Author + information
- Received December 24, 2015
- Revision received April 28, 2016
- Accepted May 3, 2016
- Published online July 26, 2016.
- Christian F. Opitz, MDa,b,∗ (, )
- Marius M. Hoeper, MDc,
- J. Simon R. Gibbs, MDd,
- Harald Kaemmerer, MD, VMDe,
- Joanna Pepke-Zaba, MDf,
- J. Gerry Coghlan, MDg,
- Laura Scelsi, MDh,
- Michele D’Alto, MDi,
- Karen M. Olsson, MDc,
- Silvia Ulrich, MDj,
- Werner Scholtz, MDk,
- Uwe Schulz, MDl,
- Ekkehard Grünig, MDm,
- Carmine D. Vizza, MDn,
- Gerd Staehler, MDo,
- Leonhard Bruch, MDp,
- Doerte Huscher, MSc, PhDq,r,
- David Pittrow, MDs and
- Stephan Rosenkranz, MDt,u
- aDepartment of Cardiology, DRK Kliniken Berlin, Berlin, Germany
- bDepartment of Cardiology, Medical University of Greifswald, Greifswald, Germany
- cDepartment of Respiratory Medicine and German Center of Lung Research (DZL), Hannover Medical School, Hannover, Germany
- dDepartment of Cardiology, National Heart & Lung Institute, Imperial College London, London, United Kingdom
- eDepartment of Pediatric Cardiology and Congenital Heart Disease, German Heart Center, München, Technical University Munich, Munich, Germany
- fPulmonary Vascular Diseases Unit, Papworth Hospital, Cambridge, United Kingdom
- gCardiology Department, Royal Free Hospital, London, United Kingdom
- hDivision of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
- iDepartment of Cardiology, Second University of Naples–Monaldi Hospital, Naples, Italy
- jClinic of Pulmonology, University Hospital Zurich, Zurich, Switzerland
- kDepartment of Cardiology, Heart and Diabetes Center North Rhine-Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany
- lClinic for Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany
- mCentre for Pulmonary Hypertension, University Hospital, Heidelberg, Germany
- nPulmonary Hypertension Unit Department of Cardiovascular and Respiratory Disease, University of Rome ‘La Sapienza,’ Rome, Italy
- oMedical Clinic I, Pneumology, Loewenstein Clinic, Loewenstein, Germany
- pDepartment of Internal Medicine, Unfallkrankenhaus Berlin, Berlin, Germany
- qEpidemiology Unit, German Rheumatism Research Centre, Berlin
- rDepartment of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany
- sInstitute for Clinical Pharmacology, Medical Faculty, Technical University Carl Gustav Carus, Dresden, Germany
- tClinic III for Internal Medicine (Cardiology), and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
- uCologne Cardiovascular Research Center (CCRC), University of Cologne, Cologne, Germany
- ↵∗Reprint requests and correspondence:
Dr. Christian F. Opitz, Department of Cardiology, DRK Kliniken Berlin, Spandauer Damm 130, 14050 Berlin, Germany.
Background Pulmonary hypertension (PH) is hemodynamically classified as pre-capillary (as seen in idiopathic pulmonary arterial hypertension [IPAH]) or post-capillary (as seen in heart failure with preserved ejection fraction [HFpEF]). Overlaps between these conditions exist. Some patients present with risk factors for left heart disease but pre-capillary PH, whereas patients with HFpEF may have combined pre- and post-capillary PH.
Objectives This study sought to further characterize similarities and differences among patient populations with either PH-HFpEF or IPAH.
Methods We used registry data to analyze clinical characteristics, hemodynamics, and treatment responses in patients with typical IPAH (<3 risk factors for left heart disease; n = 421), atypical IPAH (≥3 risk factors for left heart disease; n = 139), and PH-HFpEF (n = 226) receiving PH-targeted therapy.
