Hypertension: Tapson VF

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.

This publication has no abstract.

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.

This publication has no abstract.

Piovella F, D'Armini AM, Barone M, Tapson VF. · IRCCS Policlinico San Matteo, Pavia, Italy. · Semin Thromb Hemost. · Pubmed #17171599 No free full text.

Abstract: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease that results from obstruction of the major pulmonary arteries by incompletely resolved or organized pulmonary emboli that have become incorporated into the pulmonary artery wall, eventually causing an increase in pulmonary vascular resistance. From 0.1 to 4.0% of patients recovering from acute pulmonary embolism develop CTEPH. Without intervention, CTEPH is a progressive and lethal disease for which there is no effective medical therapy. Pulmonary endarterectomy (PEA) is the treatment of choice. Careful pre- and postoperative management is essential for a successful outcome after PEA. Lung transplantation is indicated only in few cases when PEA is not feasible. In 1994, we started a program (in Pavia, Italy) in which members of a multidisciplinary team work closely with the aim of increasing experience in the challenging problems these patients present in the evaluative, surgical, and postoperative phases of their care. To date, 134 PEAs have been performed. Preoperatively, New York Heart Association (NYHA) class distribution was three class II, 56 class III, and 75 class IV patients, respectively; mean pulmonary artery pressure and pulmonary vascular resistance values were 47 +/- 13 mm Hg and 1149 +/- 535 dyn/s/cm (-5), respectively. The overall operative mortality has been 9.7% (4.5% in 2004). Survival at 3-month, 1-year, and 3-year follow-up was 89.5 +/- 2.6%, 87.8 +/- 2.9%, and 83.3 +/- 3.5%, respectively; this last rate was unchanged up to 10 years. After PEA, mean pulmonary artery pressure and pulmonary vascular resistance values were 25 +/- 9 mm Hg and 322 +/- 229 dyn/s/cm (-5), respectively, and these results were stable over time. At the 3-year follow-up, 94% of patients were in NYHA class I or II and were being treated with oral anticoagulants only.

Tapson VF, Humbert M. · Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, NC 27710, USA. · Proc Am Thorac Soc. · Pubmed #16963534 links to  free full text

Abstract: The incidence and prevalence of chronic thromboembolic pulmonary hypertension (CTEPH) are yet to be accurately determined and may be significantly underestimated. Historically, the occurrence of CTEPH in patients diagnosed with acute pulmonary embolism (PE) has been considered rare. Data from autopsy studies estimated the incidence of CTEPH at 1-3% overall and at 0.1-0.5% in patients surviving acute PE. Data indicate that each year in the United States, approximately 600,000 individuals suffer an acute pulmonary embolic event and that the annual number of new CTEPH cases in the United States is between 500 and 2,500. This may underestimate the true frequency of CTEPH because the disease is often misdiagnosed due to nonspecific symptoms and variable disease course. A monocenter, prospective, longitudinal study assessing symptomatic CTEPH in patients with acute PE but without prior venous thromboembolism recently estimated the cumulative incidence of CTEPH to be 1.0% 6 mo after PE, 3.1% after 1 yr, and 3.8% after 2 yr; overall post-PE incidence was approximately 3%. Further studies are needed to better define the true rate of CTEPH. Acute embolic events can occur without symptoms, and symptomatic PE is often overlooked or misdiagnosed in practice. CTEPH is often identified during diagnostic work-up in patients with unexplained pulmonary hypertension, many of whom lack medical history suggesting previous PE. In a recent study in 142 consecutive patients with CTEPH, 90 (63%) had no previous history of symptomatic venous thromboembolism. Further prospective epidemiologic studies are needed to better define the incidence and prevalence of CTEPH.

Hargett CW, Tapson VF. · Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Durham, NC 27710, USA. · Semin Respir Crit Care Med. · Pubmed #16121315 No free full text.

