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L Sharples

Publications and source records attributed to L Sharples.

At least 19 recordsLinked to original sources
PubMed2006

A review of the evidence on the effects and costs of implantable cardioverter defibrillator therapy in different patient groups, and modelling of cost-effectiveness and cost-utility for these groups in a UK context.

OBJECTIVES: To update the systematic review evidence on the effectiveness, health-related quality of life (HRQoL) and cost-effectiveness of implantable cardioverter defibrillators (ICDs); compilation of new data on the service provision in the UK; and on the clinical characteristics, survival, quality of life and costs of ICD patients in the UK, and a new cost-effectiveness model using both international RCT and UK-specific data. DATA SOURCES: Electronic databases searched from November 1999 to March 2003, this was supplemented by a systematic review of research published during 2003-5. Survey data. REVIEW METHODS: Studies were selected and assessed. A survey of ICD centres was carried out. Basic data were obtained from two major implanting centres including 535 patients (approximately 10% of overall UK activity) implanted between 1991 and 2002, and retrieval of fuller data, on patient characteristics, management and resource use, from patient notes for a sample of 426 patients was attempted. A cross-sectional survey collected HRQoL data (using the Nottingham Health Profile, Short Form 36, Hospital Anxiety and Depression questionnaire, EuroQoL 5 Dimensions and disease-specific questions) on a sample of 229 patients. A Markov model combined UK patient data with data from published randomised controlled trials (RCTs) to estimate incremental costs per life-year or quality-adjusted life-year (QALY) gained. RESULTS: None of the economic analyses in the studies found could be directly applied to the UK. The multiple sources of routine data available (including the national ICD database) provide an imperfect picture of the need for and use of ICDs. Implantation rates have been rising to a rate of around 20 per million population. Mean age is increasing and most ICDs are implanted into men aged 45-74 years. There is significant geographical variation. A survey of 41 UK centres provided additional evidence, particularly of variation in level of activity and resourcing. Most detailed data were obtained for 380 patients (89%). The postal survey produced a 73% response rate. Demographic characteristics of these patients were similar to ICD recipients in the UK as a whole and patients included in secondary prevention RCTs. Mean actuarial survival at 1, 3 and 5 years was 92%, 86% and 71%, respectively. Patient age at implantation and functional status significantly affected survival. Levels of most of the HRQoL measures were lower than for a UK general population. There was no evidence of a change with time from implantation. Patients who had suffered ICD shocks had significantly poorer HRQoL. Most patients nevertheless expressed a high level of satisfaction with ICD therapy. Mean initial costs of implantation showed little variation between centres (23,300 pounds versus 22,100 pounds) or between earlier and more recent implants. There appeared to be greater variation between patients presenting along different pathways. Postdischarge costs (tests, medications and follow-up consultations) and costs of additional hospitalisations were also calculated. Using the Markov model it was found that over a 20-year horizon, mean discounted incremental costs were 70,900 pounds (35,000-142,400 pounds). Mean discounted gain was 1.24 years (0.29-2.32) or 0.93 QALYs. Cost-effectiveness was most favourable for men aged over 70 years with a left ventricular ejection fraction (LVEF) below 35%. If the treatment effect were to continue, then the cost per life-year over a lifetime might fall to around 32,000 pounds. Five RCTs of ICDs, a meta-analysis and, a cost-effectiveness analysis of ICDs used in primary prevention, and a meta-analysis of ICDs in patients with non-ischaemic cardiomyopathy have been published recently. These trials provide confirmation of survival benefit of ICDs used in primary prevention in both ischaemic and non-ischaemic cardiomyopathy patients. Costs per QALY ranged from US$34,000 in older trials to controls being both less expensive and more effective (CABG Patch, DINAMIT). More recent trials estimated cost per QALY between $50,300 and $70,200. The inconsistency in evidence for a HRQoL benefit has not been resolved and further work on risk stratification is necessary. CONCLUSIONS: The evidence of short- to medium-term patient benefit from ICDs is strong but cost-effectiveness modelling indicates that the extent of that benefit is probably not sufficient to make the technology cost-effective as used currently in the UK. One reason is the high rates of postimplantation hospitalisation. Better patient targeting and efforts to reduce the need for such hospitalisation may improve cost-effectiveness. Further cost-effectiveness modelling, underpinned by an improved ICD database with reliable long-term follow-up, is required. The absence of a robust measure of the incidence of sudden cardiac death is noted and this may be an area where further organisational changes with improved data collection would help.

