Hypertension: McLaughlin VV

McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, Anonymous00029, Anonymous00030, Anonymous00031, Anonymous00032, Anonymous00033. · No affiliation provided · J Am Coll Cardiol. · Pubmed #19389575 No free full text.

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Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. · University of Colorado Health Sciences Center, Box C-272, 4200 E. Ninth Ave, Denver, CO 80262, USA. · Chest. · Pubmed #17565025 links to  free full text

Abstract: A consensus panel convened by the American College of Chest Physicians developed guidelines for the treatment of pulmonary arterial hypertension (PAH) that were published in 2004. Subsequently, several important clinical trials have been published, and new treatments have received regulatory approval. In addition, add-on and combination therapy are being explored, which promise to open new therapeutic avenues. This article, taking into consideration studies published prior to September 1, 2006, provides an update to the previously published guidelines. The original guidelines have been summarized, a discussion of new studies has been added, and the treatment algorithm has been revised to take into account recent developments in therapy. This update provides evidence-based treatment recommendations for physicians involved in the care of patients with PAH. Due to the complexity of the diagnostic evaluation required and the treatment options available, referral of patients with PAH to a specialized center continues to be strongly recommended.

McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, Ahearn G, Anonymous00039. · University of Michigan, 1500 East Medical Center Dr, Women's Hospital-Room L3119, Ann Arbor, MI 48109-0273, USA. · Chest. · Pubmed #15249497 links to  free full text

Abstract: 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.

Badesch DB, Abman SH, Ahearn GS, Barst RJ, McCrory DC, Simonneau G, McLaughlin VV, Anonymous00036. · University of Colorado Health Sciences Center, Denver, CO 80262, USA. · Chest. · Pubmed #15249494 links to  free full text

Abstract: 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.

McLaughlin VV, Channick R. · No affiliation provided · Am J Respir Crit Care Med. · Pubmed #17545455 links to  free full text

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McLaughlin VV. · No affiliation provided · Eur Heart J. · Pubmed #16459343 links to  free full text

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McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, Harrington RA, Anderson JL, Bates ER, Bridges CR, Eisenberg MJ, Ferrari VA, Grines CL, Hlatky MA, Jacobs AK, Kaul S, Lichtenberg RC, Lindner JR, Moliterno DJ, Mukherjee D, Pohost GM, Rosenson RS, Schofield RS, Shubrooks SJ, Stein JH, Tracy CM, Weitz HH, Wesley DJ, Anonymous00037. · No affiliation provided · Circulation. · Pubmed #19332472 No free full text.

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Han MK, McLaughlin VV, Criner GJ, Martinez FJ. · University of Michigan Health System, Ann Arbor, MI, USA. · Circulation. · Pubmed #18086941 links to  free full text

Abstract: The complex nature of interactions between the pulmonary and cardiovascular systems is becoming increasingly appreciated. Pulmonary vascular abnormalities are frequently present in patients with respiratory disorders, including chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, sarcoidosis, neuromuscular or chest wall disorders, and disorders of ventilatory control including sleep apnea syndromes and obesity hypoventilation syndrome. Pulmonary hypertension, classified as group III in the World Health Organization classification scheme for pulmonary hypertension, may result in severe right ventricular dysfunction caused by lung disease, also known as cor pulmonale. The development of cor pulmonale is generally associated with poorer prognosis and increased death. Systemic manifestations of lung disease, particularly obstructive disorders, are also particularly relevant because they are associated with increased cardiac death and impaired health status. This article will discuss the most common pulmonary diseases and disorders of ventilatory control that cause pulmonary vascular abnormalities and cor pulmonale, with particular concentration on how treatment of these diseases may affect the heart. In addition, the complex nature of cardiac and lung disease will also be explored, particularly with respect to the relationship between chronic obstructive pulmonary disease, systemic inflammation, atherosclerosis, and cardiovascular death, which is currently a very active focus of research.

McLaughlin VV, McGoon MD. · University of Michigan Health System, Ann Arbor, MI 48109-0273, USA. · Circulation. · Pubmed #17000921 links to  free full text

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McLaughlin VV, Rich S. · United Therapeutics. · Curr Probl Cardiol. · Pubmed #15494704 No free full text.

Abstract: 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.

