Use of outcome measures in pulmonary hypertension clinical trials

    Use of Outcome Measures in Pulmonary Hypertension Clinical Trials Kishan S. Parikh MD, Sudarshan Rajagopal MD, PhD, Kristine Arges BS, Tariq Ahmad MD, MPH, Joseph Sivak MD, Prashant Kaul MD, Svati H. Shah MD, MHS, Victor Tapson MD, Eric J. Velazquez MD, Pamela S. Douglas MD, Zainab Samad MD, MHS PII: DOI: Reference:

S0002-8703(15)00384-1 doi: 10.1016/j.ahj.2015.06.010 YMHJ 4926

To appear in:

American Heart Journal

Received date: Accepted date:

16 June 2015 16 June 2015

Please cite this article as: Parikh Kishan S., Rajagopal Sudarshan, Arges Kristine, Ahmad Tariq, Sivak Joseph, Kaul Prashant, Shah Svati H., Tapson Victor, Velazquez Eric J., Douglas Pamela S., Samad Zainab, Use of Outcome Measures in Pulmonary Hypertension Clinical Trials, American Heart Journal (2015), doi: 10.1016/j.ahj.2015.06.010

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Use of Outcome Measures in Pulmonary Hypertension Clinical Trials

Kishan S. Parikh, MD1, Sudarshan Rajagopal, MD, PhD1,2*, Kristine Arges, BS1*, Tariq

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Ahmad, MD, MPH1, Joseph Sivak, MD1, Prashant Kaul, MD3, Svati H. Shah, MD, MHS1,

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Victor Tapson, MD4, Eric J. Velazquez, MD1,5, Pamela S. Douglas, MD1,5, Zainab Samad, MD,

Division of Cardiology, 2Center for Pulmonary Vascular Diseases, Department of

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MHS1

Medicine, Duke University Medical Center, Durham, NC

Center for Pulmonary Vascular Diseases and Venous Thromboembolism, Cedars-Sinai

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Division of Cardiology, University of North Carolina, Chapel Hill, NC

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Medical Center, Los Angeles CA

Duke Clinical Research Institute, Durham, NC

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Co-authors contributed equally to the manuscript

Brief title: Outcome Measures in PH Trials Funding Source: This study was internally funded by the Division of Cardiology, Duke Medicine Correspondence to: Zainab Samad, MD, MHS DUMC 3254 Durham, NC 27710 Phone: (919) 684-7097 Fax: (919) 668-3575

ACCEPTED MANUSCRIPT Abstract Objectives: To evaluate the use of surrogate measures in pulmonary hypertension (PH) clinical

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trials and how it relates to clinical practice.

Background: Studies of pulmonary arterial hypertension (PAH) employ a variety of surrogate

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measures in addition to clinical events because of a small patient population, participant burden,

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and costs. The use of these measures in PH drug trials is poorly defined. Methods: We searched PubMed/MEDLINE/Embase for randomized or prospective cohort PAH

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clinical treatment trials from 1985 to 2013. Extracted data included intervention, trial duration, study design, patient characteristics, and primary and secondary outcome measures. To compare

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with clinical practice, we assessed the use of surrogate measures in a clinical sample of patients

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on PH medications at Duke University Medical Center between 2003 and 2014.

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Results: Between 1985-2013, 126 PAH trials were identified and analyzed. Surrogate measures served as primary endpoints in 119 trials (94.0%). Inclusion of invasive hemodynamics

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decreased over time (78.6%, 75.0%, 52.2%; P for trend = 0.02), while functional testing (7.1%, 60.0%, 81.5%; P for trend <0.0001) and functional status or quality of life (0%, 47.6%, 62.8%; P for trend <0.0001) increased in PAH trials over the same time periods. Echocardiography data was reported as a primary or secondary outcome in 32 trials (25.4%) with increased use from 1985-94 to 1995-2004 (7.1% vs. 35.0%, P = 0.04), but the trend did not continue to 2005-2013 (25.0%). In comparison, among 450 patients on PAH therapies at our institution between 20032013, clinical assessments regularly incorporated serial echocardiography and 6-minute walk distance tests (92% and 95% of patients, respectively) and repeat measurement of invasive hemodynamics (46% of patients).

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ACCEPTED MANUSCRIPT Conclusions: The majority of PAH trials have utilized surrogate measures as primary endpoints. The use of these surrogate endpoints has evolved significantly over time with increasing use of

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patient-centered endpoints and decreasing or stable use of imaging and invasive measures. In

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contrast, imaging and invasive measures are commonly used in contemporary clinical practice.

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Further research is needed to validate and standardize currently used measures.

Key Words: pulmonary hypertension; clinical trials; surrogate endpoints; echocardiography

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Abbreviations list: pulmonary hypertension (PH); pulmonary arterial hypertension (PAH); World Health Organization (WHO): phosphodiesterase-5 (PDE5); right ventricle (RV); tricuspid

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annular plane systolic excursion (TAPSE); 6-minute walk distance (6MWD)

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ACCEPTED MANUSCRIPT Introduction The diagnosis of pulmonary arterial hypertension (PAH) portends a poor outcome (1)

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despite the development of therapies targeting functional capacity, mortality and disease

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progression (2-7). Surrogate endpoints have played a critical role in PAH clinical trials because of disease rarity, participant burden and cost. However, the utility of surrogate measures of

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disease progression is poorly understood. Prior PAH risk scores have primarily relied on baseline

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assessments, but recent studies suggest that serial changes in several surrogate measures may be more predictive than initial measurements (8-14). Appropriate utilization of cardiac imaging is

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particularly unclear. Although right heart function deterioration is the central determinant of outcome in PAH (15-19), and echocardiography is recommended for the evaluation of the right

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heart in patients with known or suspected PH (3,20-22), the choice and use of echocardiographic

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parameters reporting on the right heart in clinical trials is not well-described. As the PH clinical research landscape evolves, a comprehensive understanding of

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endpoints that have been utilized in PH clinical trials and practice is necessary to inform future

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research design methodology and clinical management. To address this question, we performed a systematic review of clinical drug trials in PAH to describe the use of surrogate endpoints and outcome measures. As a secondary aim, to compare and contrast how surrogate endpoint selection in PAH trials corresponds to clinical practice, we retrospectively reviewed practice patterns of a pulmonary arterial hypertension clinic at a single tertiary medical center.