Aged↗
PubMed2006

Evaluation of the ventricular assist device programme in the UK.

OBJECTIVES: To summarise the relevant clinical effectiveness and cost-effectiveness literature, to collect data on survival, transplantation rates, health-related quality of life (HRQoL) and resource use for ventricular assist device (VAD) and non-VAD transplant candidates in the UK, and to construct cost-effectiveness and cost-utility models of VADs in a UK context. Also to investigate the factors that drive costs and survival. DESIGN: A comprehensive systematic review was carried out. Data were collected from April 2002 to December 2004, with follow-up to March 2005. Cost-effectiveness and cost-utility models of VAD devices were developed based on UK activity and outcomes collected from April 2002 to March 2005. SETTING: National Specialist Commissioning Advisory Group funded VAD implantation was carried out at the Freeman, Harefield and Papworth transplant centres in the UK. PARTICIPANTS: Seventy patients were implanted with a VAD as a bridge to transplantation between April 2002 and December 2004. Non-VAD-supported transplant candidates (n = 250), listed at the three centres between April 2002 and December 2004, were divided into an inotrope-dependent group (n = 71) and a non-inotrope-dependent group (n = 179). Although patients in the inotrope-dependent group were closest to the VAD group they were less sick. The last group comprised a hypothetical worst case scenario, which assumed that all VAD patients would die in the intensive care unit (ICU) within 1 month without VAD technology. INTERVENTIONS: Patients were included who were implanted with a VAD designed for circulatory support for more than 30 days, with intention to bridge to transplantation. A multistate model of VAD and transplant activity was constructed; this was populated by data from the UK. MAIN OUTCOME MEASURES: Survival from VAD implant or from transplant listing for non-VAD patients to 31 March 2005. Serious adverse events and quality of life measures were used. Cognitive functioning was also assessed. Utility weights were derived from EuroQoL responses to estimate quality-adjusted life-years (QALYs). Incremental cost-effectiveness ratios (ICERs) were defined as the additional cost of VADs divided by additional QALYs. Time-horizons were 3 years, 10 years and the lifetime of the patients. RESULTS: Of 70 VAD patients, 30 (43%) died pretransplant, 31 (44%) underwent transplantation, and four (6%) recovered and had the VAD removed. Five patients (7%) were still supported for median of 279 days at the end of March 2005. Successful bridge-to-transplantation/recovery rates were consistent with published rates. Survival from VAD implantation was 74% at 30 days and 52% at 12 months. There were 320 non-fatal adverse events in 62 patients during 300 months of VAD support, mostly in the first month after implantation. Commonly observed events were bleeding, infection and respiratory dysfunction. Twenty-nine (41%) patients were discharged from hospital with a VAD. The 1-year survival post-transplantation was 84%. For the inotrope-dependent and non-inotrope-dependent transplant candidates, death rates while listed were 10% and 8% and the median waiting times were 16 and 87 days, respectively. For transplant recipients, 1-year survival was 85% and 84%, respectively. Both VAD and non-VAD patients demonstrated similar significant improvements in their New York Heart Association class after transplantation. All patients had poor EQ-5D pretransplantation; after transplantation the groups had similar EQ-5D of 0.76 irrespective of time after surgery. HRQoL was poor in the first month for VAD patients but better for those who waited longer in all groups. VAD patients reported more problems with sleep and rest and with ambulation in the first month. Symptom scores were similar in all groups pretransplant. After transplantation all groups showed a marked and similar improvement in physical and psychosocial function. Mean VAD implant cost, including device, was pound 63,830, with costs of VAD support for survivors of pound 21,696 in month 1 and pound 11,312 in month 2. Main cost drivers were device itself, staffing, ICU stay, hospital stay and events such as bleeding, stroke and infection. For the base case, extrapolating over the lifetime of the patients the mean cost for a VAD patient was pound 173,841, with mean survival of 5.63 years and mean QALYs of 3.27. Corresponding costs for inotrope-dependent patients were pound 130,905, with mean survival 8.62 years and mean QALYs 4.99. Since inotrope-dependent patients had lower costs and higher QALYs than VAD patients, this group is said to be dominant. Non-inotrope-dependent transplant candidates had similar survival rates to those on inotropes but lower costs, also dominant. Compared with the worst case scenario the mean lifetime ICER for VADs was pound 49,384 per QALY. In a range of sensitivity analyses this ranged from pound 35,121 if the device cost was zero to pound 49,384. Since neither inotrope-dependent transplant candidates nor the worst case scenario were considered fair controls the assumption was investigated that, without VAD technology, there would be a mixture of these situations. For mixtures considered the ICER for VADs ranged from pound 79,212 per QALY to the non-VAD group being both cheaper and more effective. CONCLUSIONS: There are insufficient data from either published studies or the current study to construct a fair comparison group for VADs. Overall survival of 52% is an excellent clinical achievement for those young patients with rapidly failing hearts. However, if the worst case scenario were plausible, and one could reliably extrapolate results to the lifetime of the patients, VADs would not be cost-effective at traditional thresholds. Further randomised controlled trials are required, using current second generation devices or subsequent devices and conducted in the UK.

