Effects of dexmedetomidine on kidney and brain tissue microcirculation and histology in ovine cardiopulmonary bypass: a randomised controlled trial.

Cardiac surgery requiring cardiopulmonary bypass is associated with postoperative acute kidney injury and neurocognitive disorders, including delirium. Intra-operative inflammation and/or impaired tissue perfusion/oxygenation are thought to be contributors to these outcomes. It has been hypothesised that these problems may be ameliorated by the highly selective α2 -agonist, dexmedetomidine. We tested the effects of dexmedetomidine on renal and cerebral microcirculatory tissue perfusion, oxygenation and histology in a clinically relevant ovine model. Sixteen sheep were studied while conscious, after induction of anaesthesia and during 2 h of cardiopulmonary bypass. Eight sheep were allocated randomly to receive an intravenous infusion of dexmedetomidine (0.4-0.8 µg.kg-1 .h-1 ) from induction of anaesthesia to the end of cardiopulmonary bypass, and eight to receive an equivalent volume of matched placebo (0.9% sodium chloride). Commencement of cardiopulmonary bypass decreased renal medullary tissue oxygenation in the placebo group (mean (95%CI) 5.96 (4.24-7.23) to 1.56 (0.84-2.09) kPa, p = 0.001), with similar hypoxic levels observed in the dexmedetomidine group (6.33 (5.33-7.07) to 1.51 (0.33-2.39) kPa, p = 0.002). While no differences in kidney function (i.e. reduced creatinine clearance) were evident, a greater incidence of histological renal tubular injury was observed in sheep receiving dexmedetomidine (7/8 sheep) compared with placebo (2/8 sheep), p = 0.041. Graded on a semi-quantitative scale (0-3), median (IQR [range]) severity of histological renal tubular injury was higher in the dexmedetomidine group compared with placebo (1.5 (1-2 [0-3]) vs. 0 (0-0.3 [0-1]) respectively, p = 0.013). There was no difference in cerebral tissue microglial activation (neuroinflammation) between the groups. Dexmedetomidine did not reduce renal medullary hypoxia or cerebral neuroinflammation in sheep undergoing cardiopulmonary bypass.

Molecular diagnosis of antibody-mediated rejection in human kidney transplants.

Antibody-mediated rejection is the major cause of kidney transplant failure, but the histology-based diagnostic system misses most cases due to its requirement for C4d positivity. We hypothesized that gene expression data could be used to test biopsies for the presence of antibody-mediated rejection. To develop a molecular test, we prospectively assigned diagnoses, including C4d-negative antibody-mediated rejection, to 403 indication biopsies from 315 patients, based on histology (microcirculation lesions) and donor-specific HLA antibody. We then used microarray data to develop classifiers that assigned antibody-mediated rejection scores to each biopsy. The transcripts distinguishing antibody-mediated rejection from other conditions were mostly expressed in endothelial cells or NK cells, or were IFNG-inducible. The scores correlated with the presence of microcirculation lesions and donor-specific antibody. Of 45 biopsies with scores>0.5, 39 had been diagnosed as antibody-mediated rejection on the basis of histology and donor-specific antibody. High scores were also associated with unanimity among pathologists that antibody-mediated rejection was present. The molecular score also strongly predicted future graft loss in Cox regression analysis. We conclude that microarray assessment of gene expression can assign a probability of ABMR to transplant biopsies without knowledge of HLA antibody status, histology, or C4d staining, and predicts future failure.

Molecular diagnosis of T cell-mediated rejection in human kidney transplant biopsies.

