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J Am Coll Cardiol, 2004; 43:48-55 © 2004 by the American College of Cardiology Foundation |
* Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
Division of Cardiology, Harbor—UCLA Medical Center, Torrance, California, USA
Scottish Pulmonary Vascular Unit, Glasgow, Scotland, UK
Pulmonary Hypertension Center, Duke University Medical Center, Durham, North Carolina, USA
|| Institute of Child Health, London, United Kingdom
¶ Baylor College of Medicine, Houston, Texas, USA
Institute of Tuberculosis and Lung Diseases, University of Warsaw, Warsaw, Poland
Manuscript received November 26, 2003; accepted February 3, 2004.
*
Reprint requests and correspondence: Dr. Marius M. Hoeper, Department of Respiratory Medicine, Hannover Medical School, 30623 Hannover, Germany.
hoeper.marius{at}mh-hannover.de
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Abstract |
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 Top Abstract Clinical trial designPrimary and secondary...End points in clinical...APPENDIXReferences |
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The choice of appropriate end points for clinical trials in PAH should also take into account the requirements of regulatory agencies, which usually are the ultimate referees in the approval process of a particular treatment.
In the process of decision making for the implementation of new trials for PAH, it appears that the two main issues that need to be addressed are the trial design and the choice of the appropriate primary and secondary reinforcing end points.
The views presented here are a summary from the Third World Symposium on Pulmonary Hypertension, held in Venice, Italy, in 2003, and from an expert symposium held just prior to this meeting in Gleneagles, Scotland, in 2003, in order to prepare the topic of "Endpoints in PAH" for the Venice meeting. Participants of the task force on medical treatment and end points in Venice and the participants of the Gleneagles meeting are listed in the appendix.
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Clinical trial design |
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TopAbstractClinical trial designPrimary and secondary...End points in clinical...APPENDIXReferences |
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Placebo-controlled studies. Currently, four treatments are approved either by American (Food and Drug Administration; FDA) or European (European Agency for the Evaluation of Medicinal Products; EMEA) regulatory agencies for the treatment of PAH patients: intravenous epoprostenol for primary pulmonary hypertension (PPH) patients with NYHA/WHO functional class III and IV symptoms (FDA and EMEA), subcutaneous treprostinil for PAH patients with NYHA/WHO functional class II, III, and IV symptoms (FDA), oral bosentan for PAH patients with NYHA/WHO functional class III symptoms (EMEA) and class III and IV symptoms (FDA), and inhaled iloprost for PPH patients with NYHA/WHO functional class III symptoms (EMEA). Only epoprostenol treatment has been shown to improve survival in a randomized, controlled clinical trial (9). Treprostinil, inhaled iloprost, and bosentan have been shown to reduce clinical events, but none of them improved mortality after three to four months in the randomized trials (2,4,6). Patients enrolled in these latter studies were less compromised compared with patients in the epoprostenol study. These trials were clearly not powered for detecting any effect on mortality owing to the small sample size and the short duration of the studies.
From ethical and methodological perspectives, it might be suggested that a mortality study in PAH patients with NYHA/WHO functional class III and IV symptoms can only be performed using intravenous epoprostenol as the comparator, because only this drug has been shown to improve mortality.
Less clear is whether a placebo-controlled study whose primary end point is exercise capacity assessed after three to four months of a randomized treatment would still be acceptable, both to clinicians and regulatory authorities. Reasons supporting the continued use of placebo in randomized trials include the following: 1) prognostic superiority has not been demonstrated by any of the newer PAH drugs beyond the three to four months of randomized trial periods (mortality ranging from 1% to 3%, corresponding to 4% to 12% per year); 2) the setting of a controlled clinical trial protects patients by allowing them to be shifted to already approved treatments in case of deterioration; 3) NYHA/WHO functional class II patients have been only minimally involved in clinical trials in PAH, and are excellent candidates for placebo-controlled trials; and 4) there is no cure for PAH, and a consistent proportion of patients fail to respond to all available treatments. Therefore, hurdles should not be set too high for the investigation of new treatments.
In contrast, potential problems with continuing placebo-controlled studies include the following: 1) it may be considered unethical to expose patients to three to four months of placebo when symptomatic and clinical deterioration is known to occur in such time; 2) NYHA/WHO functional class II patients appear to be a "minority" in the population observed in clinical practice; and 3) the current priority in clinical practice might be one of comparison of new treatments with approved ones.
