Clinical evaluation of pulmonary hypertension using patient-reported outcomes: a cross-sectional study

Pulmonary hypertension (PH) is a term that comprises a variety of diseases consisting of elevated blood pressure in the pulmonary circulation. The diagnosis is determined by a resting pulmonary arterial pressure (PAPm) of ≥ 20 mmHg [1]. The most recent classification of PH comprises group 1—pulmonary arterial hypertension (PAH), group 2—PH due to left heart disease (LHD), group 3—PH due to lung diseases and/or hypoxia and group 4—chronic thromboembolic pulmonary hypertension (CTEPH) and group 5- unknown mechanism/multifactorial [2].

The clinical evaluation of these patients is made using variables such as World Health Organization functional class (WHO FC), 6-min walking distance (6MWD), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), cardiac index (CI) and right atrial pressure (RAP) [3, 4]. However, more than one variable is usually required because no single one provides enough diagnostic and prognostic information, also they do not provide information about the health status and quality of life (QoL) of patients [2, 5].

PH produces progressive, disabling symptoms that increase morbidity and mortality [6]. These symptoms (including shortness of breath, fatigue, chest pain, and lightheadedness) have a big impact on WHO FC and emotional state which adversely affects health-related quality of life (HRQoL) [7, 8]. Also, these patients need to use specific treatments: phosphodiesterase type 5 inhibitors (PDE-5 is), endothelin-receptor antagonists (ERA), soluble guanylate cyclase stimulators (sGCs), prostacyclin analogs or prostacyclin receptor agonists (PCa and PCra) [9]. These treatments are associated with very frequent adverse events (AE) including headache, flushing, and epistaxis for PDE-5 is (sildenafil and tadalafil); hepatotoxicity, peripheral edema, and anemia for ERA (bosentan, ambrisentan, and macitentan); and dizziness or hypotension for sGCs (riociguat). Finally, PCa and PCra (epoprostenol, treprostinil, iloprost, and selexipag) are associated with gastrointestinal symptoms, headache, and jaw pain [10]. These treatment-related AE together with the inconvenience of some routes of drug administration (IV, subcutaneous or inhaled especially) can negatively influence a patient´s daily life [11].

Difficulties in clinical evaluation, the impact of symptoms, and the burden of treatments make HRQoL a particularly relevant endpoint in PAH [12]. The importance of HRQoL has been well established to define patient-reported outcomes (PRO´s) as a report of the status of a patient´s health condition that comes directly from the patient, without interpretation of the patient´s response by any health professional [13]. The first instrument designed to assess PRO´s in PH patients was the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) [14]. This questionnaire has shown to be valid, reliable and responsive, and is recommended for use alongside traditional clinical measures, also, it has obtained interesting results compared to generic questionnaires such us Nottingham Health Profile (NHP), EuroQoL or SF-36 [15, 16].

The objective of our study was to evaluate PRO´s of patients receiving specific treatment for PH in a tertiary hospital using CAMPHOR in the pharmacy consultation.

Our study explored the clinical characteristics, HRQoL, and QoL of a Spanish cohort of patients diagnosed with PH. All the patients included were receiving specific treatment for PH, which was dispensed at the pharmacy consultation, and were routinely monitored.

Generic HRQoL measures employed in PH population such as the NHP, EuroQoL and SF-36 have proved to be of limited value in the assessment of PH because they are not specific for symptoms and limitations associated to this disease. CAMPHOR was developed to be a disease-specific and practical QoL instrument in these patients, using unidimensional subscales that are reproducible and valid [14]. For those reasons, it was the selected questionnaire for this study. To our knowledge, this is the first study performed in Spain using CAMPHOR as a direct measure of PRO´s. Besides, it was the first protocol which used this questionnaire in a pharmacy consultation, whereas the clinicians had the information for their routine visits.

After completion of CAMPHOR, the results obtained in the three domains show that our attended PH population (WHO FC I-III) experiences different levels of impairment due to disease. Our results were slightly lower than those reported by Reis et al. [5] in a similar cohort of patients (69.4% in WHO FC I/II vs 63.9% in our study) and reasonably lower than those reported by McCabe et al. for patients with idiopathic PAH and CTEPH) [18]. Regarding factors that could affect these results and consistent with those reported by Small et al. [19], in the three CAMPHOR domains the scores were better in those patients receiving only one drug since 65.2% of WHO FC I/II and 46.2% of WHO FC III patients in our study were undergoing monotherapy for PH. This could explain the lower scores obtained.

