Based on the data, we found that the mean age of subjects diagnosed as PAH in uncorrected secundum ASD was 38.72 years. These results are in accordance with the study of Haque et al. (2015) which stated that PAH development in secundum ASD mostly occurred in the third decade.8 Vogel et al. (1999) noted that the incidence of PAH in secundum ASD were increased in patients at the age of 18 to 40 year old.9 The majority of the subjects of this study were female (83.33%) which similar to the previous study.9 Euro Heart Survey registry also support this findings. They concluded that the incidence of PAH in female ASD was 76.6%, higher than male patients.10
All subjects have many problems in various EQ5D dimensions before starting the specific PAH therapy. In general, subjects reporting their best performance were on the self-care dimension and their worst were on pain/discomfort dimension. Severe problems experienced by 11% of subjects on the dimension of pain/discomfort and anxiety/depression while 6% of the subjects felt severe problems on performing daily activities. These three dimensions were also the most frequently reported problems by the study subjects. This result is in accordance with the study by Thompson et al. (2001) in Germany who found that the best performance of both primary and secondary PAH patients was experienced in the self-care dimension while the worst performance was reported on the dimension of daily activity. In this study, 20% of subjects experienced severe problems while performing daily activities and less than 10% experienced severe problems in other dimensions.11 Mychaskiw et al. (2010) examined the health status of PAH patients in the subjects of SUPER 1 clinical trial. The data from the study found similar to previous studies, moderate to severe problems occurring mostly in the dimensions of daily activity (77%), while the least happened in self-care dimensions (24%).12
After 12 weeks of treatment, severe problems are no longer experienced in the dimensions of pain/discomfort, anxiety/depression, and usual activities. The percentage of subjects who did not had any complain in all the 5 dimensions of EQ5D were increased. Dimensions of pain/discomfort, anxiety/depression, and usual activities had the most common complaints reported by the study subjects. The severity of each EQ5D dimension problem were decreased. In line with these results, Pepke-Zaba et al. (2008) proved in his study that improvement was achieved in all dimensions of EQ5D after 12 weeks of sildenafil therapy.13
A clinical trials by Pepke-Zaba et al. (2008) found that the utility score mean statistically significantly changed about 0.10 ± 0.04 and EQ-VAS 8 ± 2.13 The study also showed similar results with the mean difference utility score of 0.105 ± 0.164 and EQ-VAS 7.22 ± 8.613. The difference also proved statistically significant with p value 0.014 (95% CI 0.024 to 0.187) for utility score and p 0.005 (95% CI 2.32 to 11.02) for EQ-VAS score. Based on the above statistically, there is a difference of average EQ5D utility score and significant EQ-VAS score before and after sildenafil 3 × 20 mg therapy for 12 weeks.
Determination of drug effects on HRQoL is an important component in evaluating the effect of drugs on clinical outcomes and health care. Several previous studies that evaluated HRQoL after sildenafil administration showed results that are consistent with this study. Study by Sastry et al. (2004) in the population of primary lung hypertensive patients (n = 22) mentioned that there was an increase in dyspnea and fatigue components assessed by cardiac failure questionnaire after sildenafil therapy (dose 3 × 25 mg, 3 × 50 mg and 3 × 100 mg) for 12 weeks.15 Another study by Wong et al. (2007) involving 19 HAP patients (idiopathic, connective tissue disease, CHD with a shunt) also evaluated HRQoL for 3 months after sildenafil therapy (dose 3 × 25 mg and 3 × 50 mg) using SF-36 questionnaire. In the study there was an increase in scores on physical, social, and health dimensions in general.16 Tay et al. (2011) studied 12 patients with Eisenmenger syndrome who were given sildenafil 3 × 20 mg therapy. The questionnaire used in this study was a questionnaire specific disease to the pulmonary hypertension population, namely Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR). The results also show an improvement in HRQoL after 3 months of therapy.17
Demographic factors such as age, sex, marital status, education level, and employment status have an influence on HRQoL. A systematic review by Gu et al. (2016) who assessed factors affecting HRQoL of PAH patients to explain that HRQoL is influenced by demographic characteristics (such as living alone, decreased social support), mental health (such as anxiety, depression, stress), physical health (such as exercise and symptomatic capacity), and pharmacologic therapy.4 In this study, the mean utility score of subjects aged < 38 years was lower than subjects aged ≥ 38 years, but the mean EQ-VAS score was the opposite where the difference was not statistically significant. Study by Matura et al. (2014) who examined the difference in severity of symptoms and HRQoL of young, middle, and older PAH patients concluded that the decrease in HRQoL component was experienced by all age groups, but the younger age group had slightly better physical function compared to other groups. PAH more often affects young patients, active professional workers, who are mostly women.18 Symptom severity, complex therapy, or psychological stressors result in the patient having difficulty being able to work as under normal conditions. This resulted in job losses resulting in disrupted economic conditions and social isolation.19
Nilsson (2012) explains that female patients often exhibit lower HRQoL scores than men because of the way of thinking to assess the health of women and men differently. Women are more inclusive, more emphasizing on the matter though on the same thing, and prefer the emotional factors that are not always related to the disease. While men tend to assess disease, lifestyle, and functional ability as important. Another possibility of women having lower HRQoL is due to poorer living conditions and or more vulnerable social roles (sex studies) .20 Accordingly, in this study average utility scores and female EQ-VAS subjects were lower than men, although the difference between them was not statistically significant.