Weighing these arguments, the working groups in Scotland and Italy concluded that, given the outlined conditions, placebo-controlled trials for shorter periods of time (up to four months) are still justified from an ethical and scientific point of view.
Noninferiority studies. Noninferiority comparative studies can be an alternative to superiority placebo-controlled studies if the latter are considered inappropriate for ethical and/or practical reasons. In fact, comparative studies designed to demonstrate superiority would be difficult to perform in a rare disease like PAH because the required sample size would be quite large, relative to the disease prevalence. The objective of a noninferiority study is to demonstrate that no statistically significant difference exists between two compounds for a given end point. Therefore, noninferiority studies can only be performed with established primary end points that have already been investigated.
Noninferiority studies also require a setting identical to that of the pivotal study of the comparator (inclusion criteria, exclusion criteria, patient population, study protocol, among others). If the comparator were bosentan, for example, the study design would require that the 6-min walk test be used as the primary end point, as it was in the pivotal study of bosentan (2). Although a superiority study over bosentan would be prohibitive in terms of sample size, in the above scenario, the sample size would also need to be quite high (>500 patients), so that even noninferiority trials bear considerable risks and costs for the sponsors.
Withdrawal studies. Withdrawal studies can be suggested by regulatory agencies for different reasons. For example, when pivotal trials have not shown a clinically relevant benefit, or a more consistent proof of efficacy is required, the FDA may suggest or require that a withdrawal study be performed before granting regulatory approval. In a life-threatening disease such as PAH, a withdrawal study might be considered inappropriate for several reasons. Withdrawal of an effective drug may cause clinical deterioration, which could be irreversible and life-threatening even if the previous treatment were to be reinstituted. As a consequence, the end point of such a study would be to assess clinical worsening. This could be considered against the basic medical principle, primum non nocere ("First, do no harm"). For these reasons, approval of such a study by institutional review boards and patient acceptance of such a trial would be difficult.
During the Venice symposium, the Endpoints Task Force members concluded that withdrawal studies should not be recommended in PAH patients with functional class III or IV symptoms who are receiving a single active treatment that has proven to be effective in randomized, placebo-controlled trials. However, withdrawal studies may be a useful means to study the efficacy of combination therapies (see the following text).
Combination therapies. Given that no currently available PAH treatment offers the potential for cure or long-term stabilization for the majority of PAH patients (other than lung transplantation) (10–12), it is likely that a combination of active treatments will be used increasingly in the near future. Preliminary studies suggest that combinations of prostanoids and phosphodiesterase inhibitors or prostanoids and endothelin receptor antagonists are safe and effective in selected PAH patients (13,14). However, for reasons concerning efficacy, safety, and costs, it is imperative that combination treatments are carefully investigated. As stated above, one useful means to study combination treatments could be withdrawal studies. Alternatively, combinations of two (or more) compounds could be studied in an add-on design, using classical end points. Provided that the sample size is high enough, even more information might be derived from three-arm studies including both compounds alone and in combination.
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Primary and secondary reinforcing end points according to requirements of regulatory agencies |
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In PAH trials, assessment of exercise capacity using the 6-min walk test can still be considered a good choice for a primary end point for several reasons, including the possibility to compare the results with previous trials. However, it is important that the clinical relevance of a given improvement in the distance walked is defined a priori in the protocol of the study to avoid inconclusive discussions at the end of the trial. This might be accomplished by defining clinical relevance according to the treatment effect obtained with already approved treatments, because the term "clinical relevance" can be somewhat arbitrary.
Quality of life as a primary end point has been proposed, but concerns include the lack of validation that has been provided for this parameter in PAH thus far (see the following text).
Time to clinical worsening as a combined end point requires standardization to make the end point more objective and comparable. This parameter has most often been defined in PAH trials as the combination of death, hospitalizations due to worsening of PAH, and escalation of treatments (need for epoprostenol or lung transplantation). The last two events are influenced by the judgment of the attending physician, and as an end point it should be supported by some objective findings, such as predefined thresholds defining deterioration in exercise capacity or hemodynamic parameters.
Hemodynamic parameters have traditionally been considered as "secondary," or reinforcing end points, based on their prognostic value (15), and this concept has been accepted by regulatory agencies. The Endpoints Task Force members agreed that using selected echocardiographic parameters as noninvasive substitutes of hemodynamics should be explored.
