Current Clinical Management of Pulmonary Arterial Hypertension

Abstract

Over the last 2 decades there has been a tremendous evolution in the evaluation and care of patients with pulmonary arterial hypertension (PAH). The introduction of targeted PAH therapy consisting of prostacyclin and its analogues, endothelin antagonists, phosphodiestase-5 inhibitors, and now a soluble guanylate cyclase activator have increased therapeutic options and potentially reduced morbidity and mortality, yet none of the current therapies have been curative. Current clinical management of PAH has become more complex given the focus on early diagnosis, an increased number of available therapeutics within each mechanistic class, as well as the emergence of clinically challenging scenarios such as perioperative care. Efforts to standardize the clinical care of PAH patients have led to the formation of multidisciplinary PAH tertiary care programs that strive to offer medical care based on peer-reviewed evidence-based and expert consensus guidelines. Furthermore, these tertiary PAH centers often support clinical and basic science research programs to gain novel insights into the pathogenesis of PAH with the goal to improve the clinical management of this devastating disease. In this manuscript, we discuss the clinical approach and management of PAH from the perspective of a single US-based academic institution. We provide an overview of currently available clinical guidelines, and offer some insight into how we approach current controversies in clinical management of certain patient subsets. We conclude with an overview of our program structure as well as a perspective on research and the role of a tertiary PAH center in contributing new knowledge to the field.

INTRODUCTION

The last twenty years have seen a dramatic evolution in our approach to the diagnosis and management of pulmonary arterial hypertension (PAH). What was once a death sentence has now become a chronic disease partially amenable to medical and/or surgical management. A key factor to this success has been the development of a clinical classification system to help distinguish PAH from other forms of pulmonary hypertension and algorithms to guide with the diagnosis and management of PAH. Efforts to standardize the clinical care of PAH patients have led to the formation of multidisciplinary PAH tertiary care programs that strive to offer medical care based on peer-reviewed evidence-based and expert consensus guidelines. Furthermore, these tertiary PAH centers often support clinical and basic science research programs to gain novel insights into the pathogenesis of PAH with the goal to improve the clinical management of this devastating disease.

In this manuscript, we discuss the clinical approach and management of PAH from the perspective of a single US-based academic institution. We provide an overview of currently available clinical guidelines (Section 1) and offer some insight into how we approach current controversies in clinical management of certain patient subsets (Section 2). We conclude with an overview of our program structure as well as a perspective on research and the role of a tertiary PAH center in contributing new knowledge to the field (Section 3).

1. CLINICAL CARE OF PAH PATIENTS IN THE MODERN ERA

The first priority when determining the optimal management strategy for a given patient is to identify what form of pulmonary hypertension is responsible for the clinical presentation. The 2013 Nice clinical classification guidelines (Figure 1) represent an update of prior Dana Point classification scheme and provide a useful framework to help phenotype patients presenting with pulmonary hypertension (PH)¹. Changes to the 2009 Dana Point Classification are that persistent pulmonary hypertension of the newborn (PPHN) is categorized as a separate entity Group 1” PAH as it carries more differences than similarities with other entities in Group 1 PAH. Furthermore, pediatric pulmonary hypertension is now comprehensively characterized in order to create a common classification for both adults and children. Moreover, congenital or acquired left-heart inflow/outflow obstructive lesions and congenital cardiomyopathies have been added to Group 2. Pulmonary hypertension associated with chronic hemolytic anemia has been moved from Group 1 PAH to Group 5 (unclear/ multifactorial mechanism) and segmental pulmonary hypertension has been added to Group 5. SMAD9, CAV1 and KCNK3 have been added to the list of genes found in hereditary PAH. New drugs and toxins have been identified that are definitely, likely or possibly associated with PAH: Benfluorex and SSRIs have been classified as definite, Dasatinib as likely and Interferon α and β as well as amphetamine-like drugs as possible (such as entermine/topiramate to treat obesity, methylphenidate to treat attention deficit disorder, ropinirole for Parkinson’s disease as well as mazindol to treat narcolepsy).

Figure 1.

Updated Classification of Pulmonary Hypertension from the 5^th World Symposium at Nice, France. Modifications are listed in bold. (Reproduced with permission, J Am Coll Cardiol 2013;62: D34-41).

The main advantage of the Nice 2013 clinical classification is that it helps clinicians distinguish patients with Group 1 PAH from other forms of pulmonary hypertension as each of these forms has a different prognosis and demands a unique approach to management² (Figure 2). As the mechanistic understanding of the disease has advanced and imaging methods of the pulmonary vasculature and the heart have improved, identification of innovative biomarkers and new PH phenotype definitions have been suggested³. In an official ATS statement, these new pulmonary hypertension phenotypes are mainly defined on the basis of the pathobiology. These proposed “new” phenotype include a mixed pre- and post-capillary PH, severe PH in respiratory disease, maladaptive right ventricular (RV) hypertrophy, connective tissue disease-associated PH, portopulmonary hypertension, HIV-associated pulmonary arterial hypertension (PAH), PH in elderly individuals, PAH in children, metabolic syndrome, and long- term survivors. It is suggested that deep phenotyping of patients consisting of measuring and integrating genomics, transcriptomics, proteomics, metabolomics, cell biology, tissue functioning and imaging will advance the understanding of mechanisms, which then could be used to guide targeted management strategies.

Figure 2.

Recommended Nice algorithm for diagnostic workup and initiation/continuation of therapies (Reproduced with permission, J Am Coll Cardiol 2013;62: D60-72).

Current treatment algorithms use the clinical classification system to recommend specific medical and surgical interventions for a specific WHO group of PH whereas they strongly caution against them in other forms of PH for which there is not enough clinical or scientific evidence to support their use⁴. These clinical guidelines for the diagnosis and care of PH are based on state of the art clinical and scientific knowledge reviewed by experts in the field, and they represent the best paradigm for guiding the clinical care of PH patients in the modern era (Figure 2). Despite being a comprehensive resource for PAH practitioners, there are clinical scenarios that are not properly addressed by the current clinical guidelines due to lack of robust data or expert consensus. The result of such limitation is that practitioners are forced to make decisions on the basis of single provider experience or local consensus. The 2013 Nice guidelines do not provide any consensus recommendations on issues such as best first-line agent or optimal combinations of therapies. To the best of our knowledge, there are no studies that demonstrate the superiority of a specific drug class or brand. Furthermore, research is lacking to identify potential best responders to a certain therapy which would require a comprehensive phenotyping of the patient, thereby leading to a current practice pattern that encourages costly sequential or up-front combination therapy of multiple PAH drugs without knowing which patient would benefit most. Finally, it must be stressed that current clinical guidelines are unclear as to how to best approach patients with clinical features of two or more PH phenotypes (e.g. Scleroderma patients who present with PAH and interstitial lung disease) in which the choice of therapy remains controversial.

Despite the availability of a wide range of specialized therapies, mortality from PAH remains unacceptably high. While it is true that survival has improved since the introduction of modern therapies, data from both the REVEAL⁵ and French registries⁶ still demonstrate a disturbingly low survival of 67% over a three-year period, compared to that reported by the NIH Registry in 1991 of 47%⁷. These sobering facts reflect an ongoing controversy surrounding the degree to which modern, non-invasive PAH therapy can improve survival. Over the past five years, several meta-analyses collecting most of the clinical trial data published on PAH therapeutics have tried to answer this important question but the reports are conflicting. Some studies claim evidence for a survival benefit⁸ whereas others fail to confirm this observation even with combination therapy⁹. While combination therapy reduced time to clinical worsening, reduced mean PAP as well as PVR and increased 6-min walk distance, it did not influence mortality. One possible explanation might be that the quality of most currently available clinical PAH studies is inconsistent, a limitation that should be addressed in the design of future clinical trials. Until then, most data appear to support a survival benefit for IV epoprostenol¹⁰ but whether any of the other agents also share this distinction remains unclear.