Results Compared with typical IPAH, patients with atypical IPAH and PH-HFpEF were older, had a higher body mass index, had more comorbidities, and had a lower 6-min walking distance, whereas mean pulmonary artery pressure (46.9 ± 13.3 mm Hg vs. 43.9 ± 10.7 mm Hg vs. 45.7 ± 9.4 mm Hg, respectively) and cardiac index (2.3 ± 0.8 l/min/m2 vs. 2.2 ± 0.8 l/min/m2 vs. 2.2 ± 0.7 l/min/m2, respectively) were comparable among groups. After initiation of targeted PH therapies, all groups showed improvement in exercise capacity, functional class, and natriuretic peptides from baseline to 12 months, but treatment effects were less pronounced in patients with PH-HFpEF than typical IPAH; with atypical IPAH in between. Survival rates at 1, 3, and 5 years were almost identical for the 3 groups.
Conclusions Patients with atypical IPAH share features of both typical IPAH and PH-HFpEF, suggesting that there may be a continuum between these conditions.
Heart failure with preserved ejection fraction (HFpEF) is frequently accompanied by pulmonary hypertension (PH), which is associated with a poor outcome. Recent studies have suggested that PH is found in 36% to 83% of patients with HFpEF (1–3) and that both elevated pulmonary artery pressure and right ventricular (RV) dysfunction are independent predictors of death in patients with HFpEF (1,4–6).
Hemodynamically, pre-capillary PH—characterized by a mean pulmonary arterial wedge pressure (PAWP) ≤15 mm Hg—is distinguished from post-capillary PH, as indicated by a PAWP >15 mm Hg (7–11). The classic example of a disease characterized by pre-capillary PH is idiopathic pulmonary arterial hypertension (IPAH), which is caused by an obliterative pulmonary vasculopathy affecting predominantly small pulmonary arterioles. In contrast, left heart disease, such as HFpEF, causes post-capillary PH due to backward transmission of elevated left-sided filling pressures into the pulmonary circulation. The latter group may present with isolated post-capillary PH or combined post-capillary PH with a pre-capillary component, as indicated by an elevated diastolic pressure gradient and/or an increased pulmonary vascular resistance (PVR) (8,11,12).
Despite these seemingly clear definitions, a growing number of patients with PH are identified in whom criteria from multiple PH categories exist simultaneously. For example, several registries have documented a change of phenotype in patients diagnosed with IPAH, associated with increasing age (13,14). A significant number of these patients have a comorbidity profile typically found in patients with HFpEF, such as arterial hypertension, obesity, diabetes, and atrial fibrillation (15). Recently, the terms typical and atypical PAH have been proposed to distinguish between these populations (16). The AMBITION (Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension) trial excluded patients with 3 or more of these risk factors from the primary analysis set (17).
Although targeted therapies, including phosphodiesterase type 5 inhibitors (PDE5i), endothelin receptor antagonists (ERA), and prostacyclin analogues (PCA), are available for IPAH, evidence-based recommendations for the management of PH-HFpEF are lacking and current guidelines do not support the use of targeted PAH therapies in patients with PH-HFpEF (8,10,12). Additionally, patients with atypical IPAH have been under-represented or excluded in clinical trials.
To further determine similarities and differences in demographics, comorbidities, hemodynamics, treatment responses, and outcomes of patients with typical or atypical IPAH and patients with PH-HFpEF, we analyzed data from COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension), a European-based PH registry that enrolls patients with all forms of PH who receive targeted therapy (13,18).
An ongoing, investigator-initiated, noninterventional, prospective European-based registry, COMPERA is enrolling consecutive patients with all forms of PH receiving targeted therapies (NCT01347216). The present analysis included data recorded between January 2009 and April 2015 for incident patients (included into the COMPERA registry within 6 months of PH diagnosis) ages ≥18 years. The date of the first right heart catheterization confirming PH was defined as the date of diagnosis. Documentation included demographics (age, sex, body mass index [BMI], and comorbidities), type of PH according to the Nice classification, World Health Organization functional class (WHO-FC), 6-min walk distance (6MWD), hemodynamics, laboratory data, and detailed information about medications to treat PH. Data were collected at the time of diagnosis (baseline) and at 6-month intervals or whenever the patient has a pre-defined clinical event (death, transplantation, PH-related hospitalization, deterioration in WHO-FC, any unscheduled change in PAH therapy, or other serious adverse events). Out-of-range data or missing values were automatically queried during data entry, and independent onsite monitoring ensured source data verification. This study complies with the Declaration of Helsinki, the locally appointed ethics committees approved the research protocol, and informed consent was obtained from all subjects.