The usefulness has"> of biological markers as end points for clinical trials, such as brain natriuretic peptide (BNP), troponin, and endothelin, has yet to be tested and validated in clinical studies, and thus, at present, cannot be proposed to regulatory agencies as primary end points.
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End points in clinical trials |
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Clinical end points. Clinically relevant events such as death, hospitalization for right heart failure, or the requirement for the introduction of alternative ("rescue") treatments have been widely used as secondary, often combined, end points in most of the randomized clinical trials of PAH treatments. In those studies, which included mainly class III and IV patients, the active treatments were able to show a significant reduction of these events after the three- to four-month study periods (2,6,9). However, it is anticipated that observation periods will have to be much longer when patients with less advanced illness are being studied or when different active treatments are being compared to each other, or combined. In these circumstances, it is important for safety reasons that clinical end points encompass not only the aforementioned indicators of severe complications but also encompass other variables that define clinical deterioration, such as a predefined decline in 6-min walk distance or in peak oxygen consumption. One suggested combined end point might combine all of the above variables, and be termed failure-free survival.
Exercise studies: 6-min walk test and cardiopulmonary exercise testing (CPET). Assessment of functional capacity in both clinical and research applications is an important tool for evaluating disease severity. The most widely used test to assess exercise capacity in PAH patients has been the 6-min walk test, the main advantage being its ease of administration. The 6-min walk test correlates with several parameters of CPET and provides important prognostic information (10,16). Paciocco et al. (17) showed an 18% reduction in the risk of death per additional 50 m walked in patients with PPH performing the 6-min walk test.
The 6-min walk test has also been successfully used in scleroderma-associated pulmonary hypertension (18) and in the Eisenmenger syndrome (19), but there has been no study of the 6-min walk test for portopulmonary hypertension patients. In addition, the 6-min walk test has not been validated as an end point in PAH patients with less severe disease (i.e., NYHA/WHO functional class I and II symptoms).
Measurement of ventilation and pulmonary gas exchange during exercise testing provides additional information to that derived from standard exercise testing. This modality (CPET) offers an objective evaluation of functional capacity and provides information beyond that of most traditional exercise tests, some of which are independent of patient effort. Although the peak oxygen consumption (VO 2) may be limited by factors other than circulatory impairment, it is very helpful in describing the magnitude of exercise limitations in comparison to normal controls. During submaximal exercise, anaerobic or lactic acid threshold can be obtained as a surrogate for peak VO 2, and may reflect circulatory limitations. Finally, the slope of VE/VCO 2 or the VE/VCO 2 ratio measured at the anaerobic threshold is nearly always elevated in patients with PAH, and reflects the impaired pulmonary circulation that is the hallmark of PAH (20).
Several studies of CPET in PAH have significantly contributed to our understanding of the symptoms and pathophysiology of patients with PAH who experience dyspnea during exercise (20,21). In addition, Wax et al. (22) showed that in 16 PPH patients undergoing CPET, peak VO 2 and O 2 pulse increased significantly after two years of treatment with intravenous epoprostenol. Wensel et al. (23) found that baseline peak VO 2 and the baseline maximum systolic blood pressure during exercise were strong and independent predictors of survival.
The 6-min walk test has been used successfully as primary end point in many clinical studies in PAH (3,4,18,24) and is, to date, the only measure of exercise capacity that has been accepted by the FDA, based on its validation as a marker of a treatment effect. In contrast, presently there is limited experience with the use of CPET in multicenter trials. In one recent multicenter study on beraprost in PAH patients, the 6-min walk test revealed a significant improvement after three and six months of treatment, whereas there were no significant changes in CPET variables (5). These results raised several questions and concerns about the quality of the CPET studies performed at each study center, especially as the 6-min walk test itself was used as a surrogate for CPET, based on its correlation with peak VO 2. It appears that the results of CPET were largely influenced by the experience of the involved centers, whose variability was probably related to the interpretation of the CPET studies rather than to the performance of the studies. For these reasons, the Endpoints Task Force members believe that CPET cannot currently be recommended as a primary end point in multicenter trials on new treatments for PAH. However, the use of a core CPET laboratory might avoid errors in interpretation made at individual study centers. Finally, because of the substantial physiologic information provided by CPET, this technique might be used in substudies involving centers with experience in CPET in order to generate secondary end points in forthcoming studies.