In summary, the current clinical classification and treatment guidelines have helped improve the standardization of PAH care in the clinical setting and have identified areas where more research is necessary to cover gaps in our knowledge and improve the quality of care. In the next section, we discuss how our center adapts the guidelines to the evaluation and management of patients and share some of the approaches we take to respond to the challenges we face in our clinical practice.

Diagnosis and Management – The Stanford Approach

Any discussion of the management of pulmonary hypertension needs to start with an accurate diagnosis and full characterization of the disease phenotype. This includes categorizing the patient into the appropriate WHO Group as well as making a full assessment of the patient’s functional class and other co-morbid conditions. While the diagnostic work up is discussed in full in a separate article in this supplement, here, we will describe briefly our approach to patients who present to our clinic.

Patients are primarily referred to our clinic with echocardiograms that show an elevated right ventricular systolic pressure (RVSP) with or without evidence of right ventricular dysfunction and right heart failure. In our initial visit, in addition to full review of symptoms, we assess risk factors for the development of PH. In our clinic, a RVSP>45 mmHg initiates a comprehensive pulmonary hypertension workup. Specifically, patients are screened for any history or evidence of congenital heart disease, autoimmune diseases, liver disease, thromboembolic disease, history of stimulant use, underlying lung disease, heart disease, sleep disordered breathing, HIV infection. If the patient’s echocardiogram and symptoms reasonably suggest that the patient may have pulmonary hypertension, a comprehensive workup is initiated. Routine studies include a CBC, comprehensive metabolic panel, thyroid function^{11, 12}, and N-terminal pro B-type natriuretic peptide (NT-pro BNP). Additionally, hepatitis serologies, HIV, and when indicated, hypercoaguable panels are checked. If a screening anti-nuclear antibody is positive, a panel of autoimmune antibodies including anti-dsDNA anti-scl-70, anti-centromere, anti-RNP, anti-SSA, anti-SSB is checked. Screening electrocardiogram and chest x-ray are used to alert the clinician to co-existing cardiopulmonary diseases. Patients also undergo a full set of pulmonary function tests, a six minute walk test, non-contrast CT scan of the chest or CT angiogram if thromboembolic disease is suspected, and V/Q scan. With the advent of more powerful CT scanners, it is debatable whether CT angiogram or V/Q scanning is superior for diagnosis of thromboembolism. We rely on either as an initial screen, but if thromboembolism is still a likely diagnosis we require a V/Q scan. Chest imaging is a vital part of our initial evaluation given the fact that some patients with substantial parenchymal disease can present with relatively normal (pseudo-normalized) lung function^13,14. Patients are routinely referred for evaluation for possible sleep apnea. If there is a suggestion of a shunt such as history of childhood murmurs, cyanosis, findings of clubbing or flow murmurs on examination, an echocardiogram with bubble study is performed. We then have the patient return to clinic within four weeks. At this second appointment, we review the results of the study and only if all of the requisite studies are complete do we proceed with scheduling of the right heart catheterization. In our previous experience, we found that if the right heart catheterization was performed as part of the initial work up, patients would get started on therapy before their disease phenotype was completely characterized, and often, these studies would never be completed. In the initial heart catheterizations, in addition to pressure measurements, the patients also have a full saturation run (to look for intra-cardiac shunts) and a vasoreactivity challenge with inhaled nitric oxide. Formally vasoreactive patients should be started on calcium channel blocker (CCB) therapy with careful follow up evaluation and anticipation of a substantial clinical improvement (further discussed in Section 2).

With increased awareness of PH, our clinic has received a growing number of referrals for patients with echocardiogram that show borderline elevations (35-44mmHg) in RVSP. Some referrals come through screening protocols for patients with systemic sclerosis or for liver transplantation, while others are for patients in whom there is an incidental finding of elevated RVSP. An exhaustive work up might be inappropriate as there are no clear guidelines for the evaluation of patients with such borderline abnormalities on echocardiogram. Therefore, our group has devised a screening protocol which takes into consideration the patient’s RV function, symptoms, and risk factors for disease (Table 1). Ultimately, for patients with suspected WHO Groups 2, 3, and 5 PH, the evaluation is focused on optimization of the underlying condition.

Table 1.

Stanford workup algorithm for patients with borderline elevation in right ventricular systolic pressure (RVSP) on echocardiogram (Echo). PH = pulmonary hypertension, RV = right ventricle, LV = left ventricle, EF = ejection fraction, WHO = world health organization, COPD = chronic obstructive pulmonary disease, ILD = interstitial lung disease, OSA = obstructive sleep apnea, FVC = forced vital capacity, DLCO = diffusing capacity for carbon monoxide.

RVSP	RV size and/or function	Sympto ms	Risk Factors	Recommended Action
RVSP 35-45 mmHg	Abnormal	N/A	N/A	Full workup
	Normal	No symptoms	Any PH risk factors	Repeat echo q6-12 months
			No PH risk factors	Repeat echo in 12 months If echo is stable and the patient has no symptoms, discharge from clinic
		(+) Symptoms	Any WHO Group 1 risk factors	Full workup
			Diastolic dysfunction	Optimize BP and volume status and recheck echo If optimized, consider full workup
			Valvular heart disease	If MR / AR is > moderate-severe, refer to cardiology & hemodynamics testing, optimize volume status then recheck echo. If optimized, consider full workup
			LV systolic dysfunction	If EF < 35%, no further workup. Refer to cardiology
			COPD	Consider Full workup
			ILD	If FVC/DLCO > 1.6, consider full workup
			OSA	Optimize OSA treatment and repeat echo. If optimized, consider full workup
			Altitude > 3,000 ft	Consider Full workup
			Thromboembolic disease	Full workup
			Any WHO Group 5 risk factors	Consider full workup

Initial Therapy selection

The most recent guidelines provide only loose guidance in choice of initial therapy for WHO Group 1 PAH². The consensus algorithm for initial therapy remains dependent primarily on WHO functional class (likely because of medication labeling), and gives numerous options for each class with few recommendations for choosing one medication over another. This ambiguity may be understandable given the lack of head-to-head clinical trials. Therefore, the decisions around initial therapy are generally driven by local expertise, practice patterns, patient preference, and insurance considerations. The shift in recent clinical trials to a primary endpoint of long-term outcomes (i.e. morbidity and mortality) rather than changes in surrogate markers such as changes in 6MWD or hemodynamic measures in short term studies has added another factor to the decision-making dilemma. How a PAH clinician reconciles conclusions of pivotal trials with different endpoints (6MWD plus long-term extension data versus a morbidity and mortality) of approved therapeutics from the same class remains to be seen. We consider consensus documents classifying patients as either lower risk or higher risk as a guide for initial therapy¹⁵ particularly helpful in decision-making. Factors that have been shown to differentiate patients into high risk groups include: clinical evidence of RV failure, rapid progression of disease, WHO FC IV, low 6MWD, low VO₂ on cardiopulmonary exercise testing (CPET), the presence of a pericardial effusion, severe RV enlargement of dysfunction, right atrial pressure (RAP) > 20 mmHg, CI < 2.0 L/min/m2, or significantly elevated BNP¹⁶. We consider a 6MWD of less than 380 meters worrisome and less than 200 meters extremely concerning. While no single factor can determine risk, an assessment of all of these factors can be used as an optimal guide for choosing initial therapy.