IPAH was defined by mean pulmonary artery pressure (PAPm) ≥25 mm Hg, PAWP ≤15 mm Hg, and exclusion of other causes of PAH (Figure 1). Furthermore, patients with IPAH were subcategorized into typical (<3 risk factors for left heart disease) or atypical (≥3 risk factors for left heart disease) IPAH on the basis of the criteria used in the AMBITION trial. The pre-defined risk factors for left heart disease were arterial hypertension, coronary artery disease, diabetes, atrial fibrillation, and BMI >30 kg/m2 at the time of diagnosis (17).
Inclusion criteria for the patients with PH-HFpEF were a diagnosis of combined post- and pre-capillary pulmonary hypertension (Cpc-PH) indicated by: 1) PAPm ≥25 mm Hg and mean PAWP >15 mm Hg; 2) preserved left ventricular ejection fraction (>45% by echocardiography); and 3) presence of echocardiographic signs of diastolic dysfunction of the left ventricle (corresponding to Nice Group 2.2) (8,19). Patients with incomplete data regarding their risk factor profiles were excluded from the analysis.
Data are shown as mean ± SD or as median and interquartile range, respectively. For continuous data, group differences were compared using the Student t test in case of normal distribution or by the Mann-Whitney U test otherwise. Frequency differences were compared using the chi-square or Fisher exact test. Survival was evaluated with Kaplan-Meier analysis and log-rank test. Group-wise comparisons were performed with post hoc adjustment for 3 parallel tests. Predictors of treatment discontinuation were examined using logistic regression. With regard to follow-up data, the 3-month time-point allowed a time window of ±15 days and the 1-year time-point a window of ±3 months. SPSS Statistics version 19.0 (IBM Corp., Armonk, New York) was used for analysis.
Overall, 5,935 consecutive patients with PH were enrolled in the COMPERA registry between May 2007 and April 2015. Figure 1 shows the selection of patients for the present analysis. A total of 786 incident patients were eligible for the present analysis: 421 with typical IPAH, 139 with atypical IPAH, and 226 with PH-HFpEF. The mean duration of follow-up in all patients was 24.9 ± 20.1 months, and the median interval between follow-up documentations was 3.6 months.
Baseline characteristics were different between the 3 groups (Table 1). When compared with typical IPAH, patients with atypical IPAH as well as those with PH-HFpEF were significantly older, had a higher BMI, and had a lower 6MWD (all p < 0.001 vs. typical IPAH). Natriuretic peptide levels were higher in patients with PH-HFpEF when compared with typical, but not atypical, IPAH.
By definition, patients with typical IPAH had fewer comorbidities at the time of diagnosis. Although arterial hypertension was present in 43%, the other risk factors were found in <25% of these patients. In contrast, 99% of patients with atypical IPAH and 92% of those with PH-HFpEF had a history of arterial hypertension; all other risk factors were found more frequently in these groups (p < 0.001 vs. typical IPAH for all parameters).
With respect to hemodynamic severity of PH, PAPm, cardiac index, and mixed venous oxygen saturation were comparable in all 3 groups (Table 1). By definition, PAWP was higher in patients with PH-HFpEF, resulting in lower mean transpulmonary pressure gradient (TPG) and PVR compared with the other groups. Notably, right atrial pressure was considerably higher in patients with PH-HFpEF (13 ± 5 mm Hg) compared with typical IPAH (9 ± 5 mm Hg; p < 0.001) and atypical IPAH (9 ± 5 mm Hg; p < 0.001).
In the PH-HFpEF group, mean TPG was 26 ± 9 mm Hg, and the vast majority of these patients (201 of 226; 89%) had a TPG >12 mm Hg. Furthermore, mean PVR was elevated at 7.0 ± 3.4 Wood units (WU), indicating Cpc-PH (10).
As per inclusion criteria, all patients in the COMPERA registry received at least 1 targeted PH therapy. However, the treatment patterns differed significantly between the 3 groups (Table 2): PDE5i were selected as first-line therapy in 77% of the patients with typical IPAH, in 81% with atypical IPAH, and in 94% with PH-HFpEF. In contrast, ERAs were used as first-line therapy in approximately one-third of patients with typical IPAH and one-fifth with atypical IPAH, but in only 7% of the patients with PH-HFpEF. The use of PCA as first-line treatment was <5% in all groups.