Abstract: Brain or B-type natriuretic peptide (BNP) is one of the new biomarkers employed within the last decade to help clarify difficult cardiovascular problems. Plasma BNP is elevated in cardiac ventricular dysfunction and plays a key role in protecting the body from volume overload by maintaining renal function and sodium balance. Studies in patients with pulmonary arterial hypertension (PAH) have demonstrated that plasma BNP levels are raised proportionally to the extent of right ventricular (RV) dysfunction. There is growing evidence that BNP may be a potential biomarker for PAH in screening for occult disease, diagnostic evaluation, prognosis, and estimating a response to therapy. Additionally, augmentation of the natriuretic peptide system through exogenous administration of BNP or by preventing its degradation may be a promising option for the management of decompensated RV failure. Because plasma BNP levels rise in a variety of cardiopulmonary conditions and are affected by several physiological factors, BNP interpretation must not occur in isolation but rather within the context of good clinical judgment.

Hoeper MM, Oudiz RJ, Peacock A, Tapson VF, Haworth SG, Frost AE, Torbicki A. · Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany. · J Am Coll Cardiol. · Pubmed #15194178 No free full text.

Abstract: To date, randomized controlled clinical trials performed in pulmonary arterial hypertension (PAH) have been relatively short-term studies involving mainly patients with advanced disease. The primary end points in these trials have addressed exercise capacity, usually by using the 6-min walk test. Although this approach is still warranted in future trials assessing new treatments, it is likely that the focus will shift toward trials of longer duration, involving patients with less advanced disease, and that different drugs and drug-combination regimens will be compared. In such trials, it is possible that a composite of markers indicating clinical deterioration (e.g., hospitalization for right heart failure, the requirement for the introduction of an alternative treatment, and predefined indicators of worsening exercise tolerance) may be more useful as primary end points. Quality of life will become a very important issue; however, appropriate quality-of-life questionnaires for PAH have yet to be developed. In addition, hemodynamics will likely remain valuable as secondary end points, but future clinical trials should include hemodynamics obtained both during exercise and at rest. Finally, cardiopulmonary exercise testing, echocardiographic studies, and biochemical parameters, such as brain natriuretic peptide or troponin T, may also prove useful as secondary end points in the future.

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.

Frost AE, Langleben D, Oudiz R, Hill N, Horn E, McLaughlin V, Robbins IM, Shapiro S, Tapson VF, Zwicke D, DeMarco T, Schilz R, Rubenfire M, Barst RJ. · Baylor College of Medicine, Houston, TX, United States. · Vascul Pharmacol. · Pubmed #15890561 No free full text.

Abstract: BACKGROUND: PAH trials traditionally use 6MW as the primary endpoint. Concerns regarding a "ceiling effect" masking efficacy have led to exclusion of patients with milder disease from most trials (BL 6MW>450 m). STRIDE I evaluated the selective endothelin A receptor antagonist, sitaxsentan (SITAX), in a 12-week randomized, double-blind, trial (178 patients) employing placebo (PBO), 100 mg or 300 mg SITAX orally once daily in PAH and included patients with NYHA class II, congenital heart disease and a BL 6MW>450 m, groups often excluded from previous trials. METHODS: We analyzed 6MW effects For All Pts (intention-to treat) and those meeting Traditional enrollment criteria, defined as patients with NYHA class III or IV and 6MW< or =450 m at BL with idiopathic PAH or PAH related to connective tissue disease. The 100 mg and 300 mg SITAX arms are pooled based on similar treatment effects on 6MW. CONCLUSION: Existence of a "ceiling effect" is supported by these data. The magnitude of the treatment effect and statistical power when using 6MW as the endpoint. Comparisons between PAH trials that do not adjust for the effects of differing enrollment criteria require caution.

