|CURRENT TREATMENT OF PULMONARY VASCULAR DISEASES
|Year : 2009 | Volume
| Issue : 3 | Page : 150-156
How has epoprostenol changed the outcome for patients with pulmonary arterial hypertension?
Robyn J Barst
Professor Emerita of Pediatrics, Columbia University, College of Physicians & Surgeons, New York, USA
|Date of Web Publication||27-Jul-2009|
Robyn J Barst
Professor Emerita of Pediatrics, Columbia University, College of Physicians & Surgeons, New York
|How to cite this article:|
Barst RJ. How has epoprostenol changed the outcome for patients with pulmonary arterial hypertension?. PVRI Review 2009;1:150-6
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by an elevation of pulmonary artery pressure and pulmonary vascular resistance leading to right ventricular failure and death. Prior to the development of disease-specific targeted PAH therapies, the median survival for adult patients diagnosed with idiopathic PAH (IPAH; formerly termed primary pulmonary hypertension [PPH]) was reported to be approximately 2.8 years with the median survival of 10 months for pediatric patients [Figure 1]. However, these median survival rates likely underestimate current survival, as the course of the disease has been favorably altered by therapeutic advances since the National Institutes of Health (NIH) PPH Registry report from the 1980s. 
Although Ernst Von Romberg, a German physician, described an autopsy in 1891 as "pulmonary vascular sclerosis;" it is only since 1995 with the introduction of intravenous epoprostenol that disease-specific targeted medical therapies for PAH have become available. In addition, significant advances in the treatment of PAH have occurred during the past decade, with seven medical therapies now possessing regulatory approval worldwide, targeting the prostacyclin pathway, the nitric oxide pathway, and the endothelin pathway. From a therapeutic standpoint, why had it taken from 1891 until 1995 to develop a safe and efficacious therapeutic modality for the treatment of PAH? Although, several reports of young women dying of right heart failure without a diagnosis were published in 1940, it was not until pulmonary artery pressures could be recorded directly with the introduction of right heart catheterization that the physiology of the pulmonary circulation could be studied. In 1951, Dresdale tested the acute effects of tolazoline in a young woman with IPAH; the tolazoline caused a sudden decrease in pulmonary arterial pressure and pulmonary vascular resistance without significant systemic effects. Unfortunately, no drugs were available at that time for chronic treatment. However, despite this, there remained little interest in PAH until the epidemic of the aminorex-induced PAH became apparent in the late 1960s. Prompted by the aminorex-induced PAH epidemic in 1973, the World Health Organization (WHO) held its first meeting in Geneva to assess what was known regarding IPAH and what remained unknown. In 1981, the National Heart, Lung, and Blood Institute (NHLBI) of the NIH in the United States supported a national registry of patients with IPAH (from which the above median survival data were determined)  . Interestingly, despite the fact that IPAH was an orphan disease, significant interest from the scientific community rapidly ensued. Advances in the understanding of the mechanisms involved in the pathobiology of IPAH and PAH associated with other conditions focused on molecular biology, developmental biology, and genetics. Together with epidemiologic and natural history studies, collaborative efforts between the scientific community and industry led to a surge in clinical trials since the mid-1990s. Imagine a drug with the following characteristics. It is inactive orally so it has to be given intravenously. It is so unstable at physiological pH that it has to be administered in a highly alkaline buffer. The dose used is so critical that an infusion pump is required for safe administration. Continuous infusion is required because the drug is rapidly eliminated with a half-life of minutes. Most of the recipients complain of headache and are flushed. Many complain of uneasiness and fidget. Side effects can be severe because the drug is often given at the highest dose the patient will tolerate. What is the drug? It is epoprostenol, better know as prostacyclin. In their wisdom, those who approve drug names decided that we could all be in grave danger of mistaking this prostaglandin for a tetracycline; and thus, the substance was renamed. 
