Abstract
Background
The New International Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Registry, conducted between 2015 and 2019, revealed the significant impact of pulmonary endarterectomy (PEA) and balloon pulmonary angioplasty (BPA) on the long-term survival of CTEPH patients. The objective of the current pre-specified analysis was to evaluate the effect of medical treatment, including the approved oral guanylate cyclase stimulator (sGC) riociguat, in patients with or without mechanical intervention.
Methods
1009 newly diagnosed patients were included in the study, with recruitment conducted at 34 centres across 20 countries. At the outset of the registry, sGC was available in 85% of the countries involved.
Results
52% of all patients included were treated with pulmonary hypertension (PH) drugs. The proportion of patients receiving PH drugs was 38% among the 605 patients who underwent PEA, 78% among the 185 patients who underwent BPA and 76% among the 219 remaining patients who did not undergo PEA or BPA. In the “BPA” and “no PEA/BPA” groups, the 3-year survival was superior in patients who received sGC in comparison with other PH drugs. Cox regression confirmed that sGC treatment was associated with reduced mortality in the global cohort, in the BPA group and in the “no PEA/BPA” group.
Conclusion
This international CTEPH registry suggests that, although an increasing proportion of patients with CTEPH benefited from mechanical treatment, medical treatment with sGC may be associated with a survival advantage in patients undergoing BPA or no intervention. These observations confirm the results of previous randomised controlled trials in a real-world setting.
Shareable abstract
Medical treatment with sGC may be associated with a survival advantage in CTEPH patients undergoing BPA or no mechanical intervention https://bit.ly/3HdM04u
Introduction
Chronic thromboembolic pulmonary hypertension (CTEPH) represents a rare complication of massive or recurrent pulmonary embolism (PE). The incidence of CTEPH in survivors of acute PE has been reported to be 2.7% [1], whereas the incidence of CTEPH in the general population is estimated to be between 5 and 13 cases per million per year [2]. The condition is characterised by the presence of intra-luminal unresolved thrombi and fibrous stenosis, which results in the partial or complete obliteration of large pulmonary arteries. This is associated with a progressive microvasculopathy [3]. In patients with a mean pulmonary arterial pressure (PAP) in the 41–50 mmHg range who did not receive additional treatment, the 3-year survival rate was approximately 50% [4].
A previous European–Canadian registry, conducted between 2007 and 2012, demonstrated that patients with CTEPH who underwent pulmonary endarterectomy (PEA) exhibited a 3-year survival rate of 89%, in comparison to a 70% survival rate observed in patients who did not undergo surgery. The administration of medical therapy with the then-available pulmonary hypertension (PH) drugs (i.e. phosphodiesterase 5 inhibitors (PDE5i); endothelin receptor antagonists (ERAs); or prostacyclin analogues (PCAs)) to target microvasculopathy was found to have a negative association with survival in operated patients and a neutral effect in those who had not undergone surgery [5]. A new international registry, conducted from 2015 to 2019, demonstrated the significant benefit of balloon pulmonary angioplasty (BPA) for inoperable patients, with 3-year survival rates of 94% for PEA, 92% for BPA and 71% for the “no intervention” group, respectively [6]. In this latest group, however, medical treatment was associated with a reduction in mortality. Both registries were conducted by the International CTEPH Association (ICA).
In the interim period between the two registries, riociguat, an oral soluble guanylate cyclase stimulator (sGC), had been approved [7] and recommended by guidelines [8] for inoperable patients with CTEPH and patients with persistent or recurrent PH following PEA.
To enhance our comprehension of the pharmacological management of CTEPH, a detailed examination of the therapeutic efficacy of individual drugs was conducted within the new registry cohort. The current study presents the long-term outcome data pertaining to the various therapeutic interventions and the diverse forms of medical therapy.
Methods
Study design
The New International CTEPH Registry prospectively collected data on consecutive CTEPH patients, as previously described [6]. To be included in the study, patients had to be enrolled within 12 months of diagnosis and be naive to mechanical treatment. Initiation of PH drugs was left to the discretion of the treating physician.
The current pre-specified analysis had two objectives: first, to evaluate survival in patients receiving sGC versus other PH drugs versus no drugs in the “no PEA/BPA” group, and secondly, to evaluate sGC as a potential predictor of outcome in all patients and in patients undergoing PEA, BPA or no intervention.
