Patient retention gifts in clinical trials - undue inducement or justified motivational tools?

The use of retention gifts in clinical trials has been controversial, with some ethicists maintaining that such gifts represent undue inducement to the trial participants. A study was conducted at TREAD Research, a site-managed organisation based at Tygerberg Hospital, in which 302 participants completed a questionnaire that focused on their opinion with regard to such gifts. The results suggest that these gifts do not influence patients to participate in a clinical trial or influence them to remain on a trial should they wish to withdraw. However, they do act as a useful motivational tool and trial participants appreciate them.

Patients' motivations for participating in cardiovascular clinical trials: a local perspective.

OBJECTIVE: To investigate patients' motivations for participating in cardiovascular clinical trials. METHODS: Patients attending TREAD Research, located within Tygerberg Hospital, Parow, Western Cape, between January 2005 and May 2006 were approached to participate in the study. Consenting patients were given a validated questionnaire to complete in their home language. All questionnaires were anonymous and 250 consecutive patients completed the questionnaire. They provided basic demographic data and rated their response to 18 statements concerning factors that may or may not have influenced their decision to participate in a clinical trial. RESULTS: The mean (+/- SD) age of subjects was 56.3 +/- 10.9 years. A large percentage of the respondents were unemployed (66.5%). Access to medical care was a motivation for the majority of patients (90.5%). Ninety-six per cent of patients appreciated the regular follow up they received as trial participants; 90% of patients entered the trial to receive medication, which they could otherwise not afford. A substantial 98% of patients participated to learn more about their disease. Almost all (99%) wanted to further the scientific understanding of their condition. A reassuring 94% of subjects felt that they were not pressurised into the study; 80% of patients disagreed that participation in clinical trials was an easy way to obtain money. CONCLUSIONS: Access to medical care and making a contribution to scientific knowledge are two of the most common motivations for participation in cardiovascular clinical trials. The role of remuneration is relatively unimportant.

A randomized, placebo-controlled, double-blind phase 2 study of docetaxel compared to docetaxel plus zosuquidar (LY335979) in women with metastatic or locally recurrent breast cancer who have received one prior chemotherapy regimen.

PURPOSE: To determine if concomitant administration of docetaxel plus zosuquidar.3HC1 can prolong progression-free survival in patients with metastatic breast cancer. METHODS: A randomized, double-blind, multicenter, placebo-controlled clinical trial comparing docetaxel plus 500 mg zosuquidar.3HCl (DZ) with docetaxel plus placebo (DP). RESULTS: A total of 170 patients were enrolled and randomly assigned to treatment. The median age was 53 years (range, 31-74 years). 81.7% of patients had prior chemotherapy in the adjuvant setting and 18.3% in the neoadjuvant setting. The median progression-free survival time was statistically different between groups [7.2 months (DZ) vs. 8.3 months (DP)]. Once the stratification factor relative to progression following prior chemotherapy was considered, no significant treatment difference existed. CONCLUSION: The combination of zosuquidar.3HCl plus docetaxel is safe. The analysis of efficacy data is complex, but it can be concluded that there is no difference in progression-free survival, overall survival, or response rate in the study as a whole.

The diagnostic utility of adenosine deaminase isoenzymes in tuberculous pleural effusions.

SETTING: Pleural adenosine deaminase (ADA) levels have been found to be useful in diagnosing tuberculous pleuritis. Elevated ADA levels have been attributed to ADA2 isoenzyme, although no comprehensive studies have evaluated ADA2 as a diagnostic test. OBJECTIVE: To estimate the diagnostic accuracy of ADA and ADA2 in diagnosing tuberculous pleurisy. METHOD: A 3-year retrospective study was carried out. ADA and ADA2 were determined on patients diagnosed according to predetermined criteria. RESULTS: A total of 951 samples were received, including 387 patients with tuberculosis (TB). ADA values>or=52.4 U/l yielded a sensitivity, specificity and positive (PPV) and negative predictive value (NPV) respectively of 93.7% (95%CI 90.0-96.0), 88.7% (95%CI 85.7-91.3), 85.5% (95%CI 81.7-88.8) and 95.2% (95%CI 92.9-96.9). ADA2 values>or=40.6 U/l yielded a sensitivity, specificity and PPV and NPV of respectively 97.2% (95%CI 95.0-98.7), 94.2% (95%CI 91.8-96.0), 92.2% (95%CI 89.1-94.7) and 98.0% (95%CI 96.3-99.0). The chi2 and McNemar tests proved the superiority of ADA2 statistically. CONCLUSION: ADA2 is superior to ADA in the diagnosis of tuberculous pleuritis and should be used as a routine test in the diagnostic work-up of patients with pleural effusions in areas with high TB prevalence.