Following the approval of intravenous epoprostenol for the treatment of IPAH in 1995, the prostacyclin analog, treprostinil, was approved for continuous subcutaneous infusion in 2002, and for continuous intravenous infusion in 2004. In addition, use of the prostacyclin analog, iloprost, via inhalation was approved in 2004. In 2001, Bosentan, an endothelin ET A /ET B receptor antagonist (ERA), was the first oral therapy approved for the treatment of PAH, and sildenafil citrate, an oral phosphodiesterase type 5 inhibitor (PDE-5 I), was approved in 2005. In 2007, the oral ET A selective ERA ambrisentan was approved and the oral ET A selective ERA sitaxsentan was approved in the EU. In 2009, the long-acting oral PDE-5 I tadalafil was approved.
The objectives of this review are to discuss the role of continuous intravenous epoprostenol in the treatment of PAH.
Epoprostenol is the synthetic form (sodium salt) of the natural prostaglandin derivative PGI 2 . The pharmacokinetic properties of epoprostenol are dominated by the lability of the molecule in aqueous fluids at physiologic pH. The stability in solution is dependent on the pH being maintained in the alkaline region (pH ~10 in glycine buffer). The in vitro half-life of epoprostenol in human blood at physiologic temperature and pH is approximately 3-6 min. The short elimination half-life necessitates administration via continuous intravenous infusion [Figure 2]. Epoprostenol was first used to treat IPAH in the early 1980s. In 1984, Higenbottam and coworkers reported for the first time a dramatic and persistent improvement in exercise capacity and hemodynamics in a young woman with severe IPAH treated with continuous intravenous epoprostenol infusion: A young woman, bedbound with severe pulmonary hypertension, responded to intravenous epoprostenol with a fall in pulmonary vascular resistance, improved oxygenation, and a rise in exercise tolerance. For thirteen months, continuous infusion of epoprostenol enabled her to live independently at home while awaiting heart-lung transplantation.  The epoprostenol infusion was initiated as a "palliative bridge" to transplantation. The rationale being that with the majority of patients dying on waiting lists for transplantation, perhaps we could palliate patients long enough to undergo transplantation. At the time, we had no idea that treatment with epoprostenol could result in significant efficacy in select patients thereby deferring or even avoiding transplantation (due to unforeseen properties of epoprostenol). However, based on this case report and subsequent case series, we reported the results of the first randomized controlled third party blind trial comparing treatment with intravenous epoprostenol plus conventional therapy vs. conventional therapy alone in 24 patients with IPAH in 1990.  The objectives of our study were to demonstrate palliative effects in an attempt to keep patients alive while awaiting transplantation. However, interestingly, the absence of an acute hemodynamic effect with intravenous epoprostenol did not preclude the improvement we observed with long-term therapy. And thus, although our initial rationale to develop intravenous epoprostenol was as a palliative bridge to transplantation based on its systemic and pulmonary vasodilatation and inhibition of platelet aggregation and dispersion of platelet aggregates, the observed improvement raised the possibility that prostacyclin had other significant properties that may contribute to its efficacy with long-term therapy. These include: inhibition of vascular cell migration and proliferation, prevention from ischemic cell injury ("cytoprotective effect"), reduction of margination and adherence of white cells, fibrinolytic activity, improvement in pulmonary clearance of endothelin-1, a possible inotropic effect, and a possible improvement in peripheral oxygen consumption by skeletal muscles. On the basis of our first report in 1990, a second prospective controlled third party blind randomized trial was conducted which demonstrated that after 12 weeks of therapy there was a clinically relevant improvement in exercise capacity with epoprostenol as assessed by the 6-min walk (6MW) test.  In addition, modest hemodynamic improvements were observed in the epoprostenol-treated patients. Somewhat surprising, a significant improvement in survival with epoprostenol was demonstrated in this 12-week study and based on the results of this study, intravenous epoprostenol was approved by the United States Food and Drug Administration (FDA) in 1995 and subsequently approved by the EMEA for the treatment of severe IPAH. We also learned from the IPAH epoprostenol study that neither baseline functional class, i.e. III vs. IV, nor baseline hemodynamics were predictive of survival; only the baseline 6MW distance predicted outcome [Figure 3],[Figure 4]. Since that time, epoprostenol has been studied with PAH patients in whom their PAH was related to the scleroderma spectrum of disease in a randomized third party blind-controlled trial, resulting in the broadening of the US FDA label for epoprostenol.  Although no survival benefit was seen in this trial, the epoprostenol-treated patients had clinically significant improvements in exercise capacity (as assessed by the 6MW test) and hemodynamic improvements. Since that time, many open label uncontrolled observational studies have been reported in patients with PAH associated with various conditions including, but not limited to, congenital systemic-to-pulmonary shunts, HIV infection, portal-pulmonary hypertension, and connective tissue diseases in addition to scleroderma, such as systemic lupus erythematosus.
