Pulmonary arterial hypertension (PAH) remains one of the most challenging entities in cardiovascular and pulmonary medicine. It is rare, progressive, and, if left untreated, relentlessly fatal. Yet over the past three decades, the therapeutic landscape has transformed from therapeutic nihilism to structured, pathway-targeted, and increasingly aggressive pharmacotherapy.
Contemporary registry data from Japan provide a particularly instructive window into how PAH management has evolved in real-world specialist practice . These data do more than describe prescribing patterns—they reflect a philosophical shift: earlier recognition, reduced disease severity at presentation, and a strong preference for combination therapy. For clinicians interested in the practical application of PDE-5 inhibitors—especially sildenafil—this evolution is clinically meaningful.
This article explores the changing profile of PAH, the mechanistic rationale for multidrug strategies, the expanding role of phosphodiesterase type 5 (PDE-5) inhibitors, and the implications for everyday clinical decision-making.
The Changing Face of Pulmonary Arterial Hypertension
PAH is defined hemodynamically by a sustained elevation of mean pulmonary arterial pressure (mPAP ≥25 mm Hg at rest in historical definitions), pulmonary artery wedge pressure ≤15 mm Hg, and elevated pulmonary vascular resistance (PVR). While these numbers appear technical, they represent a failing pulmonary circulation under constant pressure overload.
Registry data from Japan demonstrate two notable trends over time :
- Patients are being diagnosed at an older age.
- Baseline hemodynamic severity (including mPAP and PVR) has decreased in more recent years.
This pattern suggests earlier recognition and referral, improved awareness among physicians, and perhaps more systematic screening in high-risk groups such as those with connective tissue disease.
A reduction in the proportion of patients presenting in advanced New York Heart Association (NYHA) functional class III–IV has been observed . Clinically, this is not a trivial shift. Functional class at baseline strongly predicts long-term survival. Fewer patients in class IV means fewer individuals in immediate hemodynamic collapse.
One might say that PAH has not become a benign disease—but it is being intercepted earlier.
Pathobiology and Therapeutic Targets: Why Monotherapy Is Often Not Enough
The modern management of PAH is built upon three principal molecular pathways:
- Endothelin pathway (vasoconstrictive and proliferative)
- Nitric oxide–cyclic guanosine monophosphate (NO–cGMP) pathway
- Prostacyclin (PGI₂) pathway
PAH is not a single-pathway disease. It is a multifactorial vasculopathy characterized by endothelial dysfunction, smooth muscle proliferation, thrombosis in situ, and inflammation. Targeting only one pathway may provide partial relief—but rarely comprehensive hemodynamic reversal.
The logic of combination therapy arises directly from pathobiology. If vasoconstriction is driven simultaneously by endothelin excess, impaired nitric oxide signaling, and reduced prostacyclin activity, then therapeutic synergy becomes rational rather than aggressive.
Japanese registry data confirm that clinicians have increasingly embraced this logic . Over time, oral and inhaled combination therapies became more common, while reliance on monotherapy decreased.
In this context, PDE-5 inhibitors—particularly sildenafil and tadalafil—serve as central pillars of the NO–cGMP pathway strategy.
PDE-5 Inhibitors: Mechanistic Precision in Pulmonary Vascular Disease
Phosphodiesterase type 5 inhibitors enhance the nitric oxide signaling cascade by preventing degradation of cyclic guanosine monophosphate (cGMP). Elevated cGMP promotes pulmonary vasodilation, reduces vascular remodeling, and improves right ventricular afterload.
Sildenafil, originally developed for angina and famously repurposed, has become a cornerstone of PAH therapy. Its pharmacologic effects include:
- Reduction in pulmonary vascular resistance
- Improvement in 6-minute walk distance
- Delay in clinical worsening
- Favorable impact on right ventricular function
Unlike endothelin receptor antagonists (ERAs), PDE-5 inhibitors do not rely on hepatic metabolism to the same degree and are generally well tolerated. They are also compatible with multiple combination regimens.
Japanese registry data show that nitric oxide pathway agents, including sildenafil and tadalafil, were among the most frequently prescribed drug classes . The near parity between ERA and NO-pathway prescriptions suggests that PDE-5 inhibitors are not adjunctive afterthoughts—they are foundational therapies.
Importantly, sildenafil offers flexible dosing and a well-characterized safety profile, making it especially useful in elderly patients or those with comorbidities.
The Rise of Combination Therapy: A Cultural and Clinical Shift
Between earlier and later registry periods, combination therapy became the dominant strategy . Oral/inhaled combinations increased substantially, and triple therapy became more common.
This trend reflects not only international guideline evolution but also clinician confidence.