Methods We performed searches of PubMed, Embassy and Cochrane databases for all manuscripts resulting from trials published from January 1, 1985 through January 1, 2014 studying a

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ACCEPTED MANUSCRIPT therapeutic intervention in any population of PH patients. Specifically, the PubMed keyword searches included: “pulmonary hypertension” AND “trial” with the following limits: Humans;

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English; Adult: 19+ years; Clinical Trial. Analogous searches were performed for other

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databases. Retrospective studies, reviews, editorials, and case reports were excluded. Two reviewers extracted data from the relevant articles’ texts, tables and figures and included the

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following: journal, first author, year of publication, geographic region of study, study

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intervention, dose, duration, PH group, study size, study design, endpoints including whether primary or secondary, outcome (surrogate measures, survival, or composite measure

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incorporating survival), phase of study (I-IV), and timeline of assessment. Surrogate measures were categorized as one of the following: right heart catheterization, echocardiography, cardiac

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MRI, functional assessment (e.g., NYHA or WHO functional class, Borg dyspnea scale), quality

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of life assessment (e.g., questionnaire), 6 minute walk distance (6MWD), laboratory biomarkers (e.g., BNP), cardiopulmonary exercise test, pulmonary function test. The levels of evidence

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supporting surrogate endpoints were described using a previously published algorithm (Level I,

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true clinical efficacy end point; Level II, validated surrogate endpoint; Level III, nonvalidated surrogate endpoint; Level IV, measure of biologic activity) (23). Trials were then divided by 10year intervals (1985-1994, 1995-2004, 2005-2013) to assess trends as new classes of drugs and surrogate measures were studied. In order to understand how these findings would compare with real world practice, we utilized the Decision Support Repository (DSR), a Duke University Health System electronic data warehouse that houses aggregate clinical data of patients (20,24). Patient data available in the database includes lab data, demographics, ICD-9 diagnoses, medications, and computerized physician order entry orders and its setup has been previously published (20,25). We queried the

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ACCEPTED MANUSCRIPT DSR for a cohort of PAH patients prescribed at least one of three classes of drugs for pulmonary hypertension (prostacyclin analogs, endothelin antagonists, and phosphodiesterase 5 [PDE5]

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inhibitors) between 2003-2013 using previously described methods (16,26). This time interval

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was chosen to reflect modern PH practice patterns as closely as possible. Procedures performed for this cohort (echocardiogram, six-minute walk test, and right heart catheterization) were

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identified using Current Procedural Terminology (CPT) codes. Tests included in the analysis

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may have been obtained before or after drug therapy had been initiated but were ordered for monitoring PH, and this indication was confirmed through analogous searches of cardiac

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catheterization and echocardiography databases. The study was approved by the Duke University Institutional Review Board.

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The statistical software program Prism (GraphPad; Version 5.0; LaJolla, CA) was used

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for all statistical calculations. Changes in trial design over time were assessed using the Chi-

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Results

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squared test for trend. A P-value < 0.05 was considered statistically significant.

Pulmonary Hypertension Clinical Trial Design Our literature search yielded 126 trials published between January 1, 1985 and December 31, 2013. The majority of studies (78%) were comprised of patients with PAH (WHO Group 1). Early phase (I-II) trials accounted for 65 studies (52%). By 10 year intervals, 14 of the trials (11%) were published in 1985-94, 24 trials (19.0%) in 1995-2004, and 88 (70%) in 2005-13. Endothelin receptor antagonists were the primary focus of study in 25% of the trials, PDE5 inhibitors in 20% of trials, and prostacyclins in 28% of trials. The remaining trials examined other therapies or combination regimens. Randomized controlled trial design was employed in

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ACCEPTED MANUSCRIPT 73 trials (58%), and the remaining were prospective, open-label and/or single arm trials. Study population sizes ranged between 4 and 742 subjects (median 32, interquartile range [IQR] 18-

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91). Length of follow-up to assess therapeutic response varied greatly, extending from

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immediately after the first dose (hemodynamic changes) to three years. The availability of longterm data was overall limited: 53 trials reported data past 12 weeks, and of these, only 10 trials

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included follow up past 1 year. Follow-up length did not appear to differ between Phase I-II

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clinical trials (mean 25 weeks, median 16 weeks) and Phase III-IV clinical trials (mean 24 weeks, median 16 weeks).

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Trends in Selection of Endpoints in PH Trials

Survival was specified to be the primary endpoint in three trials (2% of all trials, 5% of

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late phase trials). Surrogate measures were primary endpoints in 120 trials (95%) and secondary

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endpoints in 42 trials (33%) (Table 1). A composite clinical outcome, most commonly time to clinical worsening (TTCW), was utilized as either a primary or secondary outcome measure in

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26 trials (21%) and was used more frequently as an outcome in more recent publications (1985-

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1994, 0 trials; 1995-2004, 5 trials; 2005-2013, 21 trials, P for trend = 0.04). A summary of the trials arranged by year published is displayed in Supplemental Table 1. Several surrogate measures have been used in the reviewed PH trials. Individual surrogate measure’s frequency of use and level of validation are listed in Figure 1. Echocardiography data was reported as a primary or secondary endpoint in 32 trials (25%) overall with increased use as an outcome over time from 1985-94 to 1995-2004 (7% vs. 35%, P = 0.04), but the trend did not continue to 2005-2013 (25%). The use of invasive hemodynamics as an endpoint in trials decreased over time (79%, 76%, 52%, P for trend = 0.02), and incorporation of 6MWD (7%, 57%, 80%; P for trend <0.0001) and functional status or quality of

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ACCEPTED MANUSCRIPT life (0%, 48%, 63%; P for trend <0.0001) increased in PH drug trials over the same time periods. As primary endpoints only, the use of invasive hemodynamics and PFTs declined (P<0.01;

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P<0.05, respectively); the use of 6MWD as a primary outcome significantly increased over these

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time periods (P<0.0001) (Figure 2). Because of their common employment and discrepant frequencies, invasive hemodynamics, 6MWD, and echocardiography as endpoints were also

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examined by grouping studies as early (I-II) or late (III-IV) clinical phase (Table 1).