|Figure 2: Effects of continuous intravenous epoprostenol on total pulmonary resistance in 3 patients with IPAH|
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|Figure 3: In the pivotal epoprostenol trial in idiopathic pulmonary arterial hypertension, at baseline neither functional class, i.e., III vs. IV nor hemodynamics were predictive of survival; only the 6MW distance at baseline was an independent predictor of survival. In the placebo group, 8 deaths vs. 73 survivors: 196 +/- 63 vs. 305 +/- 14 m (P< 0.003).|
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|Figure 4: Schematic representation of the hemodynamic progression of pulmonary arterial hypertension; note that there are no time marks on the x-axis due to the marked biologic variability in PAH disease progression|
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And thus although initially proposed as a bridge to transplantation, intravenous epoprostenol is now considered the "gold standard" for the treatment of severe PAH and is used in patients with severe PAH as a first line therapy and as an alternative to lung transplantation in select patients. Although initially unexpected, with the introduction of epoprostenol, transplantation candidates began to be removed from active waiting lists because of clinical improvement with deferral or complete avoidance of transplantation. Epoprostenol is the only therapeutic modality that I have studied in clinical trials that once approved appeared equally or even more efficacious than apparent in the clinical trials with virtually every patient treated with epoprostenol improving to variable degrees. However, not all patients benefit equally from epoprostenol and it remains unclear exactly how to optimally treat patients, both pediatric patients and adult patients, with epoprostenol. Several studies have reported that reassessment after 3-12 months in adult IPAH patients is useful in predicting whether these patients should remain on the waiting list for transplantation or not. , Prognostic parameters that appear to be most useful in this determination in adult IPAH patients include reaching a threshold in exercise capacity assessed by the 6MW test, i.e., >~380 m, and/or achieving significant hemodynamic improvement, such as resolution of right heart failure, improvement from functional class III or IV to functional class II, and resolution of pericardial effusion by echocardiography.
