Long-term treatment of patients with gastro-oesophageal reflux disease in routine care - results from the ProGERD study.

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is a common condition frequently requiring long-term pharmacological treatment. AIM: To describe the long-term pattern of GERD medication use in GERD patients receiving routine care. METHODS: Patients were recruited as part of the ongoing ProGERD study, a 10-year-cohort study including 6215 patients at baseline. GERD medication and symptoms were assessed with patient questionnaires. During follow-up, medical treatment was prescribed by participating primary care physicians. Associations between patient characteristics and medication were analysed by logistic regression. RESULTS: The percentage of patients who reported using any GERD medication remained constant from year 1 to year 4 (74%, 74%, 73% and 71%). Of patients who reported using GERD medication, the majority were taking proton pump inhibitors (PPI) (79%, 84%, 85%, and 87%). Continuous PPI intake was the predominant prescription pattern (53%, 49%, 56% and 56%), followed by on-demand treatment (26%, 35%, 29% and 29%). Continuous PPI intake was strongly associated with the presence of erosive GERD. CONCLUSION: Three-quarters of the GERD population in our study reported long-term treatment with a PPI. Continuous PPI intake was the predominant treatment pattern, and the proportion of patients taking a PPI on a continuous basis remained constant over time.

Histological effects of esomeprazole therapy on the squamous epithelium of the distal oesophagus.

BACKGROUND: Proton pump inhibitor therapy has been reported to reduce proliferative changes of the oesophagus significantly in gastro-oesophageal reflux disease (GERD). AIM: To assess the histological effects of esomeprazole treatment on the oesophagus. METHODS: Data were derived from a subgroup of patients participating in the proGERD study, who had either erosive reflux disease (n = 720) or non-erosive reflux disease (n = 35) and who had biopsy data from two sites [(i) 2 cm above the z-line and (ii) at the z-line], obtained at baseline and following treatment with esomeprazole. Proliferative changes of the squamous epithelium were assessed histologically by measuring thickness of the basal cell layer and elongation of the papillae as a percentage of the whole epithelial thickness. RESULTS: In erosive reflux disease patients, the thickness of the basal cell layer and length of the papillae pretreatment were associated with the severity of oesophagitis (P < 0.05), at both biopsy sites. After esomeprazole treatment, baseline thickness and length of papillae were significantly reduced (P < 0.05) at both biopsy sites in non-erosive reflux disease and erosive reflux disease patients (particularly those with Los Angeles grades C and D). CONCLUSION: This demonstrates a strong correlation between severity of GERD and histological parameters. Esomeprazole therapy resulted in clear reversal of proliferative changes observed prior to treatment in the squamous epithelium at both biopsy locations.

Cost-of-disease analysis in patients with gastro-oesophageal reflux disease and Barrett's mucosa.

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is a common and frequently chronic condition that causes considerable costs. AIM: To estimate the economic burden caused by patients with erosive and non-erosive reflux disease, and Barrett's oesophagus. METHODS: The Progression of Gastro-oesophageal Reflux Disease study includes a total of 6,215 patients. At baseline, patients were categorized as non-erosive reflux disease, erosive reflux disease, or Barrett's oesophagus according to endoscopic findings alone or as confirmed by histology. Direct and indirect disease-related costs were calculated based on 5,273 patients with complete information in the second year of the study. RESULTS: A total of 73% of the Progression of Gastro-oesophageal Reflux Disease patients had taken GERD medication, 61% had visited a doctor, and 2% had been hospitalized because of GERD during the previous 12 months. Of all employed persons, 6% reported days off work because of GERD. This health resource utilization caused direct costs of 342+/-864 (mean+/-s.d.) and indirect costs of 40+/-473 per patient and year. Total costs for patients with Barrett's oesophagus or erosive reflux disease were higher than those for patients with non-erosive reflux disease. CONCLUSION: Patients with GERD frequently need long-term medication and doctor care. The disorder is associated with a considerable health economic burden to society.

