Epoetin beta in the treatment of anemia in patients with advanced gastrointestinal cancer.

PURPOSE: The possibility that epoetin beta (EPO) could increase hemoglobin (B-Hb) levels and improve quality of life (QoL) in patients with advanced gastrointestinal cancers was investigated. PATIENTS AND METHODS: One hundred patients with gastric, pancreatic, biliary, or colorectal cancers and subnormal B-Hb levels were included in a randomized study to test low-dose EPO (2,000 U subcutaneously thrice weekly [2,000 group]) against a higher dose (10,000 U times three [10,000 group]). Eighty-four patients were treated with chemotherapy. QoL was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 instrument. RESULTS: At baseline, mean B-Hb was 108 g/L with no difference between the groups. In the 10,000 group, an increase in B-Hb (>10 g/L) was seen in 30 (73%) patients treated with chemotherapy, after a median of 4 weeks, whereas a corresponding increase in the 2,000 group was seen in 15 (30%) patients after a median of 10 weeks (P < .001). A difference in the proportion of responders (five of eight v one of eight) was also seen in the group of patients not treated with chemotherapy. The proportion of responders was independent of baseline endogenous serum EPO level or observed/predicted log10 serum (S)-EPO levels. Patients who demonstrated improved B-Hb levels also showed improvements in QoL parameters. Tumor response was usually also associated with QoL improvements. CONCLUSION: Treatment with EPO at a dose of 10,000 U thrice weekly can rapidly and safely increase B-Hb levels in a high proportion of patients with advanced gastrointestinal cancers. QoL is influenced by the B-Hb increase, but also by the course of the underlying malignancy. It is therefore difficult to define clearly the clinical relevance of the B-Hb increase as such.

Preoperative autologous donation of 6 units of blood during rh-EPO treatment.

PURPOSE: To determine if donation of six units of blood in three weeks is possible with self-administered subcutaneous recombinant human erythropoietin (rhEPO) injections and oral iron treatment. METHODS: A prospective trial where a total of 32 otherwise healthy patients were phlebotomised before revision hip arthroplasty during rhEPO and oral iron treatment (ferrofumarate). Adverse events were noted and compliance was controlled. Routine laboratory tests were performed at each visit including reticulocytes and 2,3-DPG. The relative oxygen releasing capacity (RORC) and the oxygen releasing capacity (ORC) were calculated. Blood donation was postponed until the next visit if haemoglobin concentrations was < 115 g.l-1 (men) or < 105 g.l-1 (women). RESULTS: All but two patients were able to donate six units of blood with an acceptable haemoglobin concentration on the day of operation. One serious adverse event occurred when the Hb was 119 g.l-1, compared with 149 g.l-1 before treatment. During the first two weeks before phlebotomy there was no increase in Hb, the mean nadir was reached after six phlebotomies (31 g.l-1 below pre-study level), while at operation it was 19 g.l-1 below pre-study level. There was an increase in 2,3-DPG and oxygen releasing capacity after the initiation of rhEPO therapy, before the first phlebotomy. CONCLUSION: It is possible to donate six units of blood in a three week period before surgery during self-administered subcutaneous rhEPO treatment and oral iron therapy at a rhEPO dose of 60 U.kg-1 BW three times a week. It is suggested that rhEPO per se initiates a right-shift of the oxygen dissociation curve via an increased 2,3-DPG level, which could explain that some patients report subjective benefit of rhEPO in spite of no change in Hb concentration.

Subcutaneous epoetin beta in renal anemia: an open multicenter dose titration study of patients on continuous peritoneal dialysis.

OBJECTIVE: To establish dose requirements (target hemoglobin > 100 g/L) and safety of subcutaneously administered epoetin beta. DESIGN: Open multicenter study. PATIENTS: Forty-five anemic patients (21 female, 24 male; mean age 55 years; range 20-79 years) who had been on continuous peritoneal dialysis for 1-157 months (mean 24 months). Thirty patients required blood transfusions during the year prior to the study. Mean hemoglobin concentration pretreatment was 75 g/L (range 57-89 g/L). INTERVENTION: After a pretreatment period of two weeks, 60 IU kg-1 week-1 divided into three weekly doses of epoetin beta was administered subcutaneously. The dose was increased by 60 IU kg-1 week-1 after ten weeks, and when necessary, every fourth week in patients with hemoglobin levels below 100 g/L. MAIN OUTCOME MEASURES: Hemoglobin concentration. Analysis of factors affecting the response to epoetin beta. Safety of epoetin beta. RESULTS: Thirty-eight of the 45 patients completed six months and 21 patients completed one year in the study. Twenty-six patients reached hemoglobin 100 g/L within six months and 8 patients did later on. The mean hemoglobin concentration after three months was 93 g/L (range 64-144 g/L) and after six months was 99 g/L (range 59-130 g/L; mean epoetin beta dose 122 IU kg-1 week-1). During the second six-month period of the study, hemoglobin levels were stable in most patients. After one year, the mean hemoglobin was 110 g/L (range 84-153 g/L) and the mean epoetin beta dose was 107 IU kg-1 week-1. Prolonged correction time and impaired response to epoetin were observed in patients with infections or hemorrhages and in patients with low hemoglobin concentration before starting epoetin treatment. Iron deficiency was controlled by iron supplementation, either orally or, in 10 patients, intravenously. Increased blood pressure, requiring intensified antihypertensive treatment, was observed in 13 patients. CONCLUSIONS: Continuous peritoneal dialysis patients with moderate anemia (Hb 75-90 g/L) and without complicating disorders can be managed with subcutaneous doses of epoetin < 120 IU kg-1 week-1. The epoetin beta dose should be adjusted after the first month of treatment since most patients required higher doses than the initial 60 IU kg-1 week-1.

