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2.
Eur Heart J ; 23(3): 223-9, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11792137

ABSTRACT

AIMS: We evaluated the TIMI Risk Score for Unstable Angina and Non-ST Elevation Myocardial Infarction for predicting clinical outcomes and the efficacy of tirofiban in non-ST elevation acute coronary syndromes. METHODS AND RESULTS: Developed in TIMI 11B, the risk score is calculated as the sum of seven presenting characteristics (age > or =65 years, > or =3 cardiac risk factors, documented coronary disease, recent severe angina, ST deviation > or =0.5 mm, elevated cardiac markers, prior aspirin use). The risk score was validated in the PRISM-PLUS database (n=1915) and tested for interaction with the efficacy of tirofiban+heparin vs heparin alone. The risk score revealed an increasing gradient of risk for death, myocardial infarction or recurrent ischaemia at 14 days ranging from 7.7-30.5% (P<0.001). Dichotomized at the median, patients with a score > or =4 derived a greater relative risk reduction with tirofiban (P((Interaction))=0.025). Among patients with normal creatine kinase myocardial bands, the risk score showed a 3.5-fold gradient of risk (P<0.001) and identified a population that derived significant benefit from tirofiban (RR 0.73, P=0.027). CONCLUSION: The TIMI Risk Score is a simple clinical tool for risk assessment that may aid in the early identification of patients who should be considered for treatment with potent antiplatelet therapy.


Subject(s)
Coronary Disease/drug therapy , Electrocardiography , Platelet Aggregation Inhibitors/therapeutic use , Platelet Glycoprotein GPIIb-IIIa Complex/therapeutic use , Tyrosine/analogs & derivatives , Tyrosine/therapeutic use , Acute Disease , Aged , Angina, Unstable/blood , Angina, Unstable/drug therapy , Angina, Unstable/mortality , Anticoagulants/therapeutic use , Biomarkers/blood , Coronary Disease/blood , Coronary Disease/mortality , Creatine Kinase/blood , Creatine Kinase/drug effects , Creatine Kinase, MB Form , Endpoint Determination , Follow-Up Studies , Heparin/therapeutic use , Humans , Isoenzymes/blood , Isoenzymes/drug effects , Myocardial Infarction/blood , Myocardial Infarction/drug therapy , Myocardial Infarction/mortality , Predictive Value of Tests , Risk Assessment , Survival Analysis , Syndrome , Tirofiban , Treatment Outcome
3.
Ugeskr Laeger ; 163(40): 5514-9, 2001 Oct 01.
Article in Danish | MEDLINE | ID: mdl-11601117

ABSTRACT

INTRODUCTION: Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in type 1 diabetic patients, but similar data are not available for type 2, the most common form of diabetes. We assessed the role of the angiotensin II receptor antagonist, losartan, in type 2 diabetic patients with nephropathy. MATERIAL AND METHODS: One thousand five hundred and thirteen patients were enrolled in this randomised, placebo-controlled study of losartan (50 to 100 mg, once daily) or placebo, in addition to conventional antihypertensive treatment (calcium antagonists, diuretics, alpha- and beta-blockers, centrally acting agents) for a mean of 3.4 years. The primary outcome was the composite of doubling of baseline serum creatinine, end-stage renal disease, or death. Secondary end points included a composite of cardiovascular morbidity and mortality, proteinuria, and the progression rate of renal disease. RESULTS: Baseline demographics in the two groups were similar. Three hundred and twenty-seven patients receiving losartan reached the primary end point, as compared with 359 on placebo (risk reduction = 16 per cent, p = 0.02). Losartan reduced the incidence of doubling of serum creatinine (risk reduction = 25 per cent, p = 0.006) and end-stage renal disease (risk reduction = 28 per cent, p = 0.002), but had no effect on death. Benefits exceeded that attributable to changes in blood pressure. The composite of cardiovascular morbidity and mortality was similar in the two groups, except hospitalisation for heart failure, which was reduced with losartan (risk reduction = 32 per cent, p = 0.005). Proteinuria declined by 35 per cent with losartan (p < 0.001). DISCUSSION: Losartan conferred significant renal benefits in type 2 diabetic patients with nephropathy and was generally well tolerated.