Long-term clinical course of extra-oesophageal manifestations in patients with gastro-oesophageal reflux disease. A prospective follow-up analysis based on the ProGERD study.

BACKGROUND: Gastro-oesophageal reflux disease can be associated with extra-oesophageal reflux disease such as chronic cough or laryngeal symptoms. The aim of this study was to analyse the clinical course of extra-oesophageal reflux disease in a large population with gastro-oesophageal reflux disease and extra-oesophageal reflux disease under routine clinical care. METHODS: ProGERD is a prospective multicentre cohort study of 6215 outpatients with gastro-oesophageal reflux disease. At baseline all patients underwent endoscopies and were interviewed for extra-oesophageal reflux disease. Initial standardised treatment was esomeprazole for up to 8 weeks. After 2 years of follow-up, reflux symptoms and the prevalence of extra-oesophageal reflux disease were assessed. A multivariate analysis was performed with resolved versus persistent symptoms for chronic cough and laryngeal symptoms as dependent predictors. Independent variables were gender, age, body mass index (BMI), alcohol consumption, cigarette smoking, gastro-oesophageal reflux disease classification, history of gastro-oesophageal reflux disease in the family, duration of gastro-oesophageal reflux disease and proton pump inhibitors medication. RESULTS: Four thousand four hundred and four patients (71%) were available for analysis at 2 years, including 570 and 454 patients who had chronic cough and laryngeal disorders at baseline, respectively. In 63% and 74% of the patients, chronic cough and laryngeal disorders had resolved. Patients with persistent respiratory symptoms in year 2 had significantly more reflux symptoms. Further clinically relevant associations were smoking and non-steroidal anti-inflammatory drugs use. According to the multivariate analysis, classification of gastro-oesophageal reflux disease, proton pump inhibitors medication or duration of gastro-oesophageal reflux disease were not associated with the resolution of cough or laryngeal symptoms. CONCLUSION: In most patients with gastro-oesophageal reflux disease and extra-oesophageal reflux disease, respiratory symptoms resolve during long-term routine care. A high reflux symptom load was associated with the persistence of respiratory disorders.

Prognostic influence of Barrett's oesophagus and Helicobacter pylori infection on healing of erosive gastro-oesophageal reflux disease (GORD) and symptom resolution in non-erosive GORD: report from the ProGORD study.

BACKGROUND: Adequacy of acid suppression is a critical factor influencing healing in gastro-oesophageal reflux disease (GORD). The European prospective study ProGORD was set up to determine the endoscopic and symptomatic progression of GORD over five years under routine care, after initial acid suppression with esomeprazole. We report on factors influencing endoscopic healing and symptom resolution during the acute treatment phase. METHODS: Patients with symptoms suggestive of GORD underwent endoscopy and biopsies were obtained from the oesophagus for diagnosis of abnormalities, including Barrett's oesophagus (BO). Data from 6215 patients were included in the "intention to treat" analysis, 3245 diagnosed as having erosive reflux disease (ERD) and 2970 non-erosive reflux disease (NERD). ERD patients were treated with esomeprazole 40 mg for 4-8 weeks for endoscopic healing while NERD patients received 20 mg for 2-4 weeks for resolution of heartburn symptoms. RESULTS: Endoscopic healing occurred overall in 87.7% of ERD patients although healing was significantly lower in those with more severe oesophagitis (76.9%) and in those with BO (72.4%), particularly in Helicobacter pylori negative BO patients (70.1%). Age, sex, and body mass index appeared to have no significant impact on healing. Complete heartburn resolution was reported by 70.4% of ERD patients and by 64.8% of NERD patients at the last visit. Only H pylori infection had a significant influence on complete heartburn resolution in the NERD group (68.1% and 63.7% for H pylori positive and H pylori negative, respectively; p = 0.03). CONCLUSION: The presence of Barrett's mucosa, as well as severe mucosal damage, exerts a negative impact on healing. H pylori infection had a positive influence on healing in ERD patients with coexistent BO but no influence on those without BO.

