R. James White

Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension A Scientific Statement From the American Heart Association

Venous thromboembolism (VTE) is responsible for the hospitalization of >250 000 Americans annually and represents a significant risk for morbidity and mortality. Despite the publication of evidence-based clinical practice guidelines to aid in the management of VTE in its acute and chronic forms, the clinician is frequently confronted with manifestations of VTE for which data are sparse and optimal management is unclear. In particular, the optimal use of advanced therapies for acute VTE, including thrombolysis and catheter-based therapies, remains uncertain. This report addresses the management of massive and submassive pulmonary embolism (PE), iliofemoral deep vein thrombosis (IFDVT),and chronic thromboembolic pulmonary hypertension (CTEPH). The goal is to provide practical advice to enable the busy clinician to optimize the management of patients with these severe manifestations of VTE. Although this document makes recommendations for management, optimal medical decisions must incorporate other factors, including patient wishes, quality of life, and life expectancy based on age and comorbidities. The appropriateness of these recommendations for a specific patient may vary depending on these factors and will be best judged by the bedside clinician.

Tadalafil Therapy for Pulmonary Arterial Hypertension

Background— Treatment options for pulmonary arterial hypertension target the prostacyclin, endothelin, or nitric oxide pathways. Tadalafil, a phosphodiesterase type-5 inhibitor, increases cGMP, the final mediator in the nitric oxide pathway. Methods and Results— In this 16-week, double-blind, placebo-controlled study, 405 patients with pulmonary arterial hypertension (idiopathic or associated), either treatment-naive or on background therapy with the endothelin receptor antagonist bosentan, were randomized to placebo or tadalafil 2.5, 10, 20, or 40 mg orally once daily. The primary end point was the change from baseline to week 16 in the distance walked in 6 minutes. Changes in World Health Organization functional class, clinical worsening, and health-related quality of life were also assessed. Patients completing the 16-week study could enter a long-term extension study. Tadalafil increased the distance walked in 6 minutes in a dose-dependent manner; only the 40-mg dose met the prespecified level of statistical significance (P<0.01). Overall, the mean placebo-corrected treatment effect was 33 m (95% confidence interval, 15 to 50 m). In the bosentan-naive group, the treatment effect was 44 m (95% confidence interval, 20 to 69 m) compared with 23 m (95% confidence interval, −2 to 48 m) in patients on background bosentan therapy. Tadalafil 40 mg improved the time to clinical worsening (P=0.041), incidence of clinical worsening (68% relative risk reduction; P=0.038), and health-related quality of life. The changes in World Health Organization functional class were not statistically significant. The most common treatment-related adverse events reported with tadalafil were headache, myalgia, and flushing. Conclusions— In patients with pulmonary arterial hypertension, tadalafil 40 mg was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening.

Efficacy and Safety of Oral Treprostinil Monotherapy for the Treatment of Pulmonary Arterial Hypertension: A Randomized Controlled Trial

Background— Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with no cure. Parenteral and inhaled prostacyclin analogue therapies are effective for the treatment of PAH, but complicated administration requirements can limit the use of these therapies in patients with less severe disease. This study was designed to evaluate the safety and efficacy of the oral prostacyclin analogue treprostinil diolamine as initial treatment for de novo PAH. Methods and Results— Three hundred forty-nine patients (intent-to-treat population) not receiving endothelin receptor antagonist or phosphodiesterase type-5 inhibitor background therapy were randomized (treprostinil, n=233; placebo, n=116). The primary analysis population (modified intent-to-treat) included 228 patients (treprostinil, n=151; placebo, n=77) with access to 0.25-mg treprostinil tablets at randomization. The primary end point was change from baseline in 6-minute walk distance at week 12. Secondary end points included Borg dyspnea index, clinical worsening, and symptoms of PAH. The week 12 treatment effect for 6-minute walk distance (modified intent-to-treat population) was 23.0 m (P=0.0125). For the intent-to-treat population, 6-minute walk distance improvements were observed at peak (26.0 m; P=0.0001) and trough (17.0 m; P=0.0025) plasma study drug concentrations. Other than an improvement in the combined 6-minute walk distance/Borg dyspnea score, there were no significant changes in secondary end points. Oral treprostinil therapy was generally well tolerated; the most common adverse events (intent-to-treat) were headache (69%), nausea (39%), diarrhea (37%), and pain in jaw (25%). Conclusions— Oral treprostinil improves exercise capacity in PAH patients not receiving other treatment. Oral treprostinil could provide a convenient, first-line prostacyclin treatment option for PAH patients not requiring more intensive therapy. Clinical Trial Registration:— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00325403.

Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: A placebo-controlled trial

BACKGROUND Pulmonary arterial hypertension (PAH) remains a poorly understood and frequently lethal disease with few treatment options. METHODS We conducted a placebo-controlled trial of intravenous treprostinil, a prostacyclin analog, in treatment-naive PAH patients. During 12 weeks of treatment with treprostinil or placebo, we quantified 6-minute walk distance (6MW), clinical symptoms and 11 cytokines/growth factors. RESULTS Forty-two of 44 study patients had idiopathic/familial PAH in New York Heart Association (NYHA) Class III. Treprostinil increased 6MW by a placebo-corrected median of 83 meters (p = 0.008; mean increase 93 +/- 42 meters), reduced Borg score by a median 2.0 units (p = 0.02), and improved NYHA class by a median of 1.0 (p = 0.02). There was a trend toward improved survival with treprostinil (p = 0.051). Baseline plasma angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9) and platelet-derived growth factor (PDGF) were elevated compared with reported normal ranges. Treatment with treprostinil was associated with decreased Ang-2 levels. Improvement in 6MW distance after treatment was associated with reductions in Ang-2 and MMP-9 levels. Most of the cytokines and growth factors studied were not abnormal with disease nor did they change with treatment. CONCLUSIONS We conclude that treprostinil treatment significantly improved exercise capacity, dyspnea and functional class. Several plasma proteins that might track disease were abnormal at baseline, and changes were associated with improved exercise capacity.

Neonatal Hyperoxia Causes Pulmonary Vascular Disease and Shortens Life Span in Aging Mice

Bronchopulmonary dysplasia is a chronic lung disease observed in premature infants requiring oxygen supplementation and ventilation. Although the use of exogenous surfactant and protective ventilation strategies has improved survival, the long-term pulmonary consequences of neonatal hyperoxia are unknown. Here, we investigate whether neonatal hyperoxia alters pulmonary function in aging mice. By 67 weeks of age, mice exposed to 100% oxygen between postnatal days 1 to 4 showed significantly a shortened life span (56.6% survival, n = 53) compared to siblings exposed to room air as neonates (100% survival, n = 47). Survivors had increased lung compliance and decreased elastance. There was also right ventricular hypertrophy and pathological evidence for pulmonary hypertension, defined by reduction of the distal microvasculature and the presence of numerous dilated arterioles expressing von Willebrand factor and α-smooth muscle actin. Consistent with recent literature implicating bone morphogenetic protein (BMP) signaling in pulmonary vascular disease, BMP receptors and downstream phospho-Smad1/5/8 were reduced in lungs of aging mice exposed to neonatal oxygen. BMP signaling alterations were not observed in 8-week-old mice. These data suggest that loss of BMP signaling in aged mice exposed to neonatal oxygen is associated with a shortened life span, pulmonary vascular disease, and associated cardiac failure. People exposed to hyperoxia as neonates may be at increased risk for pulmonary hypertension.