Cost-Benefit Analysis↗
PubMed2005

Effect of lung cancer surgery on quality of life.

BACKGROUND: Health related quality of life (HRQOL) after surgery is important, although very limited data are available on the QOL after lung cancer surgery. METHODS: The effect of surgery on HRQOL was assessed in a prospective study of 110 patients undergoing potentially curative lung cancer surgery at Papworth Hospital, 30% of whom had borderline lung function as judged by forced expiratory volume in 1 second. All patients completed the EORTC QLQ-C30 and LC13 lung cancer module before surgery and again at 1, 3 and 6 months postoperatively. RESULTS: On average, patients had high levels of functioning and low levels of symptoms. Global QOL had deteriorated significantly 1 month after surgery (p = 0.001) but had returned to preoperative levels by 3 months (p = 0.93). Symptoms had worsened significantly at 1 month after surgery but had returned to baseline levels by 6 months. Low values on the preoperative HRQOL scales were not significantly associated with poor surgical outcome. However, patients with low preoperative HRQOL functioning scales and high preoperative symptom scores were more likely to have poor postoperative (6 months) QOL. The only lung function measurement to show a marginally statistically significant association with quality of life at 6 months after surgery was percentage predicted carbon monoxide transfer factor (Tlco). CONCLUSION: Although surgery had short term negative effects on quality of life, by 6 months HRQOL had returned to preoperative values. Patients with low HRQOL functioning scales, high preoperative symptom scores, and preoperative percentage predicted Tlco may be associated with worse postoperative HRQOL.

Adult↗
PubMed2005

Relationship between pulmonary function and lung cancer surgical outcome.

