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Advances in the management of pulmonary arterial hypertension
http://orcid.org/0000-0003-2086-1281Himanshu Deshwal,
Tatiana Weinstein,
Roxana Sulica
Pulmonary, Sleep and Critical Care Medicine, New York University Grossman School of Medicine, New York, New York, USA
Correspondence to Dr Roxana Sulica, Pulmonary, Sleep and Critical Care Medicine, New York University Grossman School of Medicine, New York, New York, USA; rsulica{at}yahoo.com
The management of pulmonary arterial hypertension (PAH) has significantly evolved over the last decades in the wake of more sensitive diagnostics and specialized clinical programs that can provide focused medical care. In the current era of PAH care, 1-year survival rates have increased to 86%–90% from 65% in the 1980s, and average long-term survival has increased to 6 years from 2.8 years. The heterogeneity in the etiology and disease course has opened doors to focusing research in phenotyping the disease and understanding the pathophysiology at a cellular and genetic level. This may eventually lead to precision medicine and the development of medications that may prevent or reverse pulmonary vascular remodeling. With more insight, clinical trial designs and primary end-points may change to identify the true survival benefit of pharmacotherapy. Identifying responders from non-responders to therapy may help provide individualized patient-centered care rather than an algorithm-based approach. The purpose of this review is to highlight the latest advances in screening, diagnosis, and management of PAH.
respiration disorders
lung transplantation
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Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular endothelial dysfunction, smooth muscle proliferation, fibrosis, and in situ thrombosis, eventually leading to right ventricular (RV) failure and death. The first case of PAH was discovered on autopsy in 1891 when thickening of the pulmonary artery was noted in the absence of lung or heart disease in a deceased patient. However, PAH remained unrecognized until 1951, when Dr Dresdale identified three cases and termed it primary pulmonary hypertension.1 2 Since then, significant research has shed light on its pathophysiology, disease course, and various targetable pathways for pharmacotherapy. Despite improvement in screening techniques, the diagnosis of PAH is often delayed leading to increased morbidity and mortality. While several drugs targeting different pathways associated with PAH may lead to significant improvement in functional status, hemodynamics, and quality of life, the data on survival is still minimal. The heterogeneity in the etiology and disease course has opened doors to focusing research in phenotyping the disease and understanding the pathophysiology at a cellular and genetic level.3 This may eventually lead to precision medicine and the development of medications that may prevent or reverse pulmonary vascular remodeling. With more insight, the clinical trial designs and primary end-points may change to identify the true survival benefit of pharmacotherapy. Identifying responders from non-responders to therapy may help provide individualized patient-centered care rather than an algorithm-based approach.
Newer screening methodologies are being validated for clinical use for early detection. Modern imaging and exercise testing have revolutionized the assessment of PAH patients to objectively characterize RV function and pulmonary vascular remodeling and to assess the precise etiology of a patient's exertional symptoms. Medical management has also changed due to improved diagnostic and prognostic techniques with a multidisciplinary approach, early initiation of combination therapies, and referral for lung transplantation. The purpose of this review is to highlight the current advances in the understanding and management of PAH and its impact on clinical practice and outcomes for our patients.
Changes in definitions: clinical impact
The sixth World Symposium on Pulmonary Hypertension (WSPH) revised the hemodynamic definitions of pulmonary hypertension (table 1).4 The mean pulmonary artery pressure (mPAP) was lowered from ≥25 mm Hg to >20 mm Hg based on scientific evidence suggesting normal mPAP at rest to be 14.0±3.3 mm Hg and upper limit of normal defined as 20 mm Hg, which is 2 SD above the mean.5 The definition for precapillary PH for all five groups of PH includes pulmonary artery wedge pressure (PAWP) <15 mm Hg and pulmonary vascular resistance (PVR) of ≥3 woods unit. PVR helps determine the presence of vasculopathy even in patients with co-existing left ventricular dysfunction and elevated PAWP. While it has its own limitations, it is a useful marker to differentiate isolated postcapillary pulmonary hypertension without pulmonary vasculopathy from co-existing precapillary pulmonary hypertension with pulmonary vasculopathy. The utility of the new guidelines may pave way for appropriate phenotyping of group 2 PH and assess hemodynamic response to vasodilator therapies in future clinical trials. It also guides the clinicians to optimize the left heart dysfunction before repeating right heart catheterization or trialing vasodilator therapy for underlying precapillary pulmonary hypertension.
Revised hemodynamic definitions of pulmonary hypertension4
While an ideal hemodynamic marker for pulmonary vascular disease should be independent of stroke volume and left atrial pressures, and take into account the pulsatile nature of pulmonary blood flow, PVR has most commonly been utilized in clinical practice.
The newer definition will potentially have a significant clinical impact on management and mortality in patients with pulmonary hypertension. Previous studies have demonstrated increased mortality and morbidity in patients with mPAP ranging between 21 and 24 mm Hg comparable with patients with mPAP >25 mm Hg. In patients with systemic sclerosis, initial abnormal mPAP (21–24 mm Hg) has been found to predict disease progression with mPAP greater than 25 mm Hg. This highlights a potential gap in clinical practice where early initiation of vasodilator therapy may be beneficial. If combined with improved screening techniques such as the DETECT algorithm (a systematic approach to screen for pulmonary hypertension in systemic sclerosis detailed below), novel biomarkers and non-invasive testing, the new definition may help identify many high-risk patients early in the disease course and lead to early initiation of therapy.6 7
The EARLY study had demonstrated the benefit of treating mild symptomatic PH (mPAP ≥25 mm Hg).8 It can be anticipated that aggressive pharmacotherapy early in the disease (mPAP >20 mm Hg) course may prevent pulmonary vascular remodeling and disease progression using the newer definitions. This may eventually lead to improved morbidity and mortality; however, longitudinal studies are needed to demonstrate the true benefit.
The newer definitions may also impact future clinical trials and research design to include patients with mPAP >20 mm Hg. The inclusion of these patients may provide an insight into the natural history of early disease and assist with investigating different treatment modalities for these patients. While studies have demonstrated the safety and efficacy of pharmacotherapy in patients with mPAP 21–24 mm Hg in systemic sclerosis, more extensive clinical trials are underway to assess the benefits and outcomes of these therapies in group 1 PAH9 (NCT02290613, NCT01725763).
Diagnostic advances
The current diagnostic approach includes an extensive workup to assess various causes of pulmonary hypertension (table 2). A transthoracic echocardiogram is the most common screening tool to identify RV function and signs of pulmonary hypertension based on the clinical picture. Laboratory and serologic testing are conducted to identify underlying connective tissue disease, HIV infection, and indirect biomarkers of RV dysfunction such as brain natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP). This is often followed by ECG, pulmonary function testing (PFT), and chest imaging to evaluate for underlying lung disease (obstructive or restrictive) (group 3 PH). PFTs should include spirometry, lung volumes, and diffusion capacity (DLCO). A contrast-enhanced CT of the chest or CT angiography and ventilation–perfusion scan are performed to screen for chronic thromboembolic pulmonary hypertension (CTEPH) (group 4 PH).
Clinical classification of pulmonary hypertension4
Current guidelines recommend all patients undergo nocturnal oximetry to assess for nocturnal hypoxemia, sleep disordered breathing, and sleep apnea as these disorders are highly prevalent and may worsen pulmonary hypertension.10 Right heart catheterization is the gold standard for diagnosis. Still, it is usually the last step in diagnosis as alternate causes of RV failure or pulmonary hypertension are first excluded using non-invasive testing. Once the diagnosis is made, prognostic exercise testing such as a 6 min walk test (6-MWT) or a cardiopulmonary exercise test (CPET) are often required to assess objective data to characterize functional status.
Advances in screening and diagnosis for PAH