Subject(s)
Angiotensin II/antagonists & inhibitors , Antihypertensive Agents/administration & dosage , Cardiovascular Diseases/drug therapy , Diabetes Mellitus, Type 2/complications , Diabetic Angiopathies/drug therapy , Diabetic Nephropathies/drug therapy , Losartan/administration & dosage , Adult , Aged , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Diabetes Mellitus, Type 2/drug therapy , Diabetic Angiopathies/etiology , Diabetic Angiopathies/prevention & control , Diabetic Nephropathies/etiology , Diabetic Nephropathies/prevention & control , Double-Blind Method , Humans , Male , Middle Aged , Renin-Angiotensin System/drug effects
4.
N Engl J Med ; 345(12): 861-9, 2001 Sep 20.
Article in English | MEDLINE | ID: mdl-11565518

ABSTRACT

BACKGROUND: Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy. METHODS: A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease. RESULTS: A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005). The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo). CONCLUSIONS: Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated.


Subject(s)
Angiotensin Receptor Antagonists , Antihypertensive Agents/therapeutic use , Cardiovascular Diseases/mortality , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/drug therapy , Kidney Failure, Chronic/prevention & control , Losartan/therapeutic use , Adult , Aged , Cardiovascular Diseases/epidemiology , Creatine/blood , Creatinine/blood , Diabetic Nephropathies/complications , Disease Progression , Double-Blind Method , Female , Humans , Hypertension/complications , Hypertension/drug therapy , Male , Middle Aged , Proteinuria/prevention & control
5.
Am J Cardiol ; 88(5): 488-92, 2001 Sep 01.
Article in English | MEDLINE | ID: mdl-11524055

ABSTRACT

Clinical outcomes of patients with unstable angina are variable. We sought to identify predictors of adverse clinical outcomes in patients with unstable angina and to investigate whether these factors would predict the magnitude of benefit achieved with platelet glycoprotein IIb/IIIa inhibition. We analyzed 20 variables in the 1,915 patients enrolled in the Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms trial. Five independent predictors were identified: age >65 years, prior coronary artery bypass grafting, antecedent aspirin use, antecedent beta-blocker use, and ST depressions on the presenting electrocardiogram. A risk score system was created using these predictors in which patients were assigned 1 point for the presence of each risk factor. There was a progressive increase in the rate of the composite end point of death, myocardial infarction, or refractory ischemia at 7 days with an increasing number of risk factors. For patients treated with heparin alone, the composite end point event rate was 6.5% in the group with 0 or 1 predictor, 14.6% in the group with 2 predictors, 22.7% in the group with 3 predictors, and 37.1% in the group with 4 or 5 predictors (p <0.00001). When dividing patients into low- (0 or 1 point), medium- (2 or 3 points), and high-risk (4 or 5 points) groups, the addition of tirofiban to heparin therapy was associated with no significant benefit in the low-risk group, a 5.2% absolute reduction in the medium-risk group (p = 0.05), and a 16% absolute reduction in the high-risk group (p = 0.0055). Thus, we have developed a risk score system using 5 variables that can be used to identify patients at high risk for death and cardiac ischemic events and who experience the greatest benefit from the addition of a glycoprotein IIb/IIIa inhibitor to their treatment regimen.


Subject(s)
Angina, Unstable/drug therapy , Electrocardiography , Heparin/administration & dosage , Myocardial Ischemia/diagnosis , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Tyrosine/administration & dosage , Adult , Age Distribution , Aged , Angina, Unstable/diagnosis , Angina, Unstable/mortality , Coronary Angiography , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Male , Middle Aged , Myocardial Ischemia/etiology , Myocardial Ischemia/prevention & control , Odds Ratio , Predictive Value of Tests , Probability , Proportional Hazards Models , Recurrence , Risk Assessment , Risk Factors , Sensitivity and Specificity , Severity of Illness Index , Sex Distribution , Survival Rate , Tirofiban , Treatment Outcome , Tyrosine/adverse effects , Tyrosine/analogs & derivatives
6.
Circulation ; 102(20): 2466-72, 2000 Nov 14.
Article in English | MEDLINE | ID: mdl-11076818