The British Thoracic Society and American College of Chest Physician guidelines outline criteria for investigating patients for lung cancer surgery. However, the guidelines are based on relatively old studies. Therefore, the relationship between pulmonary function test results and surgical outcome were studied prospectively in a large cohort of lung cancer patients. From January 2001 to December 2003, 110 patients underwent surgery for lung cancer. All underwent full lung function testing in order to predict post-operative lung function. The hospital mortality rate was 3% and major complication rate 22%. There was poor overall outcome in 13%. Mean pre-operative lung function values were: forced expiratory volume in one second (FEV1) 2.0 L (79.4% of the predicted value), and carbon monoxide diffusing capacity of the lung (D(L,CO)) 73.6% pred. The mean post-operative lung function values were: FEV1 1.4 L (55.6% pred), and D(L,CO) 51.3% pred. All lung function values were better predictors of poor surgical outcome when expressed as a percentage of the predicted value. Using a threshold of pre-operative FEV1 of 47% pred resulted in the most useful positive and negative predictive probabilities, 0.90 and 0.67, respectively. Lung function values expressed as a percentage of the predicted value are more useful predictors of post-operative outcome than absolute values. The threshold of predicted forced expiratory volume in one second for surgical intervention could be lower (45-50% pred) than is currently accepted without increased mortality.

Adult↗
PubMed2001

Quantitative analysis of myocardial perfusion changes with transmyocardial laser revascularization.

Transmyocardial laser revascularization (TLR) is a technique of creating left ventricular transmural channels in patients with refractory angina. We aimed to measure perfusion changes quantitatively using technetium-99m methoxyisobutyl isonitrile. Perfusion scans were performed on 94 TLRs and in 94 control patients at rest and during exercise at assessment, and 3-, 6-, and 12-month follow-up. A serial set of scans allowed direct comparison of each patient over all visits. Bull's-eyes were divided into 5 anatomic regions and a 20-region model. Severity values were calculated for rest, stress, and each cardiac region using a threshold of 1 for analysis. Higher scores indicated greater severity of ischemia and lower perfusion. At 3-month follow-up, the severity was significantly worse during TLR than in control patients both during stress (0.172 +/- 0.003 and 0.161 +/- 0.003, respectively, p = 0.007) and at rest (0.170 +/- 0.003 and 0.158 +/- 0.003, respectively, p = 0.002). At 6 months, severity during stress was 0.176 +/- 0.003 with TLR and 0.162 +/- 0.003 in controls (p = 0.001), with no significant difference at rest. At 12 months, there was no significant difference between TLR and control groups at stress and rest. Regional severity deteriorates during TLR compared with control patients anteriorly (p = 0.001, p = 0.0016, p = 0.005 at 3, 6, and 12 months), apically (p = 0.005, p = 0.0046, p = 0.032, respectively), and laterally (p <0.0001, p = 0.001, p = 0.002, respectively). An apparent improvement is observed in the inferoseptal region at 6- and 12-month follow-up-an area not lasered. Thus, TLR appears to produce deterioration in resting myocardial perfusion in lasered regions, and improvement in nonlasered regions, with no difference in exercise-induced myocardial ischemia compared with that in control patients.

Angina Pectoris↗
PubMed2001

Association of alpha(1)-antichymotrypsin deficiency with milder lung disease in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is characterised by an excess of free proteinases that destroy lung tissue. Despite this, previous studies have shown that patients with CF with a mild deficiency variant of the proteinase inhibitor alpha(1)-antitrypsin have less, rather than more, severe pulmonary disease. Alpha(1)-antichymotrypsin is another important serine proteinase inhibitor that protects the lung against proteolytic attack, and point mutations in the alpha(1)-antichymotrypsin gene that result in plasma deficiency are associated with chronic obstructive pulmonary disease. METHODS: The effect of alpha(1)-antichymotrypsin deficiency and the -15 alpha(1)-antichymotrypsin signal peptide genotype on lung function was assessed in patients with CF. RESULTS: One hundred and fifty seven patients with CF were screened and 10 were identified with a plasma deficiency of alpha(1)-antichymotrypsin (plasma concentration <0.2 g/l). In a multivariate analysis these individuals had significantly less severe lung disease than those who had normal or raised levels of alpha(1)-antichymotrypsin: forced expiratory volume in one second (FEV(1)) 69.9% predicted versus 53. 2% predicted (p=0.04) and chest radiographic score of 7.2 versus 9.7 (p=0.03) for those with and without alpha(1)-antichymotrypsin deficiency, respectively. The -15 signal peptide genotype did not affect plasma levels, but the -15 Ala/Ala signal peptide genotype was over-represented in individuals with CF compared with healthy blood donor controls. CONCLUSION: These data indicate that deficiency of alpha(1)-antichymotrypsin is associated with less severe pulmonary disease in patients with CF, and support our previous observations that mild genetic deficiency of a proteinase inhibitor is associated with an improved outcome.