The management of tuberculous pericardial effusion: experience in 233 consecutive patients.

AIM: We report on the 30-day and one-year outcome of consecutive effusive pericarditis patients, including those with tuberculous pericarditis, over a six-year-period. METHODS AND RESULTS: Patients with large pericardial effusions requiring pericardiocentesis were included in the study after having given written informed consent. Clinical and radiological evaluations were followed by echo-guided pericardiocentesis, and extended daily intermittent drainage via an indwelling pigtail catheter. A standard short-course anti-tuberculous regimen was initiated. A total of 233 patients was included. One hundred and sixty-two patients had pericardial tuberculosis (TB), including 118 (73%) with microbiological and/ or histological evidence of TB and 44 (27%) diagnosed on clinical and supportive laboratory data. Over the six-year period, two patients developed fibrous constrictive pericarditis after receiving adjuvant corticosteroid therapy. The 30-day mortality (8.0%) was statistically higher for HIV-positive patients (corresponding mortality 9.9%) than for HIV-negative patients (6.2%; p = 0.04). The one year all-cause mortality was 17.3%. It was also higher for HIV-positive (22.2%) than for IV-negative patients (12.3%; p = 0.03). Cardiac mortality was equal for HIV-positive and -negative patients. CONCLUSION: Tuberculous pericardial effusions responded well to closed pericardiocentesis and a six-month treatment of antituberculous chemotherapy. The former was effective and safe irrespective of HIV status.

The role of histopathology in establishing the diagnosis of tuberculous pericardial effusions in the presence of HIV.

AIMS: To establish the influence of human immunodeficiency virus (HIV) infection on the histopathological features of patients presenting with tuberculous pericarditis. METHODS AND RESULTS: A prospective study was carried out at Tygerberg Academic Hospital, South Africa; 36 patients with large pericardial effusions had open pericardial biopsies under general anaesthesia and were included in the study. Patients underwent pericardiocentesis, followed by daily intermittent catheter drainage; a comprehensive diagnostic work-up (including histopathology of the pericardial tissue) was also performed. Histological tuberculous pericarditis was diagnosed according to predetermined criteria. Tuberculous pericarditis was identified in 25 patients, five of whom were HIV+. The presence of granulomatous inflammation (with or without necrosis) and/or Ziehl-Neelsen positivity yielded the best test results (sensitivity 64%, specificity 100% and diagnostic efficiency 75%). CONCLUSIONS: Co-infection with HIV impacts on the histopathological features of pericardial tuberculosis and leads to a decrease in the sensitivity of the test. In areas which have a high prevalence of tuberculosis, the combination of a sensitive test such as adenosine deaminase, chest X-ray and clinical features has a higher diagnostic efficiency than pericardial biopsy in diagnosing tuberculous pericarditis.

Large pericardial effusions due to systemic lupus erythematosus: a report of eight cases.

The aim of this study was to describe the clinical, echocardiographic and laboratory characteristics of large pericardial effusions and cardiac tamponade secondary to systemic lupus erythematosus (SLE). An ongoing prospective study was conducted at Tygerberg Academic Hospital, South Africa between 1996 and 2002. All patients older than 13 years presenting with large pericardial effusions (> 10 mm) requiring pericardiocentesis were included. Eight cases (out of 258) were diagnosed with SLE. The mean (SD) age was 29.5 (10.7) years. Common clinical features were Raynaud's phenomenon, arthralgia and lupus nephritis class III/IV. Echocardiography showed Libman-Sacks endocarditis (LSE) in all the mitral valves. Two patients developed transient left ventricular dysfunction; both these patients had pancarditis. Typical serological findings included antinuclear antibodies, anti-double stranded DNA antibodies, low complement C4 levels and low C3 levels. CRP was elevated in six cases. Treatment consisted of oral steroids and complete drainage of the pericardial effusions. No repeat pericardial effusions or constrictive pericarditis developed amongst the survivors (3.1 years follow up). This study concludes that large pericardial effusions due to SLE are rare, and associated with nephritis, LSE and myocardial dysfunction. Treatment with steroids and complete drainage is associated with a good cardiac outcome.

Epidemiology of pericardial effusions at a large academic hospital in South Africa.