ABSTRACT

BACKGROUND: Diabetic patients who present with unstable angina or non-ST-elevation myocardial infarction suffer a substantially greater incidence of subsequent infarction or death compared with nondiabetic patients. The present study was undertaken to examine whether diabetic patients in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) study appeared to benefit from platelet glycoprotein IIb/IIIa receptor-mediated inhibition of platelet aggregation by tirofiban. METHODS AND RESULTS: Of the 1570 PRISM-PLUS patients treated with either tirofiban plus heparin (n=773) or heparin alone (n=797), approximately 23% in each treatment group were diabetic. A comparison of treatment outcomes in the diabetic subgroup revealed that the combination therapy compared with heparin alone was associated with reductions in the incidence of the composite primary end point of death, myocardial infarction (MI), or refractory ischemia at 2, 7, 30, and 180 days (7.7% versus 8.3%, 14. 8% versus 21.8%, 20.1% versus 29.0%, and 32.0% versus 39.9%, respectively; P=NS) and in the incidence of MI or death (0.0% versus 3.1%, P:=0.03; 1.2% versus 9.3%, P:=0.005; 4.7% versus 15.5%, P:=0. 002; and 11.2% versus 19.2%, P:=0.03). Tests for quantitative interaction between tirofiban therapy and diabetic status were significant. CONCLUSIONS: The addition of tirofiban to heparin and aspirin appears effective in the prevention of major ischemic events, particularly MI or death, in diabetic patients presenting with unstable angina and non-ST-elevation MI.


Subject(s)
Angina, Unstable/drug therapy , Diabetes Complications , Heparin/administration & dosage , Myocardial Infarction/drug therapy , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Tyrosine/analogs & derivatives , Tyrosine/administration & dosage , Aged , Angina, Unstable/complications , Anticoagulants/administration & dosage , Aspirin/therapeutic use , Disease Progression , Double-Blind Method , Drug Administration Schedule , Drug Therapy, Combination , Female , Heparin/adverse effects , Humans , Infusions, Intravenous , Likelihood Functions , Male , Middle Aged , Myocardial Infarction/complications , Platelet Aggregation Inhibitors/administration & dosage , Proportional Hazards Models , Survival Analysis , Tirofiban , Treatment Outcome , Tyrosine/adverse effects
7.
Circulation ; 100(15): 1609-15, 1999 Oct 12.
Article in English | MEDLINE | ID: mdl-10517731

ABSTRACT

BACKGROUND: The present study describes the effects of tirofiban, a nonpeptide platelet glycoprotein (GP) IIb/IIIa receptor blocker, on the characteristics of culprit lesions in patients with unstable angina (UA) or non-Q-wave myocardial infarction (NQWMI). METHODS AND RESULTS: Of 1915 patients enrolled in PRISM-PLUS, 1491 had a readable film obtained a median of 65 hours after randomization. A core laboratory examined the culprit lesions for intracoronary thrombus burden (primary end point) and for TIMI flow grade distribution and severity of the obstruction and of underlying coronary artery disease (secondary end points). The combination of tirofiban plus heparin compared with heparin alone significantly reduced the intracoronary thrombus burden of the culprit lesions (OR=0.77, P=0.022), improved the perfusion grade (OR=0.65, P=0.002), and decreased the severity of the obstruction (P=0.037), but it did not influence the severity of the underlying plaque. Persistence of a thrombus in 45% of patients was associated with a 2.4-fold increase in the odds of death at 30 days (P=0.005) and a 2-fold increase in the odds of myocardial infarction (P=0.002). CONCLUSIONS: The addition of tirofiban to heparin reduced the thrombus burden of the culprit lesion and improved distal perfusion in patients with UA or NQWMI, which supports the clinical benefit observed with the combination treatment.


