Pulmonary arterial hypertension.
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Algorithms↗
Biomedical subjects
Vallerie V McLaughlin
Publications and source records attributed to Vallerie V McLaughlin.
Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension.
RATIONALE: Small, open-label studies suggest that combinations of existing therapies may be effective for pulmonary arterial hypertension (PAH). OBJECTIVE: To evaluate the safety and efficacy of adding inhaled iloprost, a prostacyclin analog, to the endothelin receptor antagonist bosentan in patients with PAH. METHODS: In a randomized, multicenter, double-blind trial, inhaled iloprost (5 mug) or placebo was added to stable monotherapy with bosentan for 12 wk. Efficacy endpoints included change from baseline in 6-min-walk distance (6-MWD), modified New York Heart Association (NYHA) functional class, hemodynamic parameters, and time to clinical worsening. MEASUREMENTS AND MAIN RESULTS: A total of 67 patients with PAH (55% idiopathic PAH, 45% associated PAH, 94% NYHA class III, and mean baseline 6-MWD of 335 m) were randomized. At Week 12, patients receiving iloprost had a mean increase in 6-MWD of 30 m (p = 0.001); placebo patients had a mean 6-MWD increase of 4 m (p = 0.69), with a placebo-adjusted difference of +26 m (p = 0.051). NYHA status improved by one class in 34% of iloprost versus 6% of placebo patients (p = 0.002). Iloprost delayed the time to clinical worsening (p = 0.0219). Improvements were noted in postinhalation placebo-adjusted change in mean pulmonary artery pressure (-8 mm Hg; p < 0.001) and pulmonary vascular resistance (-254 dyn x s x cm(-5); p < 0.001). Combination therapy was well tolerated. CONCLUSIONS: Within the limitations of a relatively small sample size, results of this study demonstrate that the addition of inhaled iloprost in patients with PAH with reduced exercise capacity on bosentan monotherapy is safe and efficacious.
Adolescent↗
'Raising the bar' for the treatment of pulmonary arterial hypertension.
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Humans↗
Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial.
BACKGROUND: Pulmonary arterial hypertension (PAH) is a life-threatening disease for which both continuous IV epoprostenol and continuous subcutaneous treprostinil have proven effective. With continuous IV treprostinil having potential advantages over both of the above therapies, we investigated the safety and efficacy of this regimen in patients with PAH. METHODS: We conducted a 12-week, prospective, open-label, uncontrolled, multicenter study of continuous IV treprostinil in 16 patients with PAH that was idiopathic (n = 8), related to connective tissue disease (n = 6), or related to congenital heart disease (n = 2). The primary end point was change from baseline to week 12 in exercise capacity assessed by the 6-min walk (6MW) test. RESULTS: Continuous IV treprostinil increased 6MW distance (mean +/- SE) by 82 m from baseline (319 +/- 22 m) to week 12 (400 +/- 26 m) [n = 14; p = 0.001]. There were also significant improvements in the secondary end points of Naughton-Balke treadmill time (p = 0.007), Borg dyspnea score (p = 0.008), and hemodynamics (mean pulmonary artery pressure, p = 0.03; cardiac index, p = 0.002; pulmonary vascular resistance, p = 0.001) at week 12 compared with baseline. Side effects were mild and consistent with those reported with prostacyclin treatment. One death, unrelated to study drug, occurred during the 12-week study in a patient who received 3 days of treprostinil and died 2 weeks later. CONCLUSIONS: Long-term IV infusion of treprostinil is safe and appears to be effective for the treatment of patients with PAH.
Adult↗
Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension.
RATIONALE: Intravenous epoprostenol improves exercise capacity and survival in patients with pulmonary arterial hypertension. The prostacyclin analog treprostinil is also efficacious by subcutaneous infusion, is easier to administer, and has a longer half-life. With the demonstration of bioequivalence between subcutaneous and intravenous treprostinil, intravenous treprostinil may have an overall better risk-benefit profile than intravenous epoprostenol. OBJECTIVE: To evaluate the safety and efficacy of transitioning patients with pulmonary arterial hypertension from intravenous epoprostenol to intravenous treprostinil. METHODS: Patients enrolled in a 12-wk prospective open label study were switched from intravenous epoprostenol to intravenous treprostinil over 24 to 48 h. The intravenous treprostinil dose was adjusted to minimize symptoms/side effects. RESULTS: Thirty-one patients (mean age, 43 yr; 22 women) were enrolled. Twenty-seven patients completed the protocol; 4 patients transitioned back to epoprostenol. Six-minute walk distance (n = 27; baseline, 438 +/- 16 m; Week 12, 439 +/- 16 m), Naughton-Balke treadmill test time (n = 26; baseline, 582 +/- 50 s; Week 12, 622 +/- 48 s), functional class, and Borg score were maintained with intravenous treprostinil at Week 12 versus intravenous epoprostenol before transition. At Week 12, mean pulmonary artery pressure increased 4 +/- 1 mm Hg (n = 27, p < 0.01), cardiac index decreased 0.4 +/- 0.1 L/min/m2 (n = 27, p = 0.01), and pulmonary vascular resistance increased 3 +/- 1 Wood units x m2 (n = 26, p < 0.01). No serious adverse events were attributed to treprostinil. CONCLUSIONS: These data suggest that transition from intravenous epoprostenol to intravenous treprostinil is safe and effective; whether the hemodynamic differences associated with intravenous treprostinil are clinically important requires longer follow-up.
