During the congress some aspects were analyzed:
– CTEPH diagnosis. Observed incidence is 5-6 cases per million/year according to European registries but the estimated incidence should be about 17 cases per million/year. In a study of 146 patients with a diagnosis of acute pulmonary embolism, at radiological re-evaluation 4.8% of patients have signs of CTEPH. Anyway CT scan is not able to exactly date the thrombus, that’s why there are ongoing studies utilizing FDG-PET (evaluating areas of inflammation), ultrasound elastography (thrombus elasticity decreases over time) and magnetic resonance elastography (only animal studies are available up to now). Another important developed technique is dual energy CT scan that was proposed to assessed microvasculopathy according to the extent of subpleural perfusion: patients with microvasculopathy tend to have a more severe disease with higher PVR and BNP and more compromised gas exchange (higher VE/VCO2 and lower DLCO).
– development of CTEPH or CTED after an acute PE. A rule out algorithm combining electrocardiographic criteria and BNP was proposed to exclude with a high NPV the presence of echocardiographic signs of intermediate-high probability of PH. Anyway we have to consider that in patients with functional impairment after at least 6 months from an acute PE the main cause of functional impairment appears to be left heart disease (37-50% have HFpEF, 9% have VHD, 4% have HFrEF), and only 5-7% have CTEPH and 2.4-2.5% have CTED. A higher ratio PAPs/E/e’ at echo may be indicative of CTEPH/CTED rather than HFpEF as the cause of functional impairment.
– CTEPH treatment. The optimal treatment strategy should be individualized patient by patient by a CTEPH expert team. Even if treatment is not uniform worldwide (i.e. BPA preferred vs PEA in Japan) operability criteria that should be taken into account are related both to the patient (comorbidities, age, patient preference, thorax anatomy) and to the disease itself (surgical accessibility of the lesions, previous splenectomy, ventricular-atrial shunts, catheter in situ, chronic inflammatory diseases). Surgery should be performed in expert centres that are defined by: a mortality of less than 5%, at least 50 PEA performed/year and feasibility of a segmental PEA. In 50% of patients undergoing PEA anyway, after surgery, there is a significant increase of mPAP during exercise, the cardiac index reserve remains compromised at 12 months and improvement in physical capacity is correlated with the increase in cardiac index after PEA.
Regarding BPA, the technique was performed for the first time in Japan, but nowadays it is performed worldwide with excellent technical and outcome progress. BPA reduces mPAP and PVR but also pulmonary arterial compliance (PAC) consistently unloading RV systolic afterload and is able to improve haemodynamic and exercise capacity in both surgical accessible and inaccessible groups but the entity of haemodynamic and symptoms improvement is inferior in those with surgical accessible lesions that therefore should be treated with PEA. It was reported that an additional session of BPA, performed in patients that normalized the haemodynamic profile but remain hypoxic after the first cycle, is able to further improve the haemodynamic profile and
increase systemic oxygen saturation. Anyway often BPA is not able to normalize symptoms even if it improves prognosis, so medical treatment implementation may be needed to completely normalize hemodynamic profile and symptoms. Regarding PAH specific drugs it should be emphasized that in patients with high PVR (>12.5 WU) they are significantly more effective than in patients with lower PVR (despite the same efficacy reached with the subsequent BPA) and this may be due to a more severe hypertensive vasculopathy in patients with distal lesions and more severe PH. Some centres performed BPA even in symptomatic CTED patients reporting a reduction of PVR and improvement of 6MWD and symptoms.
Regarding anticoagulant treatment an observational retrospective study on 42 patients states that the safety and effectiveness (in term of disease progression) is similar between VKA and NOAC in patients with CTEPH.
– CTEPH risk stratification. Some studies presented show that GDF-15 and sST2 are associated with disease severity and sST2 is associated with the haemodynamic improvement after BPA. Moreover, CTEPH patients have higher levels of ET-1 and systemic inflammation markers and all of these parameters improve after a complete session of BPA.