Data handling
Patients were categorised according to the initial intervention performed (16 patients underwent both PEA and BPA, all of whom had undergone PEA first). Patients receiving sGC received riociguat at any point, whereas those receiving “other drugs” never received riociguat. At the commencement of the registry, sGC was available in 85% of countries participating in the study.
Statistical analysis
The results are expressed as medians with first and third quartiles (Q1–Q3) or as absolute numbers and percentages of patients. Subgroup comparisons were conducted using the Mann–Whitney U-test or the Kruskal–Wallis H-test for continuous variables and the chi-squared test for categorical variables. It is recommended that the reported p-values be interpreted in an exploratory sense.
The time to death (all-cause) was estimated using the Kaplan–Meier method and analysed using the log-rank test for comparisons.
The factors predictive of death were identified using multivariable Cox regression analysis. In addition to the variables initially considered for inclusion in the multivariable model [6], specific PH therapy variables were incorporated, namely: sGC, PCA, ERA or PDE5i received at any time; and combination treatment comprising several PH drugs received at any time. Furthermore, a sensitivity analysis was conducted by classifying patients according to their initial treatment, sGC versus other drugs (in an intention-to-treat population).
Age at diagnosis and sex were incorporated as covariates in the multivariable model to provide risk-adjusted hazard ratios, along with additional baseline variables (history of venous thromboembolism, New York Heart Association functional class (NYHA FC), right atrial pressure (RAP) and pulmonary vascular resistance (PVR)) that were identified as appropriate through preliminary stepwise modelling. The proportional hazards assumption was verified through the inspection of log(−log) plots for categorical variables and the examination of the pattern of Schoenfeld residuals for continuous variables.
The data were analysed with IBM SPSS software v.27.
Results
Patient characteristics
A total of 1009 consecutive patients with CTEPH were included in this registry. Of these, 605 (60%) underwent PEA, 185 (18%) underwent BPA and 219 (22%) did not undergo mechanical treatment. The characteristics of these patients have been described previously [6]; the disposition of PH drugs used is presented in table 1. Of the total number of patients included in the study, 54% were treated with PH drugs at any time point during the registry observation. This included 38% of patients who underwent PEA, 78% of patients who underwent BPA and 76% of patients who did not undergo PEA or BPA. Only 25% of patients undergoing PEA received PH drugs (predominantly PDE5i) prior to the procedure, in contrast to 63% of those undergoing BPA (predominantly sGC). Most patients receiving PH drugs at the 1-year post-procedural follow-up or at last follow-up for “no PEA/BPA” group were on sGC (64% of 303 patients). The use of ERA and PCA was generally less prevalent across the board. 22% of patients receiving drugs were on combination therapy.
TABLE 1.
Medical treatment disposition: all and by intervention
| All (n=1009) |
PEA (n=605, 60%) | BPA (n=185, 18%) | No PEA/BPA (n=219, 22%) | p-value | |
|---|---|---|---|---|---|
| PH drugs started prior to intervention/at diagnosis#,¶ | 37 | 25 | 63 | 49 | <0.001 |
| sGC (% of patients with PH drugs) | 38 | 24 | 57 | 38 | |
| PDE5i | 49 | 57 | 33 | 55 | |
| ERA | 21 | 27 | 19 | 14 | |
| PCA | 9 | 8 | 19 | 1 | |
| Any combination | 18 | 16 | 26 | 11 | |
| PH drugs on procedural discharge¶ | NA | 8 | 58 | NA | <0.001 |
| sGC, % of patients with PH drugs | 26 | 69 | |||
| PDE5i | 54 | 21 | |||
| ERA | 22 | 23 | |||
| PCA | 13 | 10 | |||
| Any combination | 15 | 21 | |||
| PH drugs 1 year post-procedure/last FU+,¶ | 30 | 14 | 43 | 61 | <0.001 |
| sGC, % of patients with PH drugs | 64 | 60 | 79 | 58 | |
| PDE5i | 30 | 30 | 19 | 38 | |
| ERA | 23 | 18 | 17 | 29 | |
| PCA | 5 | 5 | 5 | 5 | |
| Any combination | 21 | 16 | 17 | 26 | |
| PH drugs at any time¶ | 54 | 38 | 78 | 76 | <0.001 |
| sGC, % of patients with PH drugs | 60 | 53 | 77 | 55 | |
| PDE5i | 41 | 44 | 31 | 47 | |
| ERA | 27 | 27 | 23 | 30 | |
| PCA | 10 | 9 | 18 | 4 | |
| Any combination | 22 | 17 | 29 | 22 |
Data are presented as %. PEA: pulmonary endarterectomy; BPA: balloon pulmonary angioplasty; sGC: soluble guanylate cyclase stimulator; PDE5i: phosphodiesterase 5 inhibitor; ERA: endothelin receptor antagonist; PH: pulmonary hypertension; PCA: prostacyclin analogue; NA: not available; FU: follow-up. p-value for comparison between PEA versus BPA versus “no PEA/BPA”. #: at diagnosis for “no PEA/BPA”. ¶: more than one possible; +: at last follow-up for “no PEA/BPA” group.