Subject(s)
Angina, Unstable/drug therapy , Arteriosclerosis/complications , Coronary Artery Disease/complications , Coronary Thrombosis/drug therapy , Fibrinolytic Agents/therapeutic use , Heparin/therapeutic use , Myocardial Infarction/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Tyrosine/analogs & derivatives , Aged , Angina, Unstable/complications , Anticoagulants/administration & dosage , Anticoagulants/therapeutic use , Arteriosclerosis/diagnostic imaging , Coronary Angiography , Coronary Artery Disease/diagnostic imaging , Coronary Circulation/drug effects , Coronary Thrombosis/diagnostic imaging , Coronary Thrombosis/etiology , Double-Blind Method , Drug Therapy, Combination , Electrocardiography , Female , Fibrinolytic Agents/administration & dosage , Heparin/administration & dosage , Humans , Male , Middle Aged , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/etiology , Platelet Aggregation Inhibitors/administration & dosage , Tirofiban , Treatment Outcome , Tyrosine/administration & dosage , Tyrosine/therapeutic use
8.
Stat Med ; 18(10): 1249-60, 1999 May 30.
Article in English | MEDLINE | ID: mdl-10363343

ABSTRACT

Discriminant analysis is commonly used to classify an observation into one of two (or more) populations on the basis of correlated measurements. Classical discriminant analysis approaches require complete data for all observations. Our extension enables the use of all available longitudinal data, regardless of completeness. Traditionally a linear discriminant function assumes a common unstructured covariance matrix for both populations, which may be taken from a multivariate model. Here, we can model the correlated measurements and use a structured covariance in the discriminant function. We illustrate cases in which the estimated covariance structure is either compound symmetric, heterogeneous compound symmetric or heterogeneous autoregressive. Thus a structured covariance is incorporated into the discrimination process in contrast to standard discriminant analysis methodology. Simulations are performed to obtain a true measure of the effect of structure on the error rate. In addition, the usual multivariate expected value structure is altered. The impact on the discrimination process is contrasted when using the multivariate and random-effects covariance structures and expected values. The random-effects covariance structure leads to an improvement in the error rate in small samples. To illustrate the procedure we consider repeated measurements data from a clinical trial comparing two active treatments; the goal is to determine if the treatment could be unblinded based on repeated anxiety score measurements.


Subject(s)
Discriminant Analysis , Randomized Controlled Trials as Topic/statistics & numerical data , Anti-Anxiety Agents/therapeutic use , Computer Simulation , Female , Humans , Longitudinal Studies , Male , Models, Statistical , Sample Size
9.
Eur Heart J ; 20(2): 136-9, 1999 Jan.
Article in English | MEDLINE | ID: mdl-10099910

ABSTRACT

BACKGROUND: The CONSENSUS trial was the first study to show prognostic improvement by an ACE inhibitor. Patients in NYHA class IV heart failure were treated with enalapril or placebo. After study completion (average 183 days) all patients were offered open-label enalapril therapy. This paper reports on the survival at the 10-year follow up of the patients randomized in the CONSENSUS trial. METHODS: All 35 participating centres in CONSENSUS I were asked to complete a questionnaire on the survival status at 1 November 1996 of patients randomized in CONSENSUS. RESULTS: At 10-year follow up, one patient was lost to follow-up. Five patients, all in the enalapril group, were long-term survivors (P = 0.004). Averaged over the duration of the trial (double-blind plus open-label extension) the risk reduction was 30% (P = 0.008), with a 95% confidence interval of 11% to 46%. At the end of the double-blind study period, mortality was considerably higher among patients who did not receive open ACE inhibitor therapy compared to those who did. CONCLUSION: After a treatment period of, on average, 6 months, enalapril was shown to be effective. The effect was sustained for at least 4 years i.e. for another 3.5 years. The present follow-up is the first heart failure trial where the full life-cycle has been followed from randomization. In severe heart failure, mortality is significantly reduced by enalapril. On average, the beneficial effect is maintained for several years and overall survival time is prolonged by 50% (from 521 to 781 days).


