Where we came from and where we are going: a perspective on the practice changing recommendations from the 2022 ESC/ERS pulmonary hypertension guidelines

Great strides have been made in our understanding of pulmonary hypertension (PH) since the first description of pulmonary vascular disease-causing right heart failure by Romberg in 1891.1 The term primary pulmonary hypertension (PPH) was first used in 19512 and in 1958 the clinical features of the disease were described by Wood.3 Prompted by the European epidemic of PH in Europe linked to anorexigen drugs, the World Health Organization met in 1973 to review the current state of knowledge of the disease and called for a multicentre collaborative study to characterize PH. Beginning in 1981, a National Institutes of Health (NIH) PH registry enrolled more than 180 patients with PPH.4 The classical description of PH that resulted from this study formed the foundation upon which our current understanding of PH is built. Prior to 1996 treatment of patients with PH was limited to diuretics, digoxin, and lung transplantation, and the prognosis of PH was grim.5 The landmark randomized clinical trial of epoprostenol forever changed the landscape of PH management, turning a uniformly progressive, fatal disease into a disease that could be treated.6 However, this continuously infused intravenous medication administered to ambulatory outpatients was highly complex and side effects were common such that this treatment remained inaccessible to most patients. Shortly after the success of epoprostenol was demonstrated, the second World Symposium on PH (WSPH) convened in 1998. It was at this meeting that the five-group clinical classification system for PH was first proposed and conditions that shared the common pathologic finding of plexogenic lesions in the pre-capillary pulmonary arterioles were classified together as Group 1 PH, collectively referred to as pulmonary arterial hypertension (PAH). Soon after, in 2003 at the third WSPH, the term PPH was abandoned and replaced with the contemporary term idiopathic PAH.7 Subsequent guideline statements and WSPH proceedings have refined the classification as new insights about pathophysiology and responses to specific therapies have emerged. Importantly, PH describes all diseases in which pulmonary artery pressure (PAP) is increased (all groups 1–5), while the term PAH refers specifically and exclusively to Group 1 diseases. Now, nearly 30 years later, our understanding of the pathobiology of PH and right ventricular failure has expanded dramatically. There are more than 12 widely available medications for the treatment of PAH, with new therapies targeting novel disease mechanisms on the horizon. Despite these advances, the evaluation and care of patients with PH remain challenging and complex. Comprehensive and thoughtful diagnostic evaluations are required to accurately phenotype PH. Caution in prescribing PAH medications and close monitoring is necessary to ensure that correct therapies are prescribed and avoid the harm that can occur when some PAH medications are administered to patients with Group 2 PH from left heart disease or Group 3 associated with lung disease. Patients with PAH who are managed with oral medications may experience disease progression and require complex parenteral therapies and lung transplantation. Mortality from PAH remains high. A diagnosis of PAH frequently has devastating psychosocial effects on patients and their families which may be ameliorated with care from social workers and by PAH support groups. The development of PH in patients with left heart disease and lung disease is a marker of poor prognosis; however, most trials of PAH medications in these patients have failed to show benefit (except for inhalational treprostinil in PH associated with interstitial lung disease) and some have resulted in harm. Much remains to be learned about how best to treat PH. The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) PH guidelines8 represent an important and consequential change in the approach to PH diagnosis and management which will directly impact patients, PH specialists, and community practitioners but also may exert far-reaching effects on the healthcare system as a whole. A main theme of the guideline recommendations is the need for earlier identification of patients with possible PH and rapid referral to PH specialty centres for definitive evaluation and management. The authors have taken steps to ensure that the new guidelines are, as much as possible, based on available data, updating many prior recommendations that were either arbitrary and supported only by expert opinion, and creating new recommendations. Many of these recommendations are classified as Class 1, or strongly recommended, and will likely result in modifications of clinical practice. Some important recommendations remain similar or are strengthened, such as recommendations for multidisciplinary care and collaboration with a specialty centre. Others, such as changes to the haemodynamic definition of PH, are substantially modified or entirely new. Importantly, this is the first time that the patient perspective has been included in formulating the guidelines. In this perspective, we review the new ESC/ERS PH guidelines highlighting significant changes and discuss how these recommendations might affect patients and the PH providers who care for them. The modification in the haemodynamic definition of PH is the most consequential and controversial change in the guidelines. Inclusion in the NIH registry required subjects to have a mean PAP greater than 25 at rest; however, this cut-off was arbitrary and not evidence-based. Subsequently, haemodynamic studies in healthy subjects have shown that a normal mPAP at rest is 14 ± 3.3 mmHg suggesting that two standard deviations above this normal value or a an mPAP > 20 mmHg is abnormal.9–11 Additionally, analysis of multiple large cohort12,13 studies including veterans administration14 patients, scleroderma patients,15 and heart transplant patients16 have found worse outcomes including mortality and hospitalization among patients with mPAP > 20 mmHg. These findings led to a proposal during the 6th WSPH in 2019 to lower the diagnostic threshold for PH to a mPAP > 20 mmHg which has now been adopted in the ESC/ERS guidelines. Similarly, robust data has accumulated showing that in healthy subjects the pulmonary vascular resistance (PVR) does not exceed 2 Wood units and that the finding of a PVR > 2 Wu is associated with worse outcomes in patients with multifactorial aetiologies of PH17 and in patients with scleroderma.18 In recognition of these data, the guidelines recommend a PVR cut-off of >2 Wu. These reductions in the diagnostic thresholds of mPAP and PVR may result in larger numbers of patients diagnosed with all haemodynamic subtypes of PH even if the exact number is not clear. In addition, the above new thresholds are based mainly on retrospective analysis and prospective confirmatory data willbe required. Given the expected increased number of patients meeting the haemodynamic definition of PH, it is critical that a thoughtful and comprehensive diagnostic evaluation be performed so that PH in these patients is correctly classified. Specific recommendations are made for right heart catheterization including that the right heart catheterization be performed by an experienced operator familiar with PH assessment, that protocols exist to ensure complete data collection and that vasoreactivity testing be performed in appropriate patients. A high-quality haemodynamic assessment is necessary and incomplete haemodynamic studies are a common source of error in PH evaluation.19 Indeed, the haemodynamic profile while necessary is not sufficient to diagnose PH but must be considered in the context of a comprehensive evaluation of all required data. When evaluating patients with PH, it is also important to remember that most patients do not fit neatly into a single group. For example, a patient may have repaired congenital heart disease, a reduced LV ejection fraction, and obstructive lung disease with hypoxaemia, contributions from groups 1, 2, and 3. Careful evaluation to determine which of these causes of PH is contributing the most to PH is necessary to determine the optimal approach to patient care. Misclassification of PH is common and may result in incorrect prognostication and treatment decisions.20 For this reason, it is recommended that patients suspected to have PH should be referred to a specialty centre. Selecting the optimal approach to management following a diagnosis of PH with an mPAP of 21–24 mmHg and PVR of >2 and <3 Wu is challenging. In the PH from left heart disease (Group 2) and lung disease (Group 3), treatment is directed at the underlying disease process, and PAH-specific therapies are generally not recommended except from the interstitial lung disease group (based on Phase II studies). Diagnosing PH according to the new haemodynamic definition has the potential benefit that it could trigger the initiation or intensification of therapies and lifestyle modifications which might slow underlying heart or lung disease progression. For example, optimizing blood pressure control or increasing efforts toward smoking cessation may benefit patients with left heart failure or emphysema. These interventions are low cost and some have proven benefits in slowing or reversing the progression of important medical problems. How best to manage patients with a diagnosis of PAH who meet these lower thresholds is, however, less clear and is not specifically addressed by the guidelines. Studies that examined the progression of haemodynamic abnormalities have included patients with multifactorial aetiologies of PH and there are inadequate data to describe the risk of progression and outcomes in patients with mild haemodynamic abnormalities specifically in PAH. Additionally, randomized controlled trials of PAH therapies have required subjects have an mPAP > 25 mmHg and PVR >3 Wu so that the effects of PAH-specific therapies in patients with less severe haemodynamic abnormalities are unknown. Despite the lack of data, it is likely that many patients who have PAH according to the new guidelines will be prescribed PAH medications. Prescription of PAH therapies in these patients has the potential to be complex and costly with uncertain benefits while exposing the patient to potential adverse effects. Indeed, the prescription of PAH medications for patients in whom they are unlikely to help and may cause harm is common.21 Ultimately, well-designed randomized clinical trials are needed to inform the treatment of these patients. For the first time, the concept of shifting phosphodiesterase-5 inhibitors to riociguat is proposed in PAH intermediate-risk patients instead of escalating combination therapy. However, the data on shifting therapy to riociguat are based on unblinded studies while combination therapy is supported by large outcome-based trials (SERAPHIN,22 GRIPHON,23 FREEDOM-EV.24) Traditional blinded randomized controlled trials should have been performed before proposing a strategy that potentially may delay escalation of combination therapy. The new haemodynamics definition of PH is likely to have profound effects on the lives of patients, the healthcare providers who manage PH and the broader healthcare system. The potential benefits of earlier diagnosis must be considered in the context of the substantial costs associated and risks associated with the diagnosis. A diagnosis of PH, especially PAH may have profound consequences to patients and their caregivers. Having PAH is known to have a significant impact on quality of life, as well as on mental health with rates of depression and anxiety ranging from 40% to 50%.25 Similar negative impacts on caregivers have been reported.26 While PAH patients with PVR 2–3 Wu may have fewer physical limitations, psychosocial mental health consequences of the diagnosis may be significant and will need to be studied. Increased resources to provide adequate patient assistance programmes such as support groups and mental healthcare may be necessary. Patients with PAH often avoid exercise and become sedentary out of fear that vigorous activity may cause harm. Educational programmes to promote and coach patients diagnosed with PH may be necessary to ensure that patients remain physically active. Contraception planning and in the case of pregnancy, careful shared decision-making is recommended in PAH due to the high risk of complications including death.27 New data will be needed to correctly assess the risk of pregnancy and how to best counsel patients who meet the new criteria for PAH. In order to correctly classify patients diagnosed with PH as a result of the guidelines, many additional comprehensive diagnostic evaluations will be required. While the necessary tests are low risk many are uncomfortable and require substantial time to complete in addition to being costly. These and other costs related to PH evaluation and evaluation in a PH specialty centre such as time off work, travelling, and payment to healthcare providers will likely be burdensome to many patients. Despite the lack of evidence for PAH therapies in the patient with mPAP > 25 mmHg and PVR >3 Wu as discussed above, many additional patients will likely be treated with PAH therapies. These patients may be exposed to the potential adverse effects and the associated complexities of PAH therapies, such as the requirement for contraception in patients treated with endothelial receptor antagonists and riociguat. It is also likely that some patients will be misclassified as PAH or treated incorrectly with PAH medications for Group 2 or Group 3 disease increasing the risk of adverse effects of therapy. PAH medications are costly and may result in a significant economic burden for the individual patients but may also increase the financial strain on the healthcare system.28 The new guidelines recapitulate prior recommendations for early referral to a PH specialty centre when PH is suspected, as well as for close collaboration with a PH specialty centre for ongoing care. These recommendations are supported by data showing that hospitalizations and mortality are reduced in patients cared for by PH specialty centres.29 The increase in patients diagnosed with PH may increase the demand for PH specialty care in a way that may exceed the available capacity. To meet the increased demands, it is likely that more PH specialist providers will be required, and programmes will need to be expanded. Additionally, the number of patients diagnosed with PH who live long distances from a PH centre will likely increase. The development of more PH centres that are located outside of urban areas would be useful to improve patient access. Strategies such as training new physicians and establishing new PH specialty centres will require years and innovative solutions that can be implemented more quickly such as training nurse practitioners and physician assistants in addition to telemedicine and employing remote consultation will be needed. Substantial progress has been made in the diagnosis and management of PH in recent years. The 2022 ESC/ERS PH guidelines represent a step forward in the field of PH by providing revised recommendations based on evidence instead of traditional and arbitrary cut-offs for what defines PH. Additionally, recommendations are crafted to encourage early detection of PH and early referral to a PH expert centre for evaluation and care with the goal of reducing delays in diagnosis and improving patient outcomes. However, there are consequences associated with these new recommendations including the risk to the patient of negative psychosocial effects from being diagnosed with PH as well as the risks of testing and expansion of PAH treatment that may be of unclear benefit. The financial burden will be shared by patients and payors. The ability of the healthcare system and PH specialty centres to care for a larger number of PH patients remains uncertain. Studies to quantify the benefits, risks, and costs caused by practice changes recommended in the guidelines will be needed. No new data were generated in support of the article.