For patients with WHO FC II or III and low risk features, current guidelines recommend initial therapy with oral agents - either phosphodiesterase-5 inhibitors (PDE-5i) or endothelin receptor antagonists (ERA). In general, PDE-5i’s (sildenafil or tadalafil) are well tolerated, have minimal side effects and do not require regular monitoring. The choice between sildenafil or tadalafil is difficult to make and mostly depends on compliance as well as insurance formulary considerations. Since these therapies can cause systemic hypotension, PDE-5i’s as a first line are avoided in patients with low baseline blood pressures, i.e. systolic blood pressure < 100 mmHg. Moreover, drug-drug interactions should be carefully considered as PDE-5i’s are contraindicated in patients with active nitroglycerin use and those on protease inhibitors due to strong CYP3A4 inhibitory effects¹⁷. Currently, there are three ERA’s approved for initial PAH therapy in the United States: bosentan, ambrisentan, and macitentan. All of the ERA’s are teratogenic, so monthly pregnancy tests are required for all women of child-bearing age. Transaminitis can occur with these medications, most commonly with bosentan which requires monthly liver function test monitoring. Although this is not required for ambrisentan or macitentan, our practice has been to check LFTs at least every 3 months. Anemia is also known side effect of these meds, so checking hemoglobin level every 1-3 months is also recommended. Lastly, significant fluid retention maybe a common side effect but data from the large randomized placebo controlled trial of macitentan showed that the incidence of fluid retention was no different from the placebo group suggesting that edema may not be a significant side effect for this medication¹⁸. Because of the monthly LFT monitoring and the twice a day dosing with bosentan, ambrisentan and macitentan (dosed daily) might be preferable choices.

The soluble guanylate cyclase stimulator, riociguat, is an oral medication and has recently been approved for the treatment of IPAH, hPAH, and CTD-APAH. The pivotal PATENT-1 trial demonstrated efficacy as both monotherapy and combination therapy¹⁹. However, it is yet to be determined in what cases this drug will be used as initial therapy. It is a three times per day dosed medication which makes medication compliance an issue. Also, compared to placebo, riociguat 2.5 mg tid was associated with higher rates of mild to moderate hypotension. The PATENT-1 study excluded patients with baseline systolic blood pressure <95 mmHg and should not be used in patients on active nitroglycerin or PDE-I agents. Lastly, like ERAs, riociguat is thought to be teratogenic and requires monthly pregnancy tests in female patients of child-bearing age.

Patients who present with WHO FC IV symptoms and/or high risk features should be considered for parenteral prostacyclins as first-line therapy. Currently, there are three parenteral prostacyclins available in the US: epoprostenol, room temperature stable epoprostenol, and treprostinil. The two forms of epoprostenol are given by continuous intravenous infusion while treprostinil can be given intravenously or subcutaneously. Patients who elect to go onto this therapy need to be able to manage an indwelling catheter, mix the medication in a sterile fashion, and manage the pump. Given the challenges associated with managing parenteral prostacyclins, some patients are not willing or are not appropriate candidate for parenteral therapy. In these cases, we will start with oral or inhaled therapy, with the plan to add a second agent in quick succession. Currently there are two inhaled prostacyclins available in the US: iloprost and treprostinil. Inhaled iloprost is dosed at 6-9 treatments per day, while inhaled treprostinil is dosed up to 9 breaths four times per day. Cough is a common side effect with inhaled prostacyclins and at times can be quite severe.

While initial mono-therapy has been a well-studied approached in PAH, the utility of upfront combination therapy continues to be an unanswered question. Sitbon et al recently reported the results of a pilot study of upfront triple therapy²⁰. Patients with newly diagnosed severe PAH were offered upfront treatment with epoprostenol, bosentan and sildenafil in patients with severe PAH. This small cohort demonstrated significant improvement in 6MWD and hemodynamics and survival at 3 years was 100%. While very promising, the reporting of the study was retrospective and uncontrolled. Currently, there are two randomized clinical trials testing upfront combination therapy. The AMBITION trial (ClinicalTrials.gov Identifier: NCT01178073) is an event-driven study evaluating upfront combination therapy with tadalafil and ambrisentan compared to ambrisentan or tadalafil alone. The CONFRONT trial is a phase IV clinical study comparing upfront therapy with tadalafil and inhaled treprostinil compared to tadalafil alone (ClinicalTrials.gov Identifier: NCT01305252). Results from these two trials are anticipated in the next 6 -12 months.

Goals of therapy and treatment optimization

Once patients are started on therapy, high risk patients are re-evaluated every 2-3 months, while those with milder and more stable disease are seen every 4-6 months. At follow up, patients are reevaluated with an assessment of WHO FC, an echocardiogram, six minute walk test, and often an NT-pro BNP. Surveillance RHC at our institution is performed every 1-2 years or sooner if clinical deterioration is suspected.

In the most recent guidelines, the following targets for therapy were suggested: 1) modified WHO FC I or II; 2) echocardiography / cardiac MRI of normal/near-normal RV size and function; 3) hemodynamic parameters showing normalization of RV function (RAP <8 mm Hg and CI>2.5 to 3.0 l/min/m2); 4) 6MWD of >380 to 440 m; 5) cardiopulmonary exercise testing, including peak oxygen consumption >15ml/min/kg and VE/VCO₂ <45 l/min/l/min; and 6) normal BNP levels²¹. These targets parallel the factors used to assess risk. In short, the goal of treatment is to shift a patient from a higher risk to a lower risk phenotype.

In order to achieve these goals, combination targeted PAH therapy as well as optimization of supportive care is essential. The efficacy of sequential combination PAH therapies is suggested by several placebo-controlled, randomized clinical trials in patients on stable monotherapy. While the PACES²² and TRIUMPH-1²³ trials demonstrated an improvement in 6MWD with the addition of a second agent, others (such as STEP²⁴) were formally negative but suggestive. Results of the COMPASS-2 trial, addition of bosentan to background sildenafil, will provide further guidance on impact of step-wise combination of PAH therapies.

In our practice, the decision to add therapy mirrors the current guideline recommendations. If patients continue to have WHO class III or IV symptoms, low 6MWD, elevated NT-pro BNP, or poor prognostic markers on echocardiogram (i.e. pericardial effusion), additional PAH-specific therapies are used. For patients exhibiting persistent high-risk features, we optimize the baseline and consider adding a second agent within 3 months of treatment-initiation. In general, our second line choice is usually either an oral agent, an ERA or PDE-5i, or inhaled prostacyclin. If patients are unable to reach these goals with dual therapy, we move to triple therapy with dual oral therapy and inhaled prostacyclins. If they continue to progress, the inhaled prostacyclin is switched to a parenteral prostacyclin in patients who are willing and capable of managing this form of therapy. For high risk patients, parenteral prostacyclin is discussed and offered at every treatment decision point.

A discussion in treatment selection cannot be made without consideration of drug cost and insurance coverage. All PAH medical therapies are prohibitively expensive, and costs compound as patients are placed on combination therapies. Sildenafil is the least expensive drug therapy, estimated at $18,788 per year (for 20 mg TID) dose to $244,404 for inhaled prostacycin therapy (iloprost at 9 times a day dosing)²⁵. The cost of parenteral prostacyclin is dose dependent and can easily be as high or exceed inhaled therapies when one considers the cost of hospital admission for central line placement and drug titration or management of a blood stream infection.