Adult↗
PubMed2000

Role of computed tomographic scanning of the thorax prior to bronchoscopy in the investigation of suspected lung cancer.

BACKGROUND: Fibreoptic bronchoscopy (FOB) is the usual initial investigation of choice in patients with suspected endobronchial carcinoma, but it is often non-diagnostic. Once a positive diagnosis has been made, many patients undergo staging by computed tomographic (CT) scanning to assess the extent of the disease and its suitability for radical treatment. To determine whether initial CT scanning before FOB is a cost effective way of reducing subsequent unnecessary or unhelpful invasive diagnostic procedures, a study was undertaken in 171 patients with suspected endobronchial carcinoma. METHODS: A randomised two group study was performed with all patients undergoing an initial CT staging scan. In group A the CT scans were reviewed before FOB, allowing cancellation or a change to an alternative invasive procedure if considered appropriate. In group B all patients proceeded to FOB with the bronchoscopist blinded to the result of the CT scan until after the procedure. RESULTS: In group A six of 90 patients (7%) required no further investigations as the CT scan was either normal, consistent with benign disease, or consistent with widespread metastatic disease. Of the remainder, bronchoscopy was diagnostic in 50 of 68 (73%) in group A compared with 44 of 81 (54%) in group B (p = 0.015). Overall, a positive diagnosis was made after a single invasive investigation in 64 of 84 patients (76%) in group A compared with only 45 of 81 patients (55%) in group B (p = 0.005). Only seven of 90 patients (8%) in group A required more than one invasive investigation compared with 15 of 81 patients (18.5%) in group B. In patients with malignancy, bronchoscopy was more likely to be diagnostic in group A (50 of 56 patients (89%)) than in group B (44 of 62 (71%); p = 0. 012), and the diagnosis was more frequently made on the initial invasive investigation (group A, 63 of 70 (90%); group B, 44 of 62 (71%); p = 0.004). Because of the lower number of invasive procedures performed in group A than in group B, the cost of performing CT scans before FOB in all patients in group A would have equated to a projected cost of performing CT scans in 60% of patients after FOB in group B. CONCLUSIONS: Performing initial CT thoracic scans before bronchoscopy in patients with suspected endobronchial malignancy is a cost effective way of improving diagnostic yield from invasive diagnostic procedures and occasionally may obviate the need for any further investigation.

Adult↗
PubMed1999

Balloon mitral valvuloplasty: comparison of haemodynamic and echocardiographic assessment of mitral stenosis at different heart rates in the catheterisation laboratory.

AIMS: To compare echo-Doppler, Gorlin equation and haemodynamic methods of measuring mitral valve stenosis during right ventricular pacing-induced tachycardia before and after Inoue balloon mitral valvuloplasty to determine which method gave the most consistent results. METHODS AND RESULTS: Measurements were made before and after valvuloplasty at: baseline heart rates, paced at 115 and then 145 beats/min. Mitral valve area by echo-Doppler was 1.1(+/-0.1) cm2 (mean +/- S.E.) before and 1.8(+/-0.2) cm2 after valvuloplasty; and by Gorlin equation: 0.9(+/-0.1) cm2 before and 1.5(+/-0.1) cm2 after. Echo-Doppler measurements were heart rate dependent but those by Gorlin measurements were not. At baseline, cardiac index was 2.08(+/-0.2) l min(-1), left atrial pressure 23.3(+/-7.9) mm Hg and mean mitral diastolic gradient 16.9(+/-9.9) mm Hg. After valvuloplasty, cardiac index was 2.31(+/-0.1) l min(-1), left atrial pressure fell to 19.2(+/-5.6) mm Hg and mean diastolic gradient was reduced to 8.5(+/-1.8) mm Hg. CONCLUSIONS: The Gorlin mitral valve area appeared to be the most heart rate independent indicator of success following valvuloplasty.