The majority (over 75%) of patients who receive PDE5i get it immediately on diagnosis. Patients who underwent BPA were more likely than others to receive sGC at diagnosis. ERA and PCA were, on average, initiated later for “no intervention” patients than for intervention patients (supplementary table S1). Overall, more than 50% of patients were on therapy or start it at diagnosis because the median time from diagnosis to initiation for any therapy is zero both for the entire cohort and the groups by intervention. In other words, most, if not all, of the 54% of patients who receive drugs at any point receive them early on.
The characteristics of patients are shown in tables 2–4; those who underwent PEA (table 2), BPA (table 3) or who did not undergo PEA or BPA (table 4), according to the drugs they received (namely sGC at any time, possibly in combination; “other PH drugs” at any time excluding sGC; “no PH drugs”). A comparison of the medical strategies showed that PAP and PVR at diagnosis were lowest in patients with no PH drugs.
TABLE 2.
Patient characteristics by PH drugs at any time for patients in the PEA group
| sGC (n=124, 20% of PEA) | Other PH drugs (n=105, 17% of PEA) | No PH drug (n=376, 62% of PEA) | p-value | |
|---|---|---|---|---|
| Age, years | 61 (51–71) | 60 (49–70) | 59 (48–70) | NS |
| Male sex | 40 | 54 | 56 | 0.008 |
| Ethnicity, White/Black/Asian | 80/2/17 | 87/4/7 | 92/2/2 | NA |
| Time from symptoms to diagnosis, months | 15 (7–37) | 22 (10–46) | 14 (8–26) | 0.011 |
| History of VTE | 75 | 83 | 82 | NS |
| History of hospitalisation for RHF | 27 | 37 | 18 | <0.001 |
| NYHA FC I–II/III/IV | 23/55/22 | 14/66/20 | 30/58/12 | 0.002 |
| RAP, mmHg | 8 (5–12) | 9 (6–15) | 8 (5–11) | 0.024 |
| PAP, mmHg | 46 (40–54) | 48 (39–56) | 43 (35–50) | <0.001 |
| PAWP, mmHg | 10 (8–13) | 10 (8–13) | 10 (8–12) | NS |
| CI, L·min−1·m−2 | 2.10 (1.80–2.68) | 2.03 (1.73–2.53) | 2.22 (1.89–2.63) | NS |
| PVR, dyne·s·cm−5 | 720 (492–977) | 778 (577–947) | 610 (428–856) | <0.001 |
| Oxygen at diagnosis, | 35 | 28 | 21 | 0.009 |
| Oxygen after treatment start | 38 | 18 | 11 | <0.001 |
| PH drugs started at diagnosis# | 48 | 83 | 0 | <0.001 |
| sGC, % of patients with PH drugs | 59 | 0 | ||
| PDE5i | 31 | 72 | ||
| ERA | 20 | 31 | ||
| PCA | 7 | 8 | ||
| Any combination | 14 | 13 | ||
| PH drugs started at any time# | 100 | 100 | 0 | NA |
| sGC, % of patients with PH drugs | 100 | 0 | ||
| PDE5i | 23 | 69 | ||
| ERA | 23 | 32 | ||
| PCA | 9 | 10 | ||
| Any combination | 20 | 14 |
Data are expressed as median (Q1–Q3) or percentages. PH: pulmonary hypertension; PEA: pulmonary endarterectomy; sGC: soluble guanylate cyclase stimulator; VTE: venous thromboembolism; RHF: right heart failure; NYHA FC: New York Heart Association functional class; RAP: right atrial pressure; PAP: mean pulmonary arterial pressure; PAWP: pulmonary arterial wedge pressure; CI: cardiac index; PVR: pulmonary vascular resistance; PDE5i: phosphodiesterase 5 inhibitor; ERA: endothelin receptor antagonist; PCA: prostacyclin analogue; NA: not available; NS: not significant. p-values for comparison between sGC, other PH drugs and no PH drugs. #: more than one possible.