Nilsson (2012) mentioned that in a group of unmarried / single patients had a low HRQoL.20 Similarly, in this study the mean utility scores and EQ-VAS of unmarried subjects were lower than those married although not statistically meaningful. Self-life and minimal social support are associated with a worse HRQoL emotional dimension score. In contrast, active work is associated with a better HRQoL physical dimension score.4 According to the results of the review, in this study average utility scores and EQ-VAS group subjects that did not work were lower than those that worked although they were not statistically significant.
Delcroix and Howard (2015) published an article review on the burden of PAH disease and its impact on quality of life. It was explained that PAH patients who aged > 50 years old were reported to have more comorbid illnesses such as ischemic heart disease, coronary artery disease, hypertension, atrial fibrillation, diabetes, and hypothyroidism than younger patients. The presence of comorbidities results in delayed diagnosis of PAH in older patients. The higher burden of comorbidities also contributes to the lower survival rates of older PAH patients in the UK and Ireland, which is about 3 times higher than the younger population (≤ 50 years) with fewer comorbidities and better training capacity .21 In line with this, in this study, the average EQ5D utility score and EQ-VAS of subjects with comorbidities were lower than without comorbidities although not statistically significant.
Supportive therapies (such as diuretics, digoxin, oral anticoagulants, or oxygen) are one of the PAH patient’s management strategies mentioned in the management guidelines of PAH ESC 2015. Right heart failure leads to fluid retention, increased central venous pressure, hepatic congestion, ascites, and peripheral edema. Clinical experience shows the benefits of diuretics to reduce fluid retention symptoms, but no randomized trials have been associated with diuretic use in PAH patients. Diuretic therapy is recommended in PAH patients with signs of right heart failure and fluid retention, with recommendation class Ic. While additional aldosterone antagonist therapy may be considered along with monitoring of plasma electrolyte levels and renal function to prevent the occurrence of hypokalemia and the effects of intravascular volume depletion resulting in pre-renal failure.22
Digoxin may increase cardiac output in idiopathic PAH patients although its efficacy is unknown in long-term administration. This drug can be used also in PAH patients with atrial tachyarrhythmia to reduce ventricular rate.22 Lader et al (2003) undertook a sub-study of a Digitalis Investigation Group (DIG) clinical trial to assess the effect of digoxin therapy on HRQoL heart failure patients with sinus rhythm. A total of 589 patients with heart failure (ischemic, idiopathic, hypertensive) were sub-subjects with routine diuretic and ACE inhibitors. A total of 298 subjects were treated with digoxin and 291 subjects received placebo. Several instruments are used to assess HRQoL dimensions such as the Medical Outcomes Study Short Form-36 (MOS SF-36), Ladder of Life, Centers for Epidemiologic Studies-Depression Scale (CES-D), Spielberger State Anxiety Inventory, Spielberger State Anger Inventory, and MLHFQ. HRQoL measurements were performed at the start of the study, followed up 4 months, and 12 months. The results of this study concluded that in the subset of DIG clinical trial population the digoxin therapy had no effect on HRQoL of heart failure patients with sinus rhythm.23
On postmortem examination of idiopathic PAH patients found high prevalence of vascular thrombotic lesions. In addition, the abnormalities of the coagulation and fibrinolysis pathways in the PAH patient population have also been reported. Oral anticoagulants are administered to PAH patients with consideration of these as well as an increased risk of venous thromboembolism (heart failure and immobilization). The benefits of oral anticoagulant therapy are limited to idiopathic PAH patients, hereditary PAH, and PAH caused by anorexigen (recommendation class IIb). This is largely derived from retrospective studies with data from only one study center. While the results of registry and randomized clinical trials are randomized and inconclusive.22 Currently evidence of efficacy and safety of anticoagulant drugs in PAH patient populations is limited. The clinical guidelines do not recommend routine anticoagulant treatment in Eisenmenger syndrome patients and suggest that this therapy may be given in cases of atrial fibrillation and pulmonary artery thrombosis without major haemorrhage.24
In this study 44,44% (8) subjects received other therapy, including PAH support therapy. A subject (5.56%) was treated with oral furosemide if necessary, six (33.34%) subjects treated with oral furosemide 1 × 20 mg and oral digoxin 1 × 0.125 mg, and a subject (5.56%) with accompanying atrial fibrillation received oral support therapy in the form of furosemide 1 × 40 mg, digoxin 1 × 0,125 mg, spironolactone 1 × 25 mg, and warfarin 1 × 2 mg. The total subjects receiving furosemide were 44.44% (8), digoxin 38.89% (7 subjects), 5.56% spironolactone (1 subject), and 5.56% warfarin (1 subject). The mean EQ5D utility score and the EQ-VAS group of subjects with other therapies were lower than without comorbidities although not statistically significant.
This is in line with cross-sectional studies by Zlupko et al (2008) that evaluate HRQoL PAH patients with various etiologies such as idiopathic, familial, systemic sclerosis, CHD, human immunodeficiency virus (HIV), liver disease, anorexigen, and obstructive pulmonary venous disease. A total of 93 subjects who were recruited received epoprostenol therapy (28%), bosentan (49%), calcium channel blockers (47%), sildenafil (3%), digoxin (33%), diuretics (57%) and warfarin (49%). The HRQoL evaluation was measured by a specific PAH disease questionnaire (MLHF-PH) and from the results of the evaluation we found a severe HRQoL disorder in all subjects. There were no differences in HRQoL subjects treated with diuretics, digoxin, and oxygen in these populations.25