What parameters are relevant for the histological diagnosis of gastroesophageal reflux disease without Barrett's mucosa?

BACKGROUND/AIMS: There are still ongoing controversies as to which histological parameters allow the diagnosis of gastroesophageal reflux disease (GERD). The aim of the present analysis was to relate histological changes of the esophageal squamous epithelium to different severities of GERD. METHODS: Data were obtained from patients participating in the ProGERD study, who had either erosive reflux disease (ERD, n = 3,245) or non-erosive reflux disease (NERD, n = 2,970). 1,475 patients fulfilled our requirement of having complete biopsy data from two sites (2 cm above the z-line and at the z-line). Changes in the squamous epithelium were assessed by measuring the thickness of the basal cell layer and elongation of the papillae as a percentage of the whole epithelial thickness and counting interepithelial inflammatory cells. RESULTS: The most useful parameters for histological assessment of GERD (given as means, 2 cm above the z-line and at the z-line, respectively) were elongation of the papillae: NERD 40.7 and 48.9%; ERD 46.1 and 54.9% and basal cell hyperplasia: NERD 12.7 and 17.9%; ERD 15.7 and 23.0%. The occurrence of intraepithelial lymphocytic infiltrates, however, is dependent on the severity of GERD, and they are more common than neutrophilic and eosinophilic granulocytes. CONCLUSION: This study shows that both NERD and ERD can be diagnosed histologically if biopsies are obtained from the distal esophagus or from the z-line. Intraepithelial inflammatory cells are rare and show a high specificity, but very low sensitivity.

The effect of adjustable dosing with budesonide/formoterol on health-related quality of life and asthma control compared with fixed dosing.

BACKGROUND: Budesonide/formoterol in a single inhaler is an effective therapy for asthma. We investigated whether adjustable maintenance dosing with budesonide/formoterol could maintain health-related quality of life (HRQL) and asthma control. PATIENTS/METHODS: Asthma patients (n = 4025) received budesonide/formoterol (Symbicort 160/4.5 microg) 2 inhalations twice daily (b.i.d.) for 4 weeks during run-in of this open, multicentre study. Patients were randomised to adjustable dosing (budesonide/formoterol 1 inhalation b.i.d.; stepping up to 2 or 4 inhalations bid for 1 week if asthma worsened) or fixed dosing (budesonide/formoterol 2 inhalations b.i.d.), for 12 weeks. Change in HRQL (standardised Asthma Quality of Life Questionnaire, AQLQ[S], score) during randomised treatment was the primary efficacy variable. Secondary variables included asthma control (peak expiratory flow [PEF], symptom-severity score, nocturnal awakenings, reliever-medication use) and study-medication intake. RESULTS: Clinically significant (> or = 0.5) improvements in AQLQ(S) score (mean 0.73), morning and evening PEF (mean 42.5 and 24.8 L/min, respectively), and symptom-severity score (mean 0.36) were achieved during run-in. The improvements were maintained in both groups although, overall, adjustable-dosing patients took fewer daily inhalations of budesonide/formoterol than fixed-dosing patients (mean 2.63 versus 3.82, p < 0.001). CONCLUSION: Adjustable maintenance dosing with budesonide/formoterol maintains HRQL and asthma control as effectively as fixed dosing and is associated with a reduced drug load overall.

Risk factors of gastroesophageal reflux disease: methodology and first epidemiological results of the ProGERD study.