TABLE 4.
Patient characteristics by PH drugs at any time for patients in the “no PEA/BPA” group
| sGC (n=92, 42% of “no PEA/BPA”) | Other PH drugs (n=74, 34% of “no PEA/BPA”) | No PH drug (n=53, 24% of “no PEA/BPA”) | p-value | |
|---|---|---|---|---|
| Age, years | 70 (60–78) | 67 (54–76) | 71 (60–76) | NS |
| Sex, male | 40 | 43 | 57 | NS |
| Ethnicity, White/Black/Asian | 80/2/16 | 77/11/7 | 89/8/4 | NA |
| Time from symptoms to diagnosis, months | 14 (7–34) | 25 (13–64) | 15 (5–26) | 0.002 |
| History of VTE | 76 | 76 | 68 | NS |
| History of hospitalisation for RHF | 21 | 22 | 13 | NS |
| NYHA FC I–II/III/IV | 25/65/10 | 11/77/12 | 31/56/13 | NS |
| RAP, mmHg | 7 (4–10) | 11 (6–15) | 8 (5–11) | 0.003 |
| PAP, mmHg | 42 (34–51) | 46 (37–58) | 37 (30–50) | 0.002 |
| PAWP, mmHg | 11 (9–14) | 12 (10–14) | 10 (9–13) | NS |
| CI, L·min−1·m−2 | 2.12 (1.76–2.70) | 2.20 (1.71–2.60) | 2.60 (2.14–2.80) | 0.029 |
| PVR, dyne·s·cm−5 | 576 (398–951) | 657 (481–1041) | 506 (280–782) | 0.005 |
| Oxygen at diagnosis | 27 | 28 | 28 | NS |
| Oxygen after treatment start, | 39 | 34 | 13 | 0.004 |
| PH drugs started at diagnosis# | 52 | 81 | 0 | <0.001 |
| sGC, % of patients with PH drugs | 85 | 0 | ||
| PDE5i | 15 | 87 | ||
| ERA | 2 | 23 | ||
| PCA | 0 | 2 | ||
| Any combination | 2 | 12 | ||
| PH drugs started at any time# | 100 | 100 | 0 | NA |
| sGC, % of patients with PH drugs | 100 | 0 | ||
| PDE5i | 13 | 89 | ||
| ERA | 24 | 38 | ||
| PCA | 2 | 5 | ||
| Any combination | 20 | 24 |
Data are expressed as median (Q1–Q3) or percentages. PH: pulmonary hypertension; PEA: pulmonary endarterectomy; BPA: balloon pulmonary angioplasty; sGC: soluble guanylate cyclase stimulator; NS: not significant; NA: not available; VTE: venous thromboembolism; RHF: right heart failure; NYHA FC: New York Heart Association functional class; RAP: right atrial pressure; PAP: mean pulmonary arterial pressure; PAWP: pulmonary arterial wedge pressure; CI: cardiac index; PVR: pulmonary vascular resistance; PDE5i: phosphodiesterase 5 inhibitor; ERA: endothelin receptor antagonist; PCA: prostacyclin analogue. p-values for comparison between sGC, other PH drugs and no PH drugs. #: more than one possible.
TABLE 3.