Despite the randomized controlled trials and many reports from open label uncontrolled observational series, the optimal dosing to balance overall risks-benefits for individual patients remains unclear. This is particularly true with respect to optimal treatment for pediatric patients compared with adult patients. The dosing of epoprostenol remains unclear and varies, not infrequently, significantly amongst patients and amongst pulmonary hypertension referral centers. Consensus reports from the PH community for adult patients suggest an optimal dose range of approximately 20-50 ng/kg/min long-term although long-term epoprostenol dosages have also been reported to range from 0.5 to 270 ng/kg/min. Certainly, extremely low doses appear less effective, although extremely high doses might lead to high-output failure resulting in deterioration (with clinical improvement demonstrated with dose reduction). And thus, although the mean dose for adult patients treated chronically with epoprostenol after approximately one year is overall most likely between 20 and 50 ng/kg/min, the titration for an individual patient remains exceedingly variable. Furthermore, why a patient who is clinically and hemodynamically stable on a dose of perhaps 40 ng/kg/min may have an exacerbation of his/her symptoms if the dose is decreased from 40 to 38 ng/kg/min or, conversely, if the dose is increased from 40 to 42 ng/kg/min that the patient might have intolerable epoprostenol side effects such as severe headache and/or nausea, is poorly understood and explanations for these observations remain unknown. What we have learned over the past two decades since we began studying intravenous epoprostenol chronically in patients in the mid-late 1980s is that intravenous epoprostenol should not be used as rescue therapy, i.e., if a patient presents in cardiogenic shock, the first-line treatment should not be intravenous epoprostenol but rather cardiopulmonary resuscitation for the cardiogenic shock with the initiation of intravenous epoprostenol after the patient has been stabilized with an acceptable cardiac output. In addition, although both patients and physicians appear to want to increase the dose of epoprostenol as rapidly as possible after starting intravenous epoprostenol, aggressive titration that results in intolerable side effects is more often than not inappropriate and counterproductive with an effect being contraindicated as the epoprostenol side effects may exacerbate the pulmonary hypertension physiologically by increasing endogenous catecholamines. Thus the consensus recommendation in initiating intravenous epoprostenol is to start at 1-2 ng/kg/min and increase the dose most rapidly over the first 2-3 months with further incremental increases at a perhaps slower incremental rate from 3-6 months with achieving what is considered an optimal dose for an individual patient by approximately one year. The rate of titration is based on acceptable side effects such as headaches that can be controlled with analgesics, diarrhea that can be controlled with conservative therapy, and nausea that can be adequately treated to prevent vomiting. Increases that might be too aggressive for an individual patient resulting in severe nausea and vomiting can precipitate a fatal vasovagal episode and thus careful titration with each patient needs to be carried out under close observation. It is not in the patients' best interests to rapidly increase the dose of epoprostenol aggressively in the first few weeks nor start a patient on a dose often higher than 2 ng/kg/min; the few patients who stop epoprostenol shortly after starting are often patients that were increased to 8-10 ng/kg/min within the first several days with the patient stopping the drug and refusing to restart. Whether this is based on our 1996 report that the optimal dose by week 12 was 9.7 ng/kg/min is unclear but this aggressive approach is rarely to be recommended. Our experience with adult patients is consistent with the literature for adult PAH patients, in that further incremental increases after one year of therapy are unlikely to increase efficacy although during acute events such as bacteremia/sepsis or pneumonia, transient incremental increases may be useful with subsequent downtitration following resolution of the exacerbating event. Unfortunately, if patients remain worse following such an event as above, continued incremental increases, although not inappropriate to consider, rarely are overly effective.
With respect to optimal dosing in pediatric patients, our experience has demonstrated that pediatric patients appear to require a significantly higher dose of epoprostenol on a per kilogram basis to achieve optimal effects. Thus an average epoprostenol dose for a child after approximately one year of therapy might be 80-120 ng/kg/min with some children appearing to require even significantly higher doses. , Whether this is due to children being in an increased metabolic state compared to adult patients is one possible explanation, as pediatric PAH patients overall appear to require and do better with a higher dose per kg with virtually all of the PAH therapies used, including calcium channel blockade for true "acute responders" with acute vasodilator testing as well as the prostacyclin analog treprostinil and the PDE-5 I sildenafil. To date, although pharmacokinetic studies can be helpful, particularly in determining optimal dosing in pediatric patients, with respect to epoprostenol with its very short half-life, assessing the stable metabolite 6-keto PGF 1a has not significantly helped us establish optimal dosing nor understand why the dosing appears to be so different in pediatric patients vs. adult patients. The dosing effects are accentuated in the neonatal and infant patients in whom achieving an epoprostenol dose of 50-100 ng/kg/min is not unusual for very sick neonates and infants with these doses being achieved within 1-2 weeks. Whether these high doses are tolerated from a side effect standpoint, e.g. headache, in these young children who are severely ill and thus not infrequently on aggressive cardiopulmonary support including significant sedation is unknown. However, as the infants and young children clinically improve and are weaned from cardiopulmonary support, these young children appear to tolerate these very high epoprostenol doses without the typical side effects we would expect if these rapid incremental increases had been carried out in children who were not sedated.