Adolescent↗
Prostanoid therapy for pulmonary arterial hypertension.
Prostanoids have played a prominent role in the treatment of pulmonary arterial hypertension (PAH). Several compounds and methods of administration have been studied: chronic intravenously infused epoprostenol, chronic subcutaneously infused treprostinil, inhaled iloprost, and oral beraprost. Chronic intravenous epoprostenol therapy has had a substantial impact on the clinical management of patients with severe PAH. It improves exercise capacity, hemodynamics, and survival in patients with idiopathic pulmonary arterial hypertension (IPAH). It also improves exercise capacity and hemodynamics in patients with PAH occurring in association with scleroderma. The complexity of epoprostenol therapy (chronic indwelling catheters, reconstitution of the drug, operation of the infusion pump, and others) has led to attempts to develop other prostanoids with simpler modes of delivery. Treprostinil, a stable prostacyclin analogue with a half-life of 3 h, has been developed for subcutaneous delivery. It has beneficial effects on exercise and hemodynamics, which depend somewhat on the dose achieved. This, in turn, is determined by the patient's ability to tolerate the drug's side effects, including pain and erythema at the infusion site. Inhaled iloprost therapy may provide selectivity of the hemodynamic effects to the lung vasculature, thus avoiding systemic side effects. In a randomized and controlled trial, iloprost resulted in improvement in a combined end point incorporating the New York Heart Association functional class, 6-min walk test, and deterioration or death. Beraprost is the first orally active prostacyclin analogue. In the first of two randomized controlled trials, beraprost increased exercise capacity in patients with IPAH, with no significant changes in subjects with associated conditions. Hemodynamics did not change significantly, and no difference in survival was detected between the two treatment groups. The second study showed that beraprost-treated patients had less disease progression at six months and confirmed the results of the previous trial. However, this improvement was no longer present at 9 or 12 months. In conclusion, though treatment with prostanoids is complicated by their generally short half-lives and complicated drug delivery systems, they continue to play an important role in the treatment of PAH.
Antihypertensive Agents↗
Pulmonary Arterial Hypertension: New Management Options.
The past decade has realized remarkable advances in the treatment of pulmonary arterial hypertension (PAH), a progressive and potentially fatal disease. A small proportion of patients will have a dramatic hemodynamic response to acute vasodilator testing performed at the time of right heart catheterization and may be candidates for calcium channel blocker therapy. The vast majority of patients with PAH will not benefit from calcium channel blockers and should be treated with one of the three US Food and Drug Administration-approved therapies for PAH; bosentan, treprostinil, or epoprostenol. Because of the ease of administration relative to other therapies, the majority of patients with functional class III symptoms should be treated with the oral nonselective endothelin antagonist bosentan. Randomized controlled trials with treprostinil have demonstrated improvements in exercise endurance and hemodynamics. Patients who are critically ill, with functional class IV symptoms, should be started on epoprostenol because it is the most rapidly effective therapy. Intravenous epoprostenol improves exercise endurance, quality of life, hemodynamics, and survival in PAH. Investigational therapies on the horizon include phosphodiesterase inhibitors, prostacyclin analogues with alternative delivery routes (eg, inhaled, oral), and selective endothelin A receptor antagonists. The future of PAH therapy will likely include combinations of these therapies based on the multiple mechanisms of action.
Journal Article↗
Classification and epidemiology of pulmonary hypertension.
Pulmonary hypertension is a complex disease that can be idiopathic, familial, or associated with a wide range of disease processes. This article outlines the classification of primary pulmonary hypertension and discusses the various types of the disease.
Connective Tissue Diseases↗
Pulmonary hypertension.