The aim was to establish the prevalence of large pericardial effusions in the Western Cape Province of South Africa, and to determine the incidence of various types of effusions. A total of 233 patients presented with large pericardial effusions. Each patient underwent tests for HIV, sputum smear and culture, blood culture, blood biochemistry and serological testing. Tuberculous pericardial effusions were diagnosed according to pre-determined criteria. Eighty-four patients (36.1%) were found to be HIV positive; 81 of these (96.4 %) had tuberculous pericarditis. More than 65% of the study population was aged between 15 and 39 years. The prevalence of HIV amongst unemployed individuals was 49.0% compared to 30.0% amongst employed individuals. Tuberculous pericarditis was the most common cause of pericardial effusions (69.5%, n=162). It was concluded that tuberculosis (TB) is a leading cause of pericarditis in this province of South Africa. The prevalence of TB confounded by HIV co-infection is steadily increasing, burdening the health-care facilities.

Role of chest radiography in diagnosing patients with tuberculous pericarditis.

AIM: To describe the abnormalities on chest X-ray (CXR) in patients presenting with tuberculous pericardial effusions. METHODS: One hundred and seventy patients presented to Tygerberg Hospital with large pericardial effusions (epi-pericardial separation > 10 mm). All patients had a diagnostic work-up, which included CXR, ECG, two-dimensional echocardiography and HIV serology. Echocardiography was followed by pericardiocentesis and drainage. Pericardial fluid was analysed for adenosine deaminase (ADA), Ziehl Neelsen (ZN) stain, bacterial and mycobacterial cultures. Sputum was sent for ZN stain and mycobacterial cultures. Tuberculous pericardial effusions were diagnosed according to predetermined criteria. RESULTS: The diagnosis of tuberculous pericarditis was made in 53% (n = 90) of patients with pericardial effusions. Forty-one of the subjects (45.5%) were HIV positive. All patients had an enlarged cardiac silhouette and in the majority of cases, the cardiac shadow was globular with distinct margins. The cardiothoracic ratio (CTR) exceeded 0.55 in all patients. The amount of fluid drained correlated with the radiographic finding of cardiac enlargement. CONCLUSION: In developing countries where TB is very prevalent, CXR plays an important role in the identification of large pericardial effusions. Although sonography will still be required for a definite diagnosis, the results of this study show that CXR is a useful screening tool.

Biochemical analysis of pleural, peritoneal and pericardial effusions.

Body fluids other than blood, urine and cerebrospinal fluid are often submitted for biochemical analysis. Of these, pleural, peritoneal and pericardial fluids are the most common. Laboratory tests are a useful tool to assess the aetiology, pathophysiology and subsequent treatment of effusions. A wide range of biochemical tests may be requested. This review critically examines the various analytes that have been used to investigate these body fluids.

Cytokine production in patients with tuberculous pericarditis.

SETTING: An academic hospital in the Western Cape, South Africa. OBJECTIVE: To evaluate cytokine production (interferon-gamma [IFN-gamma], interleukin-1 [IL-1], interleukin-2 [IL-2], interleukin-6 [IL-6], interleukin-10 [IL-10], interleukin-4 [IL-4] and tumour necrosis factor-alpha [TNF-alpha]) in patients with tuberculous pericarditis. DESIGN: Subpopulation of a consecutive prospective case series. PATIENTS: Thirty patients presenting with pericardial effusions due to tuberculosis (n = 19), malignancy (n = 6) and non-tuberculous infections (n = 5), and five control subjects who had undergone open heart surgery. RESULTS: The concentration of IFN-gamma was significantly higher in tuberculous pericardial effusions than in the other diagnostic classes (P < 0.0005). The concentration of TNF-alpha was similar in both infective and tuberculous effusions, but was significantly higher than that of malignant effusions. IL-1 and IL-2 were undetectable in malignant effusions, but elevated in both infective and tuberculous pericardial effusions. The levels of IL-1 and IL-2 were furthermore significantly higher in pericardial effusions due to infective compared to tuberculous causes. The concentration of IL-6, while elevated in all diagnostic classes, was significantly higher in the malignant group. Elevated levels of IL-10 and undetectable levels of IL-4 were observed in all three diagnostic groups. CONCLUSION: These findings suggest that tuberculous pericardial effusions arise due to a hypersensitivity reaction that is orchestrated by the TH-1 lymphocytes.

Clinical experience with pericardiocentesis and extended drainage in a population with a high prevalence of HIV.