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The specific echocardiographic variables reported varied significantly and are listed in Table 2 with rates of utilization in trials. Ten of the 32 studies were multicenter trials; none of

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them reported employing core laboratories to facilitate and standardize echocardiographic measurements.

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Sample Size and Power

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We also sought to determine whether later phase clinical trials have been adequately powered to detect minimal important differences in commonly used primary endpoints. A recent

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analysis of the PHIRST trial studying tadalafil in PAH approximates the clinically significant

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threshold change (relative to standardized quality of life assessment) in 6MWD to be 33 ± 9.2 meters (27). To detect such a difference (α=0.05, β=0.2), the study size should include at least 170 subjects. In our analysis, 17/47 (36%) of the Phase III/IV trials with 6MWD specified as a primary endpoint had study size greater than 170 subjects. We were limited by available data to calculate adequate sample size for other commonly used primary endpoints. Use of Surrogate Measures in Clinical Practice We identified 450 patients prescribed medications for PH in 2003-2014 at Duke University Medical Center. Almost all patients received at least one right heart catheterization (448, 99%), echocardiogram (448, 99%), and 6MWD evaluation (447, 99%). Over this period,

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ACCEPTED MANUSCRIPT most PH patients underwent serial assessments in follow-up including right heart catheterization (mean 1.9 catheterizations; median 1, IQR 1-2); echocardiogram (mean 7.2 echocardiograms;

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median 7, IQR 4-10); 6MWD test (mean 11 walk tests; median 9, IQR 5-16). Time intervals

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between repeated assessments were the following: right heart catheterization (mean 152 days; median 126, IQR 97-182); echocardiogram (mean 260 days; median 217, IQR 172-329); 6MWD

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test (mean 152 days; median 126, IQR 97-182) (Table 3).

Discussion

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Through a comprehensive systematic review, we have identified several important trends in the use of endpoints in PAH clinical trials and their differences from clinical practice at a

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typical PH tertiary medical center. First, there was a significant change in the choice of surrogate

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measures that served as primary endpoints in the vast majority of PAH trials over time. We found an increasing use of 6MWD, functional status assessment, and clinical composite

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outcomes as primary endpoints, and stable to declining use of right heart catheterization and

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echocardiography. Second, we found that the decreasing use of right heart catheterization and echocardiography was in contrast to their near universal use in the clinical setting. Third, the likely causes for the decreasing use of imaging in these trials include 1) the absence of a standard set of imaging parameters; 2) the selection of parameters that do not report on RV function, and 3) the absence of core laboratories to ensure proper techniques for obtaining these parameters and to minimize variability in their reporting. These systematic problems in the implementation of imaging endpoints in previous PAH trials has limited the development of imaging surrogate measures that report on RV function and could serve as useful endpoints in early phase trials and to guide clinical management.

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ACCEPTED MANUSCRIPT Outcome Measures in PAH Trials Survival and Follow-up Periods

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We found very few clinical trials assessing survival as a primary endpoint. Therefore, a

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wide variety of surrogate measures were used as primary or secondary endpoints in the majority of trials. Surrogate endpoints should ideally be able to be objectively measured with minimal

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interobserver measurement variability; report on biologic/pathogenic processes or pharmacologic

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response to a therapeutic intervention; and represent the entire impact on a clinically meaningful end point (e.g., mortality or response to therapy) (21,28,29). They should also be well-validated,

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ideally before use in research or clinical practice (30). Even with all of the studies that have already been performed, it is still unclear at this point whether surrogate measures employed in

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PH clinical trials fulfill these criteria. Most trials had very limited follow-up regardless of

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clinical phase. It is possible that this approach was taken to reduce participant burden and cost. Selection of Endpoints

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Among phase III/IV clinical trials, invasive hemodynamics and 6MWD test were

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employed as a primary or secondary endpoint 64% and 90% of the time, respectively, thus providing a substantial evidence base to understand the utility of these surrogate measures in context. However, only 14 of the phase III/IV trials (23%) have used echocardiography as a primary or secondary endpoint. Furthermore, like in other diseases, measuring changes in these metrics in PH can be difficult and confounded. Because 6MWD improvement was previously an adequate endpoint for PAH drug approval, many trials have used this as their benchmark. As more PH drugs and combinations have become therapeutic options, regulatory agencies have been requiring “harder” endpoints to demonstrate benefit (30).

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ACCEPTED MANUSCRIPT PAH trial designs have more recently employed a composite TTCW endpoint of several outcome measurements, including death, hospitalizations and clinical worsening, frequently

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defined as a worsening in six minute walk distance or functional class, and need for additional

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PH therapies (2,31). We found a significant increase in its use over the last 10 years. While a composite endpoint increases trial sensitivity by increasing the number of patients meeting

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endpoints, it will have limited and overestimated value if its components have varying clinical

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relevance (23). For example, TTCW incorporates death, hospitalization for worsening PH, initiation of intravenous therapy, and worsening of functional class (2). Although clinical

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composite outcomes such as TTCW appear to be attractive primary endpoints, they are largely driven by the “softer” endpoints of hospitalization and clinical worsening and require large

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sample sizes that are not feasible in early phase trials (32). Moreover, it appears that such

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worsening is preceded by changes in RV geometry and function, which may be a more sensitive measure for worsening PH (33).

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6 Minute Walk Distance Test

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We found the 6MWD test to be the most commonly used primary endpoint with significantly increased use over the last two decades. 6MWD is easy to measure and noninvasive but is also dependent on patient effort and comorbidities. Several recent meta-analyses of PAH trials have consistently shown that while baseline 6MWD strongly predicts survival, changes in 6MWD in response to PH therapies did not predict disease outcomes (all-cause mortality, hospitalization for PAH, lung and or lung-heart transplantation, initiation of PAH rescue therapy, composite outcome) (9,11,12,34). With increasing use in clinical trials and prevalence in clinical practice, robust, prospective studies are needed to critically understand implications of the interval 6MWD test.

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ACCEPTED MANUSCRIPT Invasive Hemodynamics and Imaging as Outcome Measures

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Invasive Hemodynamics

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Invasive hemodynamics were previously the most commonly used surrogate measures used in PAH trials and in clinical practice, but our results show a trend towards declining use in

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clinical trials in recent years. Recent studies including study- and patient-level meta-analyses

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have questioned the ability of hemodynamic measures to predict clinical events in PAH therapy, which may underlie this trend toward declining use. A recent sensitivity analysis by Ventetuolo

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et al reported that changes in hemodynamics accounted for only 1.2-13.9% of the observed treatment effect (13,35).