Barst RJ, Langleben D, Frost A, Horn EM, Oudiz R, Shapiro S, McLaughlin V, Hill N, Tapson VF, Robbins IM, Zwicke D, Duncan B, Dixon RA, Frumkin LR, Anonymous00017. · Columbia University College of Physicians & Surgeons, 3959 Broadway, BHN 2-255, New York, NY 10032-1551, USA. · Am J Respir Crit Care Med. · Pubmed #14630619 links to  free full text

Abstract: Sitaxsentan may benefit patients with pulmonary arterial hypertension by blocking the vasoconstrictor effects of endothelin-A while maintaining the vasodilator/clearance functions of endothelin-B receptors. Patients with pulmonary arterial hypertension that was idiopathic, related to connective tissue disease or congenital heart disease, were randomized to receive placebo (n = 60), sitaxsentan 100 mg (n = 55), or sitaxsentan 300 mg (n = 63) orally once daily for 12 weeks. The primary endpoint was change in peak VO(2) at Week 12. Secondary endpoints included 6-minute walk, New York Heart Association class, VO(2) at anaerobic threshold, VE per carbon dioxide production at anaerobic threshold, hemodynamics, quality of life, and time to clinical worsening. Although the 300-mg group increased peak VO(2) compared with placebo (+3.1%, p < 0.01), none of the other endpoints derived from cardiopulmonary exercise testing were met. However, both the 100-mg dose and the 300-mg dose, compared with placebo, increased 6-minute walk distance (100 mg: +35 m, p < 0.01; 300 mg: +33 m, p < 0.01); functional class, cardiac index, and pulmonary vascular resistance also improved (p < 0.02 for each parameter at both doses). The incidence of elevated aminotransferase values (> three times normal) was 3% for the placebo group, 0% for the 100-mg group, and 10% for the 300-mg group.

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.

Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch DB, Roux S, Rainisio M, Bodin F, Rubin LJ. · Division of Pulmonary and Critical Care Medicine, University of California, San Diego, CA, USA. · Lancet. · Pubmed #11597664 No free full text.

Abstract: BACKGROUND: Endothelin 1, a powerful endogenous vasoconstrictor and mitogen, might be a cause of pulmonary hypertension. We describe the efficacy and safety of bosentan, a dual endothelin-receptor antagonist that can be taken orally, in patients with severe pulmonary hypertension. METHODS: In this double-blind, placebo-controlled study, 32 patients with pulmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62.5mg taken twice daily for 4 weeks then 125 mg twice daily) or placebo for a minimum of 12 weeks. The primary endpoint was change in exercise capacity. Secondary endpoints included changes in cardiopulmonary haemodynamics, Borg dyspnoea index, WHO functional class, and withdrawal due to clinical worsening. Analysis was by intention to treat. FINDINGS: In patients given bosentan, the distance walked in 6 min improved by 70 m at 12 weeks compared with baseline, whereas it worsened by 6 m in those on placebo (difference 76 m [95% CI 12-139], p=0.021). The improvement was maintained for at least 20 weeks. The cardiac index was 1.0 L min(-1) m(-2) (95% CI 0.6-1.4, p<0.0001) greater in patients given bosentan than in those given placebo. Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5) with bosentan, but increased by 191 dyn s cm(-5) with placebo (difference -415 [-608 to -221], p=0.0002). Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class. All three withdrawals from clinical worsening were in the placebo group (p=0.033). The number and nature of adverse events did not differ between the two groups. INTERPRETATION: Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.

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.

Girgis RE, Frost AE, Hill NS, Horn EM, Langleben D, McLaughlin VV, Oudiz RJ, Robbins IM, Seibold JR, Shapiro S, Tapson VF, Barst RJ. · Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA. · Ann Rheum Dis. · Pubmed #17472992 No free full text.