OBJECTIVE: We describe the design and report the first results of the Progression of Gastroesophageal Reflux Disease (ProGERD) study, to our knowledge the largest prospective study of GERD patients. STUDY DESIGN AND SETTING: Patients were recruited at 1,253 centers in Germany, Austria, and Switzerland. Following an assessment of medical history, all patients were endoscoped and received esomeprazole for 2 to 8 weeks before entering the 5-year observational phase. RESULTS: A total of 6,215 patients (53% male, age 54+/-14) were included. Of these patients, 46% reported at least daily symptoms, 15% were unable to work at least once during the prior year, and 71% had visited a physician due to reflux symptoms. Barrett's esophagus (BE) was found in 11% of our GERD patients. In polychotomous regression analysis, the main factors related to the occurrence of the three GERD subgroups (nonerosive, erosive disease, and BE) were age, gender, duration of GERD, body mass index (BMI), smoking, and previous PPI use. Factors associated with longer disease duration were increasing age, male gender, BMI, increasing symptom severity, presence of erosive GERD or BE, positive family history, and smoking. CONCLUSION: The findings indicate that GERD is a great burden for patients, and has significant socioeconomic implications. The long-term follow-up period with further endoscopic and histologic evaluations, will help further our understanding of the natural course of the disease.

Quality of life in relation to symptoms in patients with gastro-oesophageal reflux disease-- an analysis based on the ProGERD initiative.

AIMS: To determine the impact of gastro-oesophageal reflux disease (GERD) on the quality of life, to assess changes in the quality of life during treatment with esomeprazole and to define factors that can predict these changes. METHODS: Patients with GERD (n=6215) were included in a prospective cohort study (ProGERD). All patients underwent endoscopy and received esomeprazole. At baseline and after 2 weeks of treatment, symptoms and quality of life were assessed. Factors that influenced changes in the quality of life were determined by multiple regression analyses. RESULTS: At baseline, the quality of life in GERD patients was lower than that in the general population, and was similar to that in patients after acute coronary events. No differences in symptoms or quality of life were observed between the subgroups of patients with non-erosive GERD, erosive GERD and Barrett's oesophagus. After treatment with esomeprazole, the symptoms and quality of life were improved in all subscales within 2 weeks (P<0.001). The mean score of the disease-specific quality of life instrument (Quality of Life in Reflux and Dyspepsia Patients) increased from 4.6 to 6.2 points, representing a highly relevant clinical improvement. The generic quality of life (SF-36) reached levels similar to those in the general population, but, again, no difference was found between the three different subgroups of GERD patients. The main factors associated with an improvement in the quality of life after treatment were symptom relief, severe erosive reflux disease, absence of extra-oesophageal disorders, avoidance of non-steroidal anti-inflammatory drug intake and positive Helicobacter pylori status. CONCLUSIONS: GERD causes a significant impairment in the quality of life that can be attenuated or normalized within a time period as short as 2 weeks by treatment with esomeprazole. These findings were similar across the whole GERD patient spectrum.

Prevalence of extra-oesophageal manifestations in gastro-oesophageal reflux disease: an analysis based on the ProGERD Study.

BACKGROUND AND AIMS: Gastro-oesophageal reflux disease (GERD) can be associated with a variety of extra-oesophageal disorders (EED) such as chronic cough, asthma, laryngeal disorder or chest pain. The aim of the study was to estimate and compare the prevalence of EED in a population with symptomatic GERD presenting as either erosive reflux disease (ERD) or non-erosive reflux disease (NERD). METHODS: Baseline data were collected from a prospective, multicentre, open cohort study (ProGERD) in which patients will be followed for 5 years after initial treatment with esomeprazole. Within the framework of this trial, all patients underwent gastroscopy and filled out a questionnaire designed to assess EED. The influence of potential prognostic factors on the prevalence of EED was analysed by multivariate (stepwise logistic regression) analysis. RESULTS: 6215 patients (3303 male, 2912 female; mean age 54 years) presenting with heartburn were included. EED was detected in 32.8% of all patients. The proportion was significantly higher (P = 0.0002) in ERD patients (34.9%) than in NERD patients (30.5%). As judged from the multivariate analysis, female gender, age, oesophagitis of LA grade C/D, duration of GERD disease greater than 1 years and smoking were significantly associated with EED. ERD patients with oesophagitis of LA grade A or B did not have a significantly higher risk of EED than patients with NERD. CONCLUSIONS: Patients with GERD have a high probability of experiencing EED, which may be associated with a number of prognostic factors such as duration and severity of GERD. Extra-oesophageal disorders are slightly, but statistically, more prevalent in ERD than in NERD patients.