The NYHA and WHO functional classification. The NYHA functional classification system is widely used as a marker of disease severity in cardiovascular disease (25). One of the simplest and crudest assessments of exercise capacity, the NYHA functional classification has been shown to correlate with disease severity and outcome in a multitude of cardiopulmonary disorders, including PPH (10,15). The WHO functional classification system for PAH (26) is an adaptation of the NYHA system. It is nearly identical to the original NYHA functional classification text, with the references to cardiac-specific symptoms such as the deletion of angina, and the addition of references to PAH-related symptoms. In practice, many clinicians refer to both classification systems collectively as NYHA/WHO functional classification.
A major limitation to the NYHA and WHO functional classification systems is that they rely upon patients to report their own limitations. Patients who over- or under-report their physical limitations can lead the clinician to make incorrect conclusions about their patient's disease severity. In addition, even despite widely accepted definitions, great variability exists in how physicians assign functional classification. It appears that the vast majority of PAH patients reported in the published reports have been classified as having NYHA/WHO functional class III symptoms. It is also evident that this classification may not be revised by treating clinicians even when medical treatments result in subjective and objective functional improvements. A tighter, perhaps subdivided, categorization should be developed and validated. In the current version, the NYHA/WHO functional classification may be too crude to be used as a primary end point in clinical trials, though it has been utilized successfully as part of a combined primary end point (6). It is likely that functional classification will remain in use as a secondary, reinforcing end point in future clinical trials.
Mahler dyspnea index. The Mahler dyspnea index has been used in chronic lung disease (27) and in pulmonary hypertension (6). Compared to the NYHA and WHO functional classification systems, it provides a scale from 0 to 12 with equal contributions of functional impairment, magnitude of task, and magnitude of effort until dyspnea occurs. Systematic comparisons between the Mahler dyspnea index and 6-min walk test or CPET have not been made.
Hemodynamics. Progressive remodeling of the pulmonary arteriolar vessels causes an increase in pulmonary vascular resistance (PVR), which increases right ventricular (RV) afterload. Patients become symptomatic mainly because of the inability of their RV to overcome the increased RV afterload, and thus they are unable to adequately increase pulmonary blood flow (cardiac output) for the O2 exercise demand. Accordingly, a right heart catheterization with measurements of pulmonary vascular pressures and blood flow quantify both the disease process (PVR) and its main functional consequence (cardiac output [CO] limitation). It is therefore understandable that standard hemodynamic measurements in patients with PAH correlate with clinical state, functional class, exercise capacity, and prognosis (10,11,15). However, there has been disappointment related to the fact that these correlations are loose, and that mean pulmonary artery pressures (PAPs) often fail to reach statistically significant correlation with outcome in PAH treatment trials. As such, standard invasive pulmonary hemodynamic measurements have not been considered as a primary end point in randomized controlled trials of new pharmacological approaches to PAH therapy. In fact, there is a current tendency to omit hemodynamic measurements even as a secondary end point. The End Points Task Force believe, however, that a right heart catheterization with pulmonary hemodynamic measurements should be required both for confirming the initial diagnosis of PAH and for evaluating the progression and response to therapy in PAH patients.
The reasons why pulmonary hemodynamic measurements do not appear to be tightly correlated to clinical state in patients with PAH are twofold. First, in most reported studies, measurements are performed at rest only, when RV stress and related symptoms are minimal. Second, mean pulmonary artery pressure (PAPm) and CO determinations may be insufficient to accurately reflect RV afterload.
A single-point measurement of PAPm, pulmonary capillary wedge pressure (PCWP), and CO, and derived PVR calculation may be misleading because the inherent assumptions of linearity and zero crossing of the (PAPm – PCWP)/CO relationship are not met (28). It can indeed be shown that multipoint (PAPm – PCWP)/CO coordinates are described by a linear approximation, but present with a positive extrapolated pressure intercept (29,30). Single-point PVR determinations at variable flow therefore may underestimate or overestimate changes in the pulmonary circulation (28). These errors can be avoided by defining PVR along a multipoint pressure/flow line (28).
Recent studies have shown that improvement in exercise capacity with prostacyclin therapy may not be associated with significant changes in pulmonary hemodynamics at rest, whereas PVR defined by a multipoint (PAPm – PCWP)/CO plot shows a significant decrease with therapy (30). Using such a model, variation in flow can be achieved with exercise (30) or with an infusion of low-dose dobutamine (29).