Even though the clinician may not be aware of actual drug cost at time of prescribing, ultimately whether a patient receives the medication is essentially driven by the cost. For instance, despite the lack of head to head trials comparing the efficacy of oral agents, the insurance company may mandate that a patient be started on one therapy over another. This is often driven by each specific payers’ negotiation with the pharmaceutical company to achieve competitive pricing. These formulary preferences are not always apparent to the prescriber. Hence start of therapy can often be delayed due to multiple prescriptions being sent in succession simply to obtain medication coverage. Copious amount of paperwork and clinical data need to be sent in to make a drug coverage determination. Authorizations for coverage may also be given for a few months, thus repeating the cycle of paperwork submission. At our center, it is a coordinator’s full time job simply to track the authorizations and paperwork submission and filing of appeal letters should the insurance deny coverage of medications. The intense administrative burden adds to the indirect cost of PAH treatment. The American College of Cardiology and the American Heart Association recently published a cost and value methodology to be applied in developing treatment guidelines and performance measures²⁶. Given limited health care resources, cost considerations and resource utilization should be evaluated alongside future PH treatment guidelines.

Supportive therapies are essential for symptom control and optimization of hemodynamics. In patients with chronic right sided heart failure, symptoms and hemodynamics can be significantly improved with control of volume status. This is generally achieved with diuretic therapy. Observation of a low sodium diet (<2 g sodium per day) can significantly decrease the degree of fluid retention. Digoxin can add some inotropic support for the failing right ventricle²⁷. In our practice, this is often added as a supportive therapy when PAH specific therapy has been optimized. Lastly, exercise training and pulmonary rehabilitation is an important strategy for improving exercise tolerance, symptoms, and quality of life measures²⁸. Patients are encouraged to attend a pulmonary rehabilitation program soon after successful initiation of PAH-specific therapies.

Specifying discrete treatment goals lends itself to the development of formal goal-oriented therapy protocols. Interestingly, to date, there has been only one study with a specified protocol in which therapy was added if one of the treatment goals was not met²⁹. Compared to historic controls, Hoeper et al showed that goal-directed therapy improved survival. However, this study is limited by its retrospective design and lack of appropriate “control” arm. As this study was conducted over a decade ago, a number of new medications for PAH have been approved and new prognostic factors have been identified making the specific protocol less relevant. However, the concept of goal-oriented therapy is a useful one. Future studies should address optimal risk stratification factors, weight of these factors in determining a “goal”, ideal assessment intervals, order of therapies, and timing of therapeutic interventions.

One risk assessment that may be useful in a goal-oriented protocol is the REVEAL risk score. The REVEAL Registry was used to develop and validate a prognostic score for one year survival^{5, 30}. This score is derived from combination of demographics, WHO FC, vital signs, 6MWD, BNP, echocardiogram, pulmonary function test, and right heart catheterization findings but is easy to calculate and stratifies patients into one of five risk groups, ranging from low risk and very high risk. While the use of the risk score to guide therapy needs to be validated, this could potentially be used to guide initial as well as optimization of on-going therapies. Changes in the risk score over time may be a useful target for goal-oriented therapy³¹. However, clinicians must recognize that such risk scores (and their change) have not been validated in individual patients and their use in such setting is debatable³².

Timing of referral for transplantation

Current guidelines recommend that patients with an inadequate response to therapy be referred for lung transplantation. Our current practice has been to refer patients who have been started on triple therapy including parenteral prostacyclins for transplant evaluation. In the current lung allocation scoring (LAS) system, patients with PAH, based on their diagnosis, often have low scores at listing^33,34. While patients with other lung diseases (pulmonary fibrosis, COPD, and cystic fibrosis) have had a decrease in their wait time for transplant, there has been no change for IPAH patients. The LAS system has also lead to IPAH patients having a lower likelihood of being transplanted compared to idiopathic pulmonary fibrosis patients and a great risk of death while on the waiting list^35,36.

2. EMERGING PRACTICE TOPICS Genetic Screening and Counseling of PH Patients

Since the discovery of the association between heritable pulmonary arterial hypertension (HPAH) and mutations in the bone morphogenetic protein receptor (BMPR) 2 gene^{37, 38}, there has been tremendous progress in our understanding of the genetic basis of PAH. In recent years, there have been reports of association between HPAH and mutations in novel genes such as caveolin-1³⁹ and KCNK3⁴⁰ discovered via application of modern genome sequencing technologies such as whole exome sequencing (WES)⁴¹. These studies have fueled enthusiasm for the application of genomic technologies to the clinical setting as tools to help personalize the care of PAH patients and improve our ability to predict likelihood of disease development in carriers of susceptibility genes. However, more research needs to be conducted to determine how best to analyze the large data sets generated by genome sequencing and determine associations between candidate genes and critical endpoints such as prognosis, disease severity and response to therapy.

At our institution, we routinely screen all patients for a family history of pulmonary hypertension and will only recommend genetic testing when there is a high index of suspicion. Genetic counseling is offered prior to testing as both the patient and family need to be educated concerning the clinical and legal implications of finding specific gene mutations as well as the likelihood of mutation carriers developing PAH in their lifetime⁴². We routinely follow asymptomatic high-risk mutation (e.g. BMPR2) carriers with yearly echocardiograms and a visit to evaluate for the presence of symptoms concerning for PAH and conduct psychological assessment for possible stress and anxiety caused by the genetic diagnosis⁴³.

Follow-up Vasoreactivity testing

Acute vasoreactivity testing remains a key component of the initial work-up for PAH to identify subjects that will respond favorably to long-term treatment with high doses of calcium-channel blockers. Inhaled nitric oxide (iNO) is the compound of choice for the acute test but intravenous epoprostenol or adenosine may also be used as an alternative⁴⁴. Furthermore, inhaled iloprost has been able to identify patients who may benefit from long-term therapy with CCBs⁴⁵. A decrease in mean pulmonary artery pressure (mPAP) by ≥10 mmHg to an absolute level of <40 mmHg without a decrease in cardiac output (CO) is defined as a positive pulmonary vasodilator response⁴⁶ and only those responders are considered for long-term treatment with calcium channel blocker (CCB). Less than 15% of idiopathic PAH (IPAH) patients are deemed responders during testing, and even fewer exhibit long-term responsiveness to CCB⁴⁶. Independent of whether CCB are started, vasoreactivity to inhaled nitric oxide predicts long-term survival in pulmonary arterial hypertension⁴⁷. In our center, vasoreactive PAH patients are initiated on CCB therapy with close follow up with the expectation of substantial clinical improvement within 3-4 months. As choice of CCBs, long-acting amlodipine, nifedipine and diltiazem are the preferred agents.

In addition to identifying patients who would respond to CCB therapy, baseline and follow-up vasoreactivity testing in all PAH patients as part of every right heart catheter (RHC) can offer valuable additional insight into their response to therapy and possible anti-remodeling effects. Our group has shown that in addition to loss of vasoreactivitity, vasoreactivity can also be gained (using the same definition as baseline testing) over the course of the disease in idiopathic, drug and toxin’s, and connective tissue disease associated PAH (abstract AJRCCM 183;2011:A5747). In the rare case of a gain of vasoreactivity, we consider initiation of CCB therapy in addition to targeted PAH therapy, but it should be noted that this is an expert opinion driven practice, is highly preliminary, and requires future clinical testing. Once vasoreactivity is lost, we typically stop calcium channel blockers and optimize targeted PAH therapy.