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Imaging

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Of the many prognostic indicators available to clinicians, RV function has been shown to

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be one of the most important determinants of outcomes in PH (2,15,17-19). However, PH trials have not traditionally used it as an endpoint. It is possible that this trend is related to the

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problems revolving around reproducibility and quantification of RV function. Evaluation and reporting of echocardiographic parameters in PH trials appears to be decreasing over time and several reasons could account for this trend. First, various methods are available and used to assess RV pressures and function in PH trials as shown in Table 2. Because RV failure in PH manifests itself in multiple ways including changes in RV geometry, right-toleft interactions, and RV systolic dysfunction (2,4), a single metric has not been yet found to adequately report on all three aspects. Secondly, technical difficulties in reproducing right-sided measurements as well as operator and reader skill variability continue to be a major problem. In one study testing the reproducibility of several right sided echocardiographic measurements,

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ACCEPTED MANUSCRIPT interobserver variability correlation coefficients ranged between 0.27-0.79, and for intraobserver variability, 0.48-0.94 (3,8). As previously shown, the employment of core laboratories in future

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trials could greatly limit these sources of error (36). Echocardiography can provide a good estimate of RV function, yet its use to monitor

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patients on PAH therapies still lacks an evidence-based approach (1,15,17-19,37,38). The selection of echocardiographic parameters that do not report on RV function is likely the major

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contributor to the failure of echo endpoints in PH clinical trials. For example, the estimation of

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PA systolic pressure was the most frequently reported parameter in the trials utilizing echo, although PA systolic pressure is known to not be associated with outcomes in PAH (39). In

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contrast, a parameter that does assess RV function, the Tei index, has been studied prospectively and shown utility in follow-up monitoring (3,15-22). Of the echocardiographic markers we found

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to be most commonly reported (Table 2), only the Tei index, eccentricity index, pericardial

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effusion, TAPSE, and right atrial area have been shown to predict outcome in PH patients at baseline (40-43). A composite score/assessment may provide the most accurate

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echocardiographic evaluation of RV function (44) and merits further exploration. Recently, novel echocardiographic markers of RV function have been evaluated and compared against outcomes in PH patients. RV strain has recently been shown to be an independent predictor of future right heart failure and mortality in patients with pulmonary arterial hypertension (26) and in another study correlated with functional capacity more strongly than 2D echocardiographic indices (25). Three-dimensional echocardiography to assess right ventricular volume and function in patients with PH has been another promising technology that may be validated with further use in clinical trials (45,46).

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ACCEPTED MANUSCRIPT Study Size Using conservative estimates of the minimal important difference in 6MWD (27,47,48),

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we found that many phase III/IV PH clinical trials may have been underpowered for 6MWD as a primary endpoint. A hemodynamic surrogate may signal functional improvement either as an

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adjunct or even prior to observed changes in 6MWD. For example, a clinically significant change in RV stroke volume by MRI was found to be only 10 milliliters by using a receiver

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operator characteristic curve to estimate sensitivity 91% and specificity 91% against 6MWD

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change of 41 meters (49). Finally, a large trial studying TTCW for macitentan in PAH estimated a necessary sample size of 285 patients to detect HR=0.55 (macitentan vs. placebo) over 4.1

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years (α=0.01, β=0.1) (32). Using this approximation, future trial design with TTCW will likely

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Limitations

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need to incorporate sample sizes consistently larger than most prior PAH trials.

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The limitations of this systematic review are tied to the inherent limitations of the included studies. In the PAH drug trials utilizing echocardiography, whether the echocardiographic variables were predefined outcome measures was not always clearly defined. Our systematic review encompassed prospective trials of all PH groups and did not limit to WHO Group 1 (PAH) so that the search could be more comprehensive and findings more generalizable. Endpoints may have different implications with response to therapy between PH groups and this has yet to be tested.

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ACCEPTED MANUSCRIPT Conclusions Over the past three decades, the surrogate endpoints assessed in PAH trials have evolved

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significantly with stable to decreased use of invasive hemodynamics and echocardiography, and increased use of functional parameters and composite outcomes. Measures of RV function that

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are important determinants of outcome have yet to be consistently incorporated; this is especially true for echocardiography. While phase 3 RCTs will primarily use TTCW outcomes as their

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primary endpoint, they should also incorporate imaging endpoints that quantify RV function and

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that have been shown to predict outcomes. PH trial designs need to incorporate consistent, validated surrogate measures that truly reflect patient survival and quality of life. Especially in

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the case of imaging, the use of standardized data elements and parameter reporting along with the use of core laboratories across clinical trial phases will help achieve these ends. Trial designs

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that allow testing and validation of new surrogate measures while evaluating TTCW outcomes

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should be used to inform future research.

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Schulze-Neick I, Gilbert N, Ewert R, Witt C, Gruenig E, Enke B, et al. Adult patients with congenital heart disease and pulmonary arterial hypertension: first open prospective multicenter study of bosentan therapy. American Heart Journal. 2005 Oct;150(4):716.

130.

Seyfarth H-J, Pankau H, Hammerschmidt S, Schauer J, Wirtz H, Winkler J. Bosentan improves exercise tolerance and Tei index in patients with pulmonary hypertension and prostanoid therapy. Chest. 2005 Aug;128(2):709–13.

131.

Machado RF, Martyr S, Kato GJ, Barst RJ, Anthi A, Robinson MR, et al. Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension. Br J Haematol. 2005 Aug;130(3):445–53.

132.

Kataoka M, Satoh T, Manabe T, Anzai T, Yoshikawa T, Mitamura H, et al. Oral sildenafil improves primary pulmonary hypertension refractory to epoprostenol. Circ J. 2005 Apr;69(4):461–5.

133.

Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. New England Journal of Medicine. 2005 Nov 17;353(20):2148–57.

134.

Wilkins MR, Paul GA, Strange JW, Tunariu N, Gin-Sing W, Banya WA, et al. Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study. American Journal of Respiratory and Critical Care Medicine. 2005 Jun 1;171(11):1292– 7.