Taken together, right heart catheterization with pulmonary hemodynamic measurements remains central in the diagnosis of PAH, in the evaluation of severity, response to therapy, and prognosis in patients with PAH. Right heart catheterization should therefore remain an essential part of clinical trials. However, in contrast to previous studies, unless there is evidence of severe right heart dysfunction (recurrent syncope, cardiac index <1.5 l/min/m2, right atrial pressure >20 mm Hg), pulmonary hemodynamics should be measured both at rest and during exercise to define PVR by defining at least a two-point pulmonary vascular pressure/flow relationship.
Quality of life
At present, the objective of patient management in individuals with PAH is to improve survival and QoL. In an attempt to assess the impact of the condition on patients' QoL, generic health status measures, or health-related quality of life indicators such as the SF-36 (31), Nottingham Health Profile (32), Minnesota Living with Heart Failure Questionnaire (33), and EuroQoL (34) have been used in studies of PAH. However, these measures assess impairment and disability rather than QoL, and their generic content is too general to provide valid and sensitive assessments. Furthermore, such instruments fail to assess those issues that are of major concern to the QoL of patients (35).
Unlike impairment and disability, QoL questionnaires summarize the impact of both the disease and its treatment on the patient in a single score. The most widely operationalized model of QoL assessment postulates that QoL is the extent to which patients are able to meet their needs (36). This model goes beyond an assessment of impairment and disability by inquiring how impaired function affects patients' ability to satisfy their needs. Major developments have been made in the science of QoL assessment (37); however, these are only now starting to be applied in PAH. In these developments, emphasis is being placed on disease-specific measurements, with the content of instruments derived directly from patients, thereby taking account of the specific and unique impact of PAH (38).
Work is currently in progress to develop two new instruments specific to PAH, derived from qualitative, unstructured interviews with PAH patients. One instrument is designed to assess impairment and disability (i.e., health status or health-related QoL) with particular relevance to PAH. The second is a "needs"-based QoL measure specific to PAH. The former assesses overall impairment, breathlessness, edema, energy level, mood, and physical functioning. Such disease-specific measures also increase the potential for determining disease-specific utility and, consequently, determining the cost-effectiveness of clinical interventions. Once thoroughly evaluated, QoL assessments may be useful as primary or secondary end points in clinical studies on PAH.
Echocardiography
Echocardiography is the most widely available and versatile imaging test. Current data indicate that three groups of echocardiographic variables could be potentially useful as end points in PAH. Interestingly, rather than reflecting instantaneous hemodynamics such as right heart pressures and flows, most of those echocardiographic variables reflect chronic consequences of PAH such as: 1) elevated right atrial pressure as evidenced by the presence and size of pericardial effusions (39,40) and by the right atrial area/volume (39,41); 2) RV dysfunction, measured by the Doppler Tei index of myocardial performance or its surrogates (42); and 3) decreased left ventricular (LV) preload, measured by assessing LV eccentricity index or end diastolic area/volume. According to existing evidence, the improvement in LV diastolic dysfunction especially assessed by decreased LV early diastolic filling velocity seems to best reflect the effects of PAH treatment upon echocardiographic measures (39). Most of the variables listed above are simple and easy to obtain from a single apical four-chamber view in patients with PAH.
Tissue Doppler imaging (43) at echocardiography may further simplify the assessment of cardiac dynamics, by providing an assessment of the Tei index from a single tracing. It may also help to break down the Tei index, allowing for separate assessment of RV systolic and diastolic isovolumic time intervals. Also, simple measurements of the duration and flow velocity pattern of RV ejection seem to correlate with results of treatment (39). Recent experimental data suggest that myocardial acceleration during isovolumic RV contraction is load-independent, and strongly correlates with end-systolic RV elastance, the best available measure of RV contractility (44).
Stress studies using dobutamine infusions or exercise may help to increase the sensitivity of detecting abnormal hemodynamics and of following up the effects of treatment. Unfortunately, there is very limited experience with this type of assessment in patients with PAH (45,46).