Patient characteristics by PH drugs at any time for patients in the BPA group
| sGC (n=108, 58% of BPA) | Other PH drugs (n=37, 20% of BPA) | No PH drug (n=40, 22% of BPA) | p-value | |
|---|---|---|---|---|
| Age, years | 67 (57–75) | 60 (46–73) | 64 (50–72) | NS |
| Sex, male | 39 | 41 | 13 | 0.006 |
| Ethnicity, White/Black/Asian | 58/1/42 | 68/0/32 | 33/3/65 | NA |
| Time from symptoms to diagnosis, months | 11 (5–17) | 23 (13–55) | 8 (4–18) | <0.001 |
| History of VTE | 62 | 65 | 70 | NS |
| History of hospitalisation for RHF | 31 | 49 | 40 | NS |
| NYHA FC I–II/III/IV | 22/70/8 | 32/57/11 | 47/48/5 | 0.041 |
| RAP, mmHg | 7 (4–9) | 7 (4–11) | 6 (4–8) | NS |
| PAP, mmHg | 43 (37–51) | 45 (35–52) | 38 (29–45) | 0.010 |
| PAWP, mmHg | 8 (6–11) | 8 (6–11) | 8 (6–11) | NS |
| CI, L·min−1·m−2 | 2.19 (1.78–2.80) | 2.30 (2.05–2.92) | 2.56 (2.03–3.02) | NS |
| PVR, dyne·s·cm−5 | 737 (504–1025) | 633 (463–1002) | 541 (387–810) | 0.029 |
| Oxygen at diagnosis | 38 | 41 | 55 | NS |
| Oxygen after treatment start | 51 | 38 | 53 | NS |
| PH drugs started at diagnosis# | 69 | 87 | 0 | 0.033 |
| sGC, % of patients with PH drugs | 78 | 0 | ||
| PDE5i | 20 | 63 | ||
| ERA | 11 | 28 | ||
| PCA | 8 | 44 | ||
| Any combination | 18 | 31 | ||
| PH drugs started at any time# | 100 | 100 | 0 | NA |
| sGC (% of patients with PH drugs) | 100 | 0 | ||
| PDE5i | 17 | 73 | ||
| ERA | 19 | 38 | ||
| PCA | 11 | 38 | ||
| Any combination | 25 | 41 |
Data are expressed as median (Q1–Q3) or percentages. PH: pulmonary hypertension; BPA: balloon pulmonary angioplasty; sGC: soluble guanylate cyclase stimulator; NS: not significant; NA: not available; VTE: venous thromboembolism; RHF: right heart failure; NYHA FC: New York Heart Association functional class; RAP: right atrial pressure; PAP: mean pulmonary arterial pressure; PAWP: pulmonary arterial wedge pressure; CI: cardiac index; PVR: pulmonary vascular resistance; PDE5i: phosphodiesterase 5 inhibitor; ERA: endothelin receptor antagonist; PCA: prostacyclin analogue. p-values for comparison between sGC, other PH drugs and no PH drugs. #: more than one possible.
In the BPA group, PVR was the highest in the sGC treated patients, while in the PEA and “no intervention” groups it was the highest in those receiving “other PH drugs”.
In the “no intervention” group, the “other PH drugs” exhibited a higher proportion of patients in NYHA FC III/IV and a longer interval between symptom onset and diagnosis compared with the other two subgroups. Taking all observations together, patients who receive no drugs had the least severe disease, and those who were on “other PH drugs” had the most severe disease. Patients receiving “other PH” drugs generally started medication earlier after diagnosis than those receiving sGC (supplementary table S2).
Long-term outcome by PH drug regimen
Survival rates at three years were 94% for PEA, 92% for BPA, and 71% for no PEA/BPA [6]. Patients in the “no PEA/BPA” group who received sGC at any time exhibited superior survival rates compared with patients on other PH drugs or no PH drugs (85% versus 57% and 64% at 3 years; p <0.001; figure 1). A sensitivity analysis in which patients were classified according to their initial treatment (in an intention-to-treat population) corroborates the superior outcome observed in patients receiving sGC compared with other PH drugs at diagnosis, with 3-year survival rates of 77% versus 58% (p=0.033; supplementary figure S1), respectively. It is worth to notice that, in the “no drug at diagnosis” subgroup, more than half of the patients received PH drugs at some point during follow-up, which may explain the “good” survival of this “no drug at diagnosis” subgroup.
FIGURE 1.
Kaplan–Meier survival curve by intervention and with “no PEA/BPA” split by pulmonary hypertension (PH) drug regimens at any time. PEA: pulmonary endarterectomy; BPA: balloon pulmonary angioplasty; sGC: soluble guanylate cyclase stimulator. Comparisons: PEA versus BPA, p=0.074; PEA versus sGC, p=0.015; any of PEA, BPA or sGC versus any of other drugs or no drug, p<0.001; p >0.05 for all other comparisons.
In the PEA and BPA groups, the administration of any PH drugs prior to the procedure or at any other point in time did not result in a statistically significant impact on survival rates [6]. However, a more granular analysis revealed that among patients undergoing BPA (figure 2), those receiving sGC at any time exhibited superior survival outcomes compared with patients who never received sGC (95 versus 88% at 3 years, p=0.040), whereas those receiving PCA demonstrated inferior survival outcomes compared with those who never received PCA (84 versus 94% at 3 years; p=0.006). The administration of PDE5i and ERA was not significantly associated with improved survival in patients undergoing PEA or BPA.
FIGURE 2.