The non-parametric analysis of clinical characteristics and HRQoL performed in this study showed that WHO FC and 6MWD were the two items that had better relations with CAMPHOR scores. On the one hand, the WHO FC remains one of the most powerful predictors of survival during diagnosis and follow-up, and its worsening is an indicator of disease progression [2]. In our study, approximately a third of patients were in WHO FC III and no patient was found to be in WHO FC IV. These proportions were higher than those reported in the REVEAL registry [20] and previous studies with measures of HRQoL that show proportions of WHO FC III-IV near 70% [18, 19, 21]. The association between WHO FC and CAMPHOR scores has been well described in previous cohorts [5]. We found statistically significant differences for the WHO FC and the `Symptoms´ (p = 0.004), `Activities´ (p = 0.005) and `Quality of life´ (P = 0.02) domains of CAMPHOR, showing that PRO´s are good predictors of the functional capacity.

On the other hand, 6MWD is usually used to stratify the risk of PAH patients and to assess the effectiveness of PAH specific therapies [10]. A worsening value directly indicates a decrease in the functional capacity. We found worse scores of the 6MWD for patients in WHO FC III, however, they did not reach statistically significant differences (p = 0.077). In the non-parametric analysis, the differences for this test were significant for the `Activities´ domain (p = 0.002), as reported elsewhere [22] using a generic questionnaire in PH patients (SF-36) proving that the `physical´ component score was the one that obtained statistically significant differences. This parameter has proved to be superior to other parameters such as Borg dyspnea in the clinical evaluation of patients with PH.

We also found worse scores in the `Quality of life´ domain for patients who had at least one emergency visit in the previous 12 months and in the `Symptoms´ and `Quality of life´ domains for those who had been hospitalized in the last 12 months. Recent hospitalizations have been previously reported to correlate with impaired quality of life [19, 23] due to the association between the need for in-patient care with the severity of disease and other possible complications. These differences were not maintained across the three CAMPHOR domains probably due to the small sample size.

The main limitations of our study derive from the small number of patients included, but due to the low prevalence of this disease in the overall population (15–52 cases per million people), it is difficult to recruit big samples [8]. Some non-parametric analyses were likely to be significant if more patients had been included. Also, patients in our setting can be treated in different hospitals and because of that, the real proportion of this disease could be underestimated. Our centre does not perform lung or thromboendarterectomy. Therefore, patients with more advanced disease are usually recruited to other hospitals and because of that most of our patients belong to WHO FC I and II. Besides, some patients needed to be excluded from the study because we were not able to approach them or because they declined to participate. More patients would need to be assessed to have a full spectrum of PH. Finally, the CAMPHOR questionnaire, as a disease-specific instrument, was the only one performed in our study.

CAMPHOR has proved to be a specific measure of the clinical condition (symptoms and activities domains) and the impact of PH from the patient´s perspective (quality of life domain), as their scores are significantly different for patients with a worse WHO FC and recent hospitalizations. The clinical evaluation in these patients is performed using risk assessment predictors (WHO FC and 6MWD). However, they only represent one aspect of functioning, whereas the CAMPHOR scale covers wider activities of daily living and it has proved to be correlated with these two measures. Because of that, the PRO´s are highly useful in this type of patients who cannot be correctly evaluated through the other measures, as they don´t capture the full impact of the disease. Also, CAMPHOR questionnaire reports information about symptoms and burden of disease, not only functional capacity.

In some cases, and given the good relation with these measures, these questionnaires could replace invasive or unpleasant tests such as RHC or 6-min walk. The PRO´s reported in CAMPHOR are useful tools to complete clinical evaluation in these patients which is difficult for the need of using other measures (6MWD, WHO FC, Borg dyspnea) which are difficult to perform.

In conclusion, the CAMPHOR questionnaire could be useful as a complementary test to achieve an integrated evaluation of PH patients. Their relations with traditional measures used in these patients and its wide coverage of all factors (symptoms, functional capacity and burden of disease) which could affect the clinical condition are important issues to establish this quality of life test as a routine evaluation for PH. CAMPHOR questionnaire was easily completed by patients during their routine pharmacy visits, with good acceptance.

These questionnaires could be performed by other health professionals (using information and communication technologies when possible), and their results could be incorporated to the patient´s electronic medical record to be available for the cardiologist´s follow-up visit. This assessment is easy to implement in any institution and could help improve the evaluation and health outcomes of these patients.