Abstract: INTRODUCTION: Endothelin receptor antagonism has become an important component in the treatment of pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD). The purpose of this study was to analyse the safety and effectiveness of sitaxsentan, a selective antagonist of the ET(A) receptor, in a cohort of patients with PAH and CTD. Short-term clinical and haemodynamic effects and longer-term follow-up data are presented. METHODS: A post hoc subgroup analysis was performed on 42 patients who had PAH associated with CTD, out of a group of 178 patients enrolled in a 12-week, double-blind, randomised clinical trial of sitaxsentan versus placebo. Data from 33 patients assigned to sitaxsentan 100 mg or 300 mg daily were pooled and compared with nine placebo-treated patients. There were 41 patients entered into the blinded extension study, in which all patients received either 100 mg or 300 mg sitaxsentan once daily. RESULTS: Patients treated with sitaxsentan had a mean (SD) increase in 6 minute walk distance of 20 (5) m from baseline to week 12 (p = 0.037), whereas the placebo group had a decrease of 38 (84) m, resulting in a placebo-subtracted treatment effect of 58 m (p = 0.027). Parallel improvements in quality of life and haemodynamics were also observed. No patient discontinued their drug during the 12-week trial. In the blinded extension study (median treatment duration 26 weeks), more patients were in functional class I-II than in III-IV (p<0.001) at the end of the study compared with the start of active therapy. Elevation of hepatic transaminase levels occurred in two patients. CONCLUSIONS: Sitaxsentan appears to be efficacious in patients with PAH associated with CTD.

McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, Badesch DB, Barst RJ, Hsu HH, Rubin LJ. · The University of Michigan Health System, Ann Arbor, Michigan, USA. · Am J Respir Crit Care Med. · Pubmed #16946127 links to  free full text

Abstract: 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.

Joffe HV, Kucher N, Tapson VF, Goldhaber SZ. · Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. · Thromb Haemost. · Pubmed #16363241 No free full text.

Abstract: Factors that predispose to thrombus propagation from the femoropopliteal veins to the pelvic veins are poorly understood. Our goal was to determine whether there are characteristics that identify patients with massive deep vein thrombosis (DVT). We compared the 122 (2.5%) patients presenting with massive DVT (pelvic plus lower-extremity DVT) to the 4,674 (97.5%) patients with isolated lower-extremity DVT from a prospective United States multicenter DVT registry. Patients with massive DVT were younger (59.4+/-18.9 years vs. 64.3+/-16.8 years; p<0.01), less likely to have hypertension (40% vs. 51%; p=0.02), and more likely to smoke (21% vs. 13%; p=0.02) and have ongoing radiation therapy (7% vs. 3%; p=0.02). The massive DVT group more commonly presented with extremity edema (80% vs. 69%; p<0.01) and erythema (21% vs. 12%; p<0.01) than the isolated lower-extremity DVT group. However, after multivariable logistic regression analysis, extremity erythema (adjusted odds ratio 1.86; 95% CI 1.13-3.04) was the only independent sequela of massive DVT and younger age (adjusted odds ratio 1.17 per decreasing decade of age; 95% confidence interval: 1.02-1.34) was the only independent predictor of massive DVT. Thrombus propagation from the femoropopliteal system cannot be reliably predicted using demographic or clinical characteristics.

Waldo AL, Becker RC, Tapson VF, Colgan KJ, Anonymous00004. · Division of Cardiology, Case Western University/University Hospitals of Cleveland, Cleveland, Ohio 44106-5038, USA. · J Am Coll Cardiol. · Pubmed #16256877 No free full text.

