In pulmonary hypertension due to left-heart disease, pulmonary artery denervation and pulmonary vasodilators carry different risks, but no reliable overall safety ranking is established. Evidence to date suggests PADN may reduce a composite clinical-worsening endpoint when added to guideline-directed medical therapy, while remaining investigational and incompletely characterized.

Why It Matters To Your Practice

• Clinicians may be asked to compare an invasive adjunct with PAH-targeted drugs in a population where the main treatment priority remains the underlying heart disease.

• The PADN-HF-PH trial in NEJM randomized 264 patients in China to PADN plus guideline-directed medical therapy or medical therapy alone and reported a Kaplan–Meier estimated 2-year clinical-worsening incidence of 25.7% versus 51.5% (hazard ratio 0.49; 95% CI 0.30–0.82).

Clinical Implications

• The reported benefit in PADN-HF-PH was for a composite outcome that included death, transplantation, heart-failure hospitalization, outpatient worsening of heart failure, and decline in 6-minute walk distance. It does not establish reductions in mortality or heart-failure hospitalization individually.

• Median follow-up was 338 days, so the 2-year Kaplan–Meier estimates should not be read as if all participants were observed for 2 full years. The trial also was not sham-controlled, which matters because some composite components could be influenced by treatment awareness and care decisions.

Insights

• In PADN-HF-PH, the clearest documented procedural harm was vascular-access injury: access-site hematomas occurred in 2 PADN-assigned patients and 1 control patient, with no other procedural complications reported. That is reassuring but too limited to exclude rare or delayed harms.

• Plausible PADN risks include pulmonary-artery injury, thromboembolism, transient arrhythmia during catheter manipulation, sedation-related complications, and, if contrast is used, contrast reaction or kidney injury. Late effects such as pulmonary-artery stenosis or aneurysm remain insufficiently defined.

The Bottom Line

• Pulmonary vasodilators have a different risk profile rather than a clearly safer one. Endothelin-receptor antagonists raise concern for fluid retention and worsening congestion; in MELODY-1, fluid retention or worsening functional class occurred numerically more often with macitentan than placebo.

• Phosphodiesterase-5 inhibitors bring hypotension and interaction risks, and SIOVAC associated sildenafil with worse clinical outcomes than placebo after valvular-heart-disease correction. A meta-analysis of 8 randomized trials found more adverse events with endothelin-receptor antagonists or phosphodiesterase-5 inhibitors than placebo, without a statistically significant mortality difference. For now, PAH-targeted drugs should not be used routinely solely for pulmonary hypertension due to left-heart disease, and PADN is best viewed as a promising but investigational adjunct.

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