In recent years, various non-invasive modalities have gained interest in screening for PAH. A clinical approach using the DETECT algorithm has been recommended in patients with systemic sclerosis since the fifth WSPH.10 This approach includes an initial clinical assessment including features of telangiectasias, positive anticentromere antibody, elevated serum urate, and NT-proBNP, right axis deviation on ECG, and FVC%/DLCO% <1.6 on PFT. An echocardiographic assessment of the right atrial area and tricuspid regurgitation jet velocity is recommended in patients with high clinical scores. Patients with a higher pretest probability of PAH based on echocardiographic parameters are recommended to undergo right heart catheterization for confirming the diagnosis.7 11
More recently, genetic analysis and serum biomarkers have been associated with various phenotypes of pulmonary hypertension. Patients with a family history of heritable PAH are recommended to undergo genetic counseling and testing to screen for mutations commonly associated with PAH. A bone morphogenetic protein receptor 2 (BMPR2) mutation is frequently associated with heritable PAH. Montani et al 12 reported a high risk of developing PAH in carriers of BMPR2 mutations with an annual incidence of 2.3% /year. BMPR2 mutation is also associated with early and more aggressive disease courses with less response to acute vasodilator testing and increased risk of death than those without the mutation.13 A mutation in the Eukaryotic translation Initiation Factor 2 Alpha Kinase 4 (EIF2AK4) gene is classically associated with pulmonary veno-occlusive disease and worse outcomes.14
Serum biomarkers have increasingly been used in clinical practice to screen, monitor, and prognosticate patients with PAH. NT-proBNP and BNP have commonly been used in routine clinical practice to classify the severity of the patient and estimate prognosis.15 16 Several novel biomarkers are being studied in PAH, focusing on different aspects of the pathophysiology, such as inflammation, oxidative stress, pulmonary vascular endothelial dysfunction, and markers of RV dysfunction. The current interest lies in finding biomarkers that can screen for PAH, distinguish PH due to left heart disease from pulmonary vascular disease, predict severity, mortality, and response to therapy. Rhodes et al 17 studied nearly 1129 plasma proteins and found 20 proteins that could differentiate survivors from non-survivors with idiopathic pulmonary arterial hypertension (IPAH). Out of the 20 proteins, they found nine replicable and prognostic proteins for IPAH independent of NT-proBNP levels. These nine proteins included interleukin-1 receptor-like protein, erythropoietin, complement factors D and H, insulin-like growth factor binding protein-1, tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1, TIMP-2), plasminogen, and apolipoprotein E (Apo E). The authors also found that adding these biomarkers to risk stratification strategies such as the REVEAL equation significantly improved the predictive ability of the scores.17 Benza et al 18 assessed genetic differences in patients that may predict response to endothelin-1 receptor antagonists (ERAs). They found that a single nucleotide polymorphism (rs11157866) in the G-protein α and γ subunits was associated with a significant response to ERA therapy in the form of improved functional class and 6 min walk distance at 12 and 18 months.18
Cardiac magnetic resonance imaging
While echocardiogram is a readily available and good screening test, cardiac magnetic resonance imaging (CMR) is gaining frequent clinical use due to its accuracy in assessing RV morphology and function at baseline and follow-up visits.19 The accuracy of an echocardiogram depends on the operator and quality of the acoustic windows. It has inherent inaccuracies in assessing RV function, while CMR is reproducible and accurate and allows for RV assessment in a standardized manner.19 20 CMR can be used for diagnosing intracardiac shunts, aberrant pulmonary vascular morphology, left-sided disease, and other congenital anomalies.21
Interestingly, despite their seemingly similar pathophysiology, in IPAH and systemic sclerosis-related PAH, identical treatment modalities targeting RV afterload reduction result in vastly different outcomes. This divergent response to therapy in systemic sclerosis-related PAH may be partially attributed to a more nuanced interaction of the RV and pulmonary vasculature in systemic sclerosis.22 Therefore, a thorough assessment of RV function, morphology, and PA vasculature with CMR becomes critical to devise an appropriate treatment strategy. CMR can also monitor the success of pulmonary endarterectomy (PEA) in CTEPH patients.23 24 Volumetric assessment of the RV using CMR can improve risk stratification of PAH patients when added to current stratification strategies.25 In addition, CMR can identify the impaired longitudinal right atrial strain that can predict decompensated hemodynamics in PAH and predict poor outcomes.26
The most common and often the first symptom in PAH patients is exertional dyspnea. An exercise stress test can accurately assess the severity of exertional symptoms. A 6-MWT assesses exercise capacity in clinical practice and has been included as a prognostic parameter in PAH.27 However, it may be a suboptimal test in younger patients who have severe PAH and RV dysfunction but can still walk more than 500 m. This may lead to a false sense of reassurance about the severity of their disease and a less aggressive or delayed medical therapeutic approach. CPET has recently become a useful clinical tool to reliably assess patients' functional status and RV function during exercise. It provides valuable clinical information that can be utilized to monitor response to therapy and predict clinical worsening.28
Exertional dyspnea in PAH patients may occur due to two predominantly pathophysiologic mechanisms. On exertion, the oxygen delivery cannot match the oxygen demand due to the inability to increase stroke volume. This occurs due to increased venous return and worsening RV dysfunction leading to low stroke volume. Cardiac output is maintained mainly via an increase in heart rate and unable to match the O2 demand, leading to early transition to anaerobic metabolism and lactic acidosis in peripheral tissues, observed as a low anaerobic threshold. The low cardiac output and anaerobic metabolism are characterized by low O2 pulse and peak oxygen consumption (VO2), respectively. The buildup of lactic acidosis may stimulate the carotid bodies and increase ventilator drive, as observed by increased V'E on CPET. In addition, there is low mixed venous oxygen saturation and low alveolar-arterial diffusion of oxygen in PAH, leading to arterial hypoxemia. The combined effect of increased V'E and poor perfusion leads to increased V/Q mismatch causing an increase in physiologic dead space. This is reflected as a high ratio of V'E/V'CO2 or increased slope of the V'E/V'CO2 slope.29 The increase in physiologic dead space is often associated with reduced end-tidal CO2 tension (Petco2).30 Peak VO2, peak VO2% predicted, and VE/V'CO2 slope and arterial oxygen saturation are better prognostic markers for risk stratification in PAH.29 Clinical variables obtained by CPET also serve as an attractive end-point target for clinical trials and monitor response to therapy.31 32
Invasive cardiopulmonary exercise testing (iCPET)
Invasive hemodynamic monitoring with right heart catheterization during CPET (also known as invasive CPET or iCPET) is gaining significant clinical interest in understanding the etiology of symptoms in complex patients who may have PAH and underlying lung, muscular, or cardiac disease. Walkey et al 33 studied iCPET in systemic sclerosis patients. They successfully distinguished the etiology of exertional limitation when routine studies such as the echocardiogram, PFTs, and imaging were unreliable.33 The use of iCPET has led to the development of a 'Dyspnea clinic' in several PAH centers to address the multifactorial etiology of dyspnea in patients whose preliminary workup is unrevealing.34 Invasive CPET is particularly useful in patients with a suspected component of exertional post-capillary PH due to left heart disease, exercise-induced PAH, and patients who have preload limitation to exercise. In exertional post-capillary PH, the mPAP is often elevated along with normal PVR and elevated PCWP on exertion. In patients with preload limitation to exercise, the maximum right atrial pressure is less than 8 mm Hg on exertion, and VO2 max is less than 80% of predicted with otherwise normal central hemodynamics.35 36 Guth et al 37 conducted a prospective study on chronic thromboembolic disease patients to assess the impact of PEA on exercise hemodynamics. They found a significant reduction in mPAP, PVR, mPAP/cardiac output slop, and increase in peak VO2 after PEA. They also observed a significant improvement in WHO functional classification and quality of life based on the Cambridge Pulmonary Hypertension Outcome Review Questionnaire after 1 year of PEA.37
Advances in management: early aggressive treatment
Current Medical Therapy (200)
Once the diagnosis is made, several risk stratifying tools and WHO functional classification can be used clinically to determine the choice of pharmacotherapy in each individual patient (table 3).
WHO functional classification of pulmonary hypertension10