135.

Shen J, He B, Wang B. Effects of lipo-prostaglandin E1 on pulmonary hemodynamics and clinical outcomes in patients with pulmonary arterial hypertension. Chest. 2005 Aug;128(2):714–9.

136.

Morrell NW, Higham MA, Phillips PG, Shakur BH, Robinson PJ, Beddoes RJ. Pilot study of losartan for pulmonary hypertension in chronic obstructive pulmonary disease.

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MA

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RI P

T

125.

27

ACCEPTED MANUSCRIPT Respir Res. 2005;6:88. Galiè N, Badesch D, Oudiz R, Simonneau G, McGoon MD, Keogh AM, et al. Ambrisentan therapy for pulmonary arterial hypertension. JACC. 2005 Aug 2;46(3):529–35.

138.

Humbert M, Barst RJ, Robbins IM, Channick RN, Galiè N, Boonstra A, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004 Sep;24(3):353–9.

139.

Oudiz RJ, Schilz RJ, Barst RJ, Galiè N, Rich S, Rubin LJ, et al. Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease. Chest. 2004 Aug;126(2):420–7.

140.

Sastry BKS, Narasimhan C, Reddy NK, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. JACC. 2004 Apr 7;43(7):1149–53.

141.

Gonzalez-Lopez L, Cardona-Muñoz EG, Celis A, García-de la Torre I, Orozco-Barocio G, Salazar-Paramo M, et al. Therapy with intermittent pulse cyclophosphamide for pulmonary hypertension associated with systemic lupus erythematosus. Lupus. 2004;13(2):105–12.

142.

Barst RJ, Langleben D, Frost A, Horn EM, Oudiz R, Shapiro S, et al. Sitaxsentan therapy for pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine. 2004 Feb 15;169(4):441–7.

143.

Barst RJ, Mcgoon M, McLaughlin V, Tapson V, Rich S, Rubin L, et al. Beraprost therapy for pulmonary arterial hypertension. JACC. 2003 Jun 18;41(12):2119–25.

144.

Hoeper MM, Taha N, Bekjarova A, Gatzke R, Spiekerkoetter E. Bosentan treatment in patients with primary pulmonary hypertension receiving nonparenteral prostanoids. Eur Respir J. 2003 Aug;22(2):330–4.

145.

Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Kreckel A, et al. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. JACC. 2003 Jul 2;42(1):158–64.

146.

Ono F, Nagaya N, Okumura H, Shimizu Y, Kyotani S, Nakanishi N, et al. Effect of orally active prostacyclin analogue on survival in patients with chronic thromboembolic pulmonary hypertension without major vessel obstruction. Chest. 2003 May;123(5):1583–8.

147.

Galiè N, Humbert M, Vachiéry J-L, Vizza CD, Kneussl M, Manes A, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. JACC. 2002 May 1;39(9):1496–502.

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RI P

T

137.

28

ACCEPTED MANUSCRIPT Rubin LJ, Badesch DB, Barst RJ, Galiè N, Black CM, Keogh A, et al. Bosentan therapy for pulmonary arterial hypertension. New England Journal of Medicine. 2002 Mar 21;346(12):896–903.

149.

Simonneau G, Barst RJ, Galiè N, Naeije R, Rich S, Bourge RC, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. American Journal of Respiratory and Critical Care Medicine. 2002 Mar 15;165(6):800– 4.

150.

Vizza CD, Sciomer S, Morelli S, Lavalle C, Di Marzio P, Padovani D, et al. Long term treatment of pulmonary arterial hypertension with beraprost, an oral prostacyclin analogue. Heart. 2001 Dec;86(6):661–5.

151.

Launay D, Hachulla E, Hatron PY, Goullard L, Onimus T, Robin S, et al. Aerosolized iloprost in CREST syndrome related pulmonary hypertension. J Rheumatol. 2001 Oct;28(10):2252–6.

152.

Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001 Oct 6;358(9288):1119–23.

153.

Hoeper MM, Schwarze M, Ehlerding S, Adler-Schuermeyer A, Spiekerkoetter E, Niedermeyer J, et al. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med. 2000 Jun 22;342(25):1866– 70.

154.

Badesch DB, Tapson VF, Mcgoon MD, Brundage BH, Rubin LJ, Wigley FM, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med. 2000 Mar 21;132(6):425–34.

155.

Mclaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med. 1998 Jan 29;338(5):273–7.

156.

Shapiro SM, Oudiz RJ, Cao T, Romano MA, Beckmann XJ, Georgiou D, et al. Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion. JACC. 1997 Aug;30(2):343–9.

157.

Sajkov D, Wang T, Frith PA, Bune AJ, Alpers JA, McEvoy RD. A comparison of two long-acting vasoselective calcium antagonists in pulmonary hypertension secondary to COPD. Chest. 1997 Jun;111(6):1622–30.

158.

Hinderliter AL, Willis PW, Barst RJ, Rich S, Rubin LJ, Badesch DB, et al. Effects of long-term infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension. Primary

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29

ACCEPTED MANUSCRIPT Pulmonary Hypertension Study Group. Circulation. 1997 Mar 18;95(6):1479–86. Barst RJ, Rubin LJ, Long WA, Mcgoon MD, Rich S, Badesch DB, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996 Feb 1;334(5):296–301.

160.

Cargill RI, Lipworth BJ. Acute effects of ANP and BNP on hypoxic pulmonary vasoconstriction in humans. Br J Clin Pharmacol. 1995 Dec;40(6):585–90.

161.

Kreiner G, Siostrzonek P, Heinz G, Pabinger I, Roden M, Gössinger H. Drug-testing in patients with pulmonary hypertension of unknown cause. European Heart Journal. 1992 Jun;13(6):776–80.

162.

Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet. 1991 Nov 9;338(8776):1173–4.

163.

Saadjian A, Philip-Joët F, Hot B, Reynaud-Gaubert M, Durand A, Levy S, et al. Effects of nicardipine on pulmonary and systemic vascular reactivity to oxygen in patients with pulmonary hypertension secondary to chronic obstructive lung disease. J Cardiovasc Pharmacol. 1991 May;17(5):731–7.

164.

Thurm CA, Wigley FM, Dole WP, Wise RA. Failure of vasoldilator infusion to alter pulmonary diffusing capacity in systemic sclerosis. AJM. 1991 May;90(5):547–52.