BACKGROUND: The data presented were generated in a prospective study on the immunopathogenesis and management of tuberculous (TB) pericarditis at Tygerberg Hospital in Cape Town. We report our experience with 2D echocardiographically guided pericardiocentesis in 170 consecutive patients who presented to us with large pericardial effusions since 1995. METHODS: All patients referred to our department with echocardiographically confirmed large pericardial effusions underwent a clinical assessment followed by pericardiocentesis and drainage by an indwelling pigtail catheter. The appearance and amount of drained effusion were noted and fluid was sent for diagnostic assessment. The pigtail catheter was kept in place and fluid was aspirated once daily until the aspirate was less than 100 ml, at which stage the catheter was removed. RESULTS: A chest wall puncture site was chosen in 165 of the 170 patients (97%), while the subcostal approach was only used in five patients. Echocardiographic signs of tamponade were seen in 88% of cases. In the majority of patients (68.2%) a diagnosis of TB could be established and of these 46.6% were HIV positive. TB could not be proven in only three HIV-positive patients (1.8% of all patients). Neither hospital stay nor complications were increased in the HIV-positive group when compared with the HIV-negative group and no patient developed intrapericardial sepsis. No death could be attributed with certainty to the procedure. One patient developed non-fatal tamponade within 24 hours after the tap and in another patient a left ventricular thrombus was noted on echo after 16 days. Twenty-four patients underwent a pericardial window procedure according to protocol for diagnostic purposes. In another four patients a window was performed for therapeutic reasons. The most common minor complication was local pain at the site of catheter insertion. Repeat drainage was necessary in only six (3.5%) cases. CONCLUSIONS: 2D echocardiographically directed pericardiocentesis with extended catheter drainage has an excellent profile in terms of simplicity, safety and efficacy, even in a population with a very high prevalence of HIV.

Cortical lens opacities in the young patient--an indication for a lipogram?

AIM: To determine the characteristics and prevalence of lenticular opacification in patients with underlying dyslipidaemia. METHODS: Eighty patients of both genders and all ages (18-90 years) were enrolled in the trial if they met the inclusion criteria for dyslipidaemia. Patients were included if their fasting serum cholesterol and triglyceride concentrations were > 5.2 mmol/l and > 2.3 mmol/l, respectively, when measured on three separate occasions over a 1-month period. Patients were excluded if they suffered from any condition known to cause or predispose them to elevated lipid levels or lenticular opacification. Lenticular changes were assessed by means of a slit-lamp through the fully dilated pupil and other physical signs were documented subsequent to thorough physical evaluation. RESULTS: In addition to the classic clinic signs of dyslipidaemia, 31% of patients had cortical lens opacities. Cortical opacities were twice as prevalent as Achilles tendon thickening (16.3%) in our study, the second most prevalent sign of elevated lipid levels. In the subgroup of patients aged under 50 years, 55% had lenticular opacities, predominantly cortical (80%). CONCLUSIONS: Cortical lens opacification was the most prevalent sign of dyslipidaemia and it occurred at a relatively young age in our trial population in those patients who were affected. Cortical lenticular opacification should be regarded as an indication for blood lipid profile evaluation.

The use of adenosine deaminase as a diagnostic tool for peritoneal tuberculosis.

SETTING: Tygerberg Hospital, an academic hospital in the Western Cape, South Africa. OBJECTIVE: To determine the diagnostic utility of ascitic fluid adenosine deaminase (ADA) in the diagnosis of tuberculous peritonitis. DESIGN: A prospective study, carried out from February 1995 to February 1998, resulted in 178 paired ascites and serum specimens being collected from adult patients. Specimens were evaluated for biochemistry, ADA, microbiology and cytology; further investigations were done at the treating clinician's discretion. Diagnoses were made according the pre-determined criteria. RESULTS: The median (range) ADA activity in the tuberculous group was 61.6 (17.5--115.0) U/L and was significantly higher than in any other diagnostic group (p<0.05). Using ROC curves, a cut-off level of 30 U/L for the diagnosis of tuberculous peritonitis was found to yield the best results; corresponding sensitivity and specificity was 94% and 92%, respectively. No statistically significant difference in ADA activity was observed when tuberculous ascites occurred in the absence or presence of cirrhosis. CONCLUSIONS: Ascitic fluid ADA activity is useful in identifying those patients in whom the diagnosis of tuberculous peritonitis should be actively pursued to justify its routine use, at least in areas such as South Africa where TB is endemic. The presence or absence of underlying cirrhosis does not appear to distract from its diagnostic utility.

The use of simvastatin in analbuminaemia.

Congenital analbuminaemia, a rare disorder associated with defective albumin synthesis, is characterised by hyperlipidaemia. Administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGRI) to analbuminaemic rats have demonstrated no significant effect on plasma lipids, however no published information regarding HMGRI treatment could be found in human subjects. The efficacy, safety and tolerability of Simvastatin was thus investigated in 2 South African patients with analbuminaemia, a 21 year old Caucasian male (H-B) and a 61 year old black male (A-K). In the case of A-K, the lipid profile responded predictably but H-B responded less that expected from general experience with Simvastatin. Both subjects, however, experienced a three- to five-fold increase in creatine kinase. The use of HMGRI's should thus be used cautiously in these patients and it may be advisable to reserve treatment for secondary prevention.