More recently, an updated REVEAL 2.0 risk score has been validated for risk stratification of patients (figure 1). Benza et al 38 identified REVEAL 2.0 score as an excellent predictor of clinical deterioration and mortality and performed better than COMPERA, and the French Pulmonary Hypertension Registry (FPHR) scores in patients followed up for greater than 1 year. Pharmacotherapy is targeted at various pathways involved in the development of PAH (figure 2). Currently, the FDA has approved five classes of drugs to treat PAH39 (table 4). While only intravenous epoprostenol has demonstrated direct survival benefit in a 3-month controlled study of IPAH patients, other classes of drugs are associated with significant improvement in functional status, symptoms, and hemodynamics, including RV function.10 40 The primary goal of pharmacotherapy is to decrease a patient's risk to ultimately achieve and maintain a low-risk category and improve functional and hemodynamic status. It has been demonstrated that lowering the risk category can improve overall survival and functional status in PAH.10 41
Conventional pharmacotherapy for pulmonary hypertension
REVEAL 2.0 Risk score calculator for pulmonary arterial hypertension.38 BNP, brain natriuretic peptide; CTD, connective tissue disease; eGFR, estimated glomerular filtration rate; HR, heart rate; mRAP, mean right atrial pressure; NT-proBNP, N-terminal proBNP; PAH, pulmonary arterial hypertension; PVR, pulmonary vascular resistance; SBP, systolic blood pressure.
Pathogenic pathways and drug targets in pulmonary arterial hypertension. BMPR-2, bone morphogenetic protein receptor 2; cAMP, cyclic AMP; GMP, guanosine monophosphate; cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate; mPAP, mean pulmonary artery pressure; PA, pulmonary artery; PDE-5, phosphodiesterase-5; PGI2, prostaglandin I2; PVR, pulmonary vascular resistance; RV, right ventricle; sGC, soluble guanylate cyclase.
Patients with mild disease or lower risk category can be initiated on monotherapy with close follow-up and risk assessment. It is recommended for patients who are intermediate to the high-risk category to initiate combination therapy, including a parenteral pulmonary vasodilator with intravenous prostacyclin reserved for severe disease.10 42 A 3-month to 6-month follow-up is recommended with a re-assessment of risk status. If the patient is not at goal on current medical therapy, sequential combination therapy is recommended with a different class of drug.10 42 For aggressive and severe disease non-responsive to pharmacotherapy, early lung transplant referral is recommended.43 In addition, treatment of hypoxia, exercise, rehabilitation, psychosocial support, nutrition, and appropriate vaccination and age-based cancer screening is recommended to optimize the patient's overall health.
Historically, anticoagulation was recommended for patients with IPAH. This guidance was largely based on the notion that, in addition to pulmonary vascular remodeling, in situ thrombosis of the small pulmonary arteries contributed significantly to the clinical course of disease. Early clinical studies in favor of this in IPAH were largely limited to observational data, retrospective studies, and single-center experiences. Additionally, they were largely conducted prior to the introduction of many of the vasodilator therapies currently on the market. More recent randomized trials and data utilizing the REVEAL registry, however, have suggested no survival advantage in IPAH patients and in fact, according to the REVEAL registry data poorer survival in systemic sclerosis-related PAH taking warfarin.44 Thus, the most recent guidelines note that the potential benefit of anticoagulation is less clear in IPAH and lowered it to a class IIb recommendation (may be considered, usefulness is less well established by evidence/opinion).10 One notable exception is IPAH patients receiving long-term therapy intravenous therapy with prostaglandins. Anticoagulation may be of benefit in this setting due to the risk of catheter-associated thrombosis. There is a paucity of data regarding the role of the new oral anticoagulants in PAH.
Identifying super responders
During diagnostic RHC, vasodilator testing is a standard practice to identify patients who may respond to calcium channel blocker (CCB) therapy. Inhaled nitric oxide is the preferred vasodilator challenge. Adenosine and intravenous epoprostenol have also been used to assess acute vasoreactivity in the cardiac catheterization laboratory. Reduction in mPAP of >10 mm Hg to less than 40 mm Hg with preserved cardiac output and blood pressure is considered a positive vasodilator test.10 45 Patients with positive vasodilator tests often have an overall better survival and can initiate CCB monotherapy.45 46 Interestingly, these findings are specific to idiopathic PAH and do not predict better survival in patients with HIV, connective tissue disease, or portopulmonary hypertension.45 47 Raffy et al 48 demonstrated that a decrease in the total PVR index greater than 50% in response to short-term infusion of prostacyclin at the time of diagnosis predicted slow progression of the disease and better prognosis.
However, due to the heterogeneous nature of PAH, many patients who have a negative vasodilator test may respond to a different class of medication more than the others and are termed as 'super responders'.49 Identifying super responders is challenging and is an area of significant clinical interest. Various patient factors can often determine responsiveness to different classes of drugs. For example, female sex tends to be more responsive to bosentan, while GNG2 polymorphism has been associated with an excellent hemodynamic response to macitentan.18 50 51 Younger age and male sex are associated with a better response to phosphodiesterase-5 (PDE-5) inhibitors.52 With the advent of genomics and transcriptomics in translational research, genetic phenotyping may highlight the predominant pathway of disease progression and guide the titration of therapy accordingly. Hemnes et al 53 performed a quantitative PCR on peripheral blood samples from PAH patients to identify RNA expression patterns that could predict vasodilator response to CCBs. They identified 13 genes that were significantly different between vasodilator responsive PAH patients and vasodilator non-responsive PAH patients.53 Allen et al 54 used morphometric and hemodynamic measurements of the pulmonary vasculature to identify high pulmonary arteriolar shear stress load from low shear stress load that may differentiate reversible from non-reversible disease early in the disease course. They also found that treprostinil could stall progression when administered in the early phase compared with later stages, suggesting that prostacyclin therapy may delay pulmonary vascular remodeling if initiated in the early disease course.54
With more evidence to predict responsiveness to therapy and differentiate phenotypes of PAH, it may be possible to tailor therapy in a patient-centered manner in the future. This may allow shifting from an algorithmic treatment approach to individualized care in evidence-based practice.
Newer drugs in PAH
Riociguat is a soluble guanylate cyclase stimulator (sGC) that increases intracellular cyclic guanosine monophosphate by directly activating sGC, leading to pulmonary vasodilation and platelet inhibition. It was initially approved for CTEPH based on CHEST-1 trial that demonstrated significant improvement in PVR and 6MWD in CTEPH patients receiving riociguat.55 However, follow-up studies PATENT-1 and PATENT-2 by the same authors assessed the role of riociguat in iPAH and connective tissue disease-PAH patients and found an increase in 6MWD by 30 m compared with the placebo group (6 m), time to clinical worsening, increase in cardiac output, decrease in PVR and NT-proBNP, and improvement in WHO functional class.56 Following these results, riociguat was approved for group 1 PAH patients. Smoking generally reduces the bioavailability of riociguat by 50%–60%, and the patient is thus recommended to quit smoking or dose adjustment may become necessary.57 Riociguat is generally contraindicated in patients on PDE-5 inhibitors due to increased risk of hypotension. In patients with suboptimal response to PDE-5 inhibitors, riociguat is a good alternative. The RESPITE trial showed an increase in 6MWD by 31 m, a decrease in NT-proBNP, and improvement in WHO functional class in patients transitioned to riociguat from PDE-5 inhibitors.58 However, up to 52% of patients had experienced drug-related adverse events, with 16% being serious adverse events (although only 3% of serious events were felt to be study drug related). The recently concluded REPLACE trial confirmed these findings of delay in clinical worsening and disease progression in intermediate-risk PAH patients switched to riociguat from PDE-5 inhibitors.59
Selexipag
