New Injectable Therapy Achieves Significant Lp(a) Reduction in 36 Weeks

 Zerlasiran, an injectable small interfering RNA molecule, lowered lipoprotein(a) (Lp(a)) by over 80% compared with placebo at 36 weeks.

The ALPACAR trial, a phase 2 study, evaluated zerlasiran in 178 patients with stable atherosclerotic CVD and elevated Lp(a) levels.

Participants were randomly assigned to receive zerlasiran at varying doses or a placebo.

All zerlasiran regimens resulted in a time-averaged 85.6%-81.3% reduction in Lp(a) over 36 weeks compared with placebo.

At least 90% Lp(a) reduction was observed in all zerlasiran groups at week 36.

LDL cholesterol was reduced by 25.1%-31.9%, and apolipoprotein B by 9.9%-15% at week 36 in zerlasiran recipients.

Results were sustained through 48 weeks and 60 weeks with no serious adverse events attributed to the study drug.

The most common adverse effects were headache and nasopharyngitis, which were mild and manageable.

A phase 3 cardiovascular outcomes trial is required to confirm whether these reductions translate to lower morbidity and mortality.

The FDA will only approve such therapies if they demonstrate impact on cardiovascular outcomes.

The advent of nucleic acid-based therapies like zerlasiran marks a potential breakthrough in treating elevated Lp(a), a key contributor to cardiovascular disease.

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Key Takeaways

1. Major Lp(a) Reduction: Zerlasiran reduced Lp(a) levels by over 80% at 36 weeks compared with placebo.
2. Sustained Effects: The reductions were maintained at 48 weeks and 60 weeks.
3. Safety Profile: There were no serious adverse events related to the drug; minor effects included headache and nasopharyngitis.
4. Additional Benefits: Significant reductions in LDL cholesterol and apolipoprotein B were also observed.
5. Regulatory Requirements: Phase 3 trials are needed to show effects on cardiovascular morbidity and mortality for FDA approval.
6. Transformative Potential: If successful, these therapies could significantly impact cardiovascular disease management.

CMS Proposal to Expand Medicare and Medicaid Coverage for GLP-1 Drugs

 CMS has proposed expanding Medicare and Medicaid coverage to include GLP-1 receptor agonists for obesity treatment.

Current regulations prevent Medicare from covering these drugs when used solely for weight management, even though some states allow Medicaid coverage.

The high cost of these medications, often exceeding $1,000 per month, limits accessibility for many individuals.

CMS is now proposing to reinterpret statutes, requiring Medicaid and allowing Medicare Part D to cover anti-obesity medications.

The proposal, set for the contract year 2026, would make these drugs accessible to more Americans, improving health and quality of life.

Experts, such as the chief medical officer of the American College of Cardiology, applaud the effort, citing potential benefits for cardiovascular health.

Studies, including the SUMMIT trial and STEP-HFpEF trial, suggest GLP-1 drugs may benefit patients with conditions like HFpEF and cardiometabolic abnormalities.

Despite expanded coverage, challenges remain in determining which patients benefit most from GLP-1 drugs.

Prior authorization processes may also continue to limit seamless access to these therapies.

Stakeholders, including CMS, providers, and patients, must collaborate to identify eligible patients and streamline treatment delivery.

The proposal's future remains uncertain as a new presidential administration takes office in January.

Public comments on the rule change are open until January 27, 2025, via the Federal Register.

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Key Takeaways

1. Proposed Expansion: CMS aims to expand Medicare and Medicaid coverage for GLP-1 receptor agonists in obesity treatment.
2. Cost Barrier: High drug costs and restrictive policies currently limit access for many patients.
3. Implementation Year: Changes would apply starting in 2026 for Medicare Part D and Medicare Advantage plans.
4. Clinical Benefits: Trials suggest potential cardiovascular and metabolic benefits from these drugs.
5. Collaboration Needed: Stakeholders must work together to optimize patient selection and access.
6. Uncertain Future: The proposal’s success may hinge on policy continuity under the incoming administration.
7. Public Input: Comments on the proposal are being accepted until January 27, 2025.