Abstract: OBJECTIVES: The purpose of this study was to determine both treatment gaps and predictors of warfarin use in atrial fibrillation (AF) patients enrolled in a national multicenter study. BACKGROUND: The National Anticoagulation Benchmark Outcomes Report (NABOR) is a performance improvement program designed to benchmark anticoagulation prophylaxis, treatment, and outcomes among participating hospitals. METHODS: A retrospective cohort study of inpatients was performed at 21 teaching, 13 community, and 4 Veterans Administration hospitals in the U.S. Patients with an ICD-9-CM code for AF (427.31) were randomly selected. RESULTS: Among the 945 patients studied, the mean age was 71.5 (+/- 13.5) years; 43% were >75 years of age, 54.5% were men, and 67% had a history of hypertension. Most (86%) had factors that stratified them as at high risk of stroke, and only 55% of those received warfarin. Neither warfarin nor aspirin were prescribed in 21% of high-risk patients, including 18% of those with a previous stroke, transient ischemic attack, or systemic embolic event. Age >80 years (p = 0.008) and perceived bleeding risk (p = 0.022) were negative predictors of warfarin use. Persistent/permanent AF (p < 0.001) and history of stroke, transient ischemic attack, or systemic embolus (p = 0.014) were positive predictors of warfarin use, whereas high-risk stratification was not. CONCLUSIONS: This study confirms the under-use of warfarin, but also adds to published reports in several regards. It showed that risk stratification, the guidepost for treatment in international guidelines, had little effect on warfarin use, and that age >80 years and AF classification (permanent/persistent) are factors that influence warfarin use.

Krasuski RA, Wang A, Harrison JK, Tapson VF, Bashore TM. · Division of Cardiology, Wilford Hall Medical Center, Lackland AFB, TX 78236-5300, USA. · Am Heart J. · Pubmed #16209974 No free full text.

Abstract: BACKGROUND: Assessment of pulmonary vasodilator responsiveness is important in determining the prognosis and management of patients with pulmonary hypertension. Many patients, however, are already on vasodilators at the time of testing. It is unclear if these agents should be temporarily discontinued to improve the sensitivity of testing. METHODS: We examined the hemodynamic effects of nitric oxide (NO) inhalation in 60 patients with pulmonary arterial hypertension. Thirty-one of these patients were receiving medications with vasodilating properties. Vasodilator testing was performed with invasive measurement of pressure of the right side of the heart at baseline and during inhalation of 40 ppm NO. RESULTS: No significant demographic differences were seen between patients receiving and not receiving vasodilators. Similar reductions in mean pulmonary artery pressure (19 +/- 12% vs 20 +/- 12%, P = .734) and pulmonary vascular resistance (31 +/- 18 vs 32 +/- 16, P = .967) were seen in patients receiving and not receiving vasodilators. Using the definition of positive vasodilator response (> or = 20% drop in mean pulmonary artery pressure), 55% (17/31) of patients in the baseline vasodilator group had a positive response compared with 62% (18/29) of the patients not on vasodilators (P = .570). CONCLUSIONS: Concurrent use of oral vasodilators does not appear to mask a significant response to inhaled NO on the pulmonary vasculature. Therefore, routine discontinuation of pulmonary vasodilators is likely unnecessary before vasodilator testing in patients with pulmonary arterial hypertension.

McMahon TJ, Ahearn GS, Moya MP, Gow AJ, Huang YC, Luchsinger BP, Nudelman R, Yan Y, Krichman AD, Bashore TM, Califf RM, Singel DJ, Piantadosi CA, Tapson VF, Stamler JS. · Department of Medicine and Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. · Proc Natl Acad Sci U S A. · Pubmed #16203976 links to  free full text

Abstract: The mechanism by which hypoxia [low partial pressure of O(2) (pO(2))] elicits signaling to regulate pulmonary arterial pressure is incompletely understood. We considered the possibility that, in addition to its effects on smooth muscle, hypoxia may influence pulmonary vascular tone through an effect on RBCs. We report that exposure of native RBCs to sustained hypoxia is accompanied by a buildup of heme iron-nitrosyl (FeNO) species that are deficient in pO(2-)governed intramolecular transfer of NO to cysteine thiol, yielding a deficiency in the vasodilator S-nitrosohemoglobin (SNO-Hb). S-nitrosothiol (SNO)-deficient RBCs produce impaired vasodilator responses in vitro and exaggerated pulmonary vasoconstrictor responses in vivo and are defective in oxygenating the blood. RBCs from hypoxemic patients with elevated pulmonary arterial pressure (PAP) exhibit a similar FeNO/SNO imbalance and are thus deficient in pO(2)-coupled vasoregulation. Chemical restoration of SNO-Hb levels in both animals and patients restores the vasodilator activity of RBCs, and this activity is associated with improved oxygenation and lower PAPs.