Selexipag is a non-prostanoid oral drug that is highly selective to prostacyclin receptors in the pulmonary vasculature. Selexipag promotes pulmonary vasodilation, inhibits platelet aggregation, and has antiproliferative effects on pulmonary artery smooth muscle cells. The FDA has recently approved it for the treatment of PAH FC II–III patients. The dose is generally started at 200 µg twice a day and titrated up weekly to a maximum dose of 1600 µg twice a day. Selexipag was studied in the double-blinded, placebo-controlled, phase 3 RCT, the GRIPHON trial, which demonstrated a reduced risk of hospitalization and death compared with placebo.60 The trial included selexipag monotherapy or as an add-on therapy to ERA or PDE-5i or both compared with placebo and demonstrated a reduction in clinical worsening (HR 0.6, 99% CI 0.46 to 0.78, p<0.001).60 Often, patients may need to be transitioned from one drug to another based on tolerability and adverse effects. TRANSIT-1 study found that slow down titration of inhaled treprostinil and up-titration of selexipag was well tolerated and safe in PAH patients with FC II/III.61
Ralinepag
Ralinepag a selective, non-prostanoid prostacyclin receptor (IP) agonist is an immediate-release oral drug that is currently being studied in PAH. A phase 2 RCT investigating 61 patients found a significant reduction in PVR by 163.9 Dyn.sec/cm5 and an increase in 6MWD by 36.2 m in patients receiving ralinepag monotherapy or combination therapy compared with placebo.62 Currently, ADVANCE CAPACITY, ADVANCE OUTCOMES, and ADVANCE ENDURANCE are three major phase 3 trials studying the safety, efficacy, clinical outcomes, and survival benefit of extended-release ralinepag in symptomatic PAH patients63 (NCT03626688, NCT04084678).
Sotatercept
Sotatercept is a selective ligand trap for transformic growth factor beta (TGF-β) superfamily members such as activins and growth differentiation factors that can improve BMPR2 signaling and decrease pulmonary vascular smooth muscle proliferation and remodeling. It is administered by subcutaneous route every 3 weeks. The recently published PULSAR trial demonstrated improved 6MWD by 29 m and decreased NT-proBNP in the sotatercept group compared with placebo.64 Thrombocytopenia and increased hemoglobin were the most commonly identified adverse events.64 A phase 2 multicenter, open-label exploratory study, the SPECTRA trial, is also investigating the efficacy of sotatercept in PAH, with the primary outcome being the change in peak oxygen uptake (VO2 max) from baseline (NCT03738150). Being the first in its class drug, sotatercept has been designated a breakthrough therapy by the FDA. A phase 3 double-blinded RCT (STELLAR) is ongoing to evaluate the efficacy of sotatercept plus background therapy compared with placebo, with preliminary results expected in early 2023 (NCT04576988).
Several other drugs working via various mechanisms such as anti-inflammatory pathway (bardoxolone methyl), tyrosine kinase inhibitor (imatinib), vasoactive intestinal peptide, endothelial nitric oxide synthase couplers (sapropterin dihydrochloride), Rho kinase inhibitor (fasudil), serotonin recept antagonist (terguride), and apelin are currently being studied for feasibility in pulmonary hypertension.65 With significant advancement in the understanding of several pathophysiologic pathways associated with PAH development, newer drugs are being developed and studied and offer a ray of hope for this debilitating disease.
Upfront triple combination therapy for patients not at goal
Sequential combination therapy has been shown to reduce clinical worsening compared with monotherapy.66 The BREATHE-2 trial was a proof-of-concept study that showed the feasibility of upfront dual combination therapy in PAH but was underpowered to assess a significant effect on hemodynamics and functional status.67 The landmark AMBITION trial demonstrated a significant reduction in clinical failure and improvement in 6 min walk distance with upfront combination therapy of ambrisentan and tadalafil for patients not at goal.68 A post hoc analysis of the AMBITION trial found a survival advantage in the combination therapy group compared with the monotherapy group.69 An observational study also demonstrated a significant reduction in PVR, pulmonary artery pressures, and NT-proBNP in patients treated with upfront combination therapy of ERA and PDE-5 inhibitors compared with patients in the monotherapy group.70 They also found a reduction in calculated RV wall stress and volumes in the combination therapy group.70 Several other observational studies and meta-analysis have been able to replicate these results in severe PAH patients71 72
The primary goal of therapy in PAH is to improve patient's risk category and inhibit remodeling in the pulmonary vasculature and the RV. An early aggressive approach for intermediate-risk and high-risk groups appears a feasible option to normalize hemodynamics and delay clinical worsening. An upfront triple combination therapy for intermediate-risk and high-risk patients seems logical and needs longitudinal study to assess actual benefits. A pilot study evaluated the feasibility of triple combination therapy of intravenous epoprostenol, bosentan, and sildenafil in 19 PAH patients with NYHA functional class III/IV.73 They found sustained clinical and hemodynamic improvement with lower NYHA functional class I/II and 100% survival at 1, 2, and 3 years of follow-up.73 A retrospective observational study demonstrated a reduced risk of death in patients treated with subcutaneous prostacyclin and two oral drugs compared with dual combination therapy or monotherapy.74
D'Alto et al 75 studied the hemodynamic impact of a combination of subcutaneous treprostinil, ambrisentan, and tadalafil in newly diagnosed severe PAH patients. In addition to improved hemodynamics, 6MWD, and functional class, they demonstrated reversal in RV remodeling observed on follow-up echocardiogram. Early addition of selexipag to initial dual combination therapy has also been observed to have a significant clinical, functional, and hemodynamic improvement in severe PAH and CTEPH patients.76 A recent multicenter, placebo-controlled, double-blinded randomized control trial, the TRITON study, compared the effect of upfront triple (selexipag, macitentan, tadalafil) versus double (macitentan and tadalafil) therapy in PAH. The study demonstrated sustained improvement in hemodynamics, NT-proBNP, and a reduction in disease progression with triple therapy and double combination therapy, but no statistically significant difference between the two groups. However, exploratory analysis indicated a signal for improved long-term outcome with initial triple versus initial double therapy (odds raio 0.59;p=0.08)77 (NCT02558231). These findings highlight the need to consider an aggressive approach early on in treatment-naive PAH patients who are in an intermediate or high-risk group at diagnosis.
Monitoring and follow-up
There is a structured follow-up schedule recommended during the management of PAH patients. Risk stratification scoring, ECG, 6MWD, basic laboratory workup including metabolic panel, NT-proBNP, and complete blood count are recommended every follow-up visit. Transthoracic echocardiogram, CPET, blood gas analysis, and right heart catheterization are recommended at baseline and after that yearly, unless there is a change in pharmacotherapy or clinical worsening, in which case they can be repeated earlier.10 42
Implantable hemodynamic sensors known as CardioMEMS HF system have been increasingly used in patients with congestive heart failure for monitoring and predicting clinical worsening.78 Benza et al 79 studied the feasibility and safety of the CardioMEMS HF system as a monitoring tool for PAH. They found the device to be safe, and it could predict clinical worsening or medication non-adherence weeks in advance.79 They also found that implantation of the device was associated with a significant reduction in mPAP and improvement in cardiac output as treating physicians could guide therapy based on the data obtained from the device.79 The device offers excellent potential in safely predicting and preventing clinical decompensation; however, more extensive trials and longitudinal studies are currently needed to identify such implantable wireless devices' true potential in monitoring and managing PAH patients.
Multidisciplinary approach
The management of PAH has significantly evolved over the last 4–5 decades in the wake of more sensitive diagnostics and specialized clinicians who can provide focused medical care. In the current era of PAH care, 1-year survival rates have increased to 86%–90% from 65% in the 1980s, and average long-term survival has increased to 6 years from 2.8 years.80 These clinical advances have resulted in considerable economic and social burdens for patients and their caretakers who are now faced with the day-to-day management of a complicated, chronic illness. Thus, a team-based, multidisciplinary approach to care is paramount in the patient with PAH to optimize outcomes. A team often includes a range of specialist physicians and extends to include nutritionists, pharmacists, and social workers whose goal is to provide a well-rounded approach to patient care.
The first line of management in systemic hypertension includes dietary and lifestyle changes. Although there is a paucity of data regarding dietary changes in pulmonary hypertension, some preliminary studies and hypotheses have compelling results. For example, some suggest that PAH patients have a larger proportion of vitamin D deficiency, vitamin C deficiency, and iron deficiency than the general population and that this may play a role in disease severity and progression. Correcting these relative deficiencies may involve a simple modification that could potentially have a meaningful clinical impact. Involving a nutritional expert in a patient care team can be beneficial, especially as data is evolving in the field.81
