A tweet from Mark Haigney, MD, on the recent FOURIER analysis reappraisal.

Cardiology Pharmaceuticals

Repatha Re-analysis Raises Questions

Amgen’s PCSK9 inhibitor Repatha (evolocumab) is facing scrutiny after a reassessment of its FOURIER late-stage trial data revealed that the biologic may be associated with an increased risk of cardiovascular death.

The FOURIER trial laid the foundation for Repatha’s regulatory approval. The reanalysis, published in the BMJ, has identified several inconsistencies between the 2017 NEJM publication of FOURIER’s primary results and a more detailed Clinical Study Report (CSR). In cases of discrepancy between the sources, an independent committee blindly “readjudicated and restored” the cause of death according to the information in the CSR narratives.

• The reanalysis found that the number of deaths of cardiac origin was higher in the evolocumab group than the placebo group (113 vs. 88), although the relative increase in CV mortality was still non-significant (RR 1.20, p=0.13).
  
• The authors argue that the reanalysis raises the possibility that evolocumab might have specific adverse cardiac effects, a hypothesis “consistent with pharmacovigilance reports” (FAERS, Eudravigilance or VigiAccess databases), but inconsistent with the FOURIER trial finding that evolocumab decreased non-fatal myocardial infarctions.
  
• Specifically, the CSR contained a higher number of deaths due to myocardial infarction (36 vs. 25) and cardiac failure (31 vs. 16) than the NEJM report.

These findings have caused a stir in the medical community, with reactions ranging from confusion and surprise to others pointing out that the “readjudication and restoration” process may not have been more accurate than the original adjudication process, and did not even yield significant findings. However, authors of the reanalysis point out that the original investigation was terminated early, and had the investigation been carried out over the full 56-month follow-up, evolocumab-related CV mortality may have reached statistical significance. 

This new scrutiny emerges while Amgen is in a patent fight over Repatha, arguing to revive patents protecting Repatha and to block the sale of Praluent (alirocumab), a similar PCSK9 inhibitor created by Sanofi. 

The Takeaway

Discrepancies between CSRs and peer-reviewed publications are actually fairly common, and the particular discrepancies noted in the reanalysis do not dramatically change the takeaways from the original FOURIER publication. That said, this type of scrutiny is never welcome, and at the very least, the study points to the importance of data transparency.

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The Wire

• Unlocking the Potential of Genetic Testing: In a study of 330k patients from the UK Biobank, a polygenic risk score (PRS) for CAD carried more predictive power in younger individuals, and could be used to determine which patients with borderline clinical risk should begin statin therapy. In patients younger than 50 years, those with high PRS had a 3- to 4-fold increased risk of MI compared with those in the low PRS category. The relationship between CAD PRS and age was replicated in Biobank Japan (n=100k). 

• Regional Variations in Cardiac Rehab Use: A study published in JAMA Cardiology found that cardiac rehabilitation use varied based on US region and urbanization status. Residents of large urban areas had lower eligibility, participation, and completion rates than those in noncore rural areas, despite the former having more cardiac rehabilitation centers per county. Additionally, Southern rural residents had high eligibility rates but among the lowest participation rates nationally. 

• Two Year Telehealth Extension: With just two days to spare before the year-end deadline, President Biden signed a massive $1.7T omnibus spending package that included plenty of implications for US healthcare. What does $1.7T get you these days? It extends pandemic-era telehealth flexibilities for another two years, puts a two year delay on in-person screening requirements for Medicare telemental health visits, and allows providers to continue offering hospital-at-home programs. It also keeps the lights on in US government buildings until… September.

• The Plaque Hypothesis: A review in JAMA Cardiology pulls data from vascular biology, atherosclerosis imaging, and large-scale clinical trials to support what the authors call “the plaque hypothesis”–the idea that many serious heart problems may be more related to the destabilization of vulnerable plaque, obstructive or nonobstructive, rather than the amount of blood flow blockage in the artery. 

• BioFreedom Stent Gains FDA Approval: The FDA approved Biosensors International’s BioFreedom drug coated coronary stent system. BioFreedom consists of a catheter delivery system and a biolimus-coated 316L stainless steel metal stent. It is the latest in a long line of drug-eluting and drug-coated stents from the Singapore-based medical device company. 

• Measuring CAD Risk on a Spectrum: A new EHR-based ML model accurately pinpointed gradients of risk for coronary artery disease (CAD). This digital marker can potentially improve CAD diagnosis and management by taking into account variations in arterial plaque, which leads to different levels of risk for atherosclerosis and survival. The model, trained and validated on EHR data from 96k participants, produced “ISCAD” scores that predicted CAD with high sensitivity (0.84), specificity (0.88), and AUC (0.91) in an external dataset. 

• Faster Ablation: A novel catheter for very high-power short-duration ablation (vHP-SD) reduced procedure time by 42 minutes (59 vs. 101mins) and yielded similar rates of AFib/atrial tachycardia recurrence at one year compared to standard ablation in a study of 100 patients. Additionally, successful first-pass ablation and adverse events were similar between the vHP-SD and control groups.

• Plaque + Inflammation Atherosclerosis AI: A new European Heart Journal paper predicted that the growing use of CCTA exams and the evolution/adoption of CCTA AI technologies will drive continued improvements in CVD risk assessments and treatment guidance. However, the Caristo Diagnostics-funded/produced article endorsed using AI that takes into account both coronary plaque characterization and coronary inflammatory burden, suggesting that this approach better predicts treatable risks. It’s worth noting that Caristo has a unique focus on inflammation-based CVD risk.

• Post-TAVR Statin Use: Patients who underwent TAVR and filled prescriptions for statins and ACE inhibitors or angiotensin receptor blockers had an 18% reduced risk for mortality at 3 years compared with those who did not (HR = 0.82). Patients who were prescribed ACE inhibitors/angiotensin receptor blockers both before and after the procedure showed better 3-year survival compared with those who were only prescribed medication postoperatively, but the same was not true for statins (HR = 0.85).

• PET/CT MACE-Revasc Risk Scores: Intermountain Healthcare researchers developed an “easy to calculate” and “highly predictive” PET/CT-based cardiac event risk scoring system. After training and validation using 11.5k patients’ PET/CTs, a test with 5k patients’ PET/CTs showed that the Intermountain MACE-Revasc system’s risk scores outperformed ischemic burden for predicting MACE and revascularization at 90-days and one-year (AUCs: 90-day 0.85 vs. 0.83; 1yr 0.80 vs. 0.76). The MACE-Revasc system also predicted events with far higher sensitivity at 90-days and one-year than cardiologist assessments (59% vs. 29%; 48% vs. 21%).

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