A meta-analysis comparing eradication, healing and relapse rates in patients with Helicobacter pylori-associated gastric or duodenal ulcer.

AIM: To compare the effectiveness of Helicobacter pylori eradication in curing peptic ulcer disease in trials involving both gastric ulcer and duodenal ulcer. METHODS: Twenty-four relevant randomized controlled trials and randomized comparative trials met the predefined selection criteria. Only proton pump inhibitor-based eradication trials were considered for the evaluation of eradication efficacy and ulcer healing. For the determination of relapse rates, all trials independent of the eradication therapy regimen were considered. RESULTS: Data from 2102 patients were analysed comparing gastric ulcer with duodenal ulcer. No statistical differences between gastric ulcer and duodenal ulcer patients were found with regard to eradication rates (summarized odds ratio, 1.23; 95% confidence interval, 0.98-1.55) or ulcer relapse rates, whether in successfully H. pylori eradicated patients (summarized odds ratio, 0.69; 95% confidence interval, 0.26-1.84) or unsuccessfully H. pylori eradicated patients (summarized odds ratio, 1.48; 95% confidence interval, 0.85-2.56). Owing to heterogeneity, healing rates were not comparable. CONCLUSIONS: The eradication of H. pylori infection cures both gastric and duodenal ulcer, and the cure rates are similar. This suggests that H. pylori is the key factor in peptic ulcer disease independent of the ulcer site.

[Treatment of bronchial asthma using a new adjustable combination treatment plan: Asthma Control Plan (ATACO)]. / Die Behandlung des Asthma bronchiale nach einem neuen bedarfsorientierten Behandlungsplan: Asthma Control Plan (ATACO).

The current guideline of the German Respiratory League (Deutsche Atemwegsliga) recommends the synergistic combination therapy with long acting beta 2-agonists and inhalative corticosteroids only for patients suffering from moderate to severe persistent asthma (step 3 and 4 of the asthma severity scale). Now convenient fixed combinations of these substances are available, which could enhance patient's compliance. A large, randomised, parallel-group study in 8000 mild to moderate asthmatics was designed to compare a flexible asthma control plan with the conventional fixed-dose management with respect to quality of life, symptom control and treatment costs. The fixed combination of 6 micrograms Formoterol and 200 micrograms Budesonide per puff in a new dry powder device was applied either due to a novel flexible asthma control plan "ATACO" (group A) or as a standardised conventional dosing regimen (group B) inhaling two puffs b.i.d. In group A (ATACO) patients reduce the run-in dose after four weeks from two puffs b.i.d. to one puff b.i.d. with the option of doubling the dose immediately, if (pre-defined) asthma deterioration occurs. One week later the dose can be either doubled again or reduced due to the actual asthma symptoms of the patient. After run-in, group B patients continue to take two inhalations b.i.d. In this group, asthma exacerbations will be managed as usual by the physician. In contrast, the ATACO group flexible management plan allows the self-medication: an immediate increase in the dose of the fixed combination will lead to both a fast relief of bronchospasm and an automatically higher dosed corticosteroid treatment for the underlying asthmatic inflammation. Conversely, if later asthma symptoms improve, less reliever and controller medication will be needed and used. The immediate treatment of new onset bronchospasm and asthmatic inflammation by the patient himself could maintain at least the same grade of asthma control, as the conventional group B treatment, improve asthma-related quality of life and decrease treatment costs. If the concept works, fixed combinations of long-acting beta 2 agonists and inhalative corticosteroids could have an impact on future asthma guidelines.

Underestimation of 24-hour hypotensive efficacy of nifedipine GITS versus enalapril: ambulatory recording as an adjunct to clinical blood pressure measurement.