165.

Dujić Z, Tocilj J, Slavković V. Effects of nifedipine on diffusing capacity and pulmonary capillary blood volume in chronic obstructive pulmonary disease. A controlled study. Respiration. 1991;58(3-4):186–91.

166.

Scott JP, Higenbottam T, Wallwork J. The acute effect of the synthetic prostacyclin analogue iloprost in primary pulmonary hypertension. Br J Clin Pract. 1990 Jun;44(6):231–4.

167.

Rubin LJ, Mendoza J, Hood M, McGoon M, Barst R, Williams WB, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med. 1990 Apr 1;112(7):485– 91.

168.

van der Starre PJ, Feld RJ, Reneman RS. Ketanserin in the treatment of pulmonary hypertension after valvular surgery: a comparison with sodium nitroprusside. Critical Care Medicine. 1989 Jul;17(7):613–8.

169.

Evans TW, Waterhouse J, Finlay M, Suggett AJ, Howard P. The effects of long term methyldopa in patients with hypoxic cor pulmonale. Br J Dis Chest. 1988 Oct;82(4):405–13.

170.

Nenci GG, Berrettini M, Todisco T, Costantini V, Parise P. Effects of dipyridamole on the hypoxemic pulmonary hypertension of patients with chronic obstructive pulmonary

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ED

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NU

SC

RI P

T

159.

30

ACCEPTED MANUSCRIPT disease. Respiration. 1988;53(1):13–9. Vestri R, Philip-Joët F, Surpas P, Arnaud A, Saadjian A. One-year clinical study on nifedipine in the treatment of pulmonary hypertension in chronic obstructive lung disease. Respiration. 1988;54(2):139–44.

172.

Clozel JP, Delorme N, Battistella P, Breda JL, Polu JM. Hemodynamic effects of intravenous diltiazem in hypoxic pulmonary hypertension. Chest. 1987 Feb;91(2):171–5.

173.

Burghuber OC. Nifedipine attenuates acute hypoxic pulmonary vasoconstriction in patients with chronic obstructive pulmonary disease. Respiration. 1987;52(2):86–93.

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CE

PT

ED

MA

NU

SC

RI P

T

171.

31

ACCEPTED MANUSCRIPT Figure 1: Number of trials (from total N=126 identified) reporting each outcome measure as a primary or secondary endpoint. Level of evidence was assigned to each outcome based on

T

literature review (Level I, true clinical efficacy end point; Level II, validated surrogate endpoint;

AC

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PT

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MA

NU

SC

RI P

Level III, nonvalidated surrogate endpoint; Level IV, measure of biologic activity).

32

ACCEPTED MANUSCRIPT Figure 2: Outcome measures as primary endpoints in PH trials have varied significantly from 1985-2013. P-values are for reporting trends from 1985 to 2013. Abbreviations used: RHC (right

AC

CE

PT

ED

MA

NU

SC

RI P

(cardiopulmonary exercise test); PFT (pulmonary function test)

T

heart catheterization); 6MWT (6 minute walk test); QOL (quality of life); CPEX

33

ACCEPTED MANUSCRIPT Table 1. Characteristics of Endpoints in 126 Pulmonary Hypertension Trials, 1985-2013. Early Phase and Late Phase groups represent Phase I-II and Phase III-IV trials, respectively.

MA

T

NU

0 (0) 5 (8) 26 (40)

RI P

0 (0) 1 (2) 64 (98)

32 (49) 29 (45) 4 (6) 38 (58) 18 (28) 43 (66)

3 (5) 2 (3) 56 (92)

3 (2) 3 (2) 120 (95)

5 (8) 18 (30) 24 (39)

5 (4) 23 (18) 50 (40)

26 (43) 32 (52) 3 (5)

73 (58) 43 (34) 10 (8)

55 (90) 14 (23) 39 (64)

93 (74) 32 (25) 82 (65)

AC

CE

PT

Outcome Type Primary Endpoint  Survival  Composite  Surrogate measure only Secondary Endpoint (if present)  Survival  Composite  Surrogate measure only Follow-up Period ≤ 12 weeks ≤ 1 year ≤ 3 years Use of Selected Endpoints 6MWD Echocardiography Invasive Hemodynamics

Number of Trials (%) Late Phase (n=61) All Trials (n=126)

SC

Early Phase (n=65)

ED

Endpoint Characteristic

34

ACCEPTED MANUSCRIPT

RI P SC

MA

NU

Reporting Frequency (%) 18 (56.3) 5 (15.6) 4 (12.5) 4 (12.5) 3 (9.4) 3 (9.4) 2 (6.3) 2 (6.3) 2 (6.3) 2 (6.3) 1 (3.2) 1 (3.1) 1 (3.1)

AC

CE

PT

ED

Echocardiographic variable PA systolic pressure LV function Tei index Right atrial pressure TAPSE LV eccentricity index PA acceleration time Pericardial effusion RV size Isovolumic relaxation time Right atrial area RV fractional area change RV wall thickness

T

Table 2. Relative frequencies of echocardiographic variables employed as endpoints in 32 PH trials. PA (pulmonary artery); TAPSE (tricuspid annular plane systolic excursion).

35

ACCEPTED MANUSCRIPT Table 3. Serial assessments of 450 PH patients at a single tertiary PH center, 2003-14. Exam interval, days (mean) 901 260 152

AC

CE

PT

ED

MA

NU

SC

RI P

T

Exams per patient Patients with >1 (mean) exam (%) RHC* 1.9 209 (46) Echocardiogram 7.2 426 (95) # 6MWD test 11 416 (92) # *Right heart catheterization; 6-minute walk distance Procedure

36

ACCEPTED MANUSCRIPT Supplemental Table 1. Summary of the 126 PH trials identified from the systemic review. PMID

First Author

Year

Drug/Intervention

Duration

23984728 (50) 23883378 (51) 23883377 (52)

Pulido, T Ghofrani, HA Ghofrani, HA

2013 2013 2013

115 weeks 12 weeks 16 weeks

23850902 (53)