Aged↗
PubMed1999

Intravenous ganciclovir prophylaxis for cytomegalovirus in heart, heart-lung, and lung transplant recipients.

Cytomegalovirus (CMV) disease has had a significant clinical impact on the heart, heart-lung and lung transplant recipients in our centre. CMV disease has been so severe with CMV antibody-negative heart-lung transplant patients receiving organs from CMV antibody-positive donors (CMV-mismatched patients) that in 1986 we adopted the policy of not transplanting CMV-positive organs into CMV-negative heart-lung or lung recipients. In December 1992, we instituted a policy of providing intravenous ganciclovir (5 mg/kg twice a day for 28 days) during the immediate postoperative period for CMV-mismatched heart recipients and CMV antibody-positive heart-lung and lung patients, who have been the patients at greatest risk of severe CMV disease in our centre. A placebo group was not employed because of ethical considerations, ganciclovir having been shown to be effective for the treatment of CMV infections among transplant patients. Compared with a historical control group of patients receiving no prophylaxis, prophylactic ganciclovir reduced the incidence of CMV infection (39 % vs 91 %, P = 0.0006) and CMV disease (17 % vs 74 %, P = 0.0004) among CMV antibody-positive heart-lung recipients. Prophylactic ganciclovir did not significantly reduce the incidence of CMV infection or disease among heart or isolated lung recipients. Ganciclovir was well tolerated, with few adverse reactions. In the case of heart-lung transplant patients, one month of intravenous prophylactic ganciclovir significantly reduced the incidence of both CMV infection and disease when compared with patients who received no prophylaxis. With the lung transplant and heart transplant patients, there were no significant differences between the prophylaxis and nonprophylaxis groups, although there was a consistent trend towards less infection and disease in the prophylaxis groups.

Adolescent↗
PubMed1999

HLA antigen frequencies in end-stage idiopathic and ischaemic cardiomyopathy.

We investigated the distribution of HLA antigens among 413 patients with ischaemic heart disease or dilated cardiomyopathy referred for cardiac transplantation to determine if possession of certain HLA antigens predisposed to end-stage heart failure. Of the patients studied, 234 had ischaemic heart disease (218 males), mean age 49 years (SD 7.1) and 179 patients had dilated cardiomyopathy (150 males), mean age 39 years (12.8). The control group comprised 2041 kidney donors reported to the United Kingdom Transplant Service between July and August 1985. We found a significant excess of HLA DR1 (odds ratio 1.64, 95% CI 1.16-2.33, attributable risk 5.0%) and DR5 antigens (odds ratio 1.47, 95% CI 0.99-2.18, attributable risk) among patients with dilated cardiomyopathy but not of HLA DR4 as previously reported. We found a lower frequency than expected of HLA B21 (10.44 expected, none observed) among patients with ischaemic heart disease but no other significant differences. This study provides some support for the concept of the risk of developing end-stage heart failure due to dilated cardiomyopathy being associated with possession of HLA DR1 and DR5, but no such evidence in ischaemic heart disease. Larger multi-centre studies are required to confirm the validity of these findings.

Adult↗
PubMed1999

Anti-neutrophil cytoplasmic antibodies (ANCA) against bactericidal/permeability-increasing protein (BPI) and cystic fibrosis lung disease.