The prognosis for pediatric and adult patients with PAH treated with continuous intravenous epoprostenol is not infrequently difficult to determine (although reassessment by exercise capacity and repeat hemodynamic assessment certainly appears to be helpful). As schematically demonstrated in [Figure 4], the biologic variability of the natural history of PAH as well as the response to treatment can be extremely variable. Thus, based on our overall goals in treating patients with PAH, i.e., optimally to increase survival and overall quality-of-life, we attempt to defer transplantation as long as possible, i.e., as long as the patient has a reasonably good overall quality-of-life on chronic intravenous epoprostenol. Our overall goal in treating any patient with PAH is to improve their WHO functional class (Modified NYHA functional class for pulmonary hypertension) to functional class II, or if the patient was functional class II when the epoprostenol was initiated, to improve to functional class I or at a minimum maintain functional class II. Unfortunately, although long-term observational data has demonstrated to us that even if a patient is functional class IV at the time intravenous epoprostenol is initiated, if we are only able to improve the patient to functional class III, although that may be a significant improvement, long term the patient will not do well if he/she remains functional class III. For patients who have improved to functional class II and are on a "plateau", the ability to predict when a patient might develop progressive right heart failure (which can rapidly progress even with aggressive therapy) often remains exceedingly problematic; unfortunately, not infrequently by the time the patient has gone from the stable plateau to progressive right heart failure, transplantation may no longer be an option.
| Adverse Events and day-to-day Treatment Issues with Intravenous Epoprostenol Therapy|| |
Epoprostenol can only be administered by continuous intravenous infusion due to its short half-life and its inactivation at low pH. Thus all patients must have a permanent central venous catheter placed, most often in the jugular or subclavian vein, for delivery of the epoprostenol (infused continuously with the use of a portable infusion pump). Although the initial learning process for patients and their families to prepare the drug using sterile technique often appears overwhelming, virtually every patient is able to master this within two weeks with the patient and/or his caregiver spending approximately 20 min each day for drug preparation. We continue to recommend that each family member or caregiver prepare the epoprostenol at least once every week; thus in the event of an emergency every family member or caregiver will remember how to prepare the drug and use the pump. Otherwise, if the family member or caregiver only learns these techniques when the patient starts the epoprostenol, it is unlikely that he/she will remember what to do if there is an emergency 6 or 12 months later, particularly when everyone's anxiety level is high.
Unfortunately, despite epoprostenol's significant efficacy based on what we believe to be the various properties of prostacyclin, epoprostenol therapy is associated with frequent side effects which include: jaw pain, headache, flushing, leg and foot pain, diarrhea, and nausea/vomiting. Although, these side effects are generally mild and dose related and can be minimized by careful dose titration in conjunction with symptomatic therapy, they can have a significant negative impact on a patient's overall quality of life. Additional adverse events include rash, impotence, and weight loss. However, more serious complications can occur due to the short half-life of epoprostenol and the delivery system. These include infection, i.e. local central venous line site infection, bacteremia, and/or septicemia (which if not immediately identified and treated including removal of the central venous catheter, as attempts to save central venous catheters have proven exceedingly unsuccessful with not infrequent fatalities occurring with the attempt to salvage infected central venous lines) as well as thromboembolic events (with patients possessing an indwelling central venous catheter with many patients not infrequently possessing a patent foramen ovale or a created "atrial septal defect" by atrial septostomy). Based on our experience with the first patient enrolled in the first US trial  dying suddenly two weeks after starting epoprostenol (after an apparent dramatic improvement) and the second patient experiencing a transient ischemic attack, it was agreed upon that all patients treated with intravenous epoprostenol would be anticoagulated unless there was a contraindication. The regulatory authorities were seriously considering stopping the clinical development program. As you must recall, never had a chronic treatment modality required a continuous intravenous infusion 24/7. And what quality-of-life could such a treatment provide long-term? It has turned out that it can provide a very good overall quality-of-life for many patients with their returning to work full time, school, and engaging in sports activities despite being on a 24/7 infusion.
