What is the role of vericiguat in the treatment of patients with a history of acute myocardial infarction (AMI) and percutaneous coronary intervention (PCI) given its failure to meet its primary endpoint?

Vericiguat's Limited Role in Post-AMI/PCI Patients

Your skepticism about vericiguat in the post-AMI/PCI setting is justified—the drug was not studied in this specific population, and its primary endpoint failure in VICTORIA reflects the challenges of treating advanced heart failure rather than establishing a role in acute coronary syndrome management. The evidence does not support routine use of vericiguat immediately following AMI or PCI.

Understanding VICTORIA's Context and Limitations

The VICTORIA trial enrolled patients with worsening chronic HFrEF, not acute MI patients 1. While 54% of VICTORIA participants had coronary artery disease (defined as prior MI, PCI, or CABG), these were patients with established chronic heart failure who had experienced recent decompensation—not patients in the acute or subacute post-MI period 1.

Key distinction: The trial studied vericiguat as a chronic heart failure therapy in patients who had already developed HFrEF and experienced worsening symptoms, not as an intervention to prevent adverse remodeling immediately after AMI 1.

The Primary Endpoint "Failure" in Proper Context

The primary composite endpoint of cardiovascular death or HF hospitalization occurred at:

• Vericiguat group: 35.5 events per 100 patient-years
• Placebo group: 38.5 events per 100 patient-years
• Hazard ratio: 0.90 (95% CI 0.82-0.98, p=0.019) 1

This represents a statistically significant 10% relative risk reduction, though the absolute benefit was modest (approximately 3 fewer events per 100 patient-years) 1. The "failure" narrative stems from the modest effect size in an already severely ill population, not from lack of statistical significance.

Why Vericiguat Has No Established Role Post-AMI/PCI

Timing mismatch: Current AMI guidelines prioritize immediate mechanical reperfusion (primary PCI within 90-120 minutes), drug-eluting stents, and evidence-based antiplatelet/anticoagulation strategies 2, 3. Vericiguat was never tested as an acute intervention.

Population mismatch: Post-AMI management focuses on:

• Immediate reperfusion to minimize infarct size 2, 4
• Prevention of acute complications (cardiogenic shock, arrhythmias, mechanical complications) 2, 5
• Secondary prevention with aspirin, P2Y12 inhibitors, beta-blockers, ACE inhibitors, and statins 5, 4

None of these acute priorities were addressed by VICTORIA, which studied chronic HF patients months to years after their index events 1.

The Regression Analysis Concern

Your skepticism about "the amount of regressors" is clinically astute. The VICTORIA subgroup analysis for CAD versus non-CAD patients showed:

• CAD patients: 38.8 events per 100 patient-years with vericiguat vs 42.6 with placebo
• Non-CAD patients: 27.6 events per 100 patient-years with vericiguat vs 32.7 with placebo
• Interaction p-value: 0.78 (suggesting no differential effect by CAD status) 1

However, this was a post-hoc subgroup analysis, not a pre-specified endpoint, which inherently carries less evidentiary weight 1. The multiple adjustments required (age, sex, diabetes, GFR, device therapy) in patients with CAD versus without CAD suggest significant baseline heterogeneity that may not be fully captured by statistical adjustment 1.

Where Vericiguat Actually Fits (Not in Acute MI)

Vericiguat's only evidence-based indication: Chronic symptomatic HFrEF patients (NYHA class II-IV) with recent worsening HF (hospitalization or need for IV diuretics within 6 months) who remain symptomatic despite guideline-directed medical therapy 1.

Not indicated for:

• Acute MI management 2, 4
• Prevention of post-MI remodeling 2
• Routine post-PCI therapy 3
• Patients without established HFrEF 1

Practical Algorithm for Post-AMI/PCI Management (Without Vericiguat)

Immediate (0-24 hours post-PCI):

• Continue aspirin 75-162 mg daily indefinitely 5, 4
• Continue P2Y12 inhibitor (clopidogrel, ticagrelor, or prasugrel) for 12 months minimum 5, 3
• Initiate beta-blocker within 24 hours unless contraindicated (heart failure, hypotension, heart block) 5
• Start ACE inhibitor if LVEF ≤40% or pulmonary congestion present 5
• Parenteral anticoagulation until hospital discharge 5

Subacute (before discharge):

• Optimize statin therapy (high-intensity) 2
• Assess for complete revascularization if multivessel disease present 2, 3
• Echocardiography to assess LVEF and guide long-term therapy 2

Chronic (if HFrEF develops):

• Maximize guideline-directed medical therapy: ACE inhibitor/ARB/ARNI, beta-blocker, mineralocorticoid receptor antagonist, SGLT2 inhibitor 2
• Only after optimizing these therapies and if patient experiences worsening HF, consider vericiguat as add-on therapy 1

Critical Pitfall to Avoid

Do not extrapolate VICTORIA results to the acute post-MI population. The trial's modest benefit in chronic, advanced HF patients does not translate to a role in preventing HF development after AMI 1. The pathophysiology of acute ischemic injury differs fundamentally from chronic neurohormonal activation in established HF 2.

The preclinical data showing vericiguat reduces adverse remodeling in mouse MI models through CaMKII signaling 6 remains mechanistic and cannot substitute for clinical trial evidence in humans during the acute post-MI period.