Histologic diagnosis of T cell-mediated rejection is flawed by subjective assessments, nonspecific lesions and arbitrary rules. This study developed a molecular test for T cell-mediated rejection. We used microarray results from 403 kidney transplant biopsies to derive a classifier assigning T cell-mediated rejection scores to all biopsies, and compared these with histologic assessments. The score correlated with histologic lesions of T cell-mediated rejection (infiltrate, tubulitis). The accuracy of the classifier for the histology diagnoses was 89%. Very high and low molecular scores corresponded with unanimity among three pathologists on the presence or absence of T cell-mediated rejection, respectively. The molecular score had low sensitivity (50%) and positive predictive value (62%) for the histology diagnoses. However, histology showed similar disagreement between pathologists--only 45-56% sensitivity of one pathologist with diagnoses of T cell-mediated rejection by another. Discrepancies between molecular scores and histology were mostly when histology was ambiguous ("borderline") or unreliable, e.g. in cases with scarring or inflammation induced by tissue injury. Vasculitis (isolated v-lesion TCMR) was particularly discrepant, with most cases exhibiting low TCMR scores. We propose new rules to integrate molecular tests and histology into a precision diagnostic system that can reduce errors, ambiguity and interpathologist disagreement.

A randomised comparative trial of infusional ECisF versus conventional FEC as adjuvant chemotherapy in early breast cancer: the TRAFIC trial.

BACKGROUND: The epirubicin with cisplatin and infusional 5-fluorouracil (5-FU) (ECisF) regimen was found to be highly active in the treatment of metastatic breast cancer and as neoadjuvant therapy. The UK TRAFIC (trial of adjuvant 5-FU infusional chemotherapy) trial (CRUK/95/007) compared this schedule with 5-FU, epirubicin and cyclophosphamide (FEC60) as adjuvant therapy in patients with early breast cancer. METHODS: In this multicentre, open-label, phase III randomised controlled trial, 349 women were randomly assigned to receive i.v. ECisF [epirubicin 60 mg/m(2), day 1, cisplatin 60 mg/m(2), day 1 and 5-FU 200 mg/m(2) by daily 24-h infusion (n = 172)] or FEC [5-FU 600 mg/m(2), day 1, epirubicin 60 mg/m(2), day 1 and cyclophosphamide 600 mg/m(2), day 1 (n = 177)]. Both treatments were delivered every 3 weeks for six cycles. The primary end point was relapse-free interval (RFI). TRAFIC is registered as an International Standard Randomised Controlled Trial (ISRCTN 83324925). RESULTS: All randomised patients were included in the intent-to-treat population. With a median follow-up of 112 months, there was no significant difference in RFI between the treatment groups [hazard ratio 0.84 (95% confidence interval 0.60-1.19); P = 0.33]. Toxic effects were more frequent in patients allocated to ECisF. CONCLUSIONS: While limited by size, TRAFIC has long follow-up. No evidence of a clinically worthwhile benefit for the infusional treatment compared with standard treatment was observed which would justify further investigation or widespread use.

Gamma probe radioguided parathyroid forearm surgery in recurrent hyperparathyroidism.

A case is described of a successful radioguided forearm graft parathyroidectomy. This is the first report of both pre-operative diagnostic and successful intra-operative localisation during a single procedure, of autologous transplanted parathyroid tissue.

Thoracoscopic excision of mediastinal parathyroid adenomas: a report of two cases.

Two patients with primary hyperparathyroidism caused by solitary ectopic mediastinal parathyroid adenomas have been successfully treated by thoracoscopic excision. The patients were not suitable for open thoracic surgery. Both had right-sided adenomas confirmed by sestamibi and computerised tomography - one adjacent to the oesophagus at the level of D3, the other anterolateral to the ascending aorta. Both procedures were performed through one 12-mm camera port and two 5-mm operating ports, and were uncomplicated, with 30-45 minutes skin-to-skin operating time. Both patients were well enough to be discharged the next day, and both rapidly became normocalcaemic. At follow-up, neither had developed any complications. In selected cases, where an ectopic adenoma lies immediately deep to the mediastinal pleura, thoracoscopic excision offers considerable advantage over open thoracic surgery.

Axillary lymph node scarring and the association with tumour response following neoadjuvant chemoendocrine therapy for breast cancer.