The mainstay of treatment in PAH is pharmacologic therapy. However, due to the complicated delivery system and frequent dosing, patient education and adherence to the dosing schedule become challenging in clinical practice. Epoprostenol, for example, requires a continuous intravenous infusion through central access. Therapeutic success requires a dynamic conversation between the patient and their healthcare professionals. Pharmacist-driven discussions have shown to be quite helpful for patients navigating issues that arise in this domain. The Pharmacist Collaborative Care Program (PCCP) in Grenoble, France, has successfully implemented interventions in patient education, psychosocial barriers to adherence, and technical support to foster therapeutic success.82 This success has been underscored in data regarding the role of the PCCP in lung transplant teams. A retrospective analysis assessing more than 1400 patients over 7 years revealed that involving a clinical pharmacist prevented major or lethal outcomes in 7.1% of cases and moderate drug-related effects in almost 60% of cases. More importantly, the study showed that, when accepted, a clinical pharmacist presented a positive clinical impact for 98.9% of patients, and none had a negative clinical impact.83 The role of a pharmacist in patient-care teams can be an invaluable asset.
In addition to more conventional communication approaches, there is significant potential for digital and virtual healthcare support systems. Many patients already use home-based, mobile, and wearable technologies to take ownership of their health. Medical technology has not been formally studied in the realm of health literacy. Nevertheless, it provides a compelling opportunity for future directions in adverse event monitoring, therapeutic compliance, and patient engagement.84 Not only are current PAH therapies riddled with administration issues and side effects that act as patient compliance barriers, but they are also expensive. This can create significant financial stress for patients and their loved ones. Social workers are often an essential part of healthcare teams and can help navigate and counsel patients through complicated financial barriers.85
Although PAH medications have shown tremendous success in preventing clinical worsening, none are curative. Patients should be referred for a lung transplant as early as possible. Generally, the decision to list is made when the patient's status declines to the point that survival without transplant is unlikely. Transplant is recommended for patients with PAH who fall into WHO functional class III or IV on maximal medical therapy and patients with rapidly progressive disease, as evidenced by worsening 6 min walk distance, rising NT-proBNP, and worsening RV function and hemodynamics. Patients with an estimated 1-year mortality >10% based on a comprehensive assessment should also be considered for lung transplant.85–87 Certain procedures can act as a bridge to transplant or as destination palliative therapy in severe symptomatic PAH.87 Atrial septostomy is one such intervention, allowing for right heart decompression through creating an iatrogenic shunt. This procedure has been shown to improve functional class, exercise tolerance, symptoms, and even survival. RV assist devices and pulmonary artery denervation have also shown promising results in symptomatic and functional improvement. However, there is a paucity of data in general in terms of mortality benefits for any of these procedures. Veno-arterial extracorporeal membrane oxygenators have also been successfully utilized as a bridge to transplant.80 In general, the transplant listing process is a long and trying course for patients and their loved ones. An experienced multidisciplinary team is necessary to steer through the challenging road patients face.
Despite all the advances made over the last few decades with treatment modalities, PAH is still a devastating, rapidly progressive disease with a mortality of at least 50% at 7 years.88 PAH patients bear a sizeable psychological burden as they navigate a debilitating illness requiring cumbersome and expensive care. The disease itself inevitably has an enormous impact on a patients' day-to-day functioning. Frequently, patients are unable to even keep their employment due to disease burden. The emotional stress of disease has led to high rates of anxiety and depression in the PAH population, with some studies citing depression rates as high as 55%.89 Palliative care referral which focuses on symptomatic relief and quality of life should be implemented early in the diagnosis. Patients can benefit from various therapeutic avenues within the palliative care team ranging from support groups and educational tools to financial assistance and health insurance coverage support. Palliative care specialists can assist with medical management of dyspnea, anxiety, pain, and anorexia. Even some more invasive procedures such as atrial septostomy, RV assist devices, and pulmonary artery denervation can act as palliative destination therapy and improve patient's quality of life. A palliative specialist can support patients and their families through these types of procedures. Finally, as patients progress in their disease course, palliative care specialists can help guide advanced directives, end-of-life care, and even spiritual support.85
Improving outcomes in the PAH patient extends beyond just managing disease and its progression. A multidisciplinary, holistic approach is imperative to meet the needs of patients and their families. However, equally as crucial in therapeutic success is the act of patient engagement and ownership over their care. This can help tailor support and management to meet the individual patient's needs.84
Medical management of PAH has made significant strides with encouraging results from clinical trials and studies. Early referral to PH expert center, close follow-up, and using advanced technologies to accurately characterize patient's functional and risk status is of foremost importance in patient care for PAH. Current studies have demonstrated improved functional outcomes and reverse RV and pulmonary vascular remodeling in patients started on combination therapies early in the disease course. Newer therapies targeting novel receptors involved in the pathogenesis of PAH are currently understudying and offer a ray of hope for the future. A multidisciplinary approach including PH experts, transplant physicians, nursing, nutritionist, pharmacist, physical therapist, and social workers is paramount in managing PAH patients.
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. Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction. Circ Heart Fail 2014;7:935–44.doi:10.1161/CIRCHEARTFAILURE.113.001229 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25286913
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. Monitoring pulmonary arterial hypertension using an implantable hemodynamic sensor. Chest 2019;156:1176–86.doi:10.1016/j.chest.2019.06.010 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31265832
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. Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ 2018;360:j5492.doi:10.1136/bmj.j5492 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29540357
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. Impact of nutrition on pulmonary arterial hypertension. Nutrients 2020;12. doi:doi:10.3390/nu12010169. [Epub ahead of print: 07 Jan 2020].pmid:http://www.ncbi.nlm.nih.gov/pubmed/31936113
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. Development of a pharmacist collaborative care program for pulmonary arterial hypertension. Int J Clin Pharm 2011;33:898–901.doi:10.1007/s11096-011-9579-x pmid:http://www.ncbi.nlm.nih.gov/pubmed/22037987
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. International guidelines for the selection of lung transplant candidates: 2006 update--a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006;25:745–55.doi:10.1016/j.healun.2006.03.011 pmid:http://www.ncbi.nlm.nih.gov/pubmed/16818116
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. Lung transplantation for pulmonary hypertension and strategies to bridge to transplant. Semin Respir Crit Care Med 2017;38:701–10.doi:10.1055/s-0037-1606223 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29032570
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Contributors All authors contributed to the manuscript in a substantial manner. HD, TW, and RS reviewed the relevant literature and made necessary edits to the final manuscript and drafted the manuscript. RS gave final approval for submission for publication of the manuscript.
Competing interests RS has received research support from Bayer, United Therapeutics, Reata and Complexa, and served on advisory boards for Actelion, Altavant, Bayer, Gossamer, and United Therapeutics.
Provenance and peer review Commissioned; externally peer reviewed.
© American Federation for Medical Research 2021. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Pulmonary arterial hypertension: promising advances and remaining challenges
Karim El-Kersh John D Dickinson
Journal of Investigative Medicine 2021; 69 1268-1269 Published Online First: 27 Sep 2021. doi: 10.1136/jim-2021-002152


