Irala, J. (Jokin) de

Martinez-Gonzalez, M.A. (Miguel Ángel)

Ruiz-Canela, M. (Miguel)

English

Universidad de Navarra

Intention to treat analysis is related to methodological quality

Dadun, University of Navarra

full recovery. They subsequently excludedthe same groups of patients from the idealscenario in which all patients were admittedwithin the time window for thrombolysis.Had thrombolysis actually been given, theoutcomes for these patients would havebeen unknown at the time of administration.These patients should therefore have beenincluded in the analysis.Joris Berwaerts lecturer in clinical pharmacologyDepartment of Medicine and Therapeutics,University of Aberdeen, Aberdeen AB25 2ZDAndrew McDonald Johnston cardiovascularresearch fellowAcute Stroke Unit, Aberdeen Royal Infirmary,Aberdeen AB25 2ZNAMcD.Johnston@arh.grampian.scot.nhs.ukMary-Joan Macleod lecturer in clinical pharmacologyDepartment of Medicine and Therapeutics,University of Aberdeen, Aberdeen AB25 2ZD1 Jørgensen HS, Nakayama H, Kammersgaard LP, RaaschouHO, Olsen TS. Predicted impact of intravenous throm-bolysis on prognosis of general population of strokepatients: simulation model. BMJ 1999;319:288-9. (31 July.)Another trial is neededEditor—The paper by Jørgensen et alprovides a small counterbalance to theenormous propaganda behind an expen-sive, minimally tested, and potentially harm-ful intervention.1 The real ratio of benefit torisk of thrombolytics for stroke may even befar worse than Jørgensen et al calculate, forthe following reasons.Firstly, even fewer stroke patients in com-munity practice would qualify for treatmentwith alteplase if a strict three hour cut-offpoint for completion of all diagnosticactivities and initiation of the drug were used.Secondly, inclusion of even a few ofthose patients with seizure, tumour, infec-tion, etc, whose condition mimics stroke andwho constitute perhaps 15-25% of patientsdiagnosed as having “stroke” in communitypractice but were rare in the expert basedNational Institute of Neurological Disordersand Stroke (NINDS) trial,2 could easily over-whelm any benefits of alteplase, since suchpatients cannot possibly benefit from treat-ment but can certainly be harmed.Thirdly, treatment of even a few patientswith subtle haemorrhage, undetectedbecause the computed tomography scan wasnot read by a neuroradiologist, would havethe same effect—and there is good evidencethat very few general radiologists, neurolo-gists, or emergency physicians are able toidentify most or all such haemorrhages.Fourthly, treatment outside the special-ised environments used in NINDS, and with-out the experts participating in such studies,could lead to far more harm when a drug thatproduces such a high rate of intracranialhaemorrhage under ideal conditions is used.Fifthly, of seven trials of lytics in stroke todate, only the fairly small NINDS trial hashad positive results—the results of the sixthat have been either neutral or negative(including several with dramaticallyincreased mortality in patients treated withthrombolytics) are typically ignored.“Another trial is needed” is a generoussummary of the available evidence. Given theextremely limited evidence of efficacy, themarginal nature of that efficacy (under thebest of circumstances), and the stronglikelihood that such efficacy will not translateinto effectiveness in community practice—aswell as the real potential for harm—approvalof this drug in the United Kingdom, for thetreatment of stroke should be withheld unlessand until far more definitive evidence (foreffectiveness as well as for efficacy) isforthcoming.Jerome R Hoffman professor of medicineUCLA School of Medicine, Los Angeles, CA 90077,USAjrh@ucla.edu1 Jørgensen HS, Nakayama H, Kammersgaard LP, RaaschouHO, Olsen TS. Predicted impact of intravenous throm-bolysis on prognosis of general population of strokepatients: simulation model. BMJ 1999;319:288-9. (31 July.)2 National Institute of Neurological Disorders and Strokert-PA Stroke Study Group. Tissue plasminogen activatorfor acute ischemic stroke. N Engl Med J 1995;333:1581-7.Author’s replyEditor—Our simulation model of intra-venous thrombolysis (using alteplase) inpatients with acute stroke model had twopurposes: firstly, to estimate the target popu-lation for intravenous thrombolysis in anunselected population of patients with acutestroke; and, secondly, to estimate thenumber of patients who would actually ben-efit from this treatment—provided that theresults of the only trial with positive reults sofar, the National Institute of NeurologicalDisorders and Stroke (NINDS) trial,1 can bereproduced.In the study we included the 1197patients from the Copenhagen stroke study, acommunity based study in which all patientswith acute stroke from a well definedcatchment area of Copenhagen had all theiracute treatment and rehabilitation in onelarge stroke unit regardless of their age, theseverity of the stroke, and their comorbidityprior to stroke. In the first part of our analysiswe estimated the target population foralteplase treatment using the inclusion crite-ria from the NINDS trial. We includedpatients who eventually died or who recov