We observed that the axillary lymph nodes of some of our breast cancer patients who received neoadjuvant chemoendocrine therapy (NCT) showed evidence of scarring. The purpose of this study is to determine whether such scarring exists and, if so, whether it is confined to neoadjuvant patients and may be related to response to therapy of the primary tumour. We examined the axillary lymph nodes of a consecutive series of 255 breast cancer patients, all of whom had undergone radical axillary dissection. Fifty-three had received NCT; the remainder formed the control group. A scar was defined as an area of cellular fibrous tissue >0.25 mm in diameter and for each patient scar count, median size and score were recorded. Nodes with scars were stained immunohistochemically (IHC) with 2 epithelial markers for the presence of occult micrometastases. The nodes of 20.7% of patients who had received NCT contained scars compared with 13.4% of controls. The median scar size was significantly greater in neoadjuvant patients (P<0.001) and within this group scar count and score were significantly higher (P=0.026 and 0.020) in those with no or minimal evidence of residual primary tumour. Scars which were IHC-positive for micrometastases were almost exclusively confined to neoadjuvant patients. Our results suggest that axillary lymph node scarring does exist, but is not a common phenomenon. It is more significant in neoadjuvant patients and within this group is most marked in those with the greatest primary tumour response to therapy. We believe that scarring is likely to represent downstaging of axillary disease. A prospective study involving a larger group of patients receiving NCT is indicated, to confirm these preliminary findings and establish whether scarring has prognostic or predictive potential.

Survival outcomes 1 year after reperfusion therapy with either alteplase or reteplase for acute myocardial infarction: results from the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) III Trial.

BACKGROUND: New recombinant plasminogen activators have been developed to simulate the fibrinolytic action of the physiological serine protease tissue plasminogen activator (alteplase, t-PA), and have prolonged half-life features permitting bolus administration. One such activator, reteplase (r-PA), was compared with t-PA in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-III Trial. METHODS AND RESULTS: At 1-year follow-up, survival status was ascertained in 97.4% of the 15 059 patients enrolled in the GUSTO-III trial. At 1 year, the mortality rate for the t-PA-assigned group was 11.06%, and for r-PA it was 11.20% (P:=0. 77). The absolute mortality difference of 0.14% has 95% CIs of -1. 21% to 0.93%. There were no significant differences in outcome by intention-to-treat for the 2 different plasminogen activators in the prespecified groups (age, infarct location, time-to-treatment). The absolute difference in mortality rates between t-PA and r-PA progressively narrowed over the predetermined observation times after random assignment; it was 0.31% at 24 hours, 0.26% at 7 days, 0.23% at 30 days, and 0.14% at 1 year. Of note, mortality rate in the trial between 30 days and 1 year in 13 883 patients was 4.02% and did not differ between the treatment groups. However, this mortality rate was substantially greater than in GUSTO-I, in which mortality rate for t-PA versus streptokinase between 30 days and 1-year was 2.97% (heart rate 1.36, 95% CI 1.23, 1.50, P:<0.001). CONCLUSIONS: The r-PA and t-PA strategies yielded similar survival outcomes after 30 days in this trial. The increase in mortality rate during extended follow-up compared with previous trials may reflect higher-risk patients and highlights the need for improved secondary prevention strategies.

Comparison of the SF-36 health survey questionnaire with the Nottingham Health Profile in long-term survivors of a myocardial infarction.

BACKGROUND: Health-related quality of life, an important outcome measure in health interventions, can readily be assessed by questionnaire. Two widely evaluated examples are the Short Form 36 (SF-36) and Nottingham Health Profile (NHP) questionnaires, but as yet the discriminatory power of these tools has not been compared in a large population of patients with coronary heart disease. METHODS: All 4-year survivors of a myocardial infarction, identified from the Nottingham heart attack register, were sent the SF-36, NHP and additionally the Rose angina and dyspnoea questionnaires. Mean scores on the SF-36 and NHP were compared with age- and sex-adjusted norms in patients under and over 65 years. Sensitivity of the respective tools was assessed in distinguishing patients with differing degrees of cardiovascular symptomatology. RESULTS: In patients under 65 years the SF-36 and NHP differed to the same extent from normative data--scores were lower in the comparable domains physical functioning/mobility, bodily pain/pain and energy/vitality, but not in mental health/emotional reaction scores. In social functioning/social isolation results were disparate--SF-36 scores were lower and the NHP similar to normative data. In patients over 65 years mean scores in all five domains were not significantly different from normative data for either tool. The SF-36 was more sensitive than the NHP at detecting the impact of breathlessness, particularly in patients with mild symptoms. Similarly, the SF-36, but not the NHP, could distinguish the effect of differing degrees of angina severity and frequency on social functioning. CONCLUSION: At least in myocardial infarction survivors, the SF-36 appears a more sensitive tool and may have benefits for assessing health-related quality of life in this patient group.

Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial.

BACKGROUND: Although intravenous glycoprotein IIb/IIIa inhibitors are beneficial in patients with acute coronary syndromes, prolonged oral IIb/IIIa inhibition might provide an additional reduction in recurrent events. METHODS AND RESULTS: Investigators at 888 hospitals in 29 countries enrolled 10 288 patients with acute coronary syndromes, which was defined as ischemic pain at rest within 72 hours of randomization, associated with positive cardiac markers, electrocardiographic changes, or prior cardiovascular disease. Patients received aspirin and were randomized to receive, for the duration of the trial, (1) 50 mg of orbofiban twice daily (50/50 group), (2) 50 mg of orbofiban twice daily for 30 days followed by 30 mg of orbofiban twice daily (50/30 group), or (3) a placebo. The primary composite end point was death, myocardial infarction, recurrent ischemia requiring rehospitalization, urgent revascularization, or stroke. The trial was terminated prematurely because of an unexpected increase in 30-day mortality in the 50/30 orbofiban group. Mortality through 10 months was 3.7% for the placebo group versus 5.1% in the 50/30 group (P=0.008) and 4.5% in the 50/50 group (P=0.11). There were no differences in the primary end point (22.9%, 23.1%, and 22.8%, for the placebo, 50/30, and 50/50 groups, respectively). Major or severe bleeding (but not intracranial hemorrhage) was higher with orbofiban; it occurred in 2. 0%, 3.7% (P=0.0004), and 4.5% (P<0.0001) of patients, respectively. Exploratory subgroup analyses found that patients who underwent percutaneous coronary intervention had a lower mortality and a significant reduction in the composite end point (P=0.001) with orbofiban. CONCLUSIONS: -Fixed-dose orbofiban failed to reduce major cardiovascular events and was associated with increased mortality in this broad population of patients with acute coronary syndromes; however, a benefit was observed among patients who underwent percutaneous coronary intervention.

Graft material and results of platelet inhibitor trials in peripheral arterial reconstructions: reappraisal of results from a meta-analysis.

AIMS: To investigate the characteristics of published trials in order to establish the origin of the differing results obtained in trials of platelet inhibitors after peripheral bypass procedures. METHODS: Analysis of the information from 11 randomised, controlled trials of platelet inhibitors after peripheral bypass procedures published up until 1999 and involving 2302 patients undergoing peripheral bypass operations, 1250 of whom were treated with platelet inhibitors. RESULTS: There is a significant treatment benefit of platelet inhibitors on meta-analysis of the trials, but a significant heterogeneity amongst the individual trial results. The proportion of patients in a trial with prosthetic grafts was a significant factor in explaining the heterogeneity. Proportion of prosthetic grafts was associated with sample size and with the proportion of grafts above the knee, but these were not found to make an independent contribution to the heterogeneity observed. The platelet inhibitor regimen used, the severity of ischaemic symptoms and the proportion of smokers included were also not found to be important. CONCLUSIONS: The improvement of graft patency by aspirin and related platelet inhibitors in clinical trials in peripheral bypass procedures can be attributed to an effect on patients with prosthetic grafts. There is little evidence that these agents prevent occlusion of vein grafts. The conclusion of an earlier meta-analysis that antiplatelet agents should be used for all bypasses is not supported.

What should we do? Papillary thyroid carcinoma in a lymph node but normal thyroid tissue--how should we proceed?