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text:
Minnesotans on e-scooters
For better or worse, how have e-scooters changed your life?
We asked Minnesotans to share their e-scooter stories. Here's what a few folks had to say. Submit your own story via this form.
Some comments have been edited for length and clarity.
"Annoying! As a driver and a walker, I have had to dodge scooters on the road, on walking paths, and on sidewalks. Many riders do not seem to know what they are doing. As a physician, I would like to see these scooters banned due to high risk for serious injuries." — Lori
"Walking on city sidewalks has become decidedly more dangerous with scooters both for riders and pedestrians. In contrast to bicyclists, scooter riders rarely use helmets, too often use sidewalks sometimes in groups of three and with these quiet electric fast machines pedestrians are put at risk. Unless state law is enforced emergency rooms better be prepared." — Ron
"I think they are amazing, all things considered. I am definitely biased though; I am a bicycle racer and former motorcycle fanatic so two wheels is life to some extent for me. Not all scooters are created equal either. Try riding a Lime then ride a Spin. You'll notice the handling of the Spin is much, much better due to a lower handlebar. Certainly helmets should be worn by riders as they go just as fast as a bicycle but handling characteristics are far worse. Scooters can certainly benefit from improvements in tires and overall handling. As far as injuries go, with improved functionality on the scooter's end I think that should help, but people need to have some common sense. Some of the people I have seen ride these things — oh boy — please don't. It ain't gonna end well. One more thing — I so wish these were around when I was a kid of 13+ or so. Sick wheels!" — Christopher
"I have almost been run down by scooters on the sidewalks in St. Paul, in particular along Kellogg Boulevard between Lowertown and the Science Museum. Via the Saint Paul Government website, I asked about liability if I get injured by one of these scooters. I assume they thought I was being facetious since I never got a reply." — Janet
"While walking my dogs in uptown Minneapolis I was told on two different sets of teens riding on the sidewalks the following: One group told me that I needed to move off the sidewalk or they would hit me! The second group told me move or something will happen to you. One group was girls and the other was boys. I informed them they were not to be riding on the sidewalks and refused to move! Furthermore, most drivers of scooters do not obey stop signs and fly directly through intersections." — Sharon
"For worse: The majority of scooter users fail to obey traffic law and seem lacking in basic common sense as they weave back and forth onto sidewalks, into the bike lane, traffic lanes and cross intersections. The lack of visibility of users (black clothes and small vehicle size) on top of erratic behaviour is almost asking for an accident to happen." — Diane
"I don't tend to have much of a problem with people riding the scooters, most people seem to ride them fairly responsibly. I do get frustrated by what amounts to "scooter litter" all over the cities. If people left their personal scooters where they leave these rentals, I think many more people would be upset by them. Though I am tempted to blame the users, the real problem is with these companies providing zero infrastructure for the use of the scooters. The convenience of dropping scooters wherever you want benefits the companies most of all and inconveniences the rest of us. I am also skeptical about the mobility benefits. I do believe they serve as a useful mode of transportation for some, but I would rather see Minneapolis and St. Paul do business with companies that are interested in actually improving our transportation infrastructure, not simply using it for profit at the expense of the cities' residents." — Jacob
"I am bothered by the fact that people park them on the sidewalks on residential streets. I encounter scooters parked in front of houses frequently when walking around St. Paul. I would like to see designated scooter parking stations similar to the Nice Ride bikes." — Chris
"They are great for travel if you are from out of town. Especially in cities where parking is scarce. It saves money for travelers so they don't have to keep pulling their car out of the parking ramp. But the bike lanes are key. Having good paths that connect will help out with this. Smooth roads do, too. Rode them in Indianapolis and Washington DC. The helmet is a challenge because you typically don't think to travel with them. I normally wear a helmet with a bicycle." — Patty
"As a pedestrian, I have come close at least three times to being hit by the scooters which were being operated at full-speed on sidewalks. I am amazed at the speed they operate with the riders wearing no helmets and oblivious to the risks they voluntarily undertake. I wish there was more information made available to riders regarding the rules and risks." — Patti
"I am a Lowertown resident. To date I have no issues with e-scooter riders given the current level of use. I enjoy them for short hops around the hood. However at 66 years old I probably shouldn't be assuming the risk. They are fun and the phone interface is very well done." — David
"I almost never see people riding them on the street. I'd rather the scooters go away and we stick with the city bikes. If people want small motors on the bikes, I'm good with that." — Emily
"They're trash. They make bike and pedestrian lanes less safe. People riding scooters are generally less considerate than other users of paths and walkways. I really don't like them." — Jonathan
"I hate them so much! I think they are ridiculous. The bikes weren't so bad, at least people rode them on the street. I've seen scooters zip down the sidewalk where I was walking with my two small children. I don't want to have to be afraid of getting knocked over — if I wanted to get hit, I'd walk in the road!" — Eve
"They make life much worse. They're at minimum a nuisance, but in reality they a hazard. People leave them everywhere making it hard for people with disabilities to get around. People ride them on sidewalks where they run down pedestrians. In the streets where with a general disregard for safety their users criss cross the road without bothering to take account of their surroundings. People ride them two at a time. Kids ride them. They get in the way of bikes. It's just plain dangerous. Why should our safety be sacrificed so Lyft and other companies can make money." — Ian
"They are horrible, especially by the U of M. People use scooters distracted, unsafely, drunk, doubled up. When they get off, they promptly leave them wherever and are sometimes left in the road, where they can be run over. They are left in many sidewalks making it even more difficult for anyone to walk the streets and even more difficult for people with physical disabilities." — Jadin
"Scooters are great! They help people with mobility issues, they add another non-car option to transportation spaces, they can use clean/renewable energy. There needs to be more infrastructure to protect pedestrians/bikers/non-car people, and there definitely needs to be more cohesive education for safe scootering in the city — I was almost hit while walking on the sidewalk the other day! But in general, e-scooters are a good thing." — Nellie
"I like them, but I don't like how a lot of people ride them on sidewalks, which is prohibited. Also, I've yet to see a cop pullover a scooter rider for disobeying this ordinance." — Matthew
"For the better. I use the scooters during my commute to and from my parking ramp in downtown Minneapolis. Plus, the biggest 'better' I've seen the scooters do is provide a low-cost (green) transportation option for low income neighborhoods, and people." — Roxanne
"I have taken scooters about 2 miles through downtown and love them, in a similar way I loved the Car2Go services a few years ago. Being able to ride to any destination and not worry about a docking station (like NiceRides, even the dockless ones, need) is a huge relief. I do think that this is a time of struggling to train people on proper etiquette and safety. I disagree that people are ultra inconvenienced by scooters any more than other sidewalk paraphernalia or bad design — they are just the newest thing and therefore are being talked about. I love how we are talking about some injuries from scooter related crashes, but drivers hit cyclists all the time and it's just seen as a run-of-the-mill risk taken by cyclists." — Jessica
"The presence of the scooters has basically just added a distraction to my life. I have had to move a lot of them. People leave them on the sidewalk, in the middle of the walkway. People in wheelchairs can't exactly go around them, and visually impaired people have a hard time when encountering them. They are quite heavy, I try to at least move them off to the side so that nobody has any problems with them. About a week ago, I had to move two of them to help a bus driver dispatch his wheelchair ramp, because they were in the way. This was on Nicollet Mall, there was a cluster of scooters right where people would ordinarily board the bus. I saw a rider fall off of one in the middle of a crosswalk at a busy intersection (no helmet). He seemed fine, but it was kind of scary. When I'm driving, it causes some stress. For example, yesterday I was driving on a side street and three people were on scooters (no helmets) in traffic, going about 15mph (I had no choice but to match their speed). I wasn't in a hurry, but it would have been nice if there was somewhere else for them to go. The sidewalks aren't really a good option, because they get in the way of pedestrians. I don't think the city of Minneapolis is positioned to develop the necessary infrastructure for scooters to have their own safe road. I think that more alternative transportation options are inherently good, but the execution of the scooters doesn't seem to have been done with safety or being a good neighbor in mind." — Cynthia