McLaughlin VV. · Pulmonary Hypertension Program, Division of Cardiovascular Medicine, University of Michigan, Woman's RM. L3119, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0273, USA. · Cardiol Clin. · Pubmed #15302354 No free full text.

Abstract: 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.

Badesch DB, McLaughlin VV, Delcroix M, Vizza CD, Olschewski H, Sitbon O, Barst RJ. · University of Colorado Health Sciences Center, Denver, Colorado, USA. · J Am Coll Cardiol. · Pubmed #15194179 No free full text.

Abstract: 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.

Rich S, McLaughlin VV. · Rush Heart Institute Center for Pulmonary Heart Disease, Rush Medical College, Chicago, Ill, USA. · Circulation. · Pubmed #14597580 links to  free full text

Abstract: 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.

McLaughlin VV. · Rush-Presbyterian-St. Luke's Medical Centre, 1725 W Harrison Street, Suite 020, Chicago, IL 60612, USA. · Expert Opin Pharmacother. · Pubmed #11829729 No free full text.

Abstract: 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.

McLaughlin VV, Rich S. · Center for Pulmonary Heart Disease, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois, USA. · Crit Care Clin. · Pubmed #11450326 No free full text.

Abstract: Pulmonary hypertension has many causes and therapies. A meticulous evaluation is critical. Substantial advances in medical therapy have occurred over the past decade, and the future treatment of this syndrome is promising, with many new medications on the horizon.

McGoon MD, Frost AE, Oudiz RJ, Badesch DB, Galie N, Olschewski H, McLaughlin VV, Gerber MJ, Dufton C, Despain DJ, Rubin LJ. · Mayo Clinic, Rochester, MN 55905, USA. · Chest. · Pubmed #18812445 No free full text.

Abstract: BACKGROUND: Some endothelin receptor antagonists (ERAs) are associated with liver function test (LFT) result abnormalities. However, ambrisentan has an incidence of serum aminotransferase levels more than three times the upper limit of normal (ULN), similar to that observed in PAH patients who are not receiving ERAs. Because ambrisentan may provide benefits in PAH patients who have discontinued ERA therapy due to LFT abnormalities, we evaluated the safety and efficacy of ambrisentan in this patient population. METHODS: Patients who previously discontinued bosentan and/or sitaxsentan due to LFT abnormalities received ambrisentan, 2.5 mg qd, for 4 weeks followed by 5 mg/d for 8 weeks. The primary end point was the incidence of aminotransferase levels more than three times ULN considered by the investigator to be related to ambrisentan and resulting in drug discontinuation. Secondary end points included aminotransferase levels more than five times ULN requiring drug discontinuation and more than three times ULN requiring dose reduction, as well as changes in 6-min walk distance (6MWD), Borg dyspnea index, World Health Organization functional class, and Short Form-36 health survey score. Patients continued treatment beyond the 12-week end point with monthly monitoring of LFTs. RESULTS: Thirty-six patients who previously discontinued bosentan (n = 31), sitaxsentan (n = 2), or both (n = 3) were enrolled. At baseline, 69.4% of patients were receiving prostanoid and/or sildenafil therapy. No patient had an aminotransferase level more than three times ULN that required ambrisentan discontinuation. One patient had a transient aminotransferase level more than three times ULN that resolved following a temporary dose reduction. No additional aminotransferase levels more than three times ULN were observed with long-term treatment (median exposure, 102 weeks), despite dose increases to 10 mg qd in more than half of the patients. Significant improvements in 6MWD and other efficacy assessments were observed. CONCLUSIONS: Ambrisentan treatment may be an option for patients who have discontinued bosentan and/or sitaxsentan therapy due to LFT result abnormalities. Trial registration: Clinicaltrials.gov Identifier NCT00423592.

Gomberg-Maitland M, Huo D, Benza RL, McLaughlin VV, Tapson VF, Barst RJ. · Section of Cardiology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. · J Heart Lung Transplant. · Pubmed #17613405 No free full text.