Myers SA, Ahearn GS, Angelica Selim M, Tapson VF. · Division of Dermatology, Department of Medicine, Duke University Medical Center, Durham, NC 27705, USA. · J Am Acad Dermatol. · Pubmed #15243533 No free full text.

Abstract: Pulmonary arterial hypertension (PAH) is a rare debilitating disease characterized by an increase in pulmonary vascular resistance and progressive right ventricular failure. PAH may be primary or associated with other conditions such as collagen vascular disease, portal hypertension, and HIV. Intravenous epoprostenol improves the survival, exercise tolerance, hemodynamics, and quality of life in patients with PAH and is believed to work through multiple pathways including vasodilation, opposition of smooth-muscle hypertrophy, and inhibition of platelet aggregation. Common dose-limiting side effects are flushing, jaw pain, arthralgias, myalgias, and headache, which are attributed to the vasodilatory effects of epoprostenol. In clinical practice, patients often develop persistent rash that is distinct from the flushing associated with epoprostenol. The specific findings both on physical examination and on dermatopathology have not, however, been well described. This report describes the cutaneous and dermatopathologic findings of 12 patients who developed persistent rash while receiving long-term prostacyclin for PAH.

Goldhaber SZ, Tapson VF, Anonymous00037. · the Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · Am J Cardiol. · Pubmed #14715365 No free full text.

Abstract: We enrolled 5,451 patients with ultrasound-confirmed deep vein thrombosis (DVT), including 2,892 women and 2,559 men, from 183 United States sites in our prospective registry. The 5 most frequent co-morbidities were hypertension (50%), surgery within 3 months (38%), immobility within 30 days (34%), cancer (32%), and obesity (27%). Of the 2,726 patients who had their DVT diagnosed while in the hospital, only 1,147 (42%) received prophylaxis within 30 days before diagnosis.

Sitbon O, Badesch DB, Channick RN, Frost A, Robbins IM, Simonneau G, Tapson VF, Rubin LJ. · Service de Pneumologie Réanimation Respiratoire, Hôpital Antoine Béclère, 157, Avenue de la Porte Trivaux, F-92141 Clamart Cedex, France. · Chest. · Pubmed #12853530 links to  free full text

Abstract: STUDY OBJECTIVES: We report on the long-term safety and efficacy of bosentan treatment in patients with pulmonary arterial hypertension (PAH). BACKGROUND: In a preceding study, bosentan was well tolerated and significantly improved the exercise capacity and hemodynamics of patients with PAH after 12 weeks of treatment. DESIGN: The present study was an open-label extension to the preceding double-blind, placebo-controlled study of 32 patients with PAH (primary or associated with scleroderma) who received bosentan or placebo at 125 mg bid for 3 to 7 months. PATIENTS: Twenty-nine of the original 32 patients received bosentan for an additional year (62.5 mg bid for 4 weeks and then 125 mg bid). INTERVENTIONS: Study end points included long-term safety, 6-min walk distance at week 4, modified New York Heart Association (NYHA) functional class of PAH at month 12, and the occurrence of withdrawal due to clinical worsening. Additional exploratory analyses included a walk test at month 6 for 19 patients and hemodynamic assessment at month 12 for 11 patients. RESULTS: At month 6, assessed patients continuing bosentan treatment maintained the improvement in walk distance observed at the end of the previous study (mean +/- SEM, 60 +/- 11 m), and patients starting bosentan treatment improved their walk distance by 45 +/- 13 m. Long-term treatment with bosentan for > 1 year was associated with an improvement in hemodynamic parameters and modified NYHA functional class. Overall, bosentan treatment was well tolerated. No patient underwent transplantation or died. CONCLUSIONS: Long-term treatment with bosentan is safe and has sustained benefits on exercise capacity and hemodynamics in patients with PAH.