Changes in symptoms, peak expiratory flow, and sputum flora during treatment with antibiotics of exacerbations in patients with chronic obstructive pulmonary disease in general practice. Reports of clinical trials should begin and end with up-to-date systematic reviews of other relevant evidence: a status report. Amoxicillin in treatment of acute uncomplicated exacerbations of chronic bronchitis. A double-blind, placebo-controlled multicentre study in general practice. A comparison of ampicillin, erythromycin and erythromycin with sulphametopyrazine in the treatment of infective exacerbations of chronic bronchitis. Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding? Value of ampicillin in the hospital treatment of exacerbations of chronic bronchitis. Update on unethical use of placebos in randomised trials. Five-day telithromycin once daily is as effective as 10-day clarithromycin twice daily for the treatment of acute exacerbations of chronic bronchitis and is associated with reduced health-care resource utilization. The accuracy of patient history, wheezing, and laryngeal measurements in diagnosing obstructive airway disease. CARE-COAD1 Group. Clinical Assessment of the Reliability of the Examination-Chronic Obstructive Airways Disease.
BACKGROUND --Bacterial infections of the lower airways during an exacerbation in patients with asthma or chronic obstructive pulmonary disease ( COPD ) may be the cause of an exacerbation or the consequence of a viral infection or an increase in airways limitation . To determine whether bacterial infection is an important component in the pathogenesis of an exacerbation , the effects of antimicrobial treatment must be studied . METHODS -- Patients with asthma or COPD seen in general practice were studied in a double blind r and omised manner to investigate whether the antimicrobial drugs amoxicillin ( 500 mg three times daily ) , cotrimoxazole ( 960 mg twice daily ) , or a placebo , each when added to a short course of oral corticosteroids , can accelerate recovery from exacerbations . Patients were instructed to contact their own physician early in the morning when complaints of increased shortness of breath , wheezing , or exacerbations of cough with or without sputum production occurred . Treatment effects were evaluated over the next 14 days by study ing symptom scores ( wheeze , dyspnoea , cough with and without mucus production , and awakening with dyspnoea ) , peak expiratory flow values ( PEF , expressed as % predicted ) , and sublingual temperature . Bacteriological study of the sputum was made at the onset of an exacerbation and 7 , 21 and 35 days afterwards . RESULTS --Of 195 patients enrolled 71 ( 36 % ) contacted their physician for symptoms of an exacerbation . Symptoms improved in all three groups , improvements ranging from 0.54 to 0.75 points per day on a four point scale . PEF% predicted showed improvements in the three groups after the exacerbation , ranging from 0.34 % to 0.78 % predicted per day , finally returning to baseline values . Sublingual temperature did not change . Six of 71 patients consulted their physician because of a relapse between four and 24 days after the start of treatment . In only two of the 50 sputum sample s , collected during an exacerbation , and which contained > or = 10(5 ) bacteria in culture sensitive to the chosen antibiotic given , did any benefit from antimicrobial treatment occur . During the recovery period sputum purulence improved irrespective of antibiotic treatment . CONCLUSIONS --Antibiotics given with a short course of oral prednisolone during an exacerbation do not accelerate recovery as measured by changes in peak flow and symptom scores in ambulatory patients with mild to moderate asthma or COPD when treated by their general practitioners . Moreover , antibiotics do not reduce the number of relapses after treating an exacerbation OBJECTIVE Scientific and ethical justification for new clinical trials requires them to have been design ed in the light of scientifically defensible assessment s of relevant previous research . Reliable interpretation of the results of new clinical trials entails setting them in the context of up date s of the review s upon which they were deemed scientifically and ethically justifiable . We have shown previously that most reports of r and omized trials published in five general medical journals in May 1997 and in May 2001 failed to set their results in the context of the findings from similar research . In the current study , we assess whether there had been progress in this respect in 2005 and also investigate the extent to which reports begin by referring to systematic review s providing the justification for the new research reported . DESIGN Assessment of the Introduction and Discussion sections in all reports of r and omized trials published during May 2005 in five general medical journals . SETTING Reports of r and omized trials in five general medical journals . PARTICIPANTS Annals of Internal