During follow-up, the preference for PDE5i therapy in PH-HFpEF persisted (Table 2). At 1 year, 84% of the typical patients with IPAH received PDE5is, whereas 48% were treated with ERAs and 6% with PCAs. Patients with atypical IPAH showed similar preference patterns, but for patients with PH-HFpEF, there was significantly less use of ERAs (p < 0.001 vs. typical IPAH; p = 0.002 vs. atypical IPAH).
Combination therapy was initiated within 3 months after diagnosis in 18% of the patients with typical IPAH compared with only 8% of those with atypical IPAH and 3% of the patients with PH-HFpEF. At 1 year, combination therapy was used in 44% of the typical IPAH group, whereas the corresponding numbers for atypical IPAH and PH-HFpEF were 26% and 7%, respectively (Table 2).
As shown in Table 3, treatment discontinuation of PDE5i occurred significantly more often in patients with PH-HFpEF than with typical IPAH (18.4% vs. 8.8%; p = 0.005), and patients with atypical IPAH were in between at 13%. The main reasons for discontinuation in patients with PH-HFpEF were side effects in 5.3% and lack of efficacy in 10%, the latter being less frequently observed (<3%) in the other groups.
Within the small subgroup of patients with PH-HFpEF receiving an ERA, this treatment was discontinued in almost every second patient (43%; p = 0.001 vs. typical IPAH), either because of side effects (23%) or lack of improvement (11%). In patients with typical IPAH, side effects and lack of improvement were responsible for ERA discontinuation in 10% and 2%, respectively. Interestingly, patients with atypical IPAH again fell between these groups, with an ERA discontinuation rate of 23%.
Treatment discontinuations were associated with less severe hemodynamics. Patients with typical IPAH who discontinued pulmonary vasodilator therapy had lower values for PAPm (risk ratio [RR]: 0.965; 95% confidence interval [CI]: 0.933 to 0.998; p = 0.039) and right atrial pressure (RR: 0.885; 95% CI: 0.801 to 0.977; p = 0.016) compared with patients continuing this therapy. A similar pattern was observed in patients with PH-HFpEF. Patients who discontinued PDE5i therapy had lower PAPm (RR: 0.937; 95% CI: 0.897 to 0.979; p = 0.004) and TPG (RR: 0.928; 95% CI: 0.884 to 0.973; p = 0.002).
Response to therapy
After PH therapies were initiated, WHO-FC, exercise capacity, and natriuretic peptide levels improved from baseline to 12 months in all groups, but treatment effects were less pronounced in PH-HFpEF. In all 3 groups, WHO-FC improved in approximately one-third of the patients (Table 4). The percentage of patients in WHO-FC I or II at 12 months was 40% in the typical IPAH group, 26% in the atypical IPAH group (p = NS vs. typical IPAH), and 23% in the PH-HFpEF group (p = 0.026 vs. typical IPAH).
At 1 year, the mean 6MWD increased from baseline in all groups. Of note, 62% of patients with typical IPAH, 59% of patients with atypical PAH, and 43% of those with PH-HFpEF showed an improvement in 6MWD by >30 m.
Natriuretic peptide levels decreased in all groups; this was most pronounced in patients with typical IPAH (−43% from baseline) and to a lesser extent in atypical IPAH (−36% from baseline) and PH-HFpEF (−14% from baseline).
Within the first 5 years after initiation of targeted PH therapy, there was no difference in overall mortality among the 3 groups (Figure 2). However, patients with typical IPAH or atypical IPAH more often died from PH-related complications (56% and 58%, respectively) compared with patients with PH-HFpEF (32%; p = 0.026).
The current analysis compared disease characteristics, hemodynamics, treatment patterns, response to therapy, and mortality in patients with IPAH as well as in patients with PH due to HFpEF, all of whom received targeted PH therapy. Patients with IPAH were further subcategorized as typical and atypical, on the basis of the presence of risk factors for left heart disease. The risk profiles and demographic characteristics of patients with atypical IPAH resembled those of the PH-HFpEF group, whereas hemodynamics were comparable with typical IPAH. At the same time, severity of PH, as indicated by a high PAPm and a low cardiac index, was comparable in all 3 groups; the same was true for survival.