Abstract: BACKGROUND: The 6-minute walk test (6MWT) is the current standard to assess exercise capacity in pulmonary arterial hypertension (PAH). We compared the Naughton-Balke treadmill test reported in exercise metabolic equivalents (METs) with the 6MWT to evaluate whether MET could be a useful tool to assess exercise capacity. METHODS: Serial 6MWTs followed by Naughton-Balke treadmill tests were performed in 47 PAH patients initiating a change in PAH therapy at baseline (i.e., Time 0) and Weeks 6, 12, 24 and 48; New York Heart Association (NYHA) functional class (FC) was also assessed. Hemodynamics data were recorded at baseline and Weeks 12 and 48. Treadmill time was converted to MET. Generalized estimating equation models, receiver-operating characteristic curves and fixed-effect linear models were utilized to create a model comparing 6MWT to MET. RESULTS: MET correlated with 6MWT (r = 0.62). Piecewise linear function described the relationship between 6MWT and MET. 6MWT and MET were both associated with FC (p < 0.001) with similar ability to discriminate FC. Changes in hemodynamics in response to a change in PAH therapy correlated with changes in both 6MWT and MET. In less sick patients (i.e., FC II), the changes in 6MWT were less pronounced than with MET. CONCLUSIONS: MET appears to be a reliable measure of exercise capacity in PAH, and correlates with 6MWT. MET can be used in clinical assessment and is helpful in demonstrating improvements in exercise capacity in less sick patients.

Tapson VF, McLaughlin VV, Gomberg-Maitland M, Widlitz AC, Krichman AD, Laliberte KJ, Zaccardelli DS, Barst RJ. · Duke University Medical Center, Durham, NC 27710, USA. · J Vasc Access. · Pubmed #17019662 No free full text.

Abstract: PURPOSE: Treprostinil is approved for the treatment of pulmonary arterial hypertension (PAH) via continuous intravenous (IV) infusion. Treprostinil's anti-platelet aggregation characteristics and stability at room temperature may allow for low infusion rates (0.1-0.2 mL/hr) using a miniaturized infusion pump. METHODS: A 12-week, multi-center, open-label study in 12 adult PAH patients, evaluated the feasibility and safety of low-flow IV treprostinil administration via the 407C miniaturized pump. Patients receiving IV treprostinil at a stable dose were transitioned from their current CADD-Legacy pump to the 407C and were assessed for adverse events including catheter occlusions, pump alarms, and efficacy (six minute walk distance (6MWD), Borg Dyspnea Score (BDS), NYHA functional class, and PAH signs/symptoms). All patients were also maintained on therapeutic doses of warfarin, heparin or low molecular weight heparin throughout the study. RESULTS: Baseline mean (+/-SD) 6MWD was 477 +/- 76 m (n = 9) with mean BDS of 2.1 +/- 1.2 (n = 9). Week 12 mean 6MWD and BDS were 500 +/- 92 m and 2.3 +/- 1.7, respectively (n = 9). Four patients discontinued the study prematurely (3 AEs and 1 consent withdrawn). Adverse events included headache, flushing, and nausea. Pump complications occurred in 5 of 12 patients, and although no catheter occlusions occurred in any patient during the 12-week study, further study is needed regarding pump complications. CONCLUSION: This study demonstrates that treprostinil can be administered intravenously at infusion rates as low as 0.1 mL/hr for 12 weeks without catheter occlusions. Further studies are warranted because the potential for adverse events is of some concern.

Tapson VF, Gomberg-Maitland M, McLaughlin VV, Benza RL, Widlitz AC, Krichman A, Barst RJ. · Division of Pulmonary and Critical Care Medicine, Room 351 Bell Building, Duke University Medical Center, Durham, NC 27710, USA. · Chest. · Pubmed #16537868 links to  free full text

Abstract: 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.

Gomberg-Maitland M, Tapson VF, Benza RL, McLaughlin VV, Krichman A, Widlitz AC, Barst RJ. · Pulmonary Hypertension Center, University of Chicago Hospitals, 5841 South Maryland Avenue, MC 2016, Chicago, IL 60637, USA. · Am J Respir Crit Care Med. · Pubmed #16151039 links to  free full text

Abstract: 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.

McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galiè N, Rainisio M, Simonneau G, Rubin LJ. · University of Michigan, 1500 East Medical Center Drive, Women's Hospital, Room L3119, Ann Arbor, MI, USA. · Eur Respir J. · Pubmed #15684287 links to  free full text

Abstract: Primary pulmonary hypertension (PPH) is a progressive disease with high mortality. Administration of i.v. epoprostenol has demonstrated improved exercise tolerance, haemodynamics, and survival. The orally active, dual endothelin receptor antagonist bosentan improves exercise endurance, haemodynamics, and functional class over the short term. To determine the effect of first-line bosentan therapy on survival, this study followed 169 patients with PPH treated with bosentan in two placebo-controlled trials and their extensions. Data on survival and alternative treatments were collected from September 1999 (start of the first placebo-controlled study) to December 31, 2002. Observed survival up to 36 months was reported as Kaplan-Meier estimates and compared with predicted survival as determined for each patient by the National Institutes of Health Registry formula. Kaplan-Meier survival estimates were 96% at 12 months and 89% at 24 months. In contrast, predicted survival was 69% and 57%, respectively. In addition, at the end of 12 and 24 months, 85% and 70% of patients, respectively, remained alive and on bosentan monotherapy. Factors that predicted a worse outcome included World Health Organization Functional Class IV and 6-min walk distance below the median (358 m) at baseline. First-line bosentan therapy was found to improve survival in patients with advanced primary pulmonary hypertension.

McLaughlin VV, Gaine SP, Barst RJ, Oudiz RJ, Bourge RC, Frost A, Robbins IM, Tapson VF, McGoon MD, Badesch DB, Sigman J, Roscigno R, Blackburn SD, Arneson C, Rubin LJ, Rich S, Anonymous00171. · Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA. · J Cardiovasc Pharmacol. · Pubmed #12548091 No free full text.

Abstract: 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.

McLaughlin VV, Shillington A, Rich S. · Rush-Presbyterian-St Luke's Medical Center, Department of Medicine, Section of Cardiology, Chicago, Ill 60612, USA. · Circulation. · Pubmed #12234951 links to  free full text

Abstract: 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.

McLaughlin VV, Badesch DB, Delcroix M, Fleming TR, Gaine SP, Galiè N, Gibbs JS, Kim NH, Oudiz RJ, Peacock A, Provencher S, Sitbon O, Tapson VF, Seeger W. · Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan 48109-0273, USA. · J Am Coll Cardiol. · Pubmed #19555863 No free full text.

Abstract: New and emerging therapies might provide benefit in patients with pulmonary arterial hypertension. Their efficacy and safety will be compared with existing combination therapies in randomized clinical trials. Appropriate end points for these trials need to be identified: these will include exercise testing, the composite end point of time to clinical worsening, and hemodynamic markers, including advanced imaging modalities and biomarkers. Quality-of-life questionnaires are useful and important secondary end points; pulmonary arterial hypertension-specific questionnaires are currently being developed. Advantages and disadvantages of various trial designs, including placebo-controlled monotherapy or add-on trials, noninferiority studies, and withdrawal trials are also discussed.

Barst RJ, Gibbs JS, Ghofrani HA, Hoeper MM, McLaughlin VV, Rubin LJ, Sitbon O, Tapson VF, Galiè N. · Columbia University, New York, New York 10583, USA. · J Am Coll Cardiol. · Pubmed #19555861 No free full text.

Abstract: Uncontrolled and controlled clinical trials with different compounds and procedures are reviewed to define the risk-benefit profiles for therapeutic options in pulmonary arterial hypertension (PAH). A grading system for the level of evidence of treatments based on the controlled clinical trials performed with each compound is used to propose an evidence-based treatment algorithm. The algorithm includes drugs approved by regulatory agencies for the treatment of PAH and/or drugs available for other indications. The different treatments have been evaluated mainly in idiopathic PAH, heritable PAH, and in PAH associated with the scleroderma spectrum of diseases or with anorexigen use. Extrapolation of these recommendations to other PAH subgroups should be done with caution. Oral anticoagulation is proposed for most patients; diuretic treatment and supplemental oxygen are indicated in cases of fluid retention and hypoxemia, respectively. High doses of calcium-channel blockers are indicated only in the minority of patients who respond to acute vasoreactivity testing. Nonresponders to acute vasoreactivity testing or responders who remain in World Health Organization (WHO) functional class III, should be considered candidates for treatment with either an oral phosphodiesterase-5 inhibitor or an oral endothelin-receptor antagonist. Continuous intravenous administration of epoprostenol remains the treatment of choice in WHO functional class IV patients. Combination therapy is recommended for patients treated with PAH monotherapy who remain in WHO functional class III. Atrial septostomy and lung transplantation are indicated for refractory patients or where medical treatment is unavailable.