Utility of anticoagulation in PAH

The use of anticoagulation in PAH has been a subject of debate for decades. While there is evidence of in-situ thrombosis in all forms of PAH⁴⁸ as well as a recognized hypercoaguable state in severe PAH⁴⁹ most clinical studies suggesting a survival benefit of anticoagulation in PAH are retrospective or non-randomized and small^{50, 51} and mainly refer to IPAH patients at a time before targeted PAH therapy was available. Given the increased risk of bleeding with anticoagulation in subgroups of PAH such as congenital heart disease, liver disease and mixed connective tissue disease the current treatment guidelines only recommend - based on expert opinion - that anticoagulation should be considered IPAH, HPAH and anorexigens induced PAH patients and leave it up to the discretion of the treating physician whether to extend this treatment to other forms of PAH².

This insecurity and reluctance to use anticoagulation is reflected by the fact that only around 50-60% of patients with IPAH and 40% with APAH are on anticoagulation, based on data from European (COMPERA)⁵² as well as North America based (REVEAL)⁵³ PH registries. A recent analysis from the above mentioned European prospective PH registry (COMPERA) of survival rates of > 1200 patients with IPAH and other forms of PAH depending on their use of anticoagulation documented a significantly better 3-year survival in IPAH (but not APAH) patients on anticoagulation compared with patients who never received anticoagulation⁵². These data suggest that long-term anticoagulation confers a survival benefit even in the presence of PAH-specific therapies. This prospective registry is the largest series assessing the use of anticoagulation in PAH over a long observation period and further supports the recommendation to use anticoagulation in IPAH patients. Based on these data, we usually start patients on anticoagulation regardless of the PAH subtype unless limited by anemia or prior bleeding events.

β-blockers in PAH

The use of β-blockers in PAH remains controversial. Although it is well established that neurohormonal system is activated in PAH^54-57, reluctance to use β-blockers in PAH is based on the idea that PAH patients are highly dependent on their heart rate to maintain and increase their cardiac output. Neurohormonal activation was therefore interpreted as a necessary compensatory response to maintain adequate cardiac contractility and blood pressure. Although initially beneficial, chronic activation of the neurohormonal system may be detrimental in the long run⁵⁷ as it could result in a down-regulation of β1-adrenergic receptors⁵⁴ impairing the inotropic responsiveness of the heart.

Several preclinical studies in experimental rat models of PAH with RV failure as well as of isolated RV hypertrophy and failure after pulmonary artery banding have implicated beneficial effects of β-blockers on RV function and morphology^58-60. A retrospective study compared the clinical outcome of 94 PAH patients with cardiac co-morbidities with and without β-blockers. The authors found that β-blocker use was common (28%) in their cohort and not associated with worse outcomes (PAH related hospitalization or all-cause mortality)⁶¹. However, the studied patient cohort did not reflect the normal PAH population (older age, coronary artery disease etc).

Recently, a phase II clinical trial to test the safety and efficacy of the cardioselective β-1 adrenergic blocker bisoprolol finished recruitment and results are expected in the next few months (ClinicalTrials.gov Identifier: NCT01246037. PI A. Vonk-Noordegraf). Thirty IPAH patients were randomized to either bisoprolol or placebo treatment in a double-blinded fashion. A cross-over design (6 months beta blocker, 6 months placebo) was used to increase the power of the study and to assess long-term effects of bisoprolol treatment and withdrawal. As primary efficacy endpoint, improvement in RV function (reflected by RVEF) will be determined by cardiac magnetic resonance imaging. Safety of bisoprolol treatment in IPAH patients was not a primary endpoint but was regarded as a precondition for the study and thus closely monitored. We are currently not treating PAH patients with β-blockers and are awaiting the clinical trial results to see whether a safe and effective dose of selective β-blockade can be recommended in select PAH patients.

ICU care of PAH patients

Due to the generally tenuous clinical status of PAH patients, clinicians should have a low threshold to admit such patients to a higher-level care setting such as intensive (ICU) or cardiac (CCU) care units. The management of critically ill PAH patients is especially challenging given that 1) assessment of presenting critical illness is confounded or even masked by right heart failure, and 2) treatment of the acute critical illness may have paradoxically detrimental effect on RV function and the underlying pulmonary vascular disease (Figure 3).

Figure 3.

Suggested evaluation and treatment algorithm for pulmonary hypertension in the intensive care unit (Modified with permission, Crit Care Med 2007;35:2037-50)

Presentation of critical illness in the setting of RV failure in PAH usually requires immediate hemodynamic evaluation^{62, 63}. The volume status of the PH patient is notoriously elusive and non-invasive estimates of central venous pressures estimates maybe misleading. Therefore central line placement with direct measurement of central venous pressure and mixed oxygen saturation is often necessary. A pulmonary arterial catheter (PAC) can be useful in this setting but is not required.

The selection of inotropes and vasopressors is challenging in PAH patients. In this regard, a major guideline is to maintain systemic vascular resistance (SVR) greater than pulmonary vascular resistance (PVR). Unlike left ventricular coronary perfusion that occurs solely during diastole, right ventricular coronary perfusion occurs both during systole and diastole⁶⁴. Thus if the gradient shifts during systole to a state in which PVR exceeds SVR (i.e. systolic pulmonary arterial pressure (SPAP) > systolic systemic arterial pressure (SSAP)), the result is right ventricular ischemia⁶². Usually, this means that SSAP goals are higher than in non-PH patients. Inotropes that have neutral or beneficial effects on PVR include dobutamine, milrinone, and epinephrine^{62, 63}. We often utilize dobutamine over milrinone because of its shorter half-life in face of the risk of hypotension in both. We try to offset the potential drop in SVR with replacement-dose vasopressin, particularly in our septic or liver PH patients, in whom vasopressin-deficiency is common^{65, 66}. No single inotrope or pressor is entirely contraindicated in the critically ill PH patient, but each agent should be considered carefully.

Inhaled nitric oxide (iNO) has been shown to acutely decrease PVR and improve CO in PH, especially in patients who are post-coronary bypass surgery or valve replacement^{67, 68}. Its advantages are its short half-life, short onset of action, its capacity to improve oxygenation by way of augmenting ventilation-perfusion matching, and its capacity to unload an acutely failing right ventricle (RV). Most importantly, it has no detrimental effect on SVR. Its disadvantages are its significant cost, its potential to cause methemaglobinemia though usually at sustained, high doses, and its potential for tachyphylaxis. Also of note, upon weaning iNO, rebound pulmonary hypertension can occur^{69, 70} particularly in the absence of a replacement pulmonary vasodilator. In addition to select inotropes and vasopressors, we routinely employ iNO at 20 parts per million in the ICU in our hypotensive PH patients, and upon weaning, we will routinely start or restart a phosphodiesterase inhibitor as replacement therapy.

Intubation, on its own, acutely decreases right ventricular preload and increases afterload⁷¹. This, in combination with the effects of agents of induction and sedation and the associated loss of sympathetic drive once work of breathing is relieved, can instigate sudden and at times irreversible hypotension⁷² . We often call upon an experienced cardiac anesthesiologist to assist with intubation. Depending on the urgency and nature of the case, arterial line monitoring may be employed prior to the event and fiberoptic awake intubation may be utilized to avoid overstimulation of sympathetic drive, which can incite an acute increase in PVR. After intubation, a low-tidal volume strategy⁷³ to minimize increases in RV afterload is employed with the aim to keep peak pressures < 30 cmH20. If oxygenation allows, the positive end-expiratory pressures should be limited to 10cm H20 or less. Permissive hypercapnea should be avoided as acidosis and hypercapnea can acutely increase PVR. Finally, a systemic oxygen saturation of >90% should be aimed for as hypoxia can likewise acutely increase PVR^{62, 63, 71}.