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Advanced Insights on Balloon-Expandable TAVI in Small Aortic Annuli: A Five-Year Perspective

 Key Findings:

• Balloon-expandable TAVI demonstrates comparable outcomes to surgery in low-risk patients with symptomatic severe aortic stenosis across both small and large annuli at five years.
• The SMART trial earlier indicated that self-expanding valves might outperform balloon-expandable valves at one year, particularly in hemodynamic performance.
• The latest PARTNER 3 analysis suggests similar rates of aortic valve reintervention and bioprosthetic valve failure between the two treatment options.

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Clinical Insights and Outcomes:

• For patients with small annuli, the primary endpoint of death, stroke, or rehospitalization was slightly lower for TAVI (21.2%) than surgery (31.6%) at five years, though not statistically significant.
• Quality-of-life outcomes were comparable between TAVI and surgery, regardless of annular size.
• The RHEIA trial, focusing on women (who typically have smaller annuli), revealed fewer rehospitalizations with TAVI compared to surgery.

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Device Evolution and Comparisons:

• The Resilia valve, an updated balloon-expandable model, shows improved hemodynamics over older versions, narrowing the performance gap with self-expanding valves like Evolut FX.
• Despite Evolut FX maintaining superior hemodynamics, Resilia's advancements include reduced rates of paravalvular leak and better technical device success.

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Take-Home Points:

1. Annular size does not significantly impact clinical outcomes between TAVI and surgery at five years for low-risk patients.
2. Advancements in balloon-expandable valves have improved performance metrics, reducing concerns about prosthesis-patient mismatch (PPM) and hemodynamic dysfunction.
3. TAVI is a reliable option for low-risk patients, including those with small annuli, and its outcomes are comparable to surgery.
4. Long-term durability data is crucial for understanding valve performance beyond five years.

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This analysis underscores the progress in TAVI technology and clarifies clinicians when deciding between surgical and transcatheter interventions, particularly for patients with small aortic annuli.

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Plavix (Clopidogrel) and Platelet Aggregation Assay

Purpose of Platelet Aggregation Testing for Plavix

• The platelet aggregation assay is used to monitor the effectiveness of clopidogrel (Plavix), a P2Y12 receptor inhibitor.
• It assesses platelet reactivity and identifies patients who may have high residual platelet activity (low responsiveness to Plavix), putting them at risk for thrombotic events.

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Normal and Abnormal Values

The values for platelet aggregation while on Plavix depend on the method used, typically light transmittance aggregometry (LTA) or VerifyNow P2Y12 assay.

1. Light Transmittance Aggregometry (LTA)

   • Normal Response to Clopidogrel:
     • Platelet aggregation reduction by >50% in response to ADP (5-20 μM).
     • ADP-induced aggregation: typically <30% in well-responding individuals.
   • Abnormal (Clopidogrel Resistance):
     • Platelet aggregation remains ≥30-50% with ADP.
     • Indicates high on-treatment platelet reactivity (HTPR).

2. VerifyNow P2Y12 Assay (most commonly used for clopidogrel responsiveness):

   • Results reported as P2Y12 Reaction Units (PRU):
     • Normal Response: PRU < 208 (suggests effective inhibition of platelet aggregation).
     • High Residual Platelet Reactivity (Resistance): PRU ≥ 208.

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Clinical Interpretation

• Effective Clopidogrel Response:

  • Platelet aggregation significantly inhibited (low PRU or reduced ADP response).
  • Indicates reduced thrombotic risk.

• Clopidogrel Resistance (HTPR):

  • Higher PRU values or persistent platelet aggregation despite treatment.
  • Associated with increased risk of thrombotic events (e.g., stent thrombosis).

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Factors Influencing Abnormal Values

1. Genetic Variants:

   • CYP2C19 polymorphisms lead to reduced activation of clopidogrel in poor or intermediate metabolizers.

2. Drug Interactions:

   • Proton pump inhibitors (PPIs) or other CYP inhibitors may reduce clopidogrel efficacy.

3. Clinical Factors:

   • Diabetes, obesity, or advanced age can increase platelet reactivity.

Key Points

1. Platelet aggregation testing monitors clopidogrel effectiveness and identifies non-responders.
2. Normal PRU is <208, with higher values indicating clopidogrel resistance.
3. Persistent platelet aggregation despite therapy may warrant alternative antiplatelet strategies (e.g., prasugrel or ticagrelor).