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Cause of Death , Enalapril/therapeutic use , Heart Failure/drug therapy , Heart Failure/mortality , Double-Blind Method , Female , Follow-Up Studies , Humans , Male , Prognosis , Severity of Illness Index , Survival Rate
10.
J Biopharm Stat ; 8(2): 337-52, 1998 May.
Article in English | MEDLINE | ID: mdl-9598427

ABSTRACT

An investigator can compare two groups with respect to a continuous outcome variable, Y, by comparing the means of Y or by collapsing that variable into categories. For example, antihypertensive treatments can be compared on the basis of blood pressure measurements, or on the basis of the proportions of patients with blood pressure in prespecified ranges. This report is concerned with the loss of power when inherently continuous variables are dichotomized. The report will focus on the power loss when a normally distributed variable with a known, common variance in each of two groups is dichotomized. Power is shown to depend on the relationship between the means of the two groups and the cutoff point, and it varies from negligible to substantial. The results will be applied to data from the Lovastatin Restenosis Trial. Initially the trial considered a dichotomous outcome (proportion of patients with elevated percent diameter stenosis), but the endpoint was later changed to the mean percent diameter stenosis. The modification in the design of the trial was well justified because the power loss was considerable when comparing proportions.


Subject(s)
Research Design/statistics & numerical data , Algorithms , Drug Therapy , Humans , Population , Sample Size
11.
Biometrics ; 54(1): 209-18, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9574966

ABSTRACT

In some survival analysis applications, the endpoint of interest has a degree of uncertainty associated with it. These events are typically classified by the investigator or by an endpoint committee as true or false according to some decision rule, and the analysis proceeds using only the true endpoints. This procedure has two drawbacks: The cut point for the decision rule is somewhat arbitrary, and the information contained in the level of certainty is lost. This paper introduces a modification of the Cox regression model that allows all potential endpoints to be included in the analysis along with the level of certainty of each. Simulation results show this procedure to considerably increase the power of the standard procedure in a wide range of situations.


Subject(s)
Clinical Trials as Topic/statistics & numerical data , Survival Analysis , Angioplasty, Balloon , Biometry , Computer Simulation , Humans , Myocardial Infarction/prevention & control , Platelet Aggregation Inhibitors/therapeutic use , Proportional Hazards Models , Randomized Controlled Trials as Topic/statistics & numerical data , Tirofiban , Tyrosine/analogs & derivatives , Tyrosine/therapeutic use
12.
J Biopharm Stat ; 6(3): 241-51, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8854229

ABSTRACT

This paper describes a new statistical test for evaluating the efficacy of a combination therapy. This procedure is conservative and makes use of prior information in an attempt to improve power for a specific prespecified alternative. The power of this procedure is substantially greater than that of the min test when the effects of the components are equal or nearly equal and are accurately predicted. This procedure could be of value for evaluating combinations of well-studied drugs.


Subject(s)
Data Interpretation, Statistical , Drug Therapy, Combination , Humans , Mathematical Computing
13.
Am Heart J ; 132(1 Pt 1): 71-7, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8701878

ABSTRACT

Beta-blockers reduce infarct size and improve survival after acute myocardial infarction (MI). Post-MI angiotensin-converting enzyme inhibition also improves survival and may attenuate left ventricular (LV) dilatation. We evaluated the effect of early enalapril treatment on LV volumes and ejection fraction (EF) in patients on concomitant beta-blockade after MI. Intravenous enalaprilat or placebo was administered <24 hours after MI and was continued orally for 6 months. LV volumes were assessed by echocardiography 3 +/- 2 days, 1 and 6 months after MI. Change in LV diastolic volume during the first month was attenuated with enalapril (2.7 vs placebo 6.5 ml/m2 change; p < 0.05), and significantly lower LV diastolic and systolic volumes were observed with enalapril treatment compared with placebo at 1 month (enalapril 47.21 23.9 vs placebo 53.1/29.2 ml/m2; p < 0.05) and at 6 months (enalapril 47.9/24.8 vs placebo 53.8/29.6 ml/m2; p < 0.05). EF was also significantly higher 1 month after MI in these patients (enalapril 50.4% vs placebo 46.4%; p < 0.05). Our date demonstrate that early enalapril treatment attenuates LV volume expansion and maintains lower LV volumes and higher EF in patients receiving concurrent beta-blockade after MI. A possible additive effect of combined therapy should be evaluated prospectively.


Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Cardiac Volume/drug effects , Enalapril/therapeutic use , Myocardial Infarction/drug therapy , Stroke Volume/drug effects , Ventricular Function, Left/drug effects , Administration, Oral , Adrenergic beta-Antagonists/administration & dosage , Aged , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Diastole , Dilatation, Pathologic/prevention & control , Double-Blind Method , Enalapril/administration & dosage , Female , Heart Diseases/prevention & control , Humans , Injections, Intravenous , Male , Myocardial Infarction/pathology , Myocardial Infarction/prevention & control , Placebos , Prospective Studies , Survival Rate , Systole
14.
Arch Intern Med ; 156(3): 278-85, 1996 Feb 12.
Article in English | MEDLINE | ID: mdl-8572837

ABSTRACT

BACKGROUND: Angiotensin II acts at the cellular level through specific angiotensin II subtype I, AT-1 receptors. Losartan is the first of a new class of antihypertensive agents that specifically block angiotensin II at AT-1 receptors. By acting on complementary and different pharmacologic mechanisms, the concomitant use of low doses of hydrochlorothiazide with losartan may offer an additive antihypertensive activity with fewer adverse experiences. METHODS: This double-blind study evaluated losartan concomitantly administered with hydrochlorothiazide as initial therapy in 703 patients with essential hypertension. RESULTS: The greatest reduction in blood pressure was observed in the 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide group (17.2 mm Hg in sitting systolic blood pressure and 13.2 mm Hg in sitting diastolic blood pressure [P < or = .001]), and the effects of the two components appeared to be additive. Seventy-eight percent of the patients treated with 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide had an excellent or good antihypertensive response (sitting diastolic blood pressure < 90 mm Hg or > or = 90 mm Hg with a reduction of 10 mm Hg or more). Peak (6 hours after dosing) and trough placebo-adjusted ratios for the losartan-hydrochlorothiazide groups ranged from 62% to 85%, indicating that there was a smooth reduction in sitting diastolic blood pressure that was sustained over 24 hours. The most common clinical adverse experiences (> or = 4%) that occurred with an incidence slightly greater than that reported by the placebo-treated patients were headache, asthenia or fatigue, dizziness, sinusitis, and upper respiratory infection. CONCLUSION: The concomitant administration of losartan potassium, 50 mg, with 12.5 mg of hydrochlorothiazide once daily produced an additive reduction in trough sitting systolic and diastolic blood pressure and was well tolerated.


Subject(s)
Antihypertensive Agents/therapeutic use , Biphenyl Compounds/therapeutic use , Hydrochlorothiazide/therapeutic use , Hypertension/drug therapy , Imidazoles/therapeutic use , Tetrazoles/therapeutic use , Adult , Aged , Antihypertensive Agents/administration & dosage , Biphenyl Compounds/administration & dosage , Blood Pressure/drug effects , Double-Blind Method , Drug Administration Schedule , Drug Synergism , Drug Therapy, Combination , Female , Humans , Hydrochlorothiazide/administration & dosage , Hypertension/physiopathology , Imidazoles/administration & dosage , Losartan , Male , Middle Aged , Tetrazoles/administration & dosage , Treatment Outcome
15.
Clin Cardiol ; 17(4): 191-5, 1994 Apr.
Article in English | MEDLINE | ID: mdl-8187369

ABSTRACT

Due to its longer halflife, the N-terminal of ANF prohormone, ANF(1-98), has plasma concentrations that exceed those of ANF itself by a factor of 10 or more. It is also less prone to rapid changes secondary to hemodynamic alterations. To evaluate the prognostic significance of ANF(1-98) plasma levels in severe heart failure (NYHA IV), the peptide was measured by radioimmunoassay in plasma samples from patients randomized to additional treatment with enalapril (n = 78) or placebo (n = 61) (CONSENSUS study). In the placebo group there was a positive relation between mortality after 6 months and baseline ANF(1-98) level. Because of a reduced mortality, especially among patients with high ANF(1-98) levels, there was no such relation in the patients treated with enalapril. For both groups there was a positive relationship between increase in ANF(1-98) after 6 weeks of treatment and mortality, while a decrease signaled a favorable prognosis. It is concluded that the magnitude and changes of plasma ANF(1-98) provide information on prognosis and therapeutic effects with respect to mortality in patients with severe heart failure. Plasma ANF(1-98) may serve as a useful clinical biochemical parameter in the treatment of heart failure.