Chen, SL

2013

3 months

PAH

3 months

PH group 3

20

2013 2013 2013 2013 2013 2013 2013

Macitentan Riociguat Riociguat Pulmonary Artery Denervation Balloon Pulmonary Angioplasty Riociguat Inhaled Treprostinil Aerobic Exercise Imatinib Mesylate Oral Treprostinil Inhaled Treprostinil Exercise

Study Population PAH PAH CTEPH

16 weeks 12 weeks 10 weeks 24 weeks 12 weeks 12 weeks 10 weeks

201 66 24 202 349 73 23

Yes

3 weeks

PH group 2 PAH PAH PAH PAH PAH PAH PAH or CTEPH PAH with scleroderma PAH PH with COPD

20

Yes

CTEPH

29

Ley

2013

Exercise

22833239 (63)

Kumar

2013

Sildenafil

23669822 (64)

Tapson

2013

Treprostinil

23300624 (65)

Boeck L

2012

Iloprost

23132237 (66)

Kataoka M

2012

Percutatneous Transluminal Pulmonary Angioplasty

6 months

22936711 (67)

Hoeper

2012

Riociguat

12 weeks

22848542 (68) 22818063 (69)

Nagel Oudiz

2012 2012

Exercise Tadalafil

3 weeks 16 weeks

22777623 (70)

Saggar

2012

Ambrisentan

24 weeks

22628490 (70) 22385756 (71) 22362846 (72) 22362844 (73)

Tapson So Zeng Simonneau

2012 2012 2012 2012

22280813 (74)

Dumas

2012

NU 16 weeks

PT

ED

MA

2 doses

Treprostinil Beta Blocker Atorvastatin Selexipag

16 weeks 20 months 6 months 17 weeks

Dhea

3 months

Percutatneous Transluminal Pulmonary Angioplasty Sitaxsentan Ambrisentan Sildenafil

22185711 (75)

Sugimura

2012

22079088 (76) 21884013 (77) 21415281 (78)

AC

CE

3 months

Sandoval Badesch Xiong

2012 2012 2012

21081251 (79)

D'Alto

2012

Bosentan Plus Sildenafil

6 months

22117505 (80)

Judson

2011

Ambrisentan

24 weeks

22055098 (81)

2011

2011

Treprostinil Cytoxan And Steroids Ambrisentan

12 weeks

21812736 (83)

Benza MiyamichiYamamoto Yoshida

21709061 (84)

Guazzi

2011

Sildenafil

12 months

21593252 (85)

Kawut

2011

21546436 (86) 21471085 (87) 21304214 (88)

Rubin Jing Satoh

2011 2011 2011

21256048 (89)

Barst

2011

21362526 (90) 20697180 (91) 20637015 (92)

Fox Akagi Lu

2010 2010 2010

21873802 (82)

2011

Aspirin And Simvastatin Sildenafil Vardenafil Sildenafil Tadalafil Plus Bosentan Exercise Epoprostenol Sildenafil

Yes Yes Yes

T

Randomized

21

RI P

22886553 (62)

2013

SC

23775260 (55) 23496856 (56) 23478192 (57) 23403476 (58) 23307827 (59) 22970909 (60) 22922554 (61)

Andreassen, AK Bonderman, D Chen H Weinstein Hoeper MM Jing ZC Bourge RC Chan

23846611 (54)

N 742 443 261

PAH with ILD CTEPH PAH PAH with Scleroderma PAH PAH PAH PAH PH with COPD

310

Yes

16

Yes

22 35 357 11 350 94 220 43

Yes Yes Yes

8

CTEPH

12

18 weeks 24 weeks 12 weeks

PAH PAH PAH PAH with congenital heart disease PH with sarcoidosis PAH PAH with CTD PAH PH with HFPEF

98 224 90

1 year

Yes

16

12 months

24 weeks

Yes Yes Yes

Yes

32 21 206

Yes

13 25 44

Yes

6 months

PAH

92

Yes

12 weeks 24 weeks 12 weeks

PAH PAH PAH

277 66 21

Yes

16 weeks

PAH

405

Yes

12 weeks 3 years 12 weeks

PAH PAH PAH

22 16 60

37

ACCEPTED MANUSCRIPT Imatinib

24 weeks

2010

Riociguat

12 weeks

20460548 (95)

Wilkins

2010

20430262 (96)

McLaughlin

2010

20142023 (97) 20113907 (98) 20022264 (99) 19660388 (100)

Blalock Jing Hiremath Reesink

2010 2010 2010 2010

Simvastatin Treprostinil Plus Oral Therapy Ambrisentan Bosentan Treprostinil Bosentan

20560291 (101)

Baughman

2009

Iloprost

16 weeks

19909879 (102) 19644505 (103) 19609055 (104) 19470885 (105)

Oudiz Xu Kunieda Galie

2009 2009 2009 2009

Ambrisentan Sildenafil Beraprost Sodium Tadalafil

2 years 16 weeks 12 weeks 16 weeks

19293199 (106)

Valerio

2009

Bosentan

18 months

18831711 (107)

Lee

2009

Pravastatin

6 months

19237088 (108) 19095129 (109)

Vassallo Jais

2009 2008

18936500 (110)

Simonneau

2008

18577825 (111)

Akagi

2008

18572079 (112) 18263674 (113)

Galie Suntharalinga

2008 2008

Bosentan Bosentan Sildenafil Plus Epoprostenol Bosentan Plus Epoprostenol Bosentan Sildenafil

17439935 (114)

Mok

2007

Bosentan

17990150 (115)

Ulrich

2007

17985403 (116)

Badesch

2007

17785618 (117)

Lewis, GD

2007

17496227 (118)

Criner, GJ

2007

Ibrahim

16982941 (121) 16946127 (122) 16569546 (123) 16497687 (124)

Yes

12 weeks

PAH

235

Yes

3 years 12 weeks 12 weeks 16 weeks

12 92 44 25

Yes Yes

12 months 16 weeks

PAH PAH PAH CTEPH PH with sarcoidosis PAH PAH PAH PAH PH with COPD PH with COPD CTEPH CTEPH

16 weeks

PAH

1 year

PAH

8

6 months 12 weeks

168 19

NU

MA

6 months 12 weeks

Sildenafil Lung Volume Reduction

12 weeks 6 months

PH group 3

ED

Bosentan

Sildenafil

PAH CTEPH PAH with SLE CTEPH PAH with CTD PH group 2

PT

17149459 (120)