Persistent infection with Pseudomonas aeruginosa and inflammatory mechanisms play an important role in cystic fibrosis (CF) lung disease. ANCA against BPI, a potent host defence protein with anti-bacterial and anti-endotoxin properties, have been described in CF. We have assessed the relationship of anti-BPI antibodies to pulmonary disease severity in 148 CF subjects. IgA and IgG anti-BPI antibodies were found in 55.4% and 70.3% of CF patients, respectively, and higher levels were strongly associated with colonization with P. aeruginosa (P = 0.001 and 0.039 for IgA and IgG antibodies, respectively). IgA and IgG anti-BPI antibodies were independently associated with more severe lung disease as assessed by chest radiograph score (P = 0.023) and a significantly lower forced expiratory volume in 1 s (FEV1)% (P = 0.01). The pathophysiological relevance of the autoantibodies was investigated further by determining their epitope specificity and their effect on bacterial phagocytosis in vitro. Both isotypes of anti-BPI antibodies were specific for the C-terminus of BPI shown recently to be important for BPI-mediated opsonization, and in vitro affinity-purified anti-BPI antibodies significantly reduced BPI-induced phagocytosis of Escherichia coli compared with controls. These data indicate that anti-BPI autoantibodies are associated with colonization with P. aeruginosa and worse lung disease in CF. The inhibition of bacterial phagocytosis suggests that these autoantibodies may contribute to the persistence of P. aeruginosa in the CF lung and so play a role in perpetuating CF lung damage.

Adolescent↗
PubMed1999

Randomized, trough blood cyclosporine concentration-controlled trial to compare the pharmacodynamics of Sandimmune and Neoral in de novo lung transplant recipients.

The greater and more consistent absorption of cyclosporine from the microemulsion formulation (Neoral; Novartis Pharmaceuticals Ltd., Frimley, UK) when compared with that from the original form (Sandimmune; Novartis Pharmaceuticals Ltd., Frimley, UK) results in greater systemic exposure. Lung transplant recipients could particularly benefit from this enhanced exposure, but not at the expense of excessive cyclosporine toxicity. We compared the pharmacodynamics of Neoral and Sandimmune over the first postoperative year in 50 lung transplant recipients. Twenty-eight patients were randomly selected to receive Neoral and 22 to receive Sandimmune. Nine patients with cystic fibrosis (CF) were randomly selected independently (5, Neoral; 4, Sandimmune). Patients were maintained on similar trough blood cyclosporine concentrations (C0) throughout the 12-month follow-up. A limited blood sampling strategy was adopted to compare the pharmacokinetics of the two formulations at the end of weeks 1 to 4, and of weeks 13, 26, 39, 52. The influence of any difference between the pharmacokinetics of Neoral and Sandimmune on either efficacy or toxicity of the drug was investigated during the follow-up period. Patients in the Neoral and the Sandimmune groups were matched demographically. There were no differences in dose-normalized blood cyclosporine concentrations measured predose (C0) or 6 hours postdose between the two groups. However, the measurement at 2 hours postdose (C2) and the total AUC0-6 were significantly greater in the Neoral group in both CF and non-CF patients at all visits (p < 0.001). Non-CF patients required 9% lower doses of Neoral to achieve comparable C0 measurements to those patients receiving Sandimmune. However, patients with CF required 2 to 3 times the dose of both Neoral and Sandimmune to achieve the same C0 as non-CF patients. The linear rejection rate in the Sandimmune group was 1.87 episodes per patient year, which was similar to the rejection rate of 1.97 episodes per patient year in the Neoral group. Serial lung function, blood biochemistry and hematology, mortality and the incidence of severe renal dysfunction, hypertension, infection, seizures, and new-onset diabetes were all similar in the two groups. Despite equivalent C0, those in the Neoral group were consistently exposed to greater blood cyclosporine concentrations during the dosing interval than those in the Sandimmune group. This did not increase the incidence of serious cyclosporine-associated side effects or influence the rate of acute rejection either. When data from the Neoral and Sandimmune groups were combined, measurements of C0 but not C2 or C6 were associated with the risk of acute lung allograft rejection.

Adult↗
PubMed1998

Evaluating the donor pool: impact of using hearts from donors over the age of 49 years.