Pulmonary hypertension, in its simplest sense, is elevation of the pulmonary artery pressure above normal. A multitude of diseases may increase the pulmonary artery pressure and result in right ventricular dysfunction. The treatments of pulmonary hypertension are as varied as its causes. The past decade has realized remarkable growth in knowledge of the mechanisms of pulmonary arterial hypertension and, concurrently, therapies for this once uniformly fatal disease. In addition to continuous intravenous epoprostenol, subcutaneous treprostinil and oral bosentan are now FDA approved for the treatment of pulmonary arterial hypertension. Other forms of pulmonary hypertension, such as pulmonary venous hypertension, pulmonary hypertension related to diseases of the respiratory system, and thromboembolic pulmonary hypertension will be discussed.
Cardiotonic Agents↗
Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.
Pulmonary arterial hypertension (PAH) is often difficult to diagnose and challenging to treat. Untreated, it is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. The past decade has seen remarkable improvements in therapy, driven largely by the conduct of randomized controlled trials. Still, the selection of most appropriate therapy is complex, and requires familiarity with the disease process, evidence from treatment trials, complicated drug delivery systems, dosing regimens, side effects, and complications. This chapter will provide evidence-based treatment recommendations for physicians involved in the care of these complex patients. Due to the complexity of the diagnostic evaluation required, and the treatment options available, it is strongly recommended that consideration be given to referral of patients with PAH to a specialized center.
Antihypertensive Agents↗
Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.
Although idiopathic pulmonary arterial hypertension is perceived as a progressive disease with a uniformly poor outcome, the natural history of disease is heterogeneous, with some patients dying within months of diagnosis and others living for decades. The course of the disease has also been altered by advances in medical therapies. The outcome of patients with other types of pulmonary arterial hypertension (PAH) has been less well characterized. Assessment of prognosis of such patients is important, as it influences both medical therapy and referral for transplantation. This chapter will provide evidence based recommendations to assess the prognosis of patients with PAH.
Biomarkers↗
Elevated basic fibroblast growth factor levels in patients with pulmonary arterial hypertension.
STUDY OBJECTIVES: Cellular growth in the vascular wall, including endothelial and smooth-muscle cell proliferation, is recognized as a component of the obstructive vasculopathy observed in the small vessels of the lungs in pulmonary arterial hypertension (PAH). We hypothesized that angiogenic growth factors may have a role in the molecular mechanisms underlying this cellular proliferation. DESIGN: Case-control study. SETTING: Multicenter, tertiary care hospitals. PARTICIPANTS: We studied 117 patients with PAH and 60 control subjects. MEASUREMENTS: We measured levels of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in the blood and urine of these subjects using an enzyme-linked immunoassay. RESULTS: Median levels of urinary and plasma bFGF were significantly higher in patients with PAH compared to normal control subjects. There was a difference in levels of urine and plasma bFGF according to etiology of pulmonary hypertension, with the highest levels seen in patients with primary pulmonary hypertension. Levels of urine or plasma VEGF were not significantly different between patients and control subjects. CONCLUSION: Patients with PAH have substantial alterations in urine and plasma levels of bFGF. This molecule may have a role as a mitogenic factor in the endothelial and smooth-muscle cell proliferation seen in PAH.
Adolescent↗
Endothelin receptor blockers in cardiovascular disease.
The endothelin (ET) system is comprised of 4 active ETs, with ET-1 being the predominant isoform in the cardiovascular system. Because of the potent vasoconstricting and mitogenic effects of ET-1 and its involvement in various cardiovascular diseases, blockade of the ET receptor has received considerable attention. ET receptor antagonism has been demonstrated to be beneficial in patients with pulmonary hypertension. The nonselective ET receptor antagonist bosentan improves exercise capacity and increases time to clinical worsening in patients with pulmonary arterial hypertension. The selective ET A receptor antagonist sitaxsentan also improves hemodynamics and exercise capacity in patients with pulmonary arterial hypertension. Results with ET receptor antagonists in congestive heart failure have been disappointing. Although some studies have suggested benefit, larger studies have been neutral. The use of ET receptor antagonists for other conditions has not been fully explored. Future studies with the use of ET receptor antagonists as part of a multidrug regimen are also needed.
Animals↗
Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension.
Intravenous epoprostenol is currently FDA approved for management of primary pulmonary hypertension, but it requires intravenous infusion and is associated with adverse effects. The objective of this study was to evaluate the effects of an epoprostenol analog, treprostinil, for management of pulmonary hypertension. Ten tertiary care academic institutions with pulmonary hypertension programs participated in these pilot trials. In the first trial, intravenous epoprostenol and intravenous treprostinil were compared. In the second trial, intravenous treprostinil and subcutaneous treprostinil were compared. In the third trial, subcutaneous treprostinil was compared with placebo infusion during an 8-week period. Intravenous epoprostenol and intravenous treprostinil resulted in a similar reduction in pulmonary vascular resistance acutely (22% and 20%, respectively). Intravenous treprostinil and subcutaneous treprostinil also demonstrated comparable short-term decrease in pulmonary vascular resistance (23% and 28%, respectively). The placebo-controlled 8-week trial demonstrated a mean improvement of 37 +/- 17 m as measured by the 6-minute walk distance in patients receiving treprostinil compared with a 6 +/- 28 m reduction in those receiving placebo. There were trends toward an improvement in cardiac index and pulmonary vascular resistance index in the treprostinil group. Subcutaneous treprostinil has favorable hemodynamic effects when given acutely and in the short term. Treprostinil can be given safely to an ambulatory patient with a novel subcutaneous delivery pump system.
