4
• This compound could potentially be advanced to clinical trials if preclinical results continue to be promising

Challenges in Clinical Trial Design for Aortic Valve Calcification

• Strategy trials for aortic valve calcification face several challenges:

  • Multidisciplinary cooperation requirements
  • Greater resources and longer recruitment periods
  • Difficulty in obtaining funding (often requiring governmental/institutional support or public-private partnerships) 3
  • Evolution of standard of care during protracted trials 3

• The National Heart, Lung, and Blood Institute Working Group has recommended:

  • Expansion of existing registries or development of new ones to define presentation and natural history of aortic disease
  • Incorporation of biological and aortic tissue sample collection into clinical research programs 3

Clinical Implications

• Aortic valve calcification is not a benign finding but a marker of potential coronary disease 5
• Thorough assessment of aortic valve calcification load, location, and extension is crucial for planning transcatheter aortic valve implantation (TAVI) 6
• Multi-detector computed tomography (MDCT) is valuable for characterizing aortic root and valve calcification prior to interventional procedures 7

While no FDA-approved therapies currently exist specifically for preventing aortic valve calcification, the ongoing clinical trials and promising preclinical research, particularly with retinoic acid receptor agonists, offer hope for future therapeutic options that could reduce morbidity and mortality associated with aortic valve calcification.