Papillary cell carcinoma of the thyroid is a relatively indolent disease, usually presenting as an asymptomatic mass in the thyroid gland that is either noted by the patient or diagnosed at routine clinical examination. Although the prognosis is generally good there are a number of controversies in the management of this condition. The significance of age at presentation, size of the tumour and the presence of lymph node metastasis are still disputed. We present the unusual case of a woman found to have papillary cell thyroid carcinoma within a lymph node during a cosmetic thyroid lobectomy. The thyroid tissue removed was not found to contain tumour. We describe the evidence behind the decision to proceed to total thyroidectomy and the finding of a tiny focus of papillary cell thyroid carcinoma within the contralateral lobe.

Influence of ambulance crew's length of experience on the outcome of out-of-hospital cardiac arrest.

AIMS: To investigate whether an ambulance crew's length of experience affected the outcome of out-of-hospital cardiac arrest. METHODS AND RESULTS: This was a population-based, retrospective observational study of attempted resuscitations in 1547 consecutive arrests of cardiac aetiology by Nottinghamshire Emergency Ambulance Service crew. One thousand and seventy-one patients were managed by either a paramedic or a technician crew without assistance from other trained individuals at the scene of arrest. Overall, the chances of a patient surviving to be discharged from hospital alive did not appear to be affected by the paramedic's length of experience (among survivors, 18 months experience vs non-survivors 16 months experience, P = 0.347) but there appears to be a trend in the effect of a technician's length of experience on survival (among survivors, 60 months experience vs non-survivors 28 months experience, P = 0.075). However, when a technician had 4 years of experience or more and a paramedic 1 year's experience, survival rates did improve. Logistic regression analysis, adjusted for factors known to influence outcome, revealed that chances of survival increased once technicians had over 4 years of experience after qualification (odds ratio 2.71, 95% CI 1.17 to 6.32, P = 0.02) and paramedics after just 1 year of experience (odds ratio 2.68, 95% CI 1.05 to 6.82, P = 0.04). CONCLUSIONS: Survival from out-of-hospital cardiac arrest varies with the type of ambulance crew and length of experience after qualification. Experience in the field seems important as paramedics achieve better survival rates after just 1 year's experience, while technicians need to have more than 4 years' experience to improve survival.

Relevance of clinical trial results in myocardial infarction to medical practice: comparison of four year outcome in participants of a thrombolytic trial, patients receiving routine thrombolysis, and those deemed ineligible for thrombolysis.

OBJECTIVE: To assess the medium to long term outcome of patients ineligible for thrombolysis compared to those enrolled in a clinical trial of thrombolysis and patients receiving non-trial thrombolysis. DESIGN: Cohort study based on the Nottingham heart attack register. SETTING: Two district general hospitals serving a defined urban/rural population. SUBJECTS: All patients admitted with a confirmed acute myocardial infarction during 1992 categorised as either participants of a thrombolytic trial (group A, n = 140), receiving non-trial thrombolysis (group B, n = 329), or deemed ineligible for lytic treatment (group C, n = 431). MAIN OUTCOME MEASURES: Background characteristics, inhospital treatment, patterns of follow up, referrals to cardiologists, revascularisation rates, and short and long term survival. RESULTS: Clinical trial recruits were younger by almost 10 years, were less likely to have a previous history of myocardial infarction, and more likely to be in Killip class 1 on admission than those ineligible for thrombolysis. Cardiology follow up was mandatory for all surviving trial participants but 22% of patients in group B and 31% of patients in group C received no follow up, and during four years less than 50% ever saw a cardiologist. Revascularisation was performed in 17.2% of patients in group A, 13.6% of patients in group B, and 7.5% of patients in group C. Cumulative mortality at a median of four years was 24.3% in group A, 36.8% in B, and 59.6% in group C. Adjusting for age, sex, previous myocardial infarction, type of infarction, and Killip class in a logistic regression model the odds ratios (OR) of death at four years for groups B and C were 1.60 (95% confidence intervals (CI) 0.97 to 2.63, p = 0.065) and 2.64 (95% CI 1.61 to 4. 32, p < 0.001), respectively, when compared to group A (OR 1). CONCLUSIONS: Patients enrolled into thrombolytic trials are at low risk. Patients deemed ineligible for thrombolysis are high risk, receive less surveillance, are less likely to be revascularised or receive trial proven treatments, have a poor long term outcome not entirely explained by increased age or severity of infarction, and deserve further evaluation.