Treatment of myelodysplastic syndromes with recombinant human erythropoietin.

12 patients with myelodysplastic syndromes were treated with recombinant human erythropoietin (r-epo). 5 patients had stable anemia, 78-92 g/l, and 7 were transfusion-dependent. In 11 patients, r-epo was given intravenously three times a week, with dose escalation after 4 and 8 wk if hemoglobin did not increase more than 15 g/l. The doses were 600, 1500 and 3000 U/kg bodyweight/wk. The 12th patient was treated subcutaneously with a dose of 560 U/kg/wk. 3 patients showed a significant response with an increase in hemoglobin of greater than or equal to 15 g/l. 2 of these had stable anemia before treatment and increased in hemoglobin from 87 to 116 g/l and from 80 to 99 g/l, respectively. The 3rd patient was transfusion-dependent and rose to a stable hemoglobin level between 76 and 80 g/l without transfusions. 2 patients showed a reduction of their transfusion need. Mean initial serum erythropoietin in the responding group was 366 U/l compared to 1049 among the non-responders (p = 0.367). Response was observed in 5/7 patients without bone marrow sideroblasts and in 0/5 patients with sideroblasts (p = 0.027). Erythropoietin seems to be an effective and well-tolerated treatment for a certain proportion of patients with MDS. A larger patient material might provide a model for predicting responses.

Cardiac dysrhythmias in patients with acute myocardial infarction. Relation to serum potassium level and prior diuretic therapy.

A series of 676 patients with acute myocardial infarction were evaluated with regard to initial serum potassium level, prior diuretic therapy and occurrence of cardiac dysrhythmias during their first 24 hours in a coronary care unit. Serious dysrhythmias (ventricular tachycardia, ventricular fibrillation, and asystole) were significantly more frequent in hypokalemic patients. In this regard no differences were observed between patients on or off prior diuretic therapy.

Pulmonary-artery cineangiocardiography to demonstrate cardiac thrombi in patients with cerebral infarction.

The usefulness of pulmonary-artery cineangiocardiography (PACAC) to demonstrate intracardiac thrombi in patients with cerebral infarctions of possible embolic origin has been explored. PACAC was performed in 60 patients (mean age 74 years) with sudden onset of permanent neurological deficits in whom CT scan and CSF analyses had excluded intracerebral hemorrhage. Opacification of the left atrium was excellent in 52 (87%) investigations, acceptable in 7 and poor in 1. Among 33 patients with chronic atrial fibrillation, an atrial thrombus was demonstrated in 8 (24%) and a suspected thrombus in 3. Atrial clot was also demonstrated in a patient with intermittent atrial fibrillation. In 4 out of 14 patients with previous myocardial infarction, a ventricular thrombus was demonstrated. Ventricular clots were detected in 2 of 46 patients without known previous myocardial infarction. No major complications occurred during the investigation. PACAC can be to used in the search for atrial or ventricular thrombi when cardiac source of a cerebral embolus is suspected. About 1 out of 3 patients with atrial fibrillation has remaining intracardiac thrombus after stroke.

A description of diagnostic strategies in jaundice.

Diagnostic strategies applied in 144 consecutive patients with jaundice were investigated. Diagnostic hypotheses formed on the basis of initial data--history, physical findings, and results of routine laboratory tests--enabled the clinician to adopt a single-target strategy in 75 patients and a multi-target strategy in 61 patients. Four patients died very early in the course of events and another four were excluded from analysis because they were judged not to benefit from further investigations. The single-target strategy, in which the clinician explored one diagnostic hypothesis only, often led to a short diagnostic process (mean, 11 days), and in 89% of the patients the clinician's hypothesis was correct. In the multi-target strategy several diagnostic hypotheses were evaluated. In these patients the correct diagnosis was included in the first set of hypotheses in 84%, and the mean duration of the diagnostic process was 25 days. Patients with cholestatic jaundice presented the most difficult diagnostic problem, and most of these were investigated by a multi-target strategy. The possibility of an extrahepatic obstruction often forced the clinician to use invasive procedures to rule out this diagnosis. Considerable time was spent in observing the clinical course and waiting for investigations to be carried out. To reduce the investigative cost, controlled studies of diagnostic value and optimal order of investigations are warranted.

Prognosis in acute stroke with special reference to some cardiac factors.