Kaplan–Meier survival curves by procedure and by pulmonary hypertension (PH) drugs at any time. BPA: balloon pulmonary angioplasty; ERA: endothelin receptor antagonist; PCA: prostacyclin analogue; PDE5i: phosphodiesterase 5 inhibitor; PEA: pulmonary endarterectomy; sGC: soluble guanylate cyclase stimulator. Comparisons: patients undergoing BPA with versus without sGC treatment, p=0.040; patients undergoing BPA with versus without PCA treatment, p=0.006; p >0.05 for all other comparisons. “No” means no treatment with the drug class considered in the respective panel (sGC, PDE5i, ERA or PCA).
Mortality predictors
Besides the already reported prognostic indicators such as undergoing either PEA or BPA which was associated with reduced mortality rates compared with no intervention [6], the multivariable analysis identified sGC treatment at any time as an independent predictor of reduced mortality in the whole cohort (HR 0.334; 95% CI 0.209–0.532; p <0.001), in patients who underwent BPA (HR 0.249; 95% CI 0.098–0.631; p=0.003), and in the group that did not undergo PEA or BPA (HR 0.285; 95% CI 0.142–0.570; p<0.001). In contrast, other PH drugs had no impact on mortality, except for PCA at any time, which was associated with a higher mortality rate in the BPA group (HR 4.224; 95% CI 1.582–11.280; p=0.004).
Discussion
The objective of this study was to evaluate the impact of PH medical treatment on long-term survival rates among patients included in the New International CTEPH Registry [6]. PH drugs are administered in the treatment of CTEPH with the objective of addressing the microvascular remodeling in the lung areas not affected by large vessel fibrotic obstruction. The present analysis showed beneficial effects of medical treatment, predominantly attributable to sGC. Both the Kaplan–Meier method and the Cox regression analysis indicated that patients treated with sGC who underwent BPA or no intervention exhibited a superior outcome.
Long-term outcome
At the 1-year post-procedural follow-up, 14% and 43% of the patients who underwent PEA or BPA, respectively, were still treated with PH drugs. This disbalance could not be explained by persisting PH which is observed in the same proportion of patients after both procedures (69% and 68% for PAP >20 mmHg) [6]. It is more likely that this corresponds to standard practice as surgeons usually stop medical treatment after surgery, whereas BPA interventionists do not. Immediately after PEA, only 8% of patients received PH drugs, showing that some patients reinitiated therapy during the first year post-PEA.
In the cohort of patients who did not undergo PEA or BPA, a 3-year survival rate of 85% was observed in those treated with the sGC riociguat. This is the only oral drug that has been approved globally for the treatment of inoperable and persistent/recurrent CTEPH. In comparison, the survival rates for other PH drugs were 57%, whereas “no PH drugs” demonstrated a 64% survival rate. Furthermore, sGC was identified as an independent predictor of survival in the global cohort and in both the BPA and the “no PEA/BPA” groups. This remained consistent even after adjustment for PH severity (NYHA FC, RAP and PVR). However, it is not possible to rule out that other factors such as undocumented comorbidities may have influenced the less favourable outcome observed in patients treated with other drugs.
A certain degree of immortal time bias is to be expected if treatments are switched, given that medical therapy can be initiated or changed at any time at the discretion of the clinicians involved in an observational registry. In the present case, however, it is unlikely that the survival of patients receiving sGC at any time was influenced by treatments received prior to the switch to sGC because only 13% of the “no PEA/BPA” patients were treated with another drug prior to receiving sGC (supplementary table S2). Furthermore, the sensitivity analysis, which classified patients according to their initial treatment, confirmed the superior outcome observed in patients receiving sGC. These beneficial effects of sGC in inoperable patients corroborate the efficacy data from previous randomised controlled trials [7, 9, 10], in the real-world setting.
In addition, our data align with a recent analyse of the COMPERA database also suggesting that sGC may offer a survival benefit for CTEPH patients compared with other PH drugs (Held et al. [11]).
Treatment strategy
It must be acknowledged that 22% of patients not having mechanical treatment (table 1) is high by today's standards. This can be explained by the timeframe of enrolment and follow-up into the registry (2015–2019), when many centres probably were not offering BPA yet. BPA should be strongly considered in non-operable CTEPH after operability is checked by an expert centre [12–14]. In addition, 24% of the patients who did not receive any mechanical treatment never received medical therapy either (table 4). The median PVR of these patients was 506 dynes, which is still quite elevated and would warrant medical therapy under most circumstances.