AIMS: Short-acting calcium entry blockers should be used primarily in slow-release form. Furthermore, studies of the antihypertensive efficacy of drugs can be negatively influenced by between 15% and 30% of the enrolled patients not being hypertensive according to ambulatory blood pressure (BP) measurement. Thus, a randomized double-blind multicenter parallel-group study was conducted to compare the effect of nifedipine GITS (gastrointestinal therapeutic system) with enalapril. METHODS AND RESULTS: After a 2-week placebo run-in period, 186 patients with a sitting diastolic BP > or = 95 mmHg were enrolled for an 8-week treatment period. They received 30-60 mg nifedipine GITS or 5-10 mg enalapril. Diastolic BP fell comparably from 99 to 87 mmHg (p < 0.01) in the nifedipine GITS group, and from 100 to 88 mmHg (p < 0.01) in the enalapril group. The increase in BP 2 h before waking, however, was suppressed significantly more by nifedipine. Furthermore, this study highlighted the existence of "whitecoat" hypertension in a number of patients, especially when clinical BP was used to identify hypertension. Of the patients who had been identified as hypertensive before randomization by standardized BP measurement, 53 (28.5%) were identified as non-hypertensives by 24-h BP monitoring. This led to an underestimation of the efficacy of the antihypertensive therapy. CONCLUSION: Nifedipine GITS as well as enalapril are comparably effective antihypertensive drugs.

Extent of early ST segment elevation resolution: a strong predictor of outcome in patients with acute myocardial infarction and a sensitive measure to compare thrombolytic regimens. A substudy of the International Joint Efficacy Comparison of Thrombolytics (INJECT) trial.

OBJECTIVES: This study was undertaken to assess prospectively the prognostic power of early ST segment elevation resolution in a large cohort of patients with myocardial infarction and to test the value of differences in ST segment resolution as a surrogate end point. BACKGROUND: Previous studies revealed that the use of two cutoff points for three groups of ST segment resolution within 3 h after the start of thrombolysis is most effective in predicting outcome. METHODS: The International Joint Efficacy Comparison of Thrombolytics (INJECT) trial compared mortality in 6,010 patients randomized to receive either reteplase or streptokinase. The 1,909 German patients form the basis of this substudy. The three groups of ST segment resolution were defined as complete (> or = 70%), partial (70% to 30%) and no resolution (< 30% to > or = 0%). RESULTS: In 1,398 patients presenting < or = 6 h from onset of acute myocardial infarction, the 35-day mortality rate for complete, partial and no ST segment resolution was 2.5%, 4.3% and 17.5%, respectively (p < 0.0001). Peak creatine kinase levels (fraction of normal) were 9.8, 13.4 and 14.0, respectively (p < 0.0001). When baseline characteristics were included, ST segment resolution was the most powerful independent predictor of 35-day mortality. The proportion of patients with complete ST segment resolution was larger, and that with no ST segment resolution smaller, with reteplase than with streptokinase (p = 0.006). CONCLUSIONS: No ST segment resolution, indicating failed thrombolysis, predicts very high early mortality, whereas complete resolution is associated with a small infarct area and low mortality. Partial ST segment resolution also predicts larger infarct areas, but early mortality is relatively low. Different extents of ST segment resolution may serve as a sensitive surrogate end point in clinical trials.

Antihypertensive treatment with a vasodilating beta-blocker, carvedilol, in chronic hemodialysis patients.