Perioperative work-up and risk stratification

Patients with PAH are at highest risk for any major procedure or surgery that is emergent, requires significant volume shifts (e.g. intra-abdominal surgery), carries a substantial risk of pulmonary (clot or fat) thromboembolism, and mandates prolonged anesthesia. Additionally WHO FC >II, right ventricular hypertrophy on TTE, right axis deviation on electrocardiogram, and higher mean pulmonary artery pressure portend worse postoperative morbidity and mortality^74-76. The detrimental effect pulmonary hypertension has on outcomes in cardiac surgery is well-established. PH was the only baseline variable which predicted increased perioperative mortality in a large group of patients undergoing coronary artery bypass graft surgery (odds ratio 2.1)⁷⁷. Severe PH was independently associated with in-hospital mortality (adjusted odds ratio 6.9) and decreased 5-year survival (adjusted hazard ratio 2.4) in patients undergoing aortic valve replacement for severe PH⁷⁸.

The effect of PH on non-cardiac surgery outcomes is less well-studied, but there are data that suggest PH is a notable risk factor for poor outcomes. Morbidity rates range from 2-42% and include acute respiratory failure, acute heart failure, dysrhythmia, prolonged intubation and ICU stay^{74-76, 79, 80}. Mortality rates range from 1-18%. We believe that even minor procedures such as dental extractions or routine colonoscopies requiring conscious sedation should be taken seriously. Unexpected bleeding, sedation-related hypoxia or hypotension, or post-procedure pain, can incite a sudden increase in PVR and acutely stress a chronically failing RV.

A thorough preoperative evaluation and discussion of risks and benefits in advance of surgery is critical. We ask all our patients to notify us of any anticipated procedure or surgery and generally advocate that they undergo major surgery at our center. We advise that any minor procedures be performed under local sedation only if possible. At minimum, we ensure risk stratification on the basis of recent (within 3-6 months) TTE, right heart catheterization, six minute walk test, and NT-pro BNP data. We also advise our patients to avoid elective surgery unless it is anticipated to dramatically improve quality of life. We optimize PAH-specific therapy and volume status as much as possible prior to surgery. We will often cancel or delay elective surgery until this optimization is complete. Finally, we thoroughly discuss the risks from a cardiopulmonary perspective with our patients and their families.

In all major surgical cases, we assemble a multi-disciplinary team, including surgeons and cardiac anesthesiologists, and together formulate an approach to the perioperative care. This discussion focuses on the choice of induction and maintenance anesthetic agents, close intra-operative monitoring (e.g. central venous catheter, arterial line, transesophageal echocardiogram (TEE)), plan for pulmonary vasodilator therapy during and after surgery (e.g. continuous iNO may need to replace patient-delivered inhaled prostacyclins while under general anesthesia), surgical strategy, anticipated surgical complications, and close post-operative monitoring. Invariably, we admit our PAH patients post-operatively to our service in the CCU for at least 24 hours of monitoring as some of the major cardiovascular implications of surgery only manifest a day or two following the procedure. We believe that this vigilant approach best prepares the complicated PAH patient and associated care team for perioperative obstacles.

Role of ECMO, Ventricular Assist Devices and Lung Assist Devices in PAH

In patients with PAH who eventually fail medical therapy, a few mechanical therapies exist that can play a role in RV salvage. Atrial septostomy (AS) is the iatrogenic creation of an atrial septal defect which serves to offload the RV in face of a high PVR. It is rooted in evidence that PAH patients with Eisenmenger syndrome, as well as patients with a patent foramen ovale, tend to do better long-term^{81, 82}. Typically performed by experienced interventional cardiologists using a blade septostomy approach with a series of balloon dilatations⁸³, AS may increase CI, decrease right atrial pressure, improve symptoms and exercise tolerance⁸⁴. However, the risks of cardiac tamponade, arrhythmia and refractory hypoxemia are substantial. Patients with severe PAH, defined by a markedly elevated PVR, maximal arterial oxygen saturations of 80% at rest, and severe right-heart failure with low CO and high RAP are at higher risk for death⁸⁵. While this approach is used in some centers purely as a bridge to transplantation or palliative salvage therapy, there is evidence that earlier performance of AS is safer and possibly more effective⁸⁶.

The key to patient candidacy for atrial septostomy is early selection in patients with moderate to severe disease where the procedure is considered elective rather than “rescue” therapy⁸⁶. Extracorporeal membrane oxygenation (ECMO) or extracorporeal life support (ECLS) in conjunction with targeted PAH therapy is considered a mechanical-medical bridging therapy. Until recently, adverse effects of veno-arterial (VA) ECMO (including deconditioning, bleeding, thromboembolism, limb ischemia, cerebral hypoxia and pulmonary hemorrhage) have limited its utility^87,88 in the PAH patients awaiting lung transplantation. Small but promising case series data is emerging from experienced ECMO centers. Rosenzweig et al.⁸⁹ for example presented six PAH patients from 2009-2012 who were placed on physiologic VA-ECMO with either bridge to transplant (BTT) or bridge to recovery (BTR) intent. Bridge to recovery patients were deemed eligible for VA-ECMO by the consensus of a multidisciplinary team of PAH specialists, cardiothoracic surgeons, ECMO-critical care specialists and neurologists. The two transplant–eligible patients underwent successful BTT. Three of the four BTR patients survived until ECMO decannulation. Notably, PAH medical therapy was typically down-titrated in BTT patients to limit the hemodynamic side effects of PAH therapy on ECMO while it was up-titrated in BTR patients, highlighting the importance of specialized knowledge of potential medical-mechanical therapeutic interactions. Finally, an extubated, upper-body VA-ECMO cannulation approach was utilized to allow for ambulation and participation in physical therapy and to avoid the deleterious impact of general anesthesia and intubation on the right heart. This upper-body strategy to VA-ECMO is detailed by Abrams et al.⁹⁰ and Olsson et al.⁹¹ who present generally successful results. Future studies are needed to prospectively evaluate the utility and appropriateness of ECMO as either BTT or BTR intent.

Right ventricular assist devices (RVADs) have been successful in RV failure in the setting of biventricular heart failure, after left (L) VAD placement, and after heart transplantation⁹². Essentially, the RVAD is an internal device with its inflow cannula typically placed in the RA and its outflow cannula in the PA. Computational RVAD model data⁹² and two case reports^88,93 of RVAD use in cardiogenic shock secondary to PAH demonstrate RV unloading by decreases in RAP and improvement in CO at the expense of increasing PAP and pulmonary capillary wedge pressures (PCWP). Increases in PAP and PCWP in the RVAD model system seem to occur in an RVAD-flow dependent manner⁹² and hence low-flow support might be better tolerated. Given the intrinsic increased and fixed PVR in PAH, implementation of RVAD maybe problematic given the theoretical concern for resulting pulmonary vascular damage⁹⁴. The utility of RVAD therapy as bridge to recovery or transplantation will require further research and comparison with other mechanical support strategies and is not currently routinely performed in PAH.