Medicine , BMJ , JAMA , Lancet and New Engl and Journal of Medicine . INTERVENTIONS None . MAIN OUTCOME MEASURES The inclusion or mention of one or more systematic review s in the Introduction or Discussion section of each report assessed . RESULTS We found 18 reports of r and omized trials . The Introduction sections referred to systematic review s in five ( 27 % ) of these reports . None of the discussion sections of the 15 reports of trials that were not the first published trials to address the question studied placed the results of the new trial in the context of an up date d systematic review of other research . Although reference was made to relevant systematic review s in five of these 15 reports , there was no integration - quantitative or qualitative - of the results of the new trials in an up date of these review s. In the remaining ten reports there was no evidence that any systematic attempt had been made to set the new results in the context of previous trials . CONCLUSIONS There is no evidence of progress between 1997 and 2005 in the proportion of reports of trials published in general medical journals which discussed new results within the context of up-to- date systematic review s of relevant evidence from other controlled trials . Although the proportion of trials referring to systematic review s in Discussion sections has increased , the majority of reports continued to fail even to do this . Similarly , most research ers appear not to have considered a systematic review when design ing their trial . Research ers and journal editors do a disservice to the interests of the public and others involved in healthcare decision-making by acquiescing in this situation The aim of the study was to evaluate whether a broad-spectrum penicillin , amoxicillin , was superior to placebo in resolving symptoms of acute exacerbations of chronic bronchitis in patients from general practice . 131 general practitioners included 278 patients over a period of 30 months . The patients were r and omly assigned to treatment with amoxicillin 750 mg b.i.d . or corresponding placebo for 7 days . Patients with pneumonia , a temperature above 38.5 degrees C or heart rate over 100 were excluded for safety reasons . The main effect parameter -- the doctors ' overall evaluation of the treatment -- did not demonstrate any statistically significant difference between amoxicillin or placebo , 63 % versus 64 % of the patients . Resolution of symptoms was obtained by 19 % ( 25/132 ) of the patients in the amoxicillin group compared with 10 % ( 13/136 ) of the patients in the placebo group , P = 0.03 . The present findings do not favour routine use of antibiotics in an attempt to improve the course of acute exacerbations as defined in this study in patients with chronic bronchitis A comparative study of ampicillin ( 500 mg four times daily ) , erythromycin ( 500 mg four times daily ) and sulphametopyrazine ( 1 g at start of exacerbation ) followed by erythromycin ( 500 mg four times daily ) was carried out in infective exacerbations of chronic bronchitis .  Ampicillin and erythromycin were found to be equally effective , but the combination of erythromycin and sulphametopyrazine was significantly less effective . Unwanted effects were more frequent with ampicillin and with erythromycin plus sulphametopyrazine than with erythromycin alone Background Aprotinin is a serine protease inhibitor used to limit perioperative bleeding and reduce the need for donated blood transfusions during cardiac surgery . R and omized controlled trials of aprotinin evaluating its effect on the outcome of perioperative transfusion have been published since 1987 , and systematic review s were conducted in 1992 and 1997 . Methods A systematic search was conducted for all RCTs of aprotinin  that used placebo controls or were open-label with no active control treatment . Data collected included the primary outcome , objective of each study , whether a systematic review was cited or conducted as part of the background and /or rationale for the study and the number of previously published RCTs cited . Cumulative meta-analyses were performed . Results Sixty-four r and omized , controlled trials of aprotinin were found , conducted between 1987 and 2002 , reporting an endpoint of perioperative transfusion .  Median trial size was 64 subjects , with a range of 20 to 1784 . A cumulative meta- analysis indicated that aprotinin greatly decreased the need for perioperative transfusion , stabilizing at an odds ratio of 0.25 ( p , 10 2 6 ) by the 12th study , published in June of 1992 . The upper limit of the confidence interval never exceeded 0.65 and results were similar in all subgroups . Citation of previous RCTs was extremely low , with a median of 20 % of prior trials cited . Only 7 of 44 ( 15 % ) of subsequent reports referenced the largest trial ( N 1/4 1784 ) , which was 28 times larger than the median trial size . Conclusions This study demonstrates that investigators evaluating aprotinin were not adequately citing previous research , result ing in a large number of RCTs being conducted to address efficacy questions that prior trials had already definitively answered . Institutional review boards and journals could reduce the number of redundant trials by requiring investigators to conduct adequate search es for prior evidence and conducting systematic review Campbell , M. ( 1949 ) . Quart . 