Data from one of the most important European registry on CTEPH, Eur CTEPH Registry, were presented:
– the mean time from symptoms to diagnosis is 14.1 months; obesity and recurrent deep vein thrombosis are associated with a diagnostic delay instead chest pain and reduced exercise tolerance are associated with an earlier diagnosis
– 75% of patients have a history of acute pulmonary embolism
– PEA surgery is able to reduce by 60% the value of PVR, in-hospital mortality is 4.7% and peri-operative complications have a prevalence of 49%
– predictors of an operable CTEPH diagnosis are: history of acute deep vein thrombosis, previous pulmonary embolism, 0-blood group. Predictors, instead, of a misdiagnosis of idiopathic PAH are: diabetes mellitus, female gender and high mPAP
– at diagnosis 60% of patients are deemed operable. Three years survival of patients undergoing PEA is 89% in contrast with 70% of patients deemed not operable. Efficacy of medical therapy is unsatisfying both in operable and not operable patients
– women with CTEPH have a better survival, a lower burden of cardiovascular risk factors, and less frequently were treated with PEA
According to another registry of the ICA (International CTEPH Association) 14.5% of 1019 patients with CTEPH underwent at least 1 BPA session. In-hospital death was 0% but 37% of patients have peri-procedural complications. Dealing with PEA, 54% of 1019 patients underwent PEA with an in-hospital mortality of 3%.
Some new potential treatment targets were proposed: 1) the thromboxane antagonist NTP42: in the animal Sugen-hypoxia PH model it is able to reduce vessel remodeling (both as monotherapy and in combination with sildenafil) and, in combination with Sildenafil (but not as single
able to reduce mPAP and RV hypertrophy; 2) TLR9: its inhibition reduce pulmonary vascular resistance and vascular obliterative remodeling reducing perivascular inflammation/macrophages in rats; 3) ANTXR2: its expression is reduced in CHD-PAH and its overexpression inhibit PASMCs proliferation. Knockdown rats show a more severe PAH profile when exposed to systemic-to-pulmonary shunt; 4) Inhibin Beta-A: it is highly and preferentially expressed in the lung microvasculature, has anti-angiogenetic effects on human PAECs and its activation in mice leads to PH development (both in normoxya and hypoxia conditions) instead its deletion reduces PH in hypoxia conditions. Inhibin Beta-A seems to downregulate BMPR2 maybe through ActivinA; 5) MFG-E8 may play an important role in thrombus resolution and its downregulation in pulmonary artery of CTEPH patients may drive the persistence of thrombus in the pulmonary arteries; 6) NKX2.5: endothelial to mesenchymal transition of ECs in SSc seems to be associated with increased NKX2.5 mediated by TGF-beta, ERK5, CK2 and PI3K signaling; 7) RNF213: a variant allele of RNF213 (p.Arg4810Lys) was reported to be more frequent in PAH than in the general population and it is associated also to moyamoya and to a more severe disease with a worse outcome, less responsive to PAH treatment and with PVOD-like characteristics; 8) Selenoprotein P: it is a protein secreted by various cells including PASMCs and it is significantly increased in patients with PAH. Its serum levels correlate with prognosis and response to treatment.
Some new parameters were suggested to describe new pathophysiological insights in PH: 1) the ratio between right ventricular GLS/PA systolic pressure (PAPs), describing right ventricular-arterial coupling, was proposed for predicting prognosis in PAH; 2) fractional area change (FAC) at echo, a parameter that describes mainly radial contraction, correlate better with right ventricular-arterial coupling than TAPSE in left heart failure. The ratio FAC/PAPs and the ratio TAPSE/PAPs, even if they don’t improve coupling information, correlate better with pulmonary vascular load and mortality; 3) total PA stiffness (1/PAC) correlates with mPAP, PAWP and HR and is independent of age and sex. Post-capillary PH has lower total PA stiffness than IPAH even when normalized for mPAP. It was postulated that PAWP attenuates the increase in RV pulsatile loading in PH when normalized for the strain induced stiffening leading to a better coupling despite the same mPAP. Therefore, in post-capillary PH, the lower PVR and total PA stiffness may contribute to a better RV adaptation when normalized for mPAP; 4) PVR mainly reflect the properties of the pulmonary vasculature but it is well known that they are also related to blood viscosity (BV): accounting for BV, 1/3 of patients assessed for PH have a difference of at least 2 WU of calculated PVR and this difference is particularly pronounced in patients with anemia or raised Hb; 5) results of 22 patients undergoing catheter ablation for atrial flutter of atrial tachycardia show that despite RA dilatation the proportion of areas with low atrial electrogram voltage is not extended and mainly confined in adjacent to SVC posterior portion of the RA between the 2 caval veins; 6) the curvature of the IVS is correlated to PAPs and it is more pronounced during exercise: this may contribute to limited CI increase during effort.
During the congress some results about the pulmonary artery denervation (PADN) technique were presented. In particular:
– The study PADN-5 by Chen et al demonstrated that, in patients with CpcPH, PADN vs Sildenafil significantly increase 6MWD at 6 months, decrease PVR (and PAWP, and increases CI and PAC) and clinical worsening.