Sildenafil therapy is associated with improved hemodynamics in liver transplantation candidates with pulmonary arterial hypertension

Pulmonary arterial hypertension associated with portal hypertension occurs in about 5% of patients being evaluated for liver transplantation. Treatment is required to facilitate safe transplantation, and oral pulmonary vasodilators have yet to be prospectively evaluated for this disease. The objective of this study was to determine the hemodynamic outcome in a consecutive cohort of patients offered sildenafil as first‐line treatment for portopulmonary hypertension. We identified consecutive patients at the University of Rochester referred by the liver transplant team. All had catheter‐confirmed disease and were treated with sildenafil. Patients were excluded from analysis if they did not have follow‐up catheterizations. The change in pulmonary vascular resistance at the time of first follow‐up was the primary outcome. Eleven patients began sildenafil, and 9 had follow‐up right heart catheterizations during a 3‐year period. Pulmonary vascular resistance dropped in each patient; as a group, the mean dropped from 575 to 375 dynes/second/cm5. Four of 9 patients achieved a mean pulmonary artery pressure ≤ 35 mm Hg at the time of first recatheterization, and 1 patient received a successful cadaveric transplant. Four of 6 patients with more than 1 follow‐up catheterization had sustained hemodynamic benefit. One patient initially responded to therapy with favorable hemodynamics but was found in the operating room to have recrudescent disease (on therapy) that precluded safe transplantation. In conclusion, sildenafil was associated with improved hemodynamics in this small, uncontrolled cohort. A multicenter, prospective evaluation is warranted in this group uniformly excluded from phase III clinical trials. Liver Transpl 15:30–36, 2009.

G-Protein–Coupled Receptor Kinase Interacting Protein-1 Is Required for Pulmonary Vascular Development

Background— The G-protein–coupled receptor kinase interacting protein-1 (GIT1) is a multidomain scaffold protein that participates in many cellular functions including receptor internalization, focal adhesion remodeling, and signaling by both G-protein–coupled receptors and tyrosine kinase receptors. However, there have been no in vivo studies of GIT1 function to date. Methods and Results— To determine essential functions of GIT1 in vivo, we generated a traditional GIT1 knockout mouse. GIT1 knockout mice exhibited ≈60% perinatal mortality. Pathological examination showed that the major abnormality in GIT1 knockout mice was impaired lung development characterized by markedly reduced numbers of pulmonary blood vessels and increased alveolar spaces. Given that vascular endothelial growth factor (VEGF) is essential for pulmonary vascular development, we investigated the role of GIT1 in VEGF signaling in the lung and cultured endothelial cells. Because activation of phospholipase-Cγ (PLCγ) and extracellular signal-regulated kinases 1/2 (ERK1/2) by angiotensin II requires GIT1, we hypothesized that GIT1 mediates VEGF-dependent pulmonary angiogenesis by modulating PLCγ and ERK1/2 activity in endothelial cells. In cultured endothelial cells, knockdown of GIT1 decreased VEGF-mediated phosphorylation of PLCγ and ERK1/2. PLCγ and ERK1/2 activity in lungs from GIT1 knockout mice was reduced postnatally. Conclusions— Our data support a critical role for GIT1 in pulmonary vascular development by regulating VEGF-induced PLCγ and ERK1/2 activation.

Pharmacokinetics of oral treprostinil sustained release tablets during chronic administration to patients with pulmonary arterial hypertension.

Abstract: Pulmonary arterial hypertension (PAH) is a progressive vascular disease that ultimately leads to right ventricular failure and death. Treprostinil diolamine is an oral prostacyclin analogue; sustained release tablets of oral treprostinil are currently being evaluated for efficacy and safety as a potential therapy in patients with PAH. Previous attempts at developing an oral prostanoid have been limited by rapid absorption and short plasma half-life; thus, the aim of this study was to characterize the pharmacokinetic profile of treprostinil diolamine in PAH patients after chronic dosing. The study enrolled 74 PAH patients who had been taking treprostinil diolamine for a minimum of 4 weeks (range: 0.5–16 mg). We collected plasma samples over 12 hours and estimated pharmacokinetic parameters using noncompartmental methods. Seventy patients had complete data. After chronic twice-daily oral dosing of treprostinil diolamine, mean area under the curve (AUC0-12) of treprostinil increased from 5244 to 20,4086 pg·hr−1·mL−1 and mean maximum observed plasma concentration (Cmax) increased from 1383 to 33588 pg/mL. The apparent clearance (CL/F) was similar across all doses, indicating a linear dose–exposure relationship after twice-daily dosing. We conclude that twice-daily oral treprostinil provides sustained and proportional treprostinil concentrations over a wide range of doses during chronic administration to PAH patients.