Subject(s)
Atrial Natriuretic Factor/blood , Heart Failure/blood , Heart Failure/drug therapy , Protein Precursors/blood , Aged , Enalapril/therapeutic use , Female , Humans , Life Tables , Male , Norepinephrine/blood , Peptide Fragments , Placebos , Prognosis , Survival Rate
16.
Aliment Pharmacol Ther ; 8(1): 71-9, 1994 Feb.
Article in English | MEDLINE | ID: mdl-8186349

ABSTRACT

METHODS: This US multicentre, randomized, double-blind, placebo-controlled, parallel group study determined the effects of two twice daily oral famotidine regimens on symptom relief and healing of erosive oesophagitis in patients with gastro-oesophageal reflux disease. Three hundred and eighteen patients were enrolled: 66 received placebo, 125 received famotidine 20 mg b.d., and 127 received famotidine 40 mg b.d. Patients maintained diaries of their symptoms. Endoscopy was performed at weeks 0 and 6, and again at week 12 if healing had not occurred. RESULTS: Healing at 6 and 12 weeks was (respectively) 48% (P < or = 0.01 vs. placebo) and 69% (P < or = 0.01 vs. placebo) for famotidine 40 mg b.d.; 32% and 54% (P < or = 0.01 vs. placebo) for famotidine 20 mg b.d., and 18% and 29% for placebo. At both 6 and 12 weeks the healing rates of famotidine 40 mg b.d. were significantly greater than placebo and famotidine 20 mg b.d. Compared to placebo, famotidine produced more frequent global symptom improvement and more rapid heartburn relief. There were no significant differences among treatment groups in the incidence of clinical or laboratory adverse events. CONCLUSIONS: Famotidine 40 mg b.d. was a better regimen than famotidine 20 mg b.d. or placebo. The clinical efficacy paralleled the previously documented effect of the famotidine regimens on decrease of oesophageal acid exposure.


Subject(s)
Esophagitis/drug therapy , Famotidine/administration & dosage , Gastroesophageal Reflux/complications , Administration, Oral , Adult , Double-Blind Method , Esophagitis/etiology , Famotidine/adverse effects , Famotidine/therapeutic use , Female , Humans , Male , Middle Aged
17.
Stat Med ; 12(5-6): 481-92, 1993 Mar.
Article in English | MEDLINE | ID: mdl-8493426

ABSTRACT

This paper illustrates aspects of data monitoring of clinical trials in the pharmaceutical industry. Formal interim analyses are performed at least in part to address the question of whether the trial should proceed or whether there should be an early termination of the trial. For formal interim analyses, frequently independent data and safety monitoring committees are utilized for monitoring clinical trials, and adjustments to nominal significance levels for test statistics are required. Various statistical methods developed during the last fifteen years are utilized. Administrative interim analyses are those analyses that are performed without any intention to stop the trial as a consequence of those analyses. For administrative interim analyses, adjustments to significance levels may not be required, but results must still be carefully interpreted. Regardless of the interim analyses performed, it is critical that the plans for interim analyses be identified in the study protocol, and the dissemination of interim results be carefully restricted. The following clinical trials sponsored by Merck Sharp and Dohme Research Laboratories (MSDRL) will illustrate these points: CONSENSUS; CONSENSUS II; 4S; Haemophilus influenza type b efficacy trial; famotidine in upper gastrointestinal haemorrhage, and a phase II analgesic study. It is anticipated that data monitoring and interim analysis activities will increase for future clinical trials due to the availability of appropriate statistical methods and improved data management systems.