With respect to the incidence of catheter-related bacteremia, we and others have reported rates of 0.1 and 0.4 per patient year. , More recently, we reported catheter-related infections in patients with PAH receiving epoprostenol to be 0.26 per 1000 catheter days, with the majority of infections being Staphylococcus aureus and Micrococcus species. Our experience has taught us that although Micrococcus species are usually viewed as a contaminant, in PAH patients, bacteremia with Micrococcus appears to be a true pathogen. In addition, patients with Micrococcus species bacteremia not infrequently present with very mild nonspecific symptoms such as fatigue without evidence of an overt febrile illness. Furthermore, peripheral blood cultures might remain negative with positive blood cultures for Micrococcus species only obtained via the central venous line. Unfortunately, attempts to salvage the central venous line even for what appears to be a subclinical bacteremia with Micrococcus species have been unsuccessful in virtually all cases.
Due to epoprostenol's short half-life, interruption of infusion can be life threatening due to sudden interruption of the epoprostenol and thus patients need to go to an emergency room immediately for placement of a peripheral intravenous line and administration of their intravenous epoprostenol via peripheral intravenous infusion until the problem with the central venous line can be corrected, the line replaced or the pump malfunction corrected. Patients are always instructed to have a back-up pump with them at all times and school age children to have a back-up pump in the school nurse's office.
Epoprostenol is also known to cause thrombocytopenia which, although appearing to be dose related, can vary significantly between one patient and another. It may be difficult at times to determine if the thrombocytopenia is due to the epoprostenol or due to disease progression, as it is well appreciated that progressive thrombocytopenia does occur with severe disease progression which can be life threatening with the platelet count decreasing to below 10,000-20,000 per ml. Patients treated with epoprostenol also not infrequently have autoimmune dysfunction that can contribute to or exacerbate the thrombocytopenia. However, despite these severe degrees of thrombocytopenia, our approach has been to not transfuse platelets due to the possible precipitation of an acute pulmonary hypertensive crisis unless the patient is actively bleeding or has had a significant bleed with the concern for a recurrence. If patients require platelet transfusions and/or transfusion of other blood products such as fresh frozen plasma or packed red blood cells, we recommend pre-treating patients with a stress dose of corticosteroids, an antihistamine, and acetaminophen prior to transfusion to minimize the likelihood of a pulmonary hypertensive crisis. And even if a patient has tolerated one or many transfusions of blood products, the risk remains with each additional transfusion; unfortunately sudden cardiovascular collapse and death is known to occur during blood product transfusions. Whether this is due to increased circulating thromboxane A 2 and/or serotonin during the transfusion remains unclear. Although less frequent, increased ascites also appears to be an adverse effect with epoprostenol therapy, particularly in patients who have some degree of cardiac cirrhosis whether or not the patient has true documented portal hypertension. This appears to be dose related and can be quite difficult to treat. Treatment with epoprostenol can also cause systemic hypotension and coronary steal, and thus careful dose titration and maintenance of appropriate fluid balance is critical. If patients develop acute pulmonary edema on intravenous epoprostenol therapy, one should immediately consider whether the patient has pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis in which although there might be a pulmonary arterial component to the pulmonary hypertension, the pulmonary venous/venule component that is fixed or at least fixed to a greater degree than the pulmonary arterial component results in the intravenous epoprostenol increasing pulmonary blood flow without the ability for the increased pulmonary blood flow to adequately egress from the lungs.