Japanese specialist centers appear particularly inclined toward early multidrug intervention. Several factors likely contributed:
- Evidence supporting upfront dual therapy in randomized trials
- Availability of newer agents such as macitentan and selexipag
- Increasing comfort with risk-stratified escalation
The combination of an ERA with a PDE-5 inhibitor has become a typical first-line pairing. Mechanistically, this makes sense: endothelin blockade reduces vasoconstrictive signaling, while sildenafil enhances vasodilatory cGMP activity. The result is balanced hemodynamic modulation.
The philosophy seems to be: if PAH is biologically aggressive, therapy should be equally so.
Hemodynamics Over Labels: How Physicians Choose Therapy
One of the most revealing aspects of Japanese registry data is that treatment decisions were more strongly associated with hemodynamic severity than with simplified risk scores .
Patients with higher mPAP, elevated right atrial pressure (mRAP), or increased PVR were more likely to receive combination or parenteral therapy. Conversely, those with milder hemodynamic compromise were more likely to receive oral monotherapy.
Interestingly, strict French low-risk criteria did not significantly dictate prescribing patterns . In other words, clinicians appeared to look beyond checkbox stratification and instead weigh:
- Direct catheterization data
- Clinical trajectory
- Comorbidity burden
- Functional reserve
This approach is clinically sensible. Risk algorithms are valuable—but the pulmonary artery does not read guidelines.
Etiology-Specific Nuances in Treatment Strategy
Not all PAH is created equal. Registry data demonstrate that treatment intensity varied by etiology .
Patients with idiopathic or hereditary PAH often received aggressive therapy, including triple or parenteral regimens. These forms of PAH frequently present with more severe hemodynamics and carry substantial mortality risk.
In connective tissue disease–associated PAH, combination therapy was common but slightly less dominant. Comorbid systemic sclerosis and multiorgan involvement may influence therapeutic aggressiveness.
In congenital heart disease–associated PAH, combination therapy rates were strikingly high. This reflects the often advanced vascular remodeling seen in Eisenmenger physiology, where surgical correction is no longer feasible and pharmacotherapy becomes central.
Across etiologies, PDE-5 inhibitors—including sildenafil—remained widely utilized .
Parenteral Therapy: Declining but Still Essential
While oral and inhaled combination therapies increased, the proportion of patients requiring parenteral prostacyclin decreased slightly over time . This likely reflects earlier detection and earlier escalation of oral therapy before patients deteriorate to advanced right ventricular failure.
Nevertheless, parenteral epoprostenol remains lifesaving in severe PAH. No oral agent fully replicates its potency.
In clinical practice, PDE-5 inhibitors often coexist with parenteral prostacyclin. Sildenafil can enhance the vasodilatory response and reduce required prostacyclin doses in some cases. Thus, even in advanced disease, PDE-5 inhibition maintains relevance.
Practical Guidance for Clinicians
From a pragmatic standpoint, contemporary PAH management can be summarized as follows:
- Initiate therapy early once hemodynamic criteria are confirmed.
- Consider upfront dual therapy in most symptomatic patients.
- Use PDE-5 inhibitors such as sildenafil as a backbone component.
- Escalate therapy based on hemodynamic reassessment, not solely symptoms.
- Individualize strategy based on etiology, comorbidities, and tolerability.
Sildenafil remains particularly useful in:
- Elderly patients requiring flexible dosing
- Patients intolerant of systemic hypotension
- Combination regimens with ERAs
- Situations where rapid cGMP augmentation is desired
It is worth remembering that while newer agents attract attention, sildenafil has decades of accumulated experience. In PAH pharmacotherapy, reliability is not outdated—it is reassuring.
Broader Implications: What the Japanese Experience Teaches Us
The Japanese registry experience suggests that earlier detection, specialist-center management, and aggressive multidrug strategies are associated with a shift toward lower disease severity at presentation .
This does not prove causation, but the pattern is compelling.
Three broader lessons emerge:
- Specialized centers matter.
- Hemodynamic data should guide escalation.
- Combination therapy is increasingly the norm rather than the exception.
In this framework, PDE-5 inhibitors—especially sildenafil—retain a central, durable role.
Frequently Asked Questions (FAQ)
1. Why are PDE-5 inhibitors like sildenafil so important in PAH?
They enhance the nitric oxide–cGMP pathway, leading to pulmonary vasodilation and improved right ventricular function. Sildenafil has robust evidence for improving exercise capacity and delaying clinical worsening, and it integrates well into combination regimens.
2. Is combination therapy superior to monotherapy?
In most symptomatic patients, yes. Registry data and randomized trials support improved clinical outcomes with dual or triple therapy compared with single-agent treatment. Contemporary practice increasingly favors early combination therapy .
3. When should parenteral prostacyclin be used?
Parenteral therapy is generally reserved for advanced or high-risk patients, particularly those with severe hemodynamic compromise or right heart failure. However, earlier combination therapy may reduce the number of patients progressing to this stage .
4. Does risk stratification alone determine therapy?
Not necessarily. While risk scores are useful, real-world data suggest that clinicians rely heavily on direct hemodynamic measurements and overall clinical context rather than risk criteria alone .