Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are not forgiving diseases. They are chronic, progressive, and physiologically complex. Over the past two decades, targeted pharmacotherapy has transformed prognosis. Yet even the most elegant pharmacologic strategy fails if it is not taken consistently.
A recent observational study conducted in a tertiary hospital setting provides valuable insight into how patients actually use PAH-specific medications, which regimens are most common, and what factors influence adherence . The findings are clinically instructive: adherence appears high when measured objectively, lower when assessed by patient self-report, and surprisingly resilient despite frequent adverse events.
In this article, we will examine treatment patterns, dissect adherence measurement methods, analyze predictors of persistence, and discuss the central role of tadalafil in contemporary PAH therapy. More importantly, we will interpret what these data mean for clinicians striving to improve outcomes in this high-risk population.
The Therapeutic Landscape of Pulmonary Arterial Hypertension
Pulmonary arterial hypertension is characterized by progressive remodeling of the pulmonary vasculature, increased pulmonary vascular resistance, and eventual right ventricular failure. Modern treatment strategies target three major biological pathways: endothelin, nitric oxide, and prostacyclin signaling.
The study cohort analyzed 63 patients receiving 127 targeted therapies, reflecting the complexity of contemporary management . The majority of patients were female (71.4%), with a mean age of 59 years, and PAH was the predominant diagnosis (74.6%). This demographic profile mirrors the epidemiology of idiopathic and connective tissue disease–associated PAH.
Therapeutic distribution was consistent with guideline-directed care:
- Endothelin receptor antagonists (ERAs) were the most commonly prescribed class (40.2%)
- Phosphodiesterase type 5 inhibitors (PDE-5i), including tadalafil, accounted for 37.0%
- Smaller proportions received soluble guanylate cyclase stimulators, prostacyclin receptor agonists, or prostanoids
Combination therapy was not the exception but the rule. Nearly 40% of patients were on dual therapy and 31.8% on triple therapy . This reflects the modern paradigm of targeting multiple pathways simultaneously, particularly in intermediate- or high-risk disease.
Among combinations, tadalafil featured prominently. The most frequently prescribed regimens were:
- Macitentan + tadalafil
- Ambrisentan + tadalafil
This is entirely aligned with evidence from the AMBITION trial, which demonstrated superiority of initial combination therapy with ambrisentan plus tadalafil over monotherapy. In practice, tadalafil has become a backbone agent in PAH management due to once-daily dosing, favorable tolerability, and established efficacy.
Measuring Adherence: When Numbers Disagree
Adherence is a deceptively simple concept: did the patient take the medication as prescribed? In reality, measuring adherence is methodologically complex.
This study employed two approaches :
- Proportion of Days Covered (PDC) – an objective pharmacy refill–based measure, with ≥80% considered adherent
- Simplified Medication Adherence Questionnaire (SMAQ) – a patient-reported tool classifying adherence based on missed doses and behavioral patterns
The results were striking.
According to PDC, adherence was 93.7% .
According to SMAQ, adherence was 61.9% .
Agreement between methods was low (65.1%; Kappa 0.12), indicating only slight concordance .
This divergence is not trivial. PDC measures medication dispensing, not ingestion. A patient may pick up every prescription and still miss doses. Conversely, self-reported questionnaires may overclassify nonadherence because a single admission of forgetting is sufficient for classification as nonadherent.
The practical lesson is clear: adherence rates depend heavily on the instrument used. Studies reporting 90% adherence and those reporting 60% adherence may both be correct—within their methodological framework.
Treatment Patterns: Complexity Without Collapse
One might expect that complex regimens would erode adherence. Surprisingly, that was not observed.
Median number of concomitant chronic medications was four (range 2–8) . Yet adherence remained high by PDC across single, double, and triple therapy regimens.
Adherence by pharmacologic class (PDC-based) showed minimal variability :
- Macitentan: 95.7%
- Tadalafil: 94.1%
- Sildenafil: 92.0%
- Riociguat: 94.7%
- Treprostinil: 81.9%
Even agents requiring multiple daily dosing did not demonstrate dramatically reduced adherence. This challenges the assumption that dosing frequency alone predicts poor persistence.
Notably, tadalafil achieved adherence above 94% by PDC . Once-daily administration likely contributes to this performance, especially compared with sildenafil’s thrice-daily schedule. In chronic disease management, simplicity is often an underappreciated therapeutic advantage.
Adverse Events and Perception: The Human Dimension
More than half of patients (55.6%) reported adverse effects . The most frequent were headache and diarrhea. Yet 95.2% perceived their treatment as effective .
This contrast is clinically meaningful. Patients are willing to tolerate discomfort when they believe the medication works.
The perception of efficacy appears to be a powerful adherence stabilizer. Although logistic regression did not identify perception as statistically significant in this cohort, the overwhelmingly positive belief in treatment benefit likely contributed to the high objective adherence observed.