Whether "tolerance" or true "tachyphylaxis" occurs with chronic intravenous epoprostenol therapy remains unclear. As the therapy is treating the established disease and may not be treating the underlying cause(s) of the PAH, the apparent tolerance and/or tachyphylaxis might merely represent the pulmonary vascular obstructive disease, i.e., PAH, continuing to progress with the epoprostenol treating the disease and its progression and trying to stay ahead of the disease progression.
In conclusion, long-term treatment with intravenous epoprostenol currently appears to be the "gold standard" for patients with severe PAH. It improves exercise capacity, hemodynamics, and survival in the majority of patients in functional class III and IV. However, many questions remain unanswered. These include: whether initiation of intravenous epoprostenol early in the course of the disease [Figure 5], i.e. functional class II patients, perhaps in conjunction with combination therapy such as an ERA and/or PDE-5 I, could result in significant clinical and/or hemodynamic improvement that subsequently could be maintained on a less invasive and less aggressive combination therapy such as an oral ERA and/or an oral PDE-5 I, as opposed to what currently is most often done, i.e. reserving chronic intravenous epoprostenol for patients who present in functional class IV and/or added as patients fail therapies that were initiated earlier in the course of disease in an attempt to avoid using intravenous epoprostenol. It is also scientifically intriguing if intravenous epoprostenol is used early in life when the pulmonary vasculature is still in active growth and development, whether treating infants and young children with intravenous epoprostenol at least until they are 6 or 8 years of age when the lungs are fully developed, or at least almost fully developed will be more successful than initiating treatment for patients once their lungs are fully developed. We have limited experience with this subset of children; however, to date, we have successfully transitioned select children off chronic intravenous epoprostenol to combination oral therapy (and inhaled therapy in a minority) who appear to maintain their clinical and hemodynamic improvement off intravenous epoprostenol with followup to date ~1-2 years off epoprostenol (with longer followup warranted).  In addition, to the acute vasodilator effects, long-term effects of epoprostenol appear to reflect antiproliferative vascular remodeling effects. With respect to pediatric patients with IPAH compared with adult patients with IPAH, histologic findings have suggested that children have a more reactive pulmonary vascular bed than adults; thus suggesting that children may have an increased ability to repair damage compared with adult patients. The ability to repair vascular growth abnormalities with reverse remodeling provides us a hypothesis for selecting pediatric patients who might be able to be successfully transitioned off epoprostenol to oral/inhaled agents with maintenance of the efficacy demonstrated with epoprostenol, as opposed to less successful attempts to transition adult IPAH patients off epoprostenol. Previous studies have suggested that age of diagnosis and first-line treatment with epoprostenol are significant predictors of survival, i.e. IPAH children diagnosed at a young age who are started on long-term vasodilator therapy have an increased life expectancy with an improved overall quality-of-life (despite the complications and comorbidities associated with the treatment regimen) than patients started on treatment at an older age. , These data further support the long-term effects of chronic vasodilator/antiproliferative therapy in pediatric patients. However, various considerations must be taken into account when determining if a patient is an appropriate candidate for transitioning off epoprostenol and if the potential benefits of the transition outweigh the possible risks. It should be understood that such a transition is not appropriate, safe, or beneficial for all patients. To date, we have used the following criteria, which are conservative, as necessary at a minimum for consideration of transitioning a child off of intravenous epoprostenol. At the time of transition, the mean pulmonary artery pressure is <35 mm Hg, the child has a normal cardiac index, is functional class I-II, and is at least 6 years of age. Additionally, experience and a relationship with the patient and family provide important insight into whether this is an appropriate decision for a given child/family. Although chronic intravenous epoprostenol has significantly improved long-term outcomes in patient with IPAH, it does impact negatively on certain aspects of quality-of-life. Specifically with respect to children, treatment with intravenous epoprostenol often precludes young children from partaking in many activities due to the epoprostenol delivery system. When it comes to determining if transition off epoprostenol is an appropriate consideration, patients, families and physicians may have different views on what they consider the best approach in achieving an appropriate balance between therapeutic and quality-of-life benefits. However, just because quality-of-life might seem better off intravenous epoprostenol due to the removal of the invasive delivery system and elimination of many of the unpleasant side effects of epoprostenol, e.g., jaw pain, leg pain, diarrhea, merely succeeding in only short-term benefit with transition off intravenous epoprostenol to an oral/inhaled regimen does not mean that it was the correct decision for the individual child and his/her family. One of the last things we want to have happen is to have come so far treating patients with intravenous epoprostenol and then transition them off with perhaps short-term success but long-term deterioration that may not be able to be reversed even with later re-initiation of IV epoprostenol.