Resuscitation from out-of-hospital cardiac arrest: is survival dependent on who is available at the scene?

OBJECTIVE: To determine whether survival from out-of-hospital cardiac arrest is influenced by the on-scene availability of different grades of ambulance personnel and other health professionals. DESIGN: Population based, retrospective, observational study. SETTING: County of Nottinghamshire with a population of one million. SUBJECTS: All 2094 patients who had resuscitation attempted by Nottinghamshire Ambulance Service crew from 1991 to 1994; study of 1547 patients whose arrest were of cardiac aetiology. MAIN OUTCOME MEASURES: Survival to hospital admission and survival to hospital discharge. RESULTS: Overall survival from out-of-hospital cardiac arrest remains poor: 221 patients (14.3%) survived to reach hospital alive and only 94 (6.1%) survived to be discharged from hospital. Multivariate logistic regression analysis showed that the chances of those resuscitated by technician crew reaching hospital alive were poor but were greater when paramedic crew were either called to assist technicians or dealt with the arrest themselves (odds ratio 6.9 (95% confidence interval 3.92 to 26.61)). Compared to technician crew, survival to hospital discharge was only significantly improved with paramedic crew (3.55 (1.62 to 7.79)) and further improved when paramedics were assisted by either a health professional (9.91 (3.12 to 26.61)) or a medical practitioner (20.88 (6.72 to 64.94)). CONCLUSIONS: Survival from out-of-hospital cardiac arrest remains poor despite attendance at the scene of the arrest by ambulance crew and other health professionals. Patients resuscitated by a paramedic from out-of-hospital cardiac arrest caused by cardiac disease were more likely to survive to hospital discharge than when resuscitation was provided by an ambulance technician. Resuscitation by a paramedic assisted by a medical practitioner offers a patient the best chances of surviving the event.

Quality of life four years after acute myocardial infarction: short form 36 scores compared with a normal population.

OBJECTIVES: To assess the impact of myocardial infarction on quality of life in four year survivors compared to data from "community norms", and to determine factors associated with a poor quality of life. DESIGN: Cohort study based on the Nottingham heart attack register. SETTING: Two district general hospitals serving a defined urban/rural population. SUBJECTS: All patients admitted with acute myocardial infarction during 1992 and alive at a median of four years. MAIN OUTCOME MEASURES: Short form 36 (SF 36) domain and overall scores. RESULTS: Of 900 patients with an acute myocardial infarction in 1992, there were 476 patients alive and capable of responding to a questionnaire in 1997. The response rate was 424 (89. 1%). Compared to age and sex adjusted normative data, patients aged under 65 years exhibited impairment in all eight domains, the largest differences being in physical functioning (mean difference 20 points), role physical (mean difference 23 points), and general health (mean difference 19 points). In patients over 65 years mean domain scores were similar to community norms. Multiple regression analysis revealed that impaired quality of life was closely associated with inability to return to work through ill health, a need for coronary revascularisation, the use of anxiolytics, hypnotics or inhalers, the need for two or more angina drugs, a frequency of chest pain one or more times per week, and a Rose dyspnoea score of >/= 2. CONCLUSIONS: The SF 36 provides valuable additional information for the practising clinician. Compared to community norms the greatest impact on quality of life is seen in patients of working age. Impaired quality of life was reported by patients unfit for work, those with angina and dyspnoea, patients with coexistent lung disease, and those with anxiety and sleep disturbances. Improving quality of life after myocardial infarction remains a challenge for physicians.

Multimodality treatment in the control of deep musculoaponeurotic fibromatosis.

