Applying Rasch analysis to evaluate measurement equivalence of different administration formats of the Activity Limitation scale of the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR).

BACKGROUND: Electronic formats of patient-reported outcome (PRO) measures are now routinely used in clinical research studies. When changing from a validated paper and pen to electronic administration it is necessary to establish their equivalence. This study reports on the value of Rasch analysis in this process. METHODS: Three groups of US pulmonary hypertension (PH) patients participated. The first completed an electronic version of the CAMPHOR Activity Limitation scale (e-sample) and this was compared with two pen and paper administrated samples (pp1 and pp2). The three databases were combined and analysed for fit to the Rasch model. Equivalence was evaluated by differential item functioning (DIF) analyses. RESULTS: The three datasets were matched randomly in terms of sample size (n = 147). Mean age (years) and percentage of male respondents were as follows: e-sample (51.7, 16.0 %); pp1 (50.0, 14.0 %); pp2 (55.5, 40.4 %). The combined dataset achieved fit to the Rasch model. Two items showed evidence of borderline DIF. Further analyses showed the inclusion of these items had little impact on Rasch estimates indicating the DIF identified was unimportant. CONCLUSIONS: Differences between the performance of the electronic and pen and paper administrations of the CAMPHOR Activity Limitation scale were minor. The results were successful in showing how the Rasch model can be used to determine the equivalence of alternative formats of PRO measures.

Pulmonary hypertension and interstitial lung disease within PHAROS: impact of extent of fibrosis and pulmonary physiology on cardiac haemodynamic parameters.

OBJECTIVES: We sought to examine the relationship between measures of ILD severity and PH in patients with SSc. METHODS: We identified 55 subjects from 12 PHAROS sites with RHC-proven PH and HRCT evidence of ILD. Subjects with PH due to left heart disease were excluded. Baseline HRCT scans were scored by a standardised system that graded severity of ILD. Summary statistics were generated for baseline characteristics. Spearman correlation and linear regression were used to examine relationships between ILD and PH severity variables. RESULTS: The majority of subjects were white women; nearly half had limited cutaneous SSc. Most subjects were New York Heart Association functional class II or III. Pulmonary function testing revealed moderate restriction (mean FVC 64.3 ± 17.2% predicted) with severe reduction in diffusing capacity (mean DLco 34.2 ± 13.3% predicted). RHC demonstrated mild to moderate PH (mean PAP 35 ± 9 mmHg, mean PVR 5.1 ± 3.7 WU). There was no correlation between severity of ILD (by either HRCT or PFT) and cardiac haemodynamic parameters of PH. CONCLUSIONS: No association between severity of ILD and cardiac haemodynamic profiles were identified in this cohort. We believe this underscores the complex nature of PH and ILD in individuals with SSc. We do suspect that some individuals with SSc-ILD will also have concomitant pulmonary vascular disease but simple assessments to grade severity of ILD - by PFT or HRCT estimates of ILD extent - are likely not enough to reliably distinguish between PAH versus PH-ILD. Further research into how to distinguish and manage these subsets is warranted.

The management of pregnancy and pregnancy-related medical conditions in pulmonary arterial hypertension patients.

Pulmonary arterial hypertension (PAH) is a complex disorder in which pulmonary arterial obstruction leads to elevated pulmonary arterial resistance and right ventricular failure. Normal physiologic changes that occur during pregnancy and immediately postpartum may produce fatal consequence in PAH patients. Pregnancy in patients with PAH has a high maternal mortality, estimated at 30-56%. Contemporary estimates of mortality are better but still prohibitively high. Current guidelines recommend that pregnancy be avoided or terminated early in women with PAH. Some patients, despite counselling by their physician, choose to continue with their pregnancy. In addition, some women first present with PAH during pregnancy leading to complex management issues in a high-risk patient. PAH-specific therapies may allow patients to better tolerate pregnancy. These patients should be treated by experienced physicians at tertiary care centres. This review article will focus on the management of the pregnant PAH patient and the preventative options available for this high-risk cohort.

A dosing/cross-development study of the multikinase inhibitor sorafenib in patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) and cancer share elements of pathophysiology. This provides an opportunity for the cross-development of anticancer agents that can be used in improving PAH care. The adaptation of new drugs across these disease populations warrants a structured approach. This study was a 16-week, phase Ib, single-center, open-label trial of the multikinase/angiogenesis inhibitor sorafenib. In order to assess the safety of sorafenib in PAH, patients with advanced but stable disease on parenteral prostanoids (with or without oral sildenafil) were initiated on treatment at the lowest active dosage administered to cancer patients: 200 mg daily. Patients underwent weekly clinical evaluations and monthly functional testing and dose escalations to a final dosage of 400 mg twice daily. Among 12 patients (10 of them women), sorafenib was well tolerated at 200 mg twice daily. The most common adverse events were moderate skin reactions on the hands and feet and alopecia. Our conclusion was therefore that this is a tolerable dosing regimen for testing the therapeutic activity of sorafenib in PAH patients.

Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation.

The aim of the present study was to determine contemporary survival in pulmonary arterial hypertension (PAH), and to investigate whether or not the National Institutes of Health (NIH) equation remains an accurate predictor of survival. In 576 patients with PAH referred during 1991-2007, observed survival was described using the Kaplan-Meier method. In patients with idiopathic, familial and anorexigen-associated PAH (n = 247), observed versus NIH equation predicted survival was compared. A new survival prediction equation was developed using exponential regression analysis. The observed 1-, 3- and 5-yr survival in the total cohort were 86, 69 and 61%, respectively. In patients with idiopathic, familial and anorexigen-associated PAH, the observed 1-, 3- and 5-yr survival (92, 75 and 66%, respectively) were significantly higher than the predicted survival (65, 43 and 32%, respectively). The new equation (P(t) = e(-A(x,y,z)t), where P(t) is probability of survival, t the time interval in years, A(x,y,z) = e((-1.270-0.0148x+0.0402y-0.361z)), x the mean pulmonary artery pressure, y the mean right atrial pressure and z the cardiac index) performed well when applied to published contemporary studies of survival in PAH. Contemporary survival in the PAH cohort was better than that predicted by the NIH registry equation. The NIH equation underestimated survival in idiopathic, familial and anorexigen-associated PAH. Once prospectively validated, the new equation may be used to determine prognosis.

Prostacyclin therapies for the treatment of pulmonary arterial hypertension.

Prostacyclin and its analogues (prostanoids) are potent vasodilators and possess antithrombotic, antiproliferative and anti-inflammatory properties. Pulmonary hypertension (PH) is associated with vasoconstriction, thrombosis and proliferation, and the lack of endogenous prostacyclin may considerably contribute to this condition. This supports a strong rationale for prostanoid use as therapy for this disease. The first experiences of prostanoid therapy in PH patients were published in 1980. Epoprostenol, a synthetic analogue of prostacyclin, and the chemically stable analogues iloprost, beraprost and treprostinil were tested in randomised controlled trials. The biological actions are mainly mediated by activation of specific receptors of the target cells; however, new data suggest effects on additional intracellular pathways. In the USA and some European countries, intravenous infusion of epoprostenol and treprostinil, as well as subcutaneous infusion of treprostinil and inhalation of iloprost, have been approved for therapy of pulmonary arterial hypertension. Iloprost infusion and beraprost tablets have been approved in few other countries. Ongoing clinical studies investigate oral treprostinil, inhaled treprostinil and the combination of inhaled iloprost and sildenafil in pulmonary arterial hypertension. Combination of other targeted therapies with prostanoids appears to be effective and safe. After 25 yrs of continued knowledge, prostanoids remain a mainstay in the treatment of pulmonary arterial hypertension.

A USA-based registry for pulmonary arterial hypertension: 1982-2006.

The aim of this study was to define the epidemiology of World Health Organization (WHO) Group I pulmonary arterial hypertension (PAH) in a large referral centre in the USA. The Pulmonary Hypertension Connection registry, initiated in 2004, evaluated all patients in a single USA practice from 1982-2006. For comparison, the authors divided the group by incident versus prevalent cohorts, aetiology and by treatment era. In total, 578 patients (77% female) aged 48+/-14 yrs were entered. Of these, 80% had class III or IV symptoms. Over time, connective tissue disease-associated PAH increased, while referrals for HIV remained low. One-third of patients were referred on calcium channel blocker therapy even though only 4.6% had an acute response to vasodilator challenge. When compared by treatment era, there were no differences in the severity of PAH. However, survival had improved over time, with a 1-yr survival of 85% in the incident cohort. In the USA, pulmonary arterial hypertension patients are still referred to tertiary centres too late. Referral of connective tissue disease is increasing, while referral of HIV remains low. Inappropriate calcium channel blocker treatment is common. Survival rates have increased but remain low suggesting that prognosis is improving but PAH is still a progressive, fatal disease.

Delivery of intravenous treprostinil at low infusion rates using a miniaturized infusion pump in patients with pulmonary arterial hypertension.

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.

Treatment of congestive heart failure: guidelines for the primary care physician and the heart failure specialist.