Neurological assessments were done regularly during hospitalization in 283 consecutive patients (mean age 73 yr) with acute cerebrovascular disease treated at the Stroke Unit of Serafimerlasarettet. A preplanned investigation program and strict criteria for diagnosis and treatment were followed. Hospital mortality was 18%. Patients with a major cerebral infarction or haemorrhage often died very early during the hospital period and deaths due to complications increased significantly during the second week. Multivariate analysis regarding mortality showed that a low neurological score and heart failure were the most important factors for the short-term prognosis. In those patients with cerebral infarction, ambulatory capacity and ECG-diagnosed bundle branch block added significantly to the prognostic power of the neurological score. Among the 227 patients discharged alive, 1 and 2-yr mortality was 14 and 18% respectively. Here, the most important long-term prognostic factors were age and ST changes on the ECG. Again, considering only patients with cerebral infarction (N = 190), bundle branch block was found to be the single most useful predictive factor. Prognostication in acute ischemic stroke should thus be based not only on neurological findings but on careful evaluation of associated cardiac disease, especially in the long-term perspective.

Accuracy of bedside diagnosis in stroke.

The clinical diagnosis of the type of acute cerebrovascular diseases is often considered unreliable, although this has not been validated prospectively in representative patients. The accuracy of bedside diagnostics was, therefore, tested in 206 patients consecutively admitted to the Stroke Unit of the Serafimerlasarettet in Stockholm. Bedside diagnosis turned out to be correct in 69%. In 24% the diagnoses were altered after hospital investigation and in the remaining 7% no defined preliminary and/or final diagnosis could be made. When the diagnoses were considered "fairly certain" they were accurate in 87%, compared to 53% when regarded as only "probable". The diagnostic accuracy improved during the period studied. Sensitivity in identifying hemorrhages was much lower (39%) than for cerebral infarctions (83%). It is suggested that new investigational methods should be compared with what can be accomplished with bedside methods alone.

QTc intervals in acute myocardial infarction: first-year prognostic implications.

Corrected QT (QTc) intervals were measured retrospectively in 160 consecutive survivors of acute myocardial infarction under 66 years of age. Calculations were made the first 2 d in the coronary care unit (CCU), the first post-CCU day, at discharge, and at 1-3, 6, and 12 months after discharge. All patients were in sinus rhythm and without bundle branch block at discharge from the hospital. Sixteen patients died during the first follow-up year. Twenty patients suffered a reinfarction, five of whom died. The highest QTc values were registered in the CCU and the lowest at the 1-year control. Patients with subendocardial infarcts had longer QTc intervals than those with transmural infarcts, especially during the acute phase. Patients with inferior infarcts had shorter QTc intervals during the CCU period. Those who reinfarcted or died a cardiac death (particularly when sudden) during the follow-up year had longer QTc intervals during the post-CCU phase. A multivariate analysis of risk factors revealed that the QTc interval at discharge was of significant independent value for predicting major cardiac events after discharge from the hospital. It is concluded that repeated measurements of QTc may be of value when assessing prognosis after acute myocardial infarction.

Lack of effect of theophylline on the outcome of acute cerebral infarction.

In patients with acute ischemic stroke, dramatic but often transient improvements have been noticed after theophylline injections. Whether better results could be obtained by continuous infusion of the drug was evaluated in a double-blind study. Out of 46 patients with a mean age of 75 years, 22 got theophylline as aminophylline (bolus dose of 230 mg followed by 0.5 mg/kg/h) and 24 placebo during 3 days. The groups were comparable in all aspects at the outset of the trial. Serum theophylline concentrations were kept within the therapeutic range recommended for patients with asthma. No significant difference in outcome was noticed between the groups during the hospital period when repeated neurological assessments by two different scores and mortality were compared.

QTc intervals at discharge after acute myocardial infarction and long-term prognosis.

QTc intervals were measured retrospectively in 46.3 survivors of AMI with a mean age of 65 years. The measurement was made one at discharge from hospital. Patients with anterior infarcts had significantly longer QTc intervals than those with inferior or uncertain infact localization. A weak but significant correlation was found between S-GOT maximum and QTc interval. Patients with ventricular arrhythmias in the CCU had longer QTc intervals. Patients with a poor long-term prognosis had significantly shorter QTc intervals. This finding was explained by digitalis therapy. Among patients without bundle branch block, digitalis and quinidine, those below 66 years of age who died within the first six months tended to have longer QTc intervals than the survivors. It is concluded that measurements of QTc interval at discharge have no long-term predictive value. This factor may, however, have some bearing on the short-term prognosis in younger patients without therapy which affects the QTc interval.

A study of stroke patients treated in a non-intensive stroke unit or in general medical wards.

To study the representativity and outcome of patients admitted to a stroke unit (SU) (n = 269), a comparison was made with all stroke patients treated in general medical wards (GMW) (n = 225) in the same hospital during two years. There was no difference between the patient groups regarding sex, age, previous cardiovascular diseases or neurological deficit on admission. As expected, more diagnostic examinations were performed in the SU than in the GMW where a diagnosis of ill-defined stroke was very frequent. A higher frequency of lumbar puncture with CSF spectrophotometry would have increased considerably the number of specific diagnoses in the GMW. Acute and, particularly, secondary prophylactic treatment was more often given in the SU. There was no difference between the patient groups regarding mortality or length of hospital stay.