The shortage of hearts for transplantation has led to the use of organs from older donors in many centres. Despite the lack of coronary angiography on potential organ donors, hearts from carefully selected donors over 49 years of age have been used at this centre since 1988. In the study reported here looked at the impact of this strategy on morbidity and mortality. Between May 1988 and August 1996, 400 first heart transplants were performed, 35 recipients (31 male, 4 female; age 51 +/- 5.9 years) received hearts from donors over 49 years of age (group 1) while 365 (310 male, 55 female; age 49 +/- 9.7 years) had younger donors (group 2). The mean ischaemic time was 189 min (+/- 63.1) in group 1 and 180 min (+/- 59.2) in group 2 (n.s.). The main aetiology of heart failure in groups 1 and 2 was coronary artery disease in 46% and 51%, and dilated cardiomyopathy in 40% and 45% respectively (n.s.). There were no differences in the duration of stay on the intensive care unit or in hospital between the groups. One-year survival was 79% in group 1 and 82% in group 2 (n.s.) and actuarial 5-year survival 69% and 67%, respectively. Six patients in group 1 (17%) and 45 patients in group 2 (12%) died in the first 3 months; of these primary donor organ failure accounted for 50% in group 1 and 13.3% in group 2 (n.s.). Episodes of acute rejection (in the first 3 months) were similar in the two groups: 1.4 and 1.6 per 100 patient days, respectively. Infection rates were also similar: 0.5 and 0.6 per 100 patient days, respectively. The prevalence of coronary artery disease on surveillance coronary angiography at 2 years was 23% in group 1 and 9% in group 2 (P < 0.005). There was a greater proportion of CMV antibody donors in the older donor group, but the association between donor age and coronary artery disease persisted after adjusting for CMV status in multivariate analysis. Too few patients underwent angiography thereafter for valid comparisons. In summary, recipients of organs from donors aged 49 years and over can expect comparable survival rates and morbidity levels to recipients of organs from younger donors, at least in the first 2 years postoperation. There is evidence that older donors confer a significantly higher risk of cardiac allograft vasculopathy which may result in a greater attrition rate thereafter. Careful follow-up of these patients after 2 years is required.

Age Factors↗
PubMed1998

Long-term intravenous prostaglandin (epoprostenol or iloprost) for treatment of severe pulmonary hypertension.

OBJECTIVE: To investigate the relation between the severity of pulmonary hypertension and the outcome of medical treatment. METHODS: 98 patients with primary pulmonary hypertension--nine (6%) with systemic disease and pulmonary hypertension and 39 (27%) with thromboembolic pulmonary hypertension--received medical treatment and were followed between 1982 and 1995. They were given long term intravenous prostaglandin treatment (either epoprostenol (n = 61) or iloprost (n = 13)) or conventional treatment with oral anticoagulants (n = 24) with or without calcium channel blockers. Event-free survival was measured to death or transplant surgery, or pulmonary thromboendarterectomy. RESULTS: Prognosis (hazard ratio) was affected by: New York Heart Association grade, 1.52 (95% confidence interval 1.11 to 2.09); mixed venous oxygen saturation (SvO2%), 0.97 (0.95 to 0.98); cardiac index, 0.72 (0.49 to 1.06); mean right atrial pressure, 1.04 (1.01 to 1.07); and pulmonary vascular resistance, 1.02 (1.00 to 1.04). The median event-free survival time of patients with SvO2 < 60% was 239 days (0 to 502) on conventional treatment (n = 22) and 585 days (300 to 870) on prostaglandin treatment (n = 42). No difference was seen in patients with SvO2 > or = 60% between conventional treatment and prostaglandin treatment, survival being 1275 days (732 to 1818; (n = 48)) and 986 days (541 to 1431; n = 30)), respectively. Capacity for pulmonary vasodilatation did not predict outcome of treatment. CONCLUSIONS: Continuous intravenous prostaglandins were more effective than anticoagulants, with or without calcium channel blockers, in prolonging survival in patients with right heart failure. In these patients a capacity to vasodilate did not predict outcome from medical treatment.

Adult↗