Although several imaging-based signs have been shown to correlate with indices of functional capacity and survival and have been found to correlate with successful treatment (39,41,47,48), at present none seem suitable for recommendation as a single or primary end point in PAH. Nevertheless, an echocardiographic substudy of the Bosentan Randomized trial of Endothelin Antagonist Therapy (BREATHE)-1 PAH treatment trial (2) performed in centers with substantial experience with this technique provided very useful information validating clinical benefits seen from treatment by showing parallel improvement in several echocardiographic variables (39). This study may serve as a model for including echocardiographic parameters as secondary end points in future clinical studies.
Hormonal and blood studies
Several biological markers have been used to aid in our understanding of the pathophysiology of PAH. Despite reports indicating that some biochemical markers may be indicative of poorer survival, these markers have not been included in clinical trials in PAH.
An ideal marker for PAH would be heart-lung specific, abnormal in PAH, easy to collect, easy to measure, and be reproducible; it should also allow patient monitoring (it changes in one direction if patients deteriorate and in the other direction if patients improve), and it should also predict survival. Among the markers that have previously been studied, BNP, uric acid, and the troponins may be the best candidates.
Brain natriuretic peptide is mostly secreted by overloaded myocytes of the ventricles (49). Nagaya et al. (50,51) have found that initial and follow-up supramedian BNP plasma levels were independent markers of prognosis in PAH. The NT-pro BNP (its biologically inactive alternative) is a more stable marker, which may be easier to study (49). Based on the available data, BNP should be included as a secondary end point in upcoming clinical trials on patients with advanced PAH.
Troponin T is another biochemical marker that has recently been linked to the prognosis of PAH (52). Chronic leakage of troponin T can be detected with high-sensitivity tests in a subset of patients with severe pulmonary hypertension. In contrast to other markers, troponin T is indicative of ongoing damage of RV contractile proteins, which may contribute to progressive RV failure. Preliminary studies by Torbicki et al. (52) have suggested that elevation of troponin T was related to poor survival in PAH. They also noted that troponin leakage may disappear with successful treatment as well as appear with progression of the disease. If these findings can be confirmed by larger studies, troponin T may also be a useful secondary end point in trials involving patients with advanced PAH.
Serum uric acid levels correlate inversely with cardiac index and positively with right atrial pressure and PVR (53–55). Baseline and follow-up analyses of this marker indicate that it is related to survival and that hemodynamic improvements are associated with a decrease in uric acid levels (55). This marker is, however, affected by several variables, including drugs, tissue perfusion, decreased glomerular filtration, and hypoxia. Therefore, intra- and interindividual variability of serum uric acid levels may be too high to render this parameter useful for clinical trials.
Conclusions
Although short-term placebo-controlled and randomized trials are still feasible for assessing the efficacy and safety of a PAH treatment, comparative and combination studies of longer duration will likely be needed in the future. In patients with moderate to severe functional impairment, the 6-min walk test will probably remain widely used as primary end point for proving efficacy of new treatments. However, in patients with milder functional impairment, and for longer trials involving patients with advanced disease (comparative or combination studies), failure-free survival as defined above may become the most meaningful end point. Hemodynamic variables remain very useful as secondary end points, but in future trials these measurements should be obtained at rest and during exercise provided that there are no signs of advanced right heart failure. In addition, imaging studies (e.g., echocardiography and possibly magnetic resonance imaging) should be included in clinical trials. It is also important that PAH-specific QoL questionnaires be developed and tested. The usefulness of biochemical variables such as BNP or troponin T should be studied by including these parameters as secondary end points, and a similar approach may be utilized to establish the role of cardiopulmonary exercise testing in randomized clinical trials.
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APPENDIX |
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TopAbstractClinical trial designPrimary and secondary...End points in clinical...APPENDIXReferences |
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Task force on medical treatment, Third World Symposium on PAH, Venice, June 23 to June 25, 2003: Nazzareno Galiè (Chair); Lewis J. Rubin (Chair); Werner Seeger (Chair); David B. Badesch, Joan A. Barbera, Robyn R. Barst, Ardeschir Ghofrani, Sheila G. Haworth, Marius M. Hoeper, Marc Humbert, Anne Keogh, Vallerie McLaughlin, Horst Olschewski, Ronald J. Oudiz, Andrew J. Peacock, Gérald Simonneau, Olivier Sitbon, Gianni Tognoni, Adam Torbicki.
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TopAbstractClinical trial designPrimary and secondary...End points in clinical...APPENDIXReferences |
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