Endothelin-1 induces pulmonary but not aortic smooth muscle cell migration by activating ERK1/2 MAP kinase.

Endothelin 1 (ET-1) is an endogenous peptide that promotes vasoconstriction, endothelial and smooth muscle cell (SMC) proliferation, and fibrosis. ET-1 receptor antagonists are an important treatment strategy for pulmonary arterial hypertension, but less effective in systemic vascular disease. This observation suggests a special role for ET-1 in the pulmonary circulation. We hypothesized that ET-1 contributes to the pathogenesis of pulmonary arterial hypertension, in part, by promoting pulmonary vascular SMC migration. ET-1 treatment promoted migration in 3 distinct types of cultured pulmonary SMC. Pulmonary SMC migration was blocked by an ETA receptor selective agonist and a combined ETA-ETB antagonist, but not by a selective ETB antagonist. In contrast to the effect on pulmonary SMCs, ET-1 had no effect on migration of aortic SMCs. Flow cytometry showed that the ETA receptor was expressed at comparable levels on pulmonary and aortic SMCs, excluding receptor density as an explanation for the divergent effect. ET-1-induced pulmonary SMC migration was blocked by the structurally distinct MEK inhibitors PD98059 and U0126, consistent with a role for ERK1/2 MAP kinase. By Western blot in cultured cells and immunohistochemistry in ex vivo vessels, ET-1 stimulated phosphorylation of ERK1/2 as efficaciously as platelet-derived growth factor in pulmonary, but not aortic, SMCs. In conclusion, ET-1 induces SMC migration, with the ETA receptor tightly coupled to ERK1/2 phosphorylation only in the pulmonary circulation. This finding may help explain the striking difference in the efficacy of endothelin receptor blockers for pulmonary hypertension as compared to that for systemic cardiovascular disease.

Transition from parenteral to oral treprostinil in pulmonary arterial hypertension

BACKGROUND Parenteral prostanoids are effective treatment for pulmonary arterial hypertension, but long-term pump infusion systems have significant delivery-related safety and convenience limitations. METHODS Subjects with a favorable risk profile transitioned from parenteral to oral treprostinil using a protocol-driven titration during 5 days of inpatient observation. Baseline and Week 24 assessments included 6-minute walk distance, echocardiogram, right heart catheterization, pharmacokinetics, treatment satisfaction and quality of life. Thirty-three subjects (76% female, mean age 50 years) enrolled; 85% were using subcutaneous treprostinil with a median dose of 57 (range 25 to 111) ng/kg/min. Participants were using background, approved non-prostanoid therapy, including 9 on 2 oral therapies; baseline right atrial pressure and cardiac output were in the normal range. All 33 subjects transitioned to oral treprostinil therapy within 4 weeks, but 2 transitioned back to parenteral drug before Week 24. At Week 24, subjects were taking a median total daily dose of 44 (15 to 75) mg, with 25 of 31 using a 3-times-daily regimen at 7- to 9-hour intervals. RESULTS The 6-minute walk distance was preserved (median +17 m [-98 to 95 m]) at its baseline of 446 m. Hemodynamic variables, including pulmonary vascular resistance, were similar at Week 24 except for mixed venous saturation, which dropped from a median of 71% to 68% (p < 0.001). Overall quality of life and treatment satisfaction measures did not change; however, mood-related symptom and treatment convenience subscores improved. Common adverse effects included headache, nausea, flushing and diarrhea. CONCLUSIONS Lower risk patients managed on parenteral treprostinil may be candidates for transition to a more convenient, oral form of the drug.