Limitations
It should be noted that observational studies are susceptible to several confounding factors and biases. It is evident that there is indication bias present, as the patient characteristics differ between the groups. Furthermore, there is a potential for bias in the results, particularly when comparing groups with differing baseline characteristics. Worse outcomes of patients treated with PCA in the BPA group is likely due to the habit to administer PCA late and to the worst patients. Another limitation intrinsic to the observational nature of registries is missing data. Furthermore, the inclusion of patients who died within one year of diagnosis, prior to their enrolment in the registry, may introduce a potential bias in the analysis of outcomes.
There were no predefined criteria for starting PH drug therapy and the rationale behind the administration of off-label drugs to patients with more severe conditions (tables 2 and 4) remains unclear. By the time the registry started including patients, sGC was available and reimbursed in all participating countries except Australia and Brazil, where reimbursement commenced in 2016, and Slovakia, where reimbursement was initiated in 2018 (supplementary table S3). Two centres employed PDE5i but did not utilise sGC, six centres employed sGC but did not utilise PDE5i, and one centre did not employ either of these medications. Eight centres employed a greater quantity of PDE5i than sGC (of these, four were UK centres).
Conclusion
In conclusion, the results of the New International CTEPH Registry, conducted between 2015 and 2019, differ from those of the first European–Canadian registry, which was conducted between 2007 and 2012. In the previous registry, PH medical therapy had no effect on mortality in patients who did not undergo intervention. In contrast, in the new registry, PH medical treatment was associated with reduced mortality in the “no PEA/BPA” group. Our present analysis shows that this difference may be attributed to the introduction of riociguat into the therapeutic armamentarium for CTEPH, as evidenced by the correlation between sGC and enhanced survival outcomes in the entire cohort, as well as in both the BPA and the “no PEA/BPA” groups. This interesting observation needs further confirmation in a controlled setting.
Acknowledgements
The authors acknowledge the contribution of the following investigators: Joan A. Barberà, Hospital Clínic–IDIBAPS, CIBER Enfermedades Respiratorias, University of Barcelona, Barcelona, Spain; Gerry J. Coghlan, Department of Cardiology, Royal Free London National Health Services Foundation Trust, London, UK; Gustavo Heresi, Department of Pulmonary and Critical Care Medicine, Cleveland Clinic, Cleveland, OH, USA; Hsao-Hsun Hsu, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Kim Kerr, Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, CA, USA; Jerzy Lewczuk, Regional Specialist Hospital and Medical University, Wroclaw, Poland; Trevor Williams, Department of Cardiothoracic Surgery, Lung Transplantation, Anaesthesia and Intensive Care, The Alfred Hospital, Melbourne, Victoria, Australia; Kirill V. Mershin, Russian Cardiology Research and Production Complex, Ministry of Health of Russia, Moscow, Russia; Toru Satoh, Division of Cardiology, Second Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan; Nobuhiro Tanabe, Department of Respirology, Graduate School of Medicine, Chiba University, Chiba City, Japan; and Anton Vonk Noordegraaf, Amsterdam UMC, Vrije Universiteit Amsterdam, Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands. The authors also thank David Bowers for statistical analyses, and Simone Lerch and Sonja Mariotti (ICA, Switzerland) for project management. The CTEPH Registry is owned and managed by the ICA. The association is headed by an Executive Board, composed of CTEPH experts. The Executive Board of the association was responsible for the design of the registry, provided input into the analyses, decided on medical interpretation and oversaw the development of the manuscript.
Footnotes
Provenance: Submitted article, peer reviewed.
This study is prospectively registered with ClinicalTrials.gov as NCT02656238.
Ethics statement: Local institutional review boards or independent ethics committees approved the protocol, and written informed consent was obtained from all patients.