|Figure 5: Schematic representation in pulmonary arterial hypertension: Does early aggressive intervention improve long-term outcome?|
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Although the current treatment era considers intravenous epoprostenol a rescue therapy, our experience suggests that there might be pediatric IPAH patients who would benefit from early initiation of IV epoprostenol therapy with subsequent transition off as suitable [Figure 5]. Thus, although the best therapeutic approach in improving long-term outcomes remains unknown, whether early initiation of IV epoprostenol is preferable vs. deferral of IV epoprostenol until oral and/or inhaled therapy fails are two different treatment paradigms that need further study. Furthermore, additional investigation is needed to determine if using intravenous epoprostenol as a first-line treatment has greater long-term efficacy in children (that may not be as significant with adult patients) than starting with oral and/or inhaled agents as first-line treatment. Thus, although we have made dramatic advances in improving the treatment options and outcomes for patients with IPAH, we must remain cognizant that the appropriate treatment decisions might often be difficult and should be based on experience and reason. We should not merely defer to a preference to not start a continuous intravenous therapy; no one would elect to start treatment with an intravenous drug if they thought an alternative treatment would be as efficacious or even nearly as efficacious. However, those data are not currently available, at least for pediatric patients. Thus the decisions for the physician taking care of these patients are difficult ones, and may be even harder when treating children when what we want is to improve long-term survival and overall quality-of-life. The balance of treatment objectives for pediatric patients vs. adult patients are different and should be different.
It is important to remember that although epoprostenol remains the "gold standard" for the treatment of pulmonary arterial hypertension, it is not a cure for PAH. Survival certainly is improved with chronic intravenous epoprostenol, but the overall median survival for adult patients for IPAH, although no longer 2.8 years as shown in the NIH PPH Registry from the 1980s, remains approximately 65% at 3 years. , The survival benefit with pediatric IPAH patients appears greater, with an over 90% 5-year survival although again by 10 years on chronic intravenous epoprostenol the survival in children is decreased to approximately 75%.  Thus, what we appear to be doing is pushing the envelope which to me is the right thing to do as long as the overall quality-of-life remains reasonably good on the treatment(s). However, all patients with PAH, regardless of their therapy, require close serial follow-up with adjustments in their medical regimens as clinically needed. It will be exceedingly useful if we can determine whether or not we should initiate treatment in all PAH patients with a very aggressive antiproliferative medical regimen including epoprostenol in a manner similar to how we approach the treatment of oncology. This might seem initially a peculiar analogy, although histologically, the proliferative response seen in the pulmonary vasculature is not unlike that seen in many forms of cancer.
Many questions remain, e.g., identification of patient populations who will most benefit from a specific therapy, determining when treatment should be initiated, and establishing optimal drug sequencing and combinations. We remain cautiously optimistic that by further increasing our understanding of the pathobiology of PAH we will one day be able to prevent and cure this disease. However, in the interim, it is imperative that we base our treatment regimens on evidence-based studies. As stated by Hippocrates in Precepts (approximately 440 BCE), In medicine one must pay attention not to plausible theorizing but to experience and reason together … I agree that theorizing is to be approved provided that it is based on facts, and systematically makes its deductions from what is observed … but conclusions drawn from unaided reason can hardly be serviceable; only those drawn from observed fact.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]