"I got a concussion and a trip to the ER in an ambulance the first time I rode one. I would ride one again someday, but not without a helmet!" — Julia
"Worse. They frequently block sidewalks and bike paths where I go running. I often run with a stroller and it is difficult to get around them. Riders on the scooters often take them on the sidewalk, because it is dangerous to ride them in the street, but I have been hit or nearly hit by several scooter riders not paying attention. I have also nearly crashed with riders leaving the road to park on a sidewalk without looking for foot traffic. I'm all about other ways to get beyond cars, but the scooters are a terrible solution. I miss the nice ride bikes. So much safer for everyone." — April
"The event I'm describing took place in Minneapolis at the intersection of 10th Ave S and 25th Street. I was coming out of work and a young man/teen was zooming down middle of 10th Ave S heading north and straight into the intersection not looking at cross streets or anything. A car was coming down 25th Street headed west, there is a stop sign but the car did not stop and was going too fast, maybe 25 mph. The back end of scooter just barely cleared the right front end (hood) of car — just beforehand I saw and braced and gasped thinking there would be impact. Car did not stop nor the scooter rider — car driver unless impaired had to know how close it was." — Mary
"Most people using a bike or scooter use the sidewalk in front of my house. I live on Lexington Parkway in St. Paul which is a busy street. However, there is a designated bike lane on Lexington and I have not seen people on scooters using the bike lane. When I am out for a walk with my dog I am usually forced to move off the sidewalk when a bike or scooter approaches. They really will not move to the side so I can pass on the sidewalk. I have gotten very assertive about having the right of way but to no avail. It is like playing a game of chicken with people on bikes and scooters. Why do we have bike lanes when so few people use the bike lane? They prefer the sidewalks. There should be a lot more citations for bikers and scooters on sidewalks!" — Jeanne
"I've been very concerned about the scooters' lack of visibility, especially when used at dusk or after dark. The tail lights are totally inadequate!" — Elena
"Tried them today. Not for me. Got a tutorial from a patient friend and went over the Stone Arch Bridge two times. I brought a bike helmet. G-D that was scary! I probably won't ever ride one again. They are fine for others if that's what they want. Just not for me (52-year-old woman)." — Gail
"My nephew who is 34 rented an e-scooter. He hit a pothole. He broke every bone in his face. Broke his jaw and pallet, nose and cheek bones. They could not fix the bones in his forehead and he had to get titanium plates and screws in. Also, had skull surgery. He was unrecognizable. He also had to have a tracheotomy put in. He is recovering now but it is a long road ahead with therapy and more surgeries. These scooters are so dangerous. Why are they in downtown busy areas? Construction and all of the texting and driving is so scary." — Lori
"On the University of Minnesota campus, they are everywhere — in the middle of sidewalks, being ridden on pedestrian only paths, and interfering with traffic in illegal ways. I hate them." — Tracy
"For better. As I read the complaints I observe that the issue is more about the scooter user than the scooter itself. It sounds like the problem is that people are being inconsiderate and thoughtless in how they use the scooter. I finally was able to use a scooter the other day and I loved it. I stayed on bike paths and remained to the right of the path, using the same courtesy I would if I was on a bike. Then, I placed the scooter in an area off to the side where it would not be in the way. It is common sense. The problem is people who are inconsiderate. How do we fix that? Get rid of scooters for everyone because some people are terrible?" — Dana
"While sitting in my car at a stoplight in downtown St Paul, two scooter riders coming down a sidewalk nearly rode them into my car. They managed to stop, barely. One was looking at her cellphone while riding and they both seemed to be novices at scooter riding. This is one more subset with cars/bikes/motorcycles/mopeds/pedestrians on the Venn diagram of "I have every right to be here" and "We all bleed." Folks, let's take a deep breath, use common sense and stay safe." — Katy
"... I sometimes wonder if, since in most generations alive today riding a scooter of that design was (to the best of my knowledge) only something you did in grade school, people just go back to that childish mindset of lack of regard for other people or safety. That's how people seem to act on them. People riding them literally ride right up to us (on otherwise empty sidewalks mind you) and stare right at us without saying a word but seemingly expecting that we will move and will drag our dogs away for them. Scooters do have a great promise, but right now the way people use them and their lack of regulation is just a recipe for disaster and the worst form of capitalism — companies making money at the expense of (in this case) the health of people at large." — Marie
"One day I turned the corner onto a fairly busy St. Paul street and ahead of me was a young man on a scooter who was intentionally weaving back and forth and showing off all over the lane. My car is quiet, so he wasn't even aware I was slowly driving behind him. Because of traffic in the oncoming lane, I couldn't pass, and I didn't want to startle him by honking, so I had to drive behind until I could turn off the block. I got out of that situation without an incident but that kind of reckless scooter driving is definitely an accident waiting to happen. I can't stop thinking about that kid and wishing there was something I could have done." — Joann
"They have made my life much worse. I have a brain injury and, as a result, I rarely drive anymore. Instead, I walk everywhere. When a scooter comes up behind me and zooms by, it makes me lose my balance. It's one of the few things that causes me to lose balance. People are constantly riding scooters on sidewalks. If I fall and hit my head, I'm in big trouble . So, I hate the scooters. They really are limiting my mobility. I cringe at all the under 18 people on them." — Jessica
I welcome any low-carbon mode of transportation that gets people out of their cars, however, the misbehavior on the scooters is really infuriating. Also, people park them in incredibly inconsiderate ways, and they completely ignore the law about riding on the sidewalk. I also hate how the Bay Area Brogrammers who came up with these things dumped them in Minneapolis before getting proper Council approval. Just shows the level of solipsism that is inherent in these little scooters.
by Jeremy 9/18/2019 8:55:15 PM
"Scooters get people out of cars. Cars are the most deadly form of transportation statistically, hands down. A scooter, weighing 40 pounds with a 200 lb person attached, going a maximum of 15 mph, will not kill me. A car, weighing 2,000 pounds and going the speed limit of 30 mph, has a 50 percent chance of killing me. Scooters ride on sidewalks because they feel unsafe with cars. Who doesn't? Scooters should be on roads not sidewalks, sure. But roadways should be safer for scooters, bicyclists, pedestrians, transit riders, and other modes who, by the Complete Streets policy law, come first. I am all for any technology that gets people out of cars and face-to-face with the world around them." — Abigail
I agree with the arguments for scooters, but I also live by the Stone Arch Bridge. I have never seen anyone wear a helmet on them, even the people legally required to. And it is very, very rare for them to obey the "don't ride on the side walk" laws. I tire of the scooters strewn about that I often move to clear way for the wheel chair users in my building. I tire of being run off the sidewalks and fearing that one day someone will kill my dog when we're walking. The early adopters have been a nuisance and that hasn't been a great thing for scooters.
by Barb Yau 9/20/2019 6:48:02 PM
"As with other cities that have had e-scooters arrive in, there is a period of adaptation — for cyclists, drivers, walkers, and riders. The banter in Minneapolis and St. Paul is not new, just new to this city. I've been riding scooters, shared bikes, hybrid bikes in cities all over our nation for a few years now, with no issues, but it takes time for adaptation in each new city, by everyone. It is a paradigm shift in mobility for me, and I use everything from buses, trains, subways, to Uber/Lyft, rental cars, and taxis. There are obvious risks, but it just isn't significant comparatively. The responsibility of the rider is paramount, but also responsibilities of others in the use arena is important. Be considerate, and I'll give you the same. We'll all learn together. I think it's a little immature to complain about the scooters themselves as dangerous; it's users, or perhaps even anti-scooter people that inflate the inconvenience and risk. I do think there is a place for municipalities to assure good business practices through regulation, and it's incumbent upon each city to be proactive. Cities with mature alternative transportation systems in use, effectively, and safely, are good models." — Wayne