Subject(s)
Clinical Trials as Topic/standards , Drug Industry , Humans , Professional Staff Committees , Statistics as Topic
18.
Stat Med ; 11(5): 659-72, 1992 Mar.
Article in English | MEDLINE | ID: mdl-1594808

ABSTRACT

Conditional probability procedures offer a flexible means of performing sequential analysis of clinical trials. Since these procedures are not based on repeated significance test, the number and schedule of the interim analyses is less important than with group sequential procedures. Their main disadvantage is that the magnitude of their effect on the significance level is difficult to assess. This paper describes a conditional probability procedure which attempts to maintain the overall significance level by balancing the probabilities of false early rejection and false early acceptance. Monte Carlo sampling results suggest that this procedure can achieve a large reduction in expected sample size without greatly affecting either the significance level or power of the trial.


Subject(s)
Clinical Trials as Topic/standards , Monte Carlo Method , Probability , Sampling Studies , Binomial Distribution , Enalapril/therapeutic use , Humans , Myocardial Infarction/drug therapy , Myocardial Infarction/mortality
19.
Am J Cardiol ; 69(1): 103-7, 1992 Jan 01.
Article in English | MEDLINE | ID: mdl-1729857

ABSTRACT

All surviving patients in a double-blind study comparing the effects of enalapril and placebo on survival in severe congestive heart failure were recommended to be treated with active drug after stopping the trial. Two-year follow-up from the end of the blinded trial demonstrated that among 77 survivors of 127 patients originally allocated to the group with enalapril, 38 were still alive. Of 126 patients allocated to the group with placebo 58 survived the blinded study, and after 2-year follow-up 26 were still alive. Thus, the difference between the original treatment groups remained, despite that treatment with enalapril was made available to all surviving patients and that those in the group with enalapril were sicker at baseline than those in the group with placebo. If enalapril was prescribed, the mortality was 47% compared with 75% if it was not. Life-table analysis suggests a marked carry-over effect of treatment in the group with enalapril that lasted for up to 15 months before mortality rates became comparable in the 2 treatment groups. This strongly suggests that enalapril confers structural protection to the failing myocardium.


Subject(s)
Enalapril/therapeutic use , Heart Failure/drug therapy , Heart Failure/mortality , Adult , Aged , Aged, 80 and over , Double-Blind Method , Follow-Up Studies , Humans , Life Tables , Middle Aged , Survival Rate
20.
Am J Cardiol ; 66(19): 1363-7, 1990 Dec 01.
Article in English | MEDLINE | ID: mdl-2123074

ABSTRACT

Respiratory gas exchange data were collected from 77 men greater than 6 months after acute myocardial infarction. Maximal exercise was performed on an ergometer cycle programmed for a ramp protocol of 15 W/min. The gas exchange anaerobic threshold (ATge) was determined by analysis of the carbon dioxide elimination (VCO2) vs oxygen consumption (VO2) curve below a respiratory exchange ratio of 1.00 using a computerized algorithm. This value was estimated at the inflection of VCO2 from a line with a slope of 1 which intersects the VCO2 vs VO2 curve. The relation of the ATge to the lactate acidosis threshold was studied in 29 patients. The reproducibility of the ATge method was studied in 77 patients. Mean (+/- standard deviation) VO2 for the ATge was 905 +/- 220 vs 866 +/- 299 ml/min for the lactate acidosis threshold (r = 0.86, p less than 0.001). Mean VO2 at the ATge for test 1 was 968 +/- 225 vs 952 +/- 217 ml/min for test 2 (r = 0.71, p less than 0.001). Mean peak VO2 was 1,392 +/- 379 vs 912 +/- 202 ml/min at the ATge (r = 0.76, p less than 0.001). Results demonstrate that this ATge method correlates well with the lactate acidosis threshold, is reproducible, and should be useful as an objective measure of submaximal exercise performance.


Subject(s)
Mathematical Computing , Myocardial Infarction/physiopathology , Pulmonary Gas Exchange/physiology , Aged , Algorithms , Carbon Dioxide/blood , Exercise Test , Humans , Lactates/blood , Male , Middle Aged , Oxygen Consumption/physiology , Reproducibility of Results
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