– 50 patients with an indication for mitral valve surgery and mPAP > 40 mmHg (and “vasoreactive” at NO test) were randomized: the 25 patients undergoing intraoperative epicardial PA ablation have a significant lower mPAP pressure the day after the procedure and a better 6MWD at 1 year.
– Results about the new technique utilizing ultrasound ablation were presented. This technique seems safer than RF ablation because it doesn’t cause vessel necrosis, causes less pain, doesn’t require full contact with vessel wall, requires less contrast and may be more effective penetrating more deeply in the vessel wall. A European/Israel/USA study in 22 patents with PAH (CTD, Drug induced and idiopathic) on combination therapy shows a significant improvement at 4-6 months of PVR, mPAP, CI, RAP and 6MWD.
– Another study on PADN (performed using remote magnetic navigation system communicating with a 3D electroanatomical mapping system) in 50 patients with CTEPH and residual PH after PEA show that PADN vs Riociguat is able to reduce more consistently PVR and mPAP at 12 months. It reduces also HF hospitalization and increases 6MWD.
Some concepts of the current diagnostic and treatment algorithm were highlighted:
– The importance of an early diagnosis: 50% of patients have symptoms for more than 1 year at diagnosis and this may portend a worse outcome.
– New diagnostic criteria: current definition of PAH (mPAP >20 mmHg and PAWP ≤15 mmHg) reclassify 1.4% of patients with SSc screened for PAH considering a threshold of PVR of 3 WU (comparable data can be derived also for patients without SSc). Anyway as the prognosis is worse in patients with PVR >2 WU is has been suggested that also the threshold of PVR should be reduced to reclassify a consistent number of patients with a relevant pulmonary vascular disease.
– The importance of risk stratification: it is important to have a patient-focused approach and a risk stratification guided treatment (not only NYHA functional class has to be evaluated because also NYHA II may benefit from therapy escalation at an early disease stage and ¼ of patient in NYHA II can be not at low risk and 1/3 of NYHA III patients can be at low risk).
– Regarding risk stratification a comparison of 3 different risk stratification tools were done: the Swedish, the French invasive an not invasive methods both at baseline and at first follow-up in patients with SSc-PAH. All methods well stratified the patients but only the Swedish registry is able to stratify patients in case of missing data. In SSc-PAH the prevalence of high risk criteria is high and this can explain the worst outcome.
– Regarding treatment strategies: a small study on 20 patients at high risk PAH evaluate the efficacy of initial triple combination therapy with ambrisentan, tadalafil and subcutaneous treprostinil. At 12 months all patients were alive and at follow-up WHO-FC, exercise
capacity, NT-proBNP, and haemodynamics significantly improved compared with baseline. No patient discontinued the therapy due to serious adverse events.
– PAH diagnosis in CTD is frequently difficult due to the high prevalence of conditions such has left heart disease (70%), lung disease (50%), PVOD (15%), antiphospholipid syndrome in SLE (a possible cause of CTEPH). The diagnosis is also difficult because 40% of patients with PAH have a TR velocity <2.8 m/s. A possible tool to improve PAH detection in SSc is multiplying the TR velocity x PA diameter at CT scan: combining these 2 measures the NPV rise up to 94%. Another study underlines the importance of taking into account echocardiographic findings supportive of PH diagnosis other than TR velocity independently of the PH haemodynamic definition of 20 or 25 mmHg. A cut-off of PAPs <40 mmHg during effort was proposed as having a very high NPV in excluding the development of PAH up to 10 years after the evaluation.
– Taking into account patients with GUCH it is well known that the development of PH is associated with a worse prognosis. It was highlighted that the most prevalent PH types are PAH (group 1) and, among PAH, Eisenmenger syndrome (ES), even if group 5 PH has the most dismal prognosis (maybe because of a high prevalence of single ventricle pathophysiology). Moreover it was underlined that, in the United States, the median time to transplant was significantly longer for all ES patients on the waitlist for bilateral sequential lung transplantation (BSLT) or heart-lung transplantation (HLTx) compared to patients listed for other indications. Waitlist mortality was substantially higher for all ES patients regardless of whether they were listed for BSLT or HLTx compared to patients listed for other indications. Eventually, the long-term survival of patients with Eisenmenger syndrome with ASD or VSD undergoing BSLT + CHD repair and HLTx is similar.
The controversial issue of PAH-specific therapy in group 2 PH was also analyzed: the main considerations in favor of the use of these drugs in post-capillary PH are that 1) RV failure in HFpEF worsen prognosis despite stable left heart parameters; 2) monitoring PAP in HFpEF with CardioMEMS can be used to effectively guide therapy adjustment and reduce hospitalization; 3) in CpcPH (defined as a mPAP >20 mmHg, PAWP >15 mmHg and PVR >3 WU) there is a pre-capillary component that can be a potential target of PAH specific drugs. ANYWAY: current published trials of PAH specific therapy in group 2 PH are almost all negative except three small trials with PDE5-I that consider, as primary endpoint, VO2 (and PVR in one) but all other trials were neutral or some of them showed that PAH specific drug can even be harmful. In a meta-analysis, PAH specific drugs in group 2 PH were able to improve haemodynamic parameters and 6MWD but there is a trend toward worsening heart failure (i.e. the recently published MELODY trial with Macitentan showed an increase of fluid retention) and death. Moreover, among the possible causes of failure of these trials we can exclude that the wrong drugs were chosen (all classes failed) or that the wrong population was selected (in SIOVAC patients with CpcPH treated with sildenafil have the worst prognosis). Nevertheless there are some other ongoing trials (SERENADE, with Macitentan, and PASSION, with Tadalafil, in HFpEF and SOPRANO with Macitentan in patients with LVAD) and we will soon be able to add these results to current Literature knowledge.
Some post-marketing data and post-hoc analysis of trials on PAH specific drugs were presented:
– OPUS and OrPHeUS trials evaluate post-marketing data on Macitentan concerning demographic, disease characteristics, treatment pattern, hepatic safety and survival in a real-world setting. What emerge is that there are still off-label prescriptions (10.8 have group 2 or 3 PH and 6.2 have group 5 PH), despite a documented undertreatment of patients (30-40% of patients are still on monotherapy). The relatively hepatic safety profile of the drug was confirmed.
– In a post-hoc analysis of the AMBITION trial, initial combination therapy with ambrisentan and tadalafil reduced the risk of hospitalization for worsening PAH by 63% compared with pooled monotherapy, but it should be underlined that hospitalizations were mainly driven by initiation of prostacyclin therapy and worsening of PAH. The benefit seems to be similar irrespective of the etiology of PAH, baseline WHO FC, 6MWD, age, geographic region, and sex. The most important predictors of hospitalization for worsening PAH are initial monotherapy, 6MWD, and NT-proBNP level. Another post-hoc analysis of AMBITION trial showed that the benefit of initial combination therapy is consistent across all levels of risk at baseline.
– The SPHERE prospective US registry on selexipag use in the real-world setting shows that the uptitration velocity is less than 200 mcg b.i.d./week but the proportion of people in low/intermediate/high dose strata is similar to GRIPHON study.
– A post hoc analysis of GRIPHON data evaluate the role of comorbidities on the efficacy of Selexipag. In patients with at least 3 CV comorbidities (among obesity, essential hypertension, diabetes mellitus, or historical evidence of significant coronary artery disease) Selexipag had a beneficial effect on long-term outcome equal to patients without CV comorbidities with comparable safety.
– A possible concern raised regarding the active metabolite of Selexipag MRE-269: it increases more strongly ETB than ETA receptor in PASMCs resulting in accelerated cell proliferation by ET-1 predominantly via ETB (so maybe a dual ET receptor blocker may be preferred in combination with Selexipag).
Finally, during the congress the stock of the situation was taken about some current/recent trials in PAH: a phase 1 clinical trial on Elafin (elastase inhibitor), the REPLACE (riociguat as replacement of PDE-5i therapy in PAH) and the AFFILIATE (effects of sildenafil on mortality when administered at the 3 doses: 80 mg, 20 mg or 5 mg TID) trials are recruiting; CATALYST (bardoxolone in CTD-PAH) is completed; TRITON (initial triple combination therapy vs double initial combination therapy) is active, not recruiting, unblinding is planned in the next months; OPTIMA (effect of first line dual oral combination therapy with macitentan and tadalafil on PVR in patients with PAH) and Freedom EV (effect of oral treprostinil in reducing time to clinical worsening in PAH) were positive meeting their primary endpoints (respectively: reduction of PVR at 16 weeks and time to clinical worsening); INO-vation (inhaled NO in PAH) was stopped for futility; ASK1 inhibitor Selosertib fails in the phase 2 ARROW trial (no significant changes at 24 weeks of PVR, 6MWD, FC and NT-proBNP in patients with PAH).