The lung assist device (LAD) membrane oxygenator system, or Novalung®, is a pumpless device which relies on the pressure gradient between the pulmonary artery and left atrium to function^95-97. Novalung® is the most promising of the mechanical support strategies for PAH and is gaining momentum as RV salvage technology because of its ability to partially bypass the high resistance pulmonary vascular bed. Novalung® is connected to the heart and lungs in parallel, as opposed to in series as the RVAD system; this allows for the lowest resistance circuit possible. Essentially, the LAD’s inflow cannula is placed in the main PA and the outflow cannula in the LA, creating a shunt across the damaged pulmonary vasculature. It is an external device that typically receives approximately20% of total CO^95-97. Usually, this degree of blood flow is sufficient in removing carbon dioxide, but not in improving oxygenation. Severe hypoxemia mandates LAD modifications⁹⁷ which are challenging but technically feasible. Such approach importantly evades the requirement for intubation and mechanical ventilation. Schmid et al.⁹⁶ reported a case of a PAH patient who survived 62 days on an LAD before undergoing successful bilateral lung transplantation. Strueber et al.⁹⁵ reported four cases of PH patients (three pulmonary veno-occlusive disease patients and one CTEPH patients) who developed refractory cardiogenic shock and survived 8-30 days on an LAD until successful heart-lung or bilateral lung transplantation with dramatic improvements in hemodynamics, inotropic requirements and gas exchange parameters in the interim. Of note, two of the four patients required ECMO upon LAD implantation, due to complications of general anesthesia. Therefore, it should be recognized that LAD implantation is not without risk and requires a skilled, multidisciplinary team experienced with both ECMO and LAD technologies. If the early experience with LAD strategy continues to show promise in larger series, it may address the dilemma of long transplant waiting times which are still common for PAH patients in the post LAS era^34,35. Regardless of the modality, the use of assist devices as a BTT in PAH remains extremely rare³⁶, but promising for the future.

3. STRUCTURE AND FUNCTION OF A PAH PROGRAM

The structure and function of modern day pulmonary vascular disease programs is highly specific to the environment in which they function. Community-based programs are typically set in private-practice models and thus are highly focused on the clinical care of PAH patients with some involvement in pharmaceutical clinical trials. Academic programs on the other hand are usually a combination of clinical expertise along with basic, translational, or clinical research programs depending on the depth and breadth of experience. Like other academic programs, our mission in the Stanford Adult Pulmonary Hypertension Program is to provide excellent patient care, carry-out cutting-edge clinical-translational research, and provide an educational environment for training physicians in pulmonary vascular diseases. As such, we have developed a clinical service comprised of 1 medical director, 5 attending physician (combination of clinical and basic research scientists), 2 nurse practitioners, 1-2 pulmonary vascular “super-fellows” (post-graduate pulmonary or cardiology fellows training in pulmonary vascular diseases for 12 months), 1 medical social worker, 3 clinical research staff, and 3 patient coordinators. While modest in size, in order to realize the educational and research goals of a rare-disease program, we have established a multidisciplinary structure optimizing clinical care-research interactions (Figure 4). For example, during outpatient clinic visits, several research associates also attend clinic to screen clinical trials subjects, consent and collect samples for database and biobank.

Figure 4.

Schematic depicting a clinical and research collaborative model build around pulmonary hypertension academic programs.

With the expansion of knowledge and sub-specialization in pulmonary vascular diseases and advent of numerous therapeutics, it is vital that programs with specific expertise in PAH become organized and meet consensus recommendations of practice, particularly in terms of diagnostic methods. As such, the pulmonary hypertension care centers (PHCC) initiative led by the Pulmonary Hypertension Association (PHA) is an organized attempt at harmonizing care provided to patients with pulmonary hypertension in the United States. With the implementation of specific criteria and benchmarks, including quality and depth of center experience, degree of infrastructure, referral/care model, and commitment to research, the goal of the PHCC is to improve overall quality of care and ultimately to improve outcomes (http://www.phassociation.org/PHCareCenters).

Research perspective / commitment as an academic institution

With the full recognition that care of PAH patients occurs at variety of types of institutions (from community to major tertiary medical centers with or without academic programs), patients with such a rare and lethal cardiopulmonary disease should have access to cutting edge clinical research - both clinical trials as well as observation registries and bio-banking programs. These initiatives are usually instituted at academic centers where active, bi-directional collaboration between the basic and clinical scientists exist (Figure 4). A highly productive model would be based on mutual collaboration between bench science and clinicians in which active bi-directional collaboration would initiate laboratory based approaches which ultimately can empower future therapeutic testing in the clinical environment. There are numerous global examples of such research pipeline such as the repurposing of Dichloroacetate (DCA)⁹⁸ (ClinicalTrials.gov Identifier NCT01083524), Imatinib^99-101, and FK506 which has recently taken place at our institution¹⁰² (ClinicalTrials.gov Identifier NCT01647945).

Prerequisites for success of translational research are a supportive institutional environment that fosters basic and clinician scientists to engage in research in PAH as well as a clinical team that is well connected with the research team and eager to translate scientific findings into the clinic. Two important tools which have facilitated clinical and translational research at our institution have been the clinical database and tissue biobank. The Vera Moulton Wall Center PH database (VMWC-DB) was established in 2000 and has collected records of more than 1,000 patients with PH from 1996 to present. This relational database captures more than 300 demographic, clinical, and research related parameters and was originally designed on an Access platform which required clinical staff to collect and enter all data manually – a tremendously time consuming process. With the implementation of electronic medical records (EMR), our database has now migrated to an Oracle platform with back-end access to EMR substantially reducing the manual data entry needs. While it is difficult to report exact cost, we estimate the initial development and implementation of VMW-DB cost approximately $250,000 and has required on-going programing, up-keep, and server fees along with 1 full time database manager support. Initiated in 2006, our tissue biobank has been tasked with collecting blood, urine, saliva, and exhaled breath condensate from control and PH patients. Initially, we attempted to collect samples at baseline and every six months in any clinical environment. However, we found this process to be complex and usually incomplete, especially in the outpatient setting. We have now formulated a coordinated protocol which samples fasting subjects prior to cardiac catheterization which not only allows for available hemodynamic correlates but also standardizes collection. The task of biobanking also creates the need for data management (i.e. sample inventory and tracking). Until recently we have used Freezerworks Unlimited software (Dataworks Development, Inc. Mountlake Terrace, WA) but have now integrated biobank data into our own databse. Implementation and upkeep of our biobank has required 1-2 full time research associate support beyond the basic facilities costs. Finally, it has been extremely useful that our research associates are integrated to the clinical workings of the service and have paging/call access for collection of samples at unusual times such as is customary with transplant tissue procurement. The availability of such infrastructure along with academic collaboration facilitate initiation of institution-base studies which have the advantage of evaluating multiple clinical and translational research questions and may eventually lead to multi-center phase II/III trials when appropriate.

While participation in multicenter clinical trials are encouraged, not every tertiary PAH center participates in every study. A national and international network and subsequent collaboration of PAH centers could allow for development of research infrastructure, including cross referrals and inclusion in clinical trials in a different center in close proximity. The ClinicalTrials.gov (www.clinicaltrials.gov) and PHA (http://www.phassociation.org/Patients/Research) are simple accessible platforms which provide overview and information about all trials for PAH and should be used as a reference for patients and physicians. During the clinic visit the patient should ask the PAH physician about current clinical trials, the individual might qualify for. The PAH physician then should explain the details of the trial, the proposed mechanism of action, whether a special sub-type of PAH is targeted in the trial and what the risks and benefits might be for the patient. Although often not of immediate clinical benefit for a patient, participation in a clinical trial has the advantage of close follow-up by the PAH team, a possible earlier availability of a study drug and of knowing that by participating in a clinical trial, research in PAH is advanced with possible implications for future PAH treatments. Emerging new treatments and targets for PAH that are currently in clinical phase I-III trials are summarized in Table 2.

Table 2.