During the past 10 years, the philosophy of heart failure treatment has evolved from symptom control to a combined prevention and symptom-management strategy. Recent clinical trials have proved that early detection can delay progression. Treatment of asymptomatic left ventricular dysfunction is as important as treatment of symptomatic disease. The purpose of this review is to simplify recent guidelines for pharmacological management of chronic systolic heart failure for the primary care physician and the heart failure specialist. Early recognition and prevention therapies, combined with lifestyle modification, are essential in the treatment of heart failure. Therapy with angiotensin-converting enzyme inhibitors, beta-blockers, and diuretics is now standard. Digoxin is added to improve clinical symptoms, especially in patients with atrial fibrillation. Aldosterone antagonists may be recommended in select patients with stable New York Heart Association class III or IV heart failure. If angiotensin-converting enzyme inhibitors are not tolerated, angiotensin receptor blockers, hydralazine hydrochloride, and isosorbide dinitrate are recommended. The data on antiarrhythmic and anticoagulation therapies are inconclusive.

Differences between male and female patients with regard to baseline demographics and clinical outcomes in the Asymptomatic Cardiac Ischemia Pilot (ACIP) Trial.

BACKGROUND: Coronary artery disease (CAD) is a common problem in men and women; however, men and women with similar clinical presentations of myocardial ischemia may receive different revascularization treatments. HYPOTHESIS: Using the data base of the Asymptomatic Cardiac Ischemia Pilot (ACIP) trial, this study was undertaken to compare by gender the baseline demographic data and the clinical outcome results in patients randomized to various treatments in the ACIP study. METHODS: This randomized trial compared three treatment regimens [pharmacologic management of angina, pharmacologic management of angina and ambulatory electrocardiographic (ECG) evidence of ischemia, and revascularization--that is, angioplasty and coronary artery bypass surgery], in patients with known CAD, positive stress ECG tests, and ECG evidence of ischemia during 48 h ambulatory monitoring. In all, 558 patients were randomized, 79 of whom were women (mean age: men 61.6 years, women 60.6 years) Ambulatory ECG evidence of ischemia, clinical events, that is, death, myocardial infarction, hospital admission for coronary events, and exercise performance were monitored. RESULTS: Although of the same age as men at baseline, women had a higher prevalence of hypertension and diabetes. Women had less severe CAD by angiography and higher left ventricular ejection fractions. Men had longer exercise tolerance times on the treadmill. However, men and women had similar numbers and duration of ambulatory ECG ischemic abnormalities. Regarding revascularization, men more commonly underwent coronary artery bypass surgery (p = 0.025) while women underwent percutaneous transluminal coronary angioplasty more frequently (p = 0.10). Clinical outcomes were comparable in men and women, although the numbers of events were relatively small. CONCLUSIONS: Men and women of comparable age manifest CAD with similar ischemic ECG abnormalities seen on both exercise tolerance and ambulatory ECG examinations. In ACIP, women tended to have more risk factors for CAD and less severity in anatomical disease, which may explain why women are less likely than men to have coronary bypass surgery.

Thyroid hormone and cardiovascular disease.

Thyroid hormone directly affects the heart and peripheral vascular system. The hormone can increase myocardial inotropy and heart rate and dilate peripheral arteries to increase cardiac output. An excessive deficiency of thyroid hormone can cause cardiovascular disease and aggravate many preexisting conditions. In severe systemic illness and after major surgical procedures changes in thyroid function can occur, leading to the "euthyroid sick syndrome." Patients will have normal or decreased levels of T4, decreased free and total T3, and usually normal levels of thyroid stimulating hormone. This syndrome may be an adaptive response to systemic illness that usually will revert to normal without hormone supplementation as the illness subsides. Recently, however, many investigators have explored the benefits of thyroid hormone supplementation in those diseases associated with euthyroid sick syndrome. Thyroid hormone's effects on the cardiovascular system make it an attractive therapy for those patients with impaired hemodynamics and low T3. Thyroid hormone has also been considered a treatment for patients with congestive heart failure, for patients undergoing cardiopulmonary bypass and heart transplantation, and for patients with hyperlipidemia. At present there is no evidence suggesting a favorable treatment outcome using thyroid hormone supplementation for any systemic condition except in those patients with documented hypothyroidism.

Recombinant growth hormone: a new cardiovascular drug therapy.

GH has an important role in normal cardiovascular physiologic functioning, working indirectly through effects on IGF-1. An excess or deficiency of GH causes an increased rate of cardiovascular disease, including cardiomyopathy. A relative GH deficiency in older subjects may also increase cardiovascular morbidity and mortality risk. In replacement doses, GH can enhance myocardial contractility; can decrease peripheral vascular resistance; and can reduce total cholesterol and LDL-cholesterol values and fibrinogen and PAI levels. These effects of GH, coupled with the ability to improve skeletal muscle function and reduce adiposity, make it an attractive treatment for patients with CHF and a potential maintenance drug for elderly people. Clinical trials, including studies with GHRH that may reduce the adverse effects of GH therapy, such as hyperglycemia and hypertension, are now in progress.