Adolescent↗
Successful management of pregnancy in a patient with eisenmenger syndrome with epoprostenol.
Pregnancy in the setting of pulmonary hypertension and Eisenmenger physiology is associated with a substantial maternal and fetal risk. Such patients are advised against pregnancy. We report a case of a woman with an Eisenmenger atrial septal defect diagnosed during the last trimester of pregnancy. On presentation, she was critically ill and there was evidence of fetal distress. She was emergently treated with IV epoprostenol, and her status improved. She underwent cesarean section and delivered a male infant with Apgar scores of 8 and 9. Her dyspnea improved, and she was characterized as World Health Organization functional class II on a subsequent clinical visit. Although pregnancy should be discouraged in women with Eisenmenger syndrome, we have demonstrated that IV epoprostenol successfully treated a woman with Eisenmenger syndrome diagnosed in the third trimester.
Adult↗
Survival in primary pulmonary hypertension: the impact of epoprostenol therapy.
BACKGROUND: Primary pulmonary hypertension (PPH) is a severe and progressive disease. Without treatment, the median survival is 2.8 years, with survival rates of 68%, 48%, and 34% at 1, 3, and 5 years, respectively. Intravenous epoprostenol was the first Food and Drug Administration-approved therapy for PPH. The long-term impact that epoprostenol has made on PPH remains to be defined. METHODS AND RESULTS: One hundred sixty-two consecutive patients diagnosed with PPH and treated with epoprostenol were followed for a mean of 36.3 months (median, 31 months). Data including functional class, exercise tolerance, and hemodynamics were recorded in a customized database. Vital status was verified in each patient. Observed survival with epoprostenol therapy at 1, 2, and 3 years was 87.8%, 76.3%, and 62.8% and was significantly greater than the expected survival of 58.9%, 46.3%, and 35.4% based on historical data. Baseline predictors of survival included exercise tolerance, functional class, right atrial pressure, and vasodilator response to adenosine. Predictors of survival after the first year of therapy included functional class and improvement in exercise tolerance, cardiac index, and mean pulmonary artery pressure. CONCLUSIONS: Intravenous epoprostenol improves long-term survival in PPH.
Adult↗
Detection of subclinical cardiovascular disease: the emerging role of electron beam computed tomography.
BACKGROUND: Although extraordinary advances have been made in the management of advanced coronary artery disease, little progress has been made in its prevention. Traditional screening methods utilizing risk factor profiles and exercise treadmill tests have failed to identify populations who will subsequently have coronary events with a high degree of predictive accuracy. METHODS: We review the pathobiologic basis and clinical utility of electron beam computed tomography (EBCT) to detect coronary artery calcium as a screening tool for subclinical coronary artery disease. Because EBCT is able to perform subsecond imaging of the heart, it can detect and quantitate coronary artery calcium with a high degree of precision. Coronary artery calcium is a marker of complex atherosclerosis. RESULTS: Over 4,000 asymptomatic patients in several series have been studied with EBCT and followed prospectively for an average of 42 months (range 37-72 months). A positive scan is associated with a risk ratio for future coronary events of 8.7 (95% confidence interval 2.67 to 28.13). These data indicate that EBCT has the ability to detect subclinical coronary artery disease and predict future coronary events better than any previous existing method or technology. CONCLUSION: EBCT coronary artery screening may prove to be a valuable adjunct to the traditional methods for the detection of subclinical coronary artery disease and to identify those who would benefit from focused preventive therapies.
Aged↗
Medical management of primary pulmonary hypertension.
Primary pulmonary hypertension (PPH) is a rare disease effecting the pulmonary vasculature. Patients present with dyspnoea on exertion, chest pain, near syncope and evidence of right heart failure. The natural history of PPH was described in the 1980s and the survival rate was quite poor. The introduction of iv. epoprostenol in the early 1990s has significantly altered the natural history of this disease. Due to the complicated nature of this therapy, inhaled, sc. and oral prostacyclins have also been evaluated for treatment of PPH. The most recent class of medications added to the armamentarium for the treatment of PPH are the endothelin receptor antagonists. This paper reviews the available therapies for the treatment of PPH.
Bosentan↗