Carvedilol is an antihypertensive agent which displays unselective beta-blocking, alpha 1-blocking and antioxidant properties. It is primarily metabolized by the liver and excreted via the biliary system. The compound is highly lipophilic and strongly bound to plasma proteins. Consequently, there is no elimination during hemodialysis. The efficacy, safety, and pharmacokinetic profile of carvedilol titrated to effect were investigated in an open clinical trial in 15 long-term hemodialysis patients with arterial hypertension over a period of 12 weeks. The drug was administered only on days without dialysis. After a wash-out phase of one week, carvedilol was started in a dose of 12.5 mg per day. All 15 patients were titrated according to the antihypertensive effect to a daily dose of 25 mg of carvedilol. Carvedilol was effective in lowering blood pressure in hemodialysis patients (RR systolic: 170 +/- 11 vs. 144 +/- 9 mmHg; RR diastolic: 98 +/- 10 vs. 85 +/- 10 mmHg). The pharmacokinetic parameters of carvedilol and its active metabolite M2, assessed in 12 of the 15 patients, were not influenced by the lack of renal function or intermittend haemodialysis. In particular, there was no accumulation of carvedilol or its metabolite M2. In terms of side effects, three patients had to be withdrawn from the trial, because of hypoglycemia (n = 1), insufficient blood pressure control (n = 1) and prolonged hypotension (n = 1). Taken together, these results indicate that carvedilol is a safe and efficacious antihypertensive agent which can be used in patients maintained by maintenance dialysis treatment.

Dose finding with a novel recombinant plasminogen activator (BM 06.022) in patients with acute myocardial infarction: results of the German Recombinant Plasminogen Activator Study. A study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK).

OBJECTIVES: The aim of this study was to determine the appropriate dose of a novel recombinant tissue-type plasminogen activator (BM 06.022) for thrombolysis in patients with acute myocardial infarction. BACKGROUND: BM 06.022 is a mutant of tissue-type plasminogen activator expressed in Escherichia coli that can be given as a single bolus because of a prolonged half-life, which might obviate the need for complicated regimens. METHODS: BM 06.022 given as a single bolus was investigated in 142 patients in a multicenter sequential dose-finding study. Efficacy of the drug was assessed from infarct-related artery patency by coronary angiography. RESULTS: With the first dose of 10 MU of BM 06.022, the predefined minimal 90-min patency of 70% was not achieved, as indicated by the sequential probability ratio test after treatment of 42 patients (group A). The second dose of 15 MU of BM 06.022 was given subsequently in the preset maximum of 100 patients (group B). Angiography 30, 60 and 90 min after the bolus injection of BM 06.022 revealed a patent infarct-related artery (Thrombolysis in Myocardial Infarction trial [TIMI] grade 2 or 3) in 65% and 66%, 73% and 74% and 66% and 75% of patients in groups A and B, respectively. Very early reocclusion up to the 90-min angiogram occurred in 17% and 13%, late reocclusion until predischarge angiography occurred in 7% and 5%, and rescue percutaneous transluminal coronary angioplasty after the 90-min angiogram was performed in 6 and 14 patients in groups A and B, respectively. Plasma fibrinogen decreased from 2.79 g/liter (range 0.94 to 4.75) to 1.69 g/liter (range 0.0 to 3.95) in group A and from 2.54 g/liter (range 0.0 to 5.02) to 0.92 g/liter (range 0.0 to 2.68) in group B. Two bleeding complications requiring transfusion or surgical intervention and one nonfatal intracranial hemorrhage were encountered. Eight patients had a reinfarction, and five patients died, all of cardiac causes. CONCLUSIONS: With BM 06.022 given as a single bolus, a high early patency rate of the infarct-related coronary artery can be achieved. The speed of thrombolysis seems to be superior to standard thrombolytic drugs. The compound warrants further evaluation with respect to safety and efficacy by clinical end points.

Relationships between ambulatory blood pressure, forearm vascular resistance, and left ventricular mass in hypertensive and normotensive subjects.