For tadalafil specifically, common adverse effects such as headache or flushing are generally transient and manageable. Its favorable safety profile relative to prostanoids may also support sustained adherence.
The broader implication is that communication matters. When patients understand why they are taking a drug—and see clinical benefit—they are more likely to continue.
Predictors of Adherence: Surprisingly Few
Regression analysis did not reveal significant predictors of adherence when measured by PDC . Age, education, employment status, time since diagnosis, number of concomitant medications, and perceived adverse effects were not statistically associated with refill-based adherence.
When using SMAQ, only female sex was associated with lower adherence (OR 0.23; p = 0.035) . However, this finding was not replicated with PDC and may reflect sample size limitations.
The absence of strong predictors is intriguing. In many chronic diseases, younger age, polypharmacy, or socioeconomic barriers drive nonadherence. In this Spanish cohort, those factors did not emerge as dominant influences.
One plausible explanation is system-level support. Spain’s public healthcare coverage reduces financial barriers. Moreover, patients received medications via hospital pharmacy with regular follow-up, which likely reinforced persistence.
This underscores an often overlooked truth: adherence is not merely a patient characteristic. It is a healthcare system outcome.
The Role of the Clinical Pharmacist
The study authors emphasize the contribution of hospital pharmacists to adherence support . Patients collected medications every 2–3 months and received ongoing counseling.
Pharmacists can:
- Reinforce education about dosing and side effects
- Coordinate refills and minimize gaps
- Monitor tolerability and escalate concerns
- Improve continuity of care
In complex diseases like PAH, pharmacist involvement may be as important as the pharmacology itself. High adherence rates in this cohort may reflect structured multidisciplinary engagement rather than intrinsic patient characteristics.
Where Tadalafil Fits in Modern PAH Strategy
Tadalafil occupies a strategic position in PAH therapy.
As a PDE-5 inhibitor, it enhances nitric oxide signaling, promotes vasodilation, and improves exercise capacity. Its pharmacokinetic profile allows once-daily dosing, which simplifies regimens in patients already managing multiple medications.
In this cohort, tadalafil was the most prescribed PDE-5 inhibitor (33 patients) with a mean adherence of 94.1% by PDC . It was also a cornerstone of the most common combination regimens.
From a clinician’s perspective, tadalafil offers several practical advantages:
- Predictable efficacy in improving functional class
- Favorable safety profile
- Compatibility with ERAs in dual therapy
- Simplified once-daily dosing
When adherence and long-term persistence are essential, these properties matter.
Limitations and Interpretive Caution
No observational study is without constraints.
This cohort was small (63 patients) and derived from a single center . HPTEC representation was limited. The PDC threshold of 80%—although standard—remains somewhat arbitrary. Financial factors were not evaluated due to the structure of the Spanish healthcare system.
Nevertheless, the findings align with international literature suggesting that PAH patients demonstrate relatively high medication persistence compared with other chronic conditions.
Future multicenter studies with larger populations and integrated patient-reported outcomes could refine these observations.
Clinical Implications: From Data to Practice
The central lessons are pragmatic:
First, adherence measurement tools matter. Refill data and patient-reported tools capture different dimensions of behavior.
Second, combination therapy—often including tadalafil—does not necessarily erode adherence, even in polypharmacy contexts.
Third, patient perception of efficacy appears robust despite frequent adverse events.
Fourth, structured pharmacist involvement and healthcare system support may be critical determinants of sustained treatment engagement.
In PAH, survival depends not only on selecting the right molecule but ensuring it is taken reliably. The difference between theoretical efficacy and real-world effectiveness lies in adherence.
FAQ
1. Why do adherence rates differ so dramatically between PDC and SMAQ?
PDC measures prescription refills, not actual ingestion, and may overestimate adherence. SMAQ relies on patient self-report and may classify individuals as nonadherent based on even minor lapses. Each method captures different aspects of medication behavior, explaining the discrepancy .
2. Does combination therapy reduce adherence in PAH?
In this cohort, no significant reduction in adherence was observed among patients receiving dual or triple therapy . Objective adherence remained above 90%, suggesting that regimen complexity alone does not predict poor persistence.
3. How important is tadalafil in current PAH management?
Tadalafil is a key PDE-5 inhibitor widely used in combination regimens, particularly with endothelin receptor antagonists. In this study, it was the most prescribed PDE-5 inhibitor and demonstrated high adherence rates (94.1% by PDC) , reinforcing its central role in modern treatment strategies.
Pulmonary arterial hypertension demands precision medicine. Yet precision alone is insufficient. Drugs must be taken consistently, tolerated realistically, and supported structurally. When adherence remains high—even in the presence of side effects—we are reminded that patients understand the stakes.
And when tadalafil becomes part of that sustained therapeutic architecture, its value extends beyond vasodilation. It becomes part of a system that works—not only in trials, but in real life.