Emerging Therapies

Drugs	Proposed Mechanism	NCT Identifier	Clinical trial
Vasodilators
Sapropterindihydrochloride (6R- BH4)	Increase Nitric oxide	NCT00435331	Phase I
Selexipag	Non-prostanoid IP receptor agonist	NCT01106014	Phase III
Inhaled nitric oxide	Increase Nitric oxide	NCT01457781	Phase II
Beet Juice	Increase Nitric oxide	NCT02000856	Phase I
Apelin	Increase Apelin levels with infusion	NCT01590108	Phase I
Cardizem	Calcium Channel Blockade	NCT01645826	Phase III
Inhaled Nitrite	Increase Nitric oxide	NCT01431313	Phase II
Ranolazine	Inhibition of Sodium Current	NCT01757808	Phase I
		NCT01953965	Phase II
Metabolism
Dichloroacetate	Inhibition of of Pyruvate Dehydrogenase Kinase	NCT01083524	Phase I
Anastrazole	Aromatase Inhibitors	NCT01545336	Phase II
Ferinject	Target Iron deficiency	NCT01288651	Phase II
Right Ventricular Remodeling
Carvediol	HIF activation, NO synthesis, beta-adrenergic recovery	receptor	NCT01586156 Phase II
Cell Damage/ endothelial dysfunction
Coenzyme Q-10	Antioxidant	NCT01148836	unkown
(−)-Epicatechin	Improvement of endothelial function	NCT01880866	Phase I
Anti-Proliferative
Sorafenib	Inhibition of protease-activated receptor (PAR)	NCT00452218	Phase I
Hydroxyurea	Decrease level of circulating immature bone marrow cells	NCT01950585	Phase 0
Nilotinib	Tyrosin Kinase Inhibitor	NCT01179737	Phase II
Anti-Inflammatory
Rituximab	Restore B-cell dysregulation	NCT01086540	Phase II
Bardoxolone Methyl	Nrf2 and NF-κB suppression	NCT02036970	Phase II
Saquinavir and Ritonavir	HIV protease inhibitors	NCT02023450	Phase 0
TheraSorb® Ig flex adsorber	Immunoabsorption	NCT01613287	Medical Device
BMPR2 modulators
FK506	Increasing BMPR2 signaling	NCT01647945	Phase II

Historically, major therapeutic clinical trials (both pre-clinical as well as pivotal studies) have been largely sponsored by the pharmaceutical industry. The success of the last two decades has been the advent and approval of therapeutics that have altered the course of PAH but are arguably not curative. These organizations have assumed great financial risks in order to bring therapeutics to the field and are positioned in an expert role in conduct of major multi-center, global clinical trials. We believe that the time has come to foster a different brand of collaboration for rare disorders such as PAH – closer collaboration between industry, academic institutions, and governmental research institutions such as the United States National Institutes of Health (NIH). The advantage of collaborative trials conducted by an industry-NIH collaborative would be combination of expertise in clinical trial design and management, organizational support, cost-sharing, as well as establishment of early proof of concept clinical trials which offer the most potential for discovery of curative therapies but are deemed financially “high risk”. Such initiatives could also expedite novel clinical trial design¹⁰³ to overcome the limitations of current studies. Ultimately, complacency with the current process of drug discovery may result in continued production of highly specific “me too” drugs – only improving specific aspects of existing therapeutics. Ideally, an academic-industry collaborative would be tasked to better define “disease modification” as a necessary concept in the path to “curative” therapeutics and encourage the testing of such modalities.

The current era of PAH management is characterized by increasingly number of therapeutics, more clinical sub-specialization, and more complex clinical decision making – a process in which not only the clinician but also the patient must actively participate. Initiatives such as large registries^5,6,104 have transformed our clinical understanding and have allowed a deeper understanding of concepts such as risk stratification and early diagnosis. The next phase of growth for the field should come from refinement of practice standards, both scientifically through clinical studies as well as structurally. Initiatives, such as the PHA PHCC to standardize practice patterns are highly relevant for countries (such as the United States of America) where the care of PAH patients is not centralized (compared to those in France and the United Kingdom). Finally, development of future therapeutics should focus on characterization and testing of disease modifying drugs.

A Patient Asks Questions….

You mentioned that there are 3 classes of medications available to me; which is the best? Will I eventually be in all of them? I am insured but will I be able to afford this? – treatments appear to be so expensive…

It depends on the severity of the disease at diagnosis, feasibility, the patient’s preference, the PH center’s expertise and unfortunately insurance coverage which drug a patient will be started on. If the patient is in WHO functional class II/III (in other words moderate to moderately severe disease), oral phosphodiesterase type 5 inhibitors (the first drug on this class approved in PAH was sildenafil, and others followed) or endothelin receptor antagonists (the first drug on this class approved in PAH was bosentan and others followed) would be the current preferred choice. For WHO functional class IV (i.e. severe disease), most PAH clinicians in the US would choose an intravenous prostacycline. No head to head study has been done to answer which drug is superior to another. Combination therapy (in other words use two or three classes of medications at the same time) is very common and is currently evaluated as a first line therapy (i.e. start two classes of drugs from the beginning, instead of starting one and adding another later on).

In the US, patient assist programs are in place for all available drugs to help with drug cost coverage. Patients should ask their physician and social worker for information about financial aid. In Canada and many European countries approved therapies are covered for all patients at no or low cost.

Research is actively performed to potentially discover which class of medications is best for a given patient. This may dramatically facilitate our decision making for the best choice of therapy, as more drugs are getting approved.

Should I be optimistic about the future? It appears that there are so many cures for PAH in animal research but the currently available therapies do not cure the disease – why?

The research in humans with therapies developed in animals is called “translational research” and we now know that it “suffers” not only in the PAH field but across all the fields of medicine. It is a complicated, long and often quite expensive process. The scientific community is now specifically focusing to increase the efficiency of transferring knowledge from animals to patents and young physicians and scientists are starting to be gain the required skills. The field of PAH is still relatively new and considering that it often takes 10 years to prove that a promising therapy in animals is also effective in humans, we expect to see many more new therapies entering clinical trials in the immediate future. New theories hold promise for the development of more effective drugs with fewer side effects than the currently available ones. Many promising drugs developed from animal studies and currently evaluated in clinical trials are reviewed in this Compendium and in addition to this, they are also listed in the next two papers.

You mentioned there will be many research trials in the future that I may consider. How should I be best informed on which one is the most promising?

The best resource to learn about clinical trials in PAH is the PH physician in a specialized PAH center. In addition, the ClinicalTrials.gov (www.clinicaltrials.gov) and PHA websites (http://www.phassociation.org/Patients/Research) are simple accessible platforms, which provide overview and information (in a language often appropriate to be understood by the average informed patient) about all ongoing trials for PAH and should be used as a reference for patients and physicians alike.

For the case description, see introductory article by E.D. Michelakis, page xxx

Non-standard Abbreviations and Acronyms

6MWD

Distance Walked in 6 Minutes

BTT

Bridge To Transplantation

BTR

Bridge To Recovery

CTD-APAH

Connective Tissue Disease associated PAH

ECMO

Extracorporeal Membrane Oxygenation

ERA

Endothelin Receptor Antagonist

HPAH

Heritable PAH

IPAH

Idiopathic PAH

LVAD

Left Ventricular Assist Device

LAD

Lung Assist Device

NT-pro BNP

N-terminal pro B-type Natriuretic Peptide

PAH

Pulmonary Arterial Hypertension

PDE-5i

Phosphodiesterase-5 Inhibitors

PHCC

Pulmonary Hypertension Care Centers

PHA

Pulmonary Hypertension Association

RV

Right Ventricle

RVAD

Right Ventricular Assist Device

RVSP

Right Ventricular Systolic Pressure

VE/VCO₂

Ventilatory Equivalent for Carbon Dioxide