Ambulant 24 h blood pressure was recorded in 97 untreated hypertensive subjects (50 with, 47 without echocardiographic signs of left ventricular hypertrophy) and 45 matched normotensive subjects. Forearm vascular resistance was calculated from mean blood pressure and blood flow, which was measured by venous plethysmography during reactive hyperemia. Blood pressure variability was calculated by standard deviations of pressure values. Systolic 24 h blood pressure exhibited the closest correlation with left ventricular mass index in hypertensives (4 = 0.48; P < .001). No relation could be found between blood pressure fall during the night and left ventricular mass index. Furthermore, body weight was a significant correlate of left ventricular mass (r = 0.53; P < .001). Regression analysis indicated that body weight and 24 h blood pressure were the principal determinants of left ventricular mass. Blood pressure variability was significantly higher in hypertensive than in normotensive subjects (P < .05). The highest vascular resistance was found in hypertensive patients with left ventricular hypertrophy compared with the other groups (P < .05). A significant close correlation between systolic resting as well as 24 h blood pressure and vascular resistance was identified for the group of hypertensives and all subjects investigated. Furthermore, left ventricular mass index and vascular resistance were correlated (in hypertensives: r = 0.32; P < .01). The extent of left ventricular mass index and forearm vascular resistance are proportional to the severity of hypertension. As vascular resistance and left ventricular mass are also related, these findings could speak for a parallel development of total peripheral resistance and left ventricular hypertrophy in essential hypertension.

Open, noncontrolled dose-finding study with a novel recombinant plasminogen activator (BM 06.022) given as a double bolus in patients with acute myocardial infarction.

The novel recombinant plasminogen activator (r-PA) (BM 06.022) is a mutant of tissue-type plasminogen activator expressed in escherichia coli which can be given as a bolus because of a prolonged half-life. The primary objective of this trial was to determine the efficacy of an intravenous r-PA double bolus (first bolus of 10 MU followed by 5 MU after 30 minutes) in patients with acute myocardial infarction. All patients received heparin intravenously and acetylsalicylic acid orally. Efficacy was assessed from infarct artery patency by coronary angiography (Thrombolysis in Myocardial Infarction trial perfusion grades 2 or 3) in 50 patients. Ninety minutes after administration of the first r-PA bolus, the infarct-related coronary artery was patent in 39 of 50 patients (78%; 95% confidence interval 64 to 88%). An angiographically confirmed reocclusion occurred in 1 patient between 90 minutes and 24 to 48 hours. The reocclusion rate was influenced by 8 interventions and 1 angiogram missing at 24 to 48 hours. Measurements of hemostatic parameters showed a decrease in fibrinogen to 37% of baseline value. There were 3 clinical reinfarctions before discharge and 2 major puncture site hemorrhages. No further serious bleeding and no serious adverse event with lethal outcome occurred. The 10 + 5 MU r-PA double bolus regimen appears to be effective with regard to patency and the success of thrombolysis. The incidence of reocclusion is very low. From the limited number of patients treated in this study, one need not be concerned about the safety profile of r-PA.

Relation of regression of left ventricular hypertrophy to changes in ambulatory blood pressure after long-term therapy with perindopril versus nifedipine.

Casual as well as ambulatory 24-hour blood pressure (BP) and echocardiographic parameters were studied in 40 patients with untreated or insufficiently treated mild to moderate essential hypertension. Left ventricular (LV) hypertrophy was assessed before and after 24 weeks of therapy with either the converting enzyme inhibitor perindopril or the calcium antagonist nifedipine. The design was a double-blind parallel study with a placebo run-in period. Patients received a daily oral dosage of either 4 to 8 mg of perindopril or 40 to 80 mg of nifedipine in slow-release form. A diuretic (25 mg/day of hydrochlorothiazide) was added in nonresponders (greater than 90 mm Hg casual diastolic BP). Once-daily perindopril and twice-daily nifedipine comparably reduced both casual and ambulatory BP throughout 24 hours (p less than 0.01) without affecting 24-hour heart rate. Six subjects withdrew from the nifedipine group and 4 from the perindopril group. After 12 and 24 weeks of therapy, LV hypertrophy was significantly reduced by both agents. Before active treatment was begun, LV mass index was more closely correlated to 24-hour (p less than 0.001) than to casual BP. This correlation disappeared after treatment with both agents. The correlation between ambulatory systolic day-time BP and LV mass was only still present (r = 0.54; p less than 0.05) after 24 weeks of treatment with nifedipine. It is concluded that regression of LV hypertrophy during converting enzyme inhibition or calcium antagonism may be partly independent of dosage and magnitude of 24-hour BP decrease.