BACKGROUND: Deep musculoaponeurotic fibromatoses are rare soft tissue neoplasms with a propensity for local recurrence. METHODS: A retrospective analysis was carried out of the factors contributing to local disease control in 75 patients treated between 1963 and 1993. RESULTS: Multivariate analysis identified the type of surgical excision (P < 0.001) and involvement of pathological resection margins (P < 0.02) as significant factors contributing to local recurrence. After a median follow up of 47 months (range 24 months to 29 years) 31 (49 per cent) of the 63 patients who had an 'adequate' surgical resection developed local recurrence. The median time before development of local recurrence was 83.4 (range 8-129) months in patients with clear pathological resection margins. This was significantly shortened to 13.1 (range 2-35) months in those with positive margins (P < 0.001). CONCLUSION: Adequate surgical extirpation is the most important determinant in local disease control. Treatment of local recurrence ranged from observation during periods of disease stabilization to multimodality treatment for aggressive disease.

Inpatient deaths from acute myocardial infarction, 1982-92: analysis of data in the Nottingham heart attack register.

OBJECTIVE: To assess longitudinal trends in admissions, management, and inpatient mortality from acute myocardial infarction over 10 years. DESIGN: Retrospective analysis based on the Nottingham heart attack register. SETTING: Two district general hospitals serving a defined urban and rural population. SUBJECTS: All patients admitted with a confirmed acute myocardial infarction during 1982-4 and 1989-92 (excluding 1991, when data were not collected). MAIN OUTCOME MEASURES: Numbers of patients, background characteristics, time from onset of symptoms to admission, ward of admission, treatment, and inpatient mortality. RESULTS: Admissions with acute myocardial infarction increased from 719 cases in 1982 to 960 in 1992. The mean age increased from 62.1 years to 66.6 years (P < 0.001), the duration of stay fell from 8.7 days to 7.2 days (P < 0.001), and the proportion of patients aged 75 years and over admitted to a coronary care unit increased significantly from 29.1% to 61.2%. A higher proportion of patients were admitted to hospital within 6 hours of onset of their symptoms in 1989-92 than in 1982-4, but 15% were still admitted after the time window for thrombolysis. Use of beta blockers increased threefold between 1982 and 1992, aspirin was used in over 70% of patients after 1989, and thrombolytic use increased 1.3-fold between 1989 and 1992. Age and sex adjusted odds ratios for inpatient mortality remained unchanged over the study period. CONCLUSIONS: Despite an increasing uptake of the "proved" treatments, inpatient mortality from myocardial infarction did not change between 1982 and 1992.

Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure. Second Prospective Randomised Study of Ibopamine on Mortality and Efficacy (PRIME II) Investigators.

BACKGROUND: Drugs that improve symptoms in patients with heart failure must also be assessed for their effects on survival. Ibopamine stimulates DA-1 and DA-2 receptors and causes peripheral and renal vasodilatation; the drug improves symptoms of heart failure. We assessed the effect of ibopamine on survival in patients with advanced heart failure in a multicentre, randomised placebo-controlled study. METHODS: Patients with advanced severe heart failure (New York Heart Association classes III and IV) and evidence of severe left-ventricular disease, who were already receiving optimum treatment for heart failure, were randomly allocated oral ibopamine 100 mg three times daily or placebo. The primary endpoint was all-cause mortality. The study was designed to recruit 2200 patients, and the minimum duration of treatment would be 6 months. We did intention-to-treat and on-treatment analyses; a post-hoc subgroup analysis was also done. FINDINGS: After we had recruited 1906 patients the trial was stopped early, because of an excess of deaths among patients in the ibopamine group. 232 (25%) of 953 patients in the ibopamine group died, compared with 193 (20%) of 953 patients in the placebo group (relative risk 1.26 [95% CI 1.04-1.53], p = 0.017). The average length of follow-up was 347 days in the ibopamine group and 363 days in the placebo group. In multivariate analysis, only the use of antiarrhythmic drugs at baseline was a significant independent predictor of increased fatality in ibopamine-treated patients. INTERPRETATION: Ibopamine seems to increase the risk of death among patients with advanced heart failure who are already receiving optimum therapy, but the reasons for this increase are not clear. Our finding that antiarrhythmic treatment was a significant predictor of increased mortality in ibopamine-treated patients may be important, but exploratory analyses must be interpreted with caution.