Conflict of interest: M. Delcroix reports research grants from Janssen; speaker and consultant fees from Altavant, Acceleron, AOP, Bayer, Ferrer, Gossamer, INARI, Actelion-Janssen, J&J, United Therapeutics and MSD outside the submitted work, and all paid to her institution; and has been holder of a Janssen Chair for Pulmonary Hypertension at the KU Leuven. I.M. Lang has relationships with drug companies including AOP-Health, Actelion-Janssen, MSD, United Therapeutics, Bayer-Schering, Pulnovo, Medtronic, Neutrolis, Daiichi Sankyo, SciPharm Sàrl and Sanofi; in addition to being investigator in trials involving these companies, relationships include consultancy service, research grants and membership of scientific advisory boards. A.M. D'Armini reports consultancy fees from Actelion, Janssen, J&J, Acceleron, MDS, Merck and Bayer; and payment or honoraria for lectures, presentations, manuscript writing or educational events from Actelion, Janssen, J&J, Acceleron, MDS and Bayer. E. Fadel does not report any conflicts of interest. S. Guth reports consultancy fees and/or speaker fees, payment or honoraria for lectures, presentations, manuscript writing or educational events from Johnson & Johnson, Actelion/Janssen, Bayer AG, MSD and Pfizer; and support for attending meetings from Johnson & Johnson. S.P. Hoole does not report any conflicts of interest. D.P. Jenkins reports speaker fees and consultancy fees from Janssen, and is a board member for the ICA and on the scientific board for the World Symposium Pulmonary Hypertension. D.G. Kiely reports support for the present work from NIHR Sheffield Biomedical Research Centre; grants from Janssen Pharmaceuticals, National Institute of Health Research Sheffield Biomedical Research Centre and Ferrer; consultancy fees from Acceleron, Altavant, Ferrer, Janssen, Gossamer, Liquidia, Apollo, MSD and United Therapeutics; payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen Pharmaceuticals, Ferrer, Altavant, MSD and United Therapeutics; support for attending meetings from Janssen, Ferrer, MSD, United Therapeutics; participation on data safety monitoring boards or advisory boards with Janssen, MSD and Liquidia; and leadership roles with the Clinical Reference Group for Specialised Respiratory Medicine (NHS England) and UK National Audit of Pulmonary Hypertension. N.H. Kim reports having received speaker fees from Bayer, Janssen and Merck; consultancy fees from Bayer, Janssen, Merck, Gossamer Bio, Polarean, Pulnovo and United Therapeutics; and research support from Altavant and Gossamer Bio. M.M. Madani reports consultancy fees and royalties from Wexler Surgical; consultancy fees from Actelion-Janssen, Johnson & Johnson, Bayer and MSD and a leadership role with the ICA. H. Matsubara reports research grants from Nippon Shinyaku; speaker and consultant fees from Bayer, Janssen and MSD; speaker fees from Kaneka Medix, Mochida, Nippon Shinyaku, AOP Orphan and Nipro; payment for expert testimony from MSD; participation on a data safety monitoring board or advisory board for Bayer, Janssen, Mochida and MSD; and a leadership role with the ICA. K. Nakayama does not report any conflicts of interest. A. Ogawa does not report any conflicts of interest. J.S. Ota-Arakaki reports consulting fees, payment or honoraria for lectures, presentations, manuscript writing or educational events, support for attending meetings from Bayer, MSD and Janssen; participates on data safety monitoring boards or advisory boards with Bayer, MSD and Janssen; and holds a leadership role in the Brazilian Thoracic Society. R. Quark does not report any conflicts of interest. R. Sadushi-Kolici reports having received consultancy, speaker fees and support for attending meetings from AOP-Health, Actelion-Janssen and MSD. G. Simmoneau has received advisory board and speaker fees from Acceleron, Gossamer, Bayer, Janssen, MSD and Merck. C.B. Wiedenroth reports speaker fees and/or consultant honoraria from Johnson & Johnson, Actelion/Janssen, AOP Orphan Pharmaceuticals AG, Inari, Bayer AG, BTG, MSD, OrphaCare and Pfizer; and participation on a data safety monitoring board or advisory board for MSD. B. Yildizeli does not report any conflicts of interest. E. Mayer has received consultancy and/or speaker fees from Actelion/Janssen, Bayer and MSD. J. Pepke-Zaba reports research grants from MSD; consultancy fees from Ferrer, Gossamer, Janssen and MSD; payment or honoraria for lectures, presentations, manuscript writing or educational events from MSD; and support for attending meetings from AOP and Janssen.
Support statement: The ICA received financial support from Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson & Johnson, and Bayer Pharma AG to run the registry. The sponsors were not involved in the management of or in the decisions related to the Registry, and had no access to the database. They performed a courtesy review of the manuscript. For Actelion/Janssen, this courtesy review was done by the medical team (noncommercial functions). The authors maintained the authority to decide whether or not to implement any comments received. Funding information for this article has been deposited with the Open Funder Registry.
Supplementary material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material
00769-2025.SUPPLEMENT
Data availability
The data that support the findings of this study are available from the ICA upon reasonable request (info@cteph-association.org).
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material
00769-2025.SUPPLEMENT
Data Availability Statement
The data that support the findings of this study are available from the ICA upon reasonable request (info@cteph-association.org).