The selection of PH therapies and the evoked treatment response showed considerable differences among groups. Although treatment patterns in patients with typical IPAH were comparable with other cohorts (20), >90% of the patients with PH-HFpEF received first-line treatment with a PDE5i, whereas ERAs were rarely used. The therapeutic approach to atypical IPAH was in between these 2 conditions. The observed changes in WHO-FC, exercise capacity, and natriuretic peptide levels indicated some efficacy of targeted therapies in all 3 populations, with the greatest improvements seen in patients with typical IPAH, the least improvements in patients with PH-HFpEF, and atypical IPAH again in between. With respect to side effects and tolerability of PH medications, differences between the 3 groups emerged. In patients with typical IPAH, side effect profile and drug tolerability matched data reported from clinical studies (17). In patients with PH-HFpEF, targeted therapies, particularly ERAs, were less well tolerated. Here, the drug discontinuation rate due to side effects or lack of efficacy reached 34% for ERA and 16% for PDE5i therapy. In atypical PAH, drug discontinuation rates were between those of typical IPAH and PH-HFpEF.
PH in association with left heart disease is arguably 1 of the most common forms of PH. Depending on methods and definitions used, the prevalence of PH in patients with HFpEF has been reported to be as high as 80% (1). Development of PH or RV dysfunction in patients with HF carries strong negative prognostic information (1,4,6). Despite the importance of PH in HFpEF, the underlying pathomechanisms are not entirely clear. Even less clear are the treatment options; current guidelines discourage the routine use of targeted PH therapy in patients with PH-HFpEF but rather emphasize the optimized treatment of the underlying diseases and comorbidities (10,12).
Our findings reinforced previous observations that there is a subpopulation among patients with HFpEF who have severe PH with a distinct pre-capillary component (15). Except for the elevated filling pressures and the resulting lower PVR, the hemodynamic profiles of these patients were similar to what was found in patients with IPAH. Given the fact that all patients included in our series had a preserved left ventricular systolic function, it is likely that the low cardiac output seen in the patients with PH-HFpEF resulted primarily from RV rather than left ventricular dysfunction.
The presence of severe PH together with RV dysfunction was probably the rationale for the COMPERA investigators to prescribe drugs approved for PAH in patients with PH-HFpEF. According to the new European Society of Cardiology and European Respiratory Society guidelines, these patients may be categorized as having Cpc-PH (8,10). The strong preference for PDE5i as first-line therapy in PH-HFpEF may have resulted from previous studies of ERA and PDE5i in heart failure patients with reduced (21–24) and preserved ejection fraction (25). So far, almost all trials with ERA in patients with left heart disease failed to show clinical benefit and were associated with frequent side effects, predominantly fluid retention (26). The high discontinuation rate for ERA in our PH-HFpEF group was in line with these observations.
In contrast to ERA, there have been promising pre-clinical and clinical data for PDE5i in patients with PH-HFpEF, including a small positive randomized controlled trial (23,25). The largest study on the use of sildenafil in 216 patients with HFpEF, however, did not show improvement of exercise capacity or symptoms compared with placebo, but this study did not specifically include patients with PH-HFpEF (27). A recent single-center randomized clinical trial showed no efficacy of sildenafil in improving pulmonary hemodynamics or exercise capacity in 52 patients with HFpEF and predominantly post-capillary PH (28).
Our data indicated that PDE5i therapy was generally well-tolerated with comparable side effect profiles in patients with typical and atypical IPAH as well as in patients with PH-HFpEF. With respect to treatment efficacy, our results should be interpreted with particular caution. Improvements in 6MWD, WHO-FC, and natriuretic peptide levels were observed, although the changes were more pronounced with typical IPAH as compared with PH-HFpEF, whereas the responses in patients with atypical IPAH were in-between. Although efficacy failure led to treatment discontinuation in <3% of the patients with typical or atypical IPAH, this lack of improvement caused withdrawal of the PDE5i in 10% of the patients with PH-HFpEF. It is tempting to speculate that the declining contribution of a pre-capillary component of PH, as well as the increasing frequency of comorbidities from typical IPAH to atypical IPAH and PH-HFpEF, attenuated the treatment response of these patients with respect to PAH-targeted drugs. Charalampopoulos et al. (15) recently reported data supporting this concept. This would also explain the putative discrepancy between our patients with PH-HFpEF having a mean PVR of 7 WU and the previous reports mentioned earlier, which provided either no resistance data (2,27) or a median PVR of 2.6 WU (28).