7 . Med . , 18 , 379 . ( 1955 ) . Brit . Heart Y. , 17 , 511 . ( 1959 ) . Ibid . , 21 , 65 . ( 1961a ) . Brit . med 7 . , 1 , 691 . ( 1961b ) . Acta Genet . med . ( Roma ) , 10 , 443 . ( 1962 ) . Brit . Heart 7 . , 24 , 625 . ( 1963 ) . Ibid . , 25 , 803 . ( 1966 ) . In A Textbook of Paediatric Cardiology , edited by Hamish Watson . Lloyd-Luke , London . In preparation . and Baylis , J. H. ( 1956 ) . Brit . Heart 7 . , 18 , 475 . and Goodwin , J. F. ( 1965 ) . Progr . cardiovasc . 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Ibid . , 105 , 145 . ( 1952 ) . Ibid . , 120 , 469 . ( 1953 ) . Genetics , 38 , 216 . Lerner , I. M. ( 1954 ) . Genetic Homeostasis . Oliver and Boyd , Edinburgh and London . Lynas . M. A. ( 1958 ) . Ann . hum . Genet . , 22 , 289 . MacArthur , P. ( 1952 ) . Lancet , 2 , 1104 . McIntosh , R. , Merritt , K. K. , Richards , M. R. , Samuels , M. H. , and Bellows , M. T. ( 1954 ) . Pediatrics , 14 , 505 . McKeown T. , MacMahon , B. , and Parsons , C. G. ( 1953 ) . Brit . Heart Z. , 15 , 273 . and Record , R. G. ( 1951 ) . Lancet , 1 , 192 . ( 1960 ) . In Czba Foundation Symposium on Congenital Malformations , edited by G. E. W. Wolstenholme and C. M. O'Connor , p. 5 . Churchill , London . MacMahon , B. ( 1952 ) . Brit . 7 . soc . Med . , 6 , 178 . Mcktown , T. , and Record , R. G. ( 1953 ) . Brit . Heart 7 . , 15 , 121 . Mouquin , M. , Kherumnian , R. , Dur and , M. , Metianu , C. , Moullec ? J. , and Kherumian-Allary , 0 . ( 1956 ) . Bull . Acad . nat . Med . ( Parts ) , 140 , 515 . Neel , J. V. ( 1960 ) . In First International Conference on Congenital Malformations , p. 63 Pare , J. A. P. , Fraser . R. G. , Pirozynski W J. , Shanks , J. A. , and Stubington , D. ( 1961 ) . Amer . 7 . Med . , 31 , 37 . Penrose , L. S. ( 1955 .. Lancet , 2 , 312 . ( 1957 ) Amer . 7 hum . Genet . , 9 , 167 . Polana , P. E. , and Campbell , M. ( 1955 ) . Ann . hum . Genet . , 19 , 209 . -~~~ ( 1960 ) . Ibid . , 24 , 343 . Record , R. G. and Edwards , J. H. ( 1958 ) . Brit . 7 . prev . soc . Med . , 12 , 8 . and McKeown , T. ( 1953 ) . Brit . Heart 7 . , 15 , 376 . Registrar-General ( 1957 ) . Statistical Review of Engl and and Wales for 1957 , Part II , Tables , Civil , Table L. H.M.S.O. , London . Rhodes , A J. ( 1960 ) . In First International Conference on Congenital Malformations , p 106 . Roberts , J. A. F. ( 1953 - 5 ) . Med . 7 . South-West , 70 , 142 . Rutstein , D. D. , Nickerson , R. J. , and Heald , F. P. ( 1952 ) . Amer . 7 . Dis . Chila . , 84 , 199 Seldon , W. 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Wilson , J. G. ( 1959 ) . 7 . chron . Dis . , 10 , 111 . ( 1960 ) . In First International Conference on Congenital Malformations , p. 187 . Roth , C. B. , and Warkany , J. ( 1953 ) . Amer . 7 . Anat . , 92 , 189 . and Wsrkany , J. ( 1949 ) . Ibid .. 85 , 113 . Wood , P. ( 1956 ) . Diseases of the Heart and Circulation , 2nd ed . Eyre and Sinottiswoode , London . Zoethout , H. E. , Bonham Carter , R. E. , and Carter , C. 0 . ( 1964 ) . 7 . med . Genet . , 1 , 2 The most recent ( Fifth ) revision of the Declaration of Helsinki , adopted in October 2000 by the World Medical Association ( WMA ) , reinforces the longst and ing prohibition against offering placebo instead of effective therapy . The WMA left no doubt that if a beneficial treatment for a condition has already been recognised , it is unethical to offer placebo in place of such treatment to anyone in a study of the same condition . We have previously drawn attention to the discrepancy between the spirit of the Declaration and the common practice of using placebo controls in r and omised trials even if effective treatment exists . Despite the m and ates of the Declaration of Helsinki and concern from ethicists and scientists , the US Food and Drug Administration ( FDA ) continues to dem and and defend placebo-controlled evidence of efficacy and safety for the development of many new pharmaceuticals , even if effective therapy exists . We suggest that the FDA 's arguments defending their practice are insufficient to justify medical research that violates the Declaration of Helsinki STUDY OBJECTIVES To demonstrate equivalence in the clinical efficacy of telithromycin vs clarithromycin treatment of out patients with acute exacerbations of chronic bronchitis ( AECB ) , and to compare the tolerability and respiratory-related health-care re source utilization associated with these treatment regimens . DESIGN AND PATIENTS A r and omized , double-blind , multicenter , clinical study was conducted at 105 centers in 14 countries . Adult out patients ( age > or = 30 years ) received oral telithromycin , 800 mg qd for 5 days ( n = 270 ) , or oral clarithromycin , 500 mg bid for 10 days ( n = 282 ) , for the treatment of AECB . Clinical and bacteriologic outcomes were assessed at the posttherapy/test-of-cure ( TOC ) visit ( days 17 to 24 ; per- protocol population ) . Health-care re source utilization data were collected for each patient by investigators blinded to study medication up to the late posttherapy visit ( days 31 to 36 ) . RESULTS Clinical cure rates at the posttherapy/TOC visit were comparable between the groups ( telithromycin , 193 of 225 patients [ 85.8 % ] ; clarithromycin , 206 of 231 patients [ 89.2 % ] ) ; bacteriologic outcome was satisfactory for 59 of 72 telithromycin-treated patients ( 81.9 % ) vs 63 of 76 clarithromycin-treated patients ( 82.9 % ) . Health-care re source utilization assessed up to the late posttherapy visit was lower in the telithromycin treatment group than the clarithromycin treatment group , with significantly fewer hospitalizations for respiratory-related causes ( one hospitalization vs eight hospitalizations for a total of 4 inpatient days vs 39 inpatient days , respectively ) , significantly fewer AECB-related emergency department visits ( 0 vs 8) , and fewer unscheduled outpatient visits ( 11 vs 18 ) . Fewer telithromycin-treated patients reported days lost from work ( 21 of 91 patients [ 23.1 % ] ; 133 days ) compared with those receiving clarithromycin ( 30 of 98 patients [ 30.6 % ] ; 141 days ) . Telithromycin was well tolerated ; adverse events considered possibly related to study medication were reported by 61 of 269 patients ( 22.7 % ) and 100 of 280 patients ( 35.7 % ) receiving telithromycin and clarithromycin , respectively . CONCLUSIONS In this study , 5-day telithromycin treatment was as effective and well tolerated as 10-day clarithromycin treatment for patients with AECB , and was associated with a reduced utilization of health-care  re sources CONTEXT The accuracy of the clinical examination in detecting obstructive airway disease ( OAD ) is largely unknown because of a paucity of method ologically rigorous studies . OBJECTIVE To determine the accuracy of patient history , wheezing , laryngeal height , and laryngeal descent in the diagnosis of OAD . DESIGN Comparison study conducted from November 3 , 1998 , to December 4 , 1998 , evaluating 4 clinical examination elements for diagnosis of OAD vs the gold st and ard of forced expiratory volume in 1 second ( FEV1 ) and FEV1-forced vital capacity ( FVC ) ratio less than the fifth percentile ( adjusted for patient height , age , and sex ) . SETTING Twenty-five sites , including primary care and referral practice s , in 14 countries . PARTICIPANTS A total of 309 consecutive patients were recruited ( mean age , 56 years ; 43 % female ) , 76 ( 25 % ) with known chronic OAD , 114 ( 37 % ) with suspected chronic OAD , and 119 ( 39 % ) with neither known nor suspected OAD . MAIN OUTCOME MEASURES Sensitivity , specificity , and likelihood ratios ( LRs ) for each of the 4 elements of the clinical examination compared with the gold st and ard . RESULTS Mean FEV1 and FVC values were 2.1 L/s and 2.9 L ; 52 % had an FEV1 and FEV1-FVC ratio less than the fifth percentile . The LR for wheezing was 2.7 ( 95 % confidence interval [ CI ] , 1.7 - 4.2 ) and was not statistically significant in the multivariate model . The LR for laryngeal descent ranged from 0.9 ( 95 % CI , 0.5 - 1.4 ) to 1.2 ( 95 % CI , 0.4 - 3.4 ) , depending on the cut point chosen , and did not enter the multivariate model . Only 4 of the history or physical examination elements we tested were significantly associated with the diagnosis of OAD on multivariate analysis : smoking for more than 40 pack-years ( LR , 8.3 ) , self-reported history of chronic OAD ( LR , 7.3 ) , maximum laryngeal height of 4 cm [ corrected ] or less ( LR , 2.8 ) , and age at least 45 years ( LR , 1.3 ) . Patients having all 4 findings had an LR of 220 ( ruling in OAD ) ; those with none had an LR of 0.13 ( ruling out OAD ) . The area under the receiver operating characteristic curve for the model incorporating these 4 factors was 0.86 . CONCLUSIONS Further research is needed to vali date our model , but in the meantime , our data suggest that less emphasis should be placed on the presence of individual symptoms or signs ( such as wheezing or laryngeal descent ) in the diagnosis of OAD
Background R and omised trials comparing different drugs head-to-head are extremely valuable for clinical decision-making .
However , it is scientifically and ethically sensible to dem and strong evidence that a drug is effective by showing superiority over a placebo before embarking on head-to-head comparisons of potentially ineffective drugs .
Our aim was to study the evolvement of evidence from placebo-controlled and head-to-head trials on the effects of antibiotics for the treatment of mild to moderate exacerbations of chronic obstructive pulmonary disease .