2006

12 months

Sildenafil

12 months

2006

Bosentan

16 weeks

Mereles, D

2006

15 weeks

McLaughlin

2006

Singh, TP

2006

Exercise Iloprost Added To Bosentan Oral Sildenafil

Arias, MA

2006

Cpap/Sham

12 weeks

CE

Reichenberger

42

AC

16807265 (119)

59

6 months

PAH CTEPH and PAH PAH

12 weeks 6 weeks

2005

Bosentan/EchoSubstudy Of Breathe-1 Sildenafil Plus Treprostinil Bosentan

Schulze-Neick

2005

Bosentan

2.1 years

16100158 (129)

Seyfarth

2005

Bosentan

12 months

16042696 (130)

Machado

2005

Sildenafil

6 months

15791043 (131)

Kataoka M

2005

Sildenafil

12 weeks

16291984 (132) 15750042 (133) 16100159 (134) 16060962 (135)

Galie, N Wilkins, MR Shen, J Morrell, RW

2005 2005 2005 2005

Sildenafil Sildenafil/Bosentant Lipoe1 Losartan

12 weeks >16 weeks 2 weeks 48 weeks

16608951 (125)

Benza

16236895 (127)

GombergMaitland Hoeper

16209972 (128)

16253609 (126)

2006 2005

12 months

Yes

75

T

2010

Ghofrani

RI P

Ghofrani

20530034 (94)

SC

20581169 (93)

PAH with portal hypertensio n PAH with congenital heart disease PH PH on bosentan PH PH with OSA PAH with congenital heart disease

22

383 60 46 405

Yes

16

Yes

53

Yes

34 157

Yes

265

Yes

Yes Yes

4 15 45

Yes

34

Yes

110

Yes

14

10 30

Yes

67

Yes

20

Yes

23

Yes

24

12 weeks

PAH

9

3 months

CTEPH PAH with congenital disease PAH on prostanoid therapy PAH with sickle cell disease PAH on flolan PAH PAH PAH PH group 3

19 33

16

5 6 278 26 49 40

Yes Yes Yes Yes

38

ACCEPTED MANUSCRIPT 2005

Humbert M

2004

Ambrisentan Epoprostenol and Bosentan

12weeks

PAH

64

Yes

16 weeks

PAH

33

Yes

90

Yes

22

Yes

34

Yes

178

Yes

116

Yes

85

Yes

15302727 (138)

Oudiz, RJ

2004

Treprostinil

12 weeks

15063421 (139)

Sastry, BK

2004

14995003 (140)

Sildenafil Iv Cyclophosphamide Or Enalapril

6 weeks

GonzalezLopez, L

2004

6 months

Barst, RJ

2004

Sitaxsentan

12 weeks

12821234 (142)

Barst, RJ

2003

Beraprost

12 mths

12706935 (143)

Galie, N

2003

Bosentan

12952269 (31)

Hoeper MM

2003

12849677 (144)

Ghofrani

2003

12740277 (145) 11985913 (146) 11907289 (147) 11897647 (148) 11711462 (149) 11669165 (150) 11597664 (151) 10861321 (152) 10733441 (153) 9445406 (154) 9247503 (155)

Ono Galie Rubin Simonneau Vizza Launay Channick Hoeper Badesch McLaughlin Shapiro

2003 2002 2002 2002 2001 2001 2001 2000 2000 1998 1997

9187185 (156)

Sajkov

1997

9118516 (157) 8532025 (158)

Hinderliter A Barst R

NU

MA

16 weeks

Cargill R

Anp, Bnp

One hour

Kreiner

1992

Nifedipin

immediate immediate

PT

ED

1997 1996

Bosentan and Iloprost Sildenafil and Iloprost Beraprost Beraprost Bosentan Treprostinil Beraprost Iloprost Bosentan Iloprost Epoprostenol Epoprostenol Epoprostenol Amlodipine and Felodipine Epoprostenol Epoprostenol

PAH, idiopathic or connective tissue disease PAH, connective tisue or congnital disease PAH with connective tissue disease

16 months

PAH

20

12 months

PAH

14

36 months 12 weeks 12 weeks 12 weeks 1 year 13 months 12 weeks 1 year 12 weeks 16 months 330 days

CTEPH PAH PAH PAH PH PAH PAH PAH PAH PAH PAH PH with COPD PAH PAH Hypoxic pulm HTN PAH, idiopathic

43 130 213 470 13 5 32 24 111 27 18

PAH

18

Yes

10

Yes

14

Yes

17

Yes

12 24

Yes Yes

26

Yes

25

Yes

8

Yes

60

Yes

12

Yes

11

Yes

3 weeks 12 weeks 12 weeks

1995

1682593 (161)

AC

CE

PH with lupus

SC

14630619 (141)

PAH with connective tissue disease PAH

Pepke-Zaba J

1991

Nitro or Prostacylcin

1713987 (162)

Saadjian A

1991

Nicardipine

immediate

1709338 (163)

Thurm, C

1991

Iloprost

immediate

1745853 (164)

Dujic Z

1991

Nifedipine

immediate

1698429 (165) 2107780 (166)

Scott, JP Rubin, L

1990 1990

immediate 8 months

2736920 (167)

van der Starre

1990

Iloprost Epoprostenol Ketanserin/Nitropru sside

PH with COPD PAH with systemic sclerorsis PH with COPD PAH PAH

immediate

PH

3076795 (168)

Evans, T

1988

Methyldopa

12 months

3387686 (169)

Nenci

1988

Dipyridamole

3 months

3068741 (170)

Vestri, R

1988

Nifedipine

One year

3802928 (171)

Clozel, J

1987

Diltiazem

immediate

3671896 (172)

Burghuber

1987

Nifedipine

immediate

8703666 (159) 1623866 (160)

T

Galie, N

15358690 (137)

RI P

16053970 (136)

PH with COPD PH with COPD PH with COPD Hypoxic pulm HTN PH with

Yes Yes Yes

Yes Yes

10

Yes

81 81

Yes Yes

8

Yes

8

39

ACCEPTED MANUSCRIPT

1985

Hydralazine

3 days

COPD Cystic fibrosis

23

Yes

CE

PT

ED

MA

NU

SC

RI P

T

Moskowitz

AC

3900900 (173)

40