The survival curves in the 3 patient populations studied herein were almost superimposable. In the ASPIRE (Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Centre) registry (20), patients with PH-HFpEF had a 3-year-survival rate >80%, compared with 62% in our series. In contrast to our patients, patients with PH-HFpEF in ASPIRE had lower PVR values and normal cardiac output. It is conceivable that our patients’ more severe PH contributed to their higher mortality. This notion was supported by the fact that PH and right heart failure were listed as cause of death in 32% of the patients with PH-HFpEF in our series.
Our data supported the hypothesis that there may be a disease continuum ranging from typical IPAH through atypical IPAH to PH-HFpEF (Central Illustration). As in many other fields of medicine, clinical classifications were introduced to clarify complex biological systems, but often single cut-off values failed to separate disease entities, especially in multifactorial diseases and in aging patient populations (13). The hemodynamic separation of pre- from post-capillary PH by the PAWP threshold of 15 mm Hg might be such an example. On the basis of data presented here, it is most likely that a number of our patients have been labeled as IPAH despite the presence of several risk factors (as defined earlier) predisposing for the development of post-capillary PH. In the AMBITION trial, this phenomenon was observed during the early enrollment period, which led to modification of the inclusion criteria preventing further enrollment of patients with 3 or more risk factors for left heart disease, that is, atypical IPAH (16,17). Interestingly, the analysis of the 2 groups (“original” vs. “restricted” inclusion criteria) supported our findings, as it described a similar shift in age and comorbidity profile with comparable hemodynamics. As in our study, patients with atypical IPAH in the AMBITION trial did respond to PH therapies, although the response was attenuated and the rate of treatment discontinuations was higher (17).
Our study had both strengths and limitations. Strengths included the large sample size of prospectively enrolled patients with newly diagnosed, incident PH; the relatively long observation period; the low number of patients who were lost to follow-up; the “real-life” setting; and the availability of hemodynamic data from right heart catheterization at the time of diagnosis. Limitations included the registry nature of the data source, which obviously does not reach the quality of a randomized clinical trial. Hence, any data on drug effects must be interpreted with great caution. However, the COMPERA registry enrolls consecutive patients on a prospective basis, and several control measures have been implemented to ensure high data quality, including independent on-site source data monitoring. Nevertheless, comorbidities were only documented as far as they are known to be associated with the development of left heart disease and/or PH. Medications other than PAH-approved drugs and anticoagulants were not documented. Complete follow-up data were not available for all parameters, and systematic echocardiographic or hemodynamic follow-up data were lacking. Further, we did not apply statistical measures to reduce confounding (such as propensity-score matching or multivariable risk-adjusted modeling), and thus, for all results and conclusions it must be considered that groups differed in many respects at baseline. Finally, the sample of patients with PH-HFpEF described herein represented a unique subset of patients with severe PH and HFpEF who were judged as candidates for targeted PH therapies by the expert COMPERA investigators on an individual basis. Therefore, our findings are not generalizable to all patients with PH-HFpEF and should not promote uncritical and potentially dangerous use of PAH drugs in this group of patients. In addition, the elevated right atrial pressure in the PH-HFpEF group might be an indicator that the therapeutic potential of optimized volume control (29) has not fully been utilized by the COMPERA investigators.
Our findings underscored the notion that there is a population of patients with risk factors for left heart disease presenting with pre-capillary PH that is characterized by disease features lying in between typical IPAH and PH-HFpEF. Our data, in line with recent reports from the AMBITION study (16,17) and others (15), indicated that these patients benefit from PH-targeted therapies, albeit to a lesser extent than patients with typical IPAH. In addition, our results also indicated potential benefits of PH-targeted therapies in patients with HFpEF and with combined pre- and post-capillary PH. As patients with atypical IPAH and PH-HFpEF are becoming more common, future studies should aim to identify the most appropriate treatment strategies for these patient populations.
COMPETENCY IN MEDICAL KNOWLEDGE: Patients with post-capillary pulmonary hypertension due to HFpEF, those with atypical idiopathic PAH associated with multiple risk factors for left-sided heart disease, and those with pre-capillary, idiopathic PAH span a pathophysiological continuum with different clinical characteristics and responses to therapy.
TRANSLATIONAL OUTLOOK: Future studies should assess the efficacy of pulmonary vasodilator therapies in patients with HFpEF and in those with combined forms of pre- and post-capillary PH.
COMPERA is currently supported by unrestricted educational grants from Actelion, Bayer, and GlaxoSmithKline (in the past it was also supported by Lilly, Novartis, Encysive, AOP Orphan, and Pfizer). Dr. Opitz’s institution has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Novartis, and Pfizer. Dr. Hoeper has received speaker fees and honoraria for consultations from Actelion, Bayer, Gilead, GlaxoSmithKline, Lilly, Novartis and Pfizer. Dr. Gibbs has received speaker fees and honoraria for consultations from Actelion, Bayer, Gilead, GlaxoSmithKline, Lilly, Novartis, and Pfizer; has received speaker fees from AOP Orphan; and has served on the Speakers Bureau for Actelion, Bayer, and GlaxoSmithKline. Dr. Kaemmerer has received speaker fees and honoraria from Actelion and Pfizer. Dr. Pepke-Zaba has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline; and her institution has received educational and research grants from Actelion, Bayer, and GlaxoSmithKline. Dr. Coghlan has received honoraria and consultancy fees from Actelion, GlaxoSmithKline, Bayer, United Therapeutics, and Endotronix; and has received grants from Actelion and GlaxoSmithKline. Dr. Olsson has received speaker fees from Actelion, Bayer, GlaxoSmithKline, Pfizer, and United Therapeutics. Dr. Ulrich has received honoraria for lectures and/or consultancy from Actelion and Bayer; has received grant money from the Swiss National Science Foundation and Zurich Lung League; and her institution has received research grants from Actelion, Bayer, and United Therapeutics. Dr. Schulz has received an unrestricted educational grant and speaker honoraria from Actelion; and has received a research grant from Bayer. Dr. Grünig has received honorariums for consultations and/or speaking at conferences from Actelion, Bayer, Gilead, GlaxoSmithKline, Lilly, Milteney, Novartis, Pfizer, United Therapeutics, AOP Orphan, and Rotex Medica; has served as an advisory board member of GlaxoSmithKline, Actelion, Bayer, United Therapeutics, and AOP Orphan; and has received funding for clinical trials by Actelion, Bayer, GlaxoSmithKline, Encysive, Lilly, and Pfizer. Dr. Vizza has received fees for serving as a speaker, consultant, and advisory board member from Actelion, Bayer, Dompè, GlaxoSmithKline, Italfarmaco, Lilly, Pfizer, UTEL, and United Therapeutics; and his institution has received research grants from Actelion, Bayer, GlaxoSmithKline, Lilly, Pfizer, and United Therapeutics. Dr. Staehler has received honoraria for lectures and/or consultancy for Actelion, Bayer, GlaxoSmithKline, Lilly, Novartis, and Pfizer. Dr. Bruch has received speaker honoraria from Actelion and Bayer. Dr. Huscher has received consultancy fees from Actelion. Dr. Pittrow has received speaker fees or honoraria for consultations from Actelion, Bayer, Genzyme, Boehringer Ingelheim, Novartis, and Pfizer. Dr. Rosenkranz has received honoraria for lectures and/or consultancy from Actelion, Bayer, GlaxoSmithKline, Novartis, Pfizer, and United Therapeutics; and his institution has received research grants from Actelion, Bayer, Novartis, Pfizer, and United Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- endothelin receptor antagonist
- heart failure with preserved ejection fraction
- idiopathic pulmonary arterial hypertension
- mean pulmonary artery pressure
- pulmonary arterial wedge pressure
- prostacyclin analogue
- phosphodiesterase type 5 inhibitor
- pulmonary vascular resistance
- mean transpulmonary pressure gradient
- Received December 24, 2015.
- Revision received April 28, 2016.
- Accepted May 3, 2016.
- American College of Cardiology Foundation
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