redpajama_set_name: RedPajamaCommonCrawl


text:
Q: hyperlink text to mp3 without showing player How do I create a text hyperlink to an mp3 file without showing the player.  For example, if I have the word "play" on my site and it is clicked, the associated mp3 will play without leaving the page and without a visible player.  Also, when right clicked, the person has an option to save/download the file.  The closest example I have found only allows you to copy the link location and not download/save the mp3 file.  Thanks.

<audio id="audiotag" src="http://sample.mp3" autobuffer="autobuffer"></audio>

play

div#audio {
display: none;
overflow: hidden;
}

A: Make the  tag point to the mp3 file.  When you left-click, use JavaScript to play it.  When you right-click, you'll get the built-in menu with a "save link" option.
play

Then in your JavaScript, you can prevent the default action of the link:

A: The best option would be to use something like SoundManager.
It has a flash fallback for browsers that do not support html5 audio tag.
Demo of normal mp3 pimped up links: play-mp3-links

redpajama_set_name: RedPajamaStackExchange


text:
// These next comments MAY look like matches but they really are NOT: they either
// don't *start* a line or *end* a line (yes, one in here is nasty as we only appended
// a single non-whitespace character at the end of that comment line!
//
// However, when specifying a simple *string* as `replace` value the plugin will consider
// that string to be a sufficient regex to pick only the banners you are looking for.
//
// Here we have constructed a case which exhibits the limitations of grunt-banner.
//
// NOT INTENEDED AS A BUG SCENARIO: THIS IS INTENDED (BACKWARD-COMPATIBLE) BEHAVIOUR.
//
// WHEN YOU WANT 'SMARTER' BEHAVIOUR EITHER SPECIFY `replace: true` TO LET THE DEFAULT
// LOCATE-AND-MARK FUNCTION HANDLE IT ALL or SPECIFY OUR OWN LOCATE-AND-MARK FUNCTION
// INSTEAD: `replace: myOwnCustomLocateAndMarkFunction`.

var variable1 = "this is a variable";
// replace-this-comment!
var variable2 = "this is another variable";
var no_dont; // replace-this-comment
var variable3 = "this is another variable";
/* replace-this-comment */
var variable4 = "this is another variable";
// whitespace before the comment IS acceptable, however.
//
// Hence *DO REPLACE* the next comment:

                         // replace-this-comment
var variable5 = "this is another variable";

                         // Copyright some poor bugger
var variable5 = "this is another variable";

// the banner
var variable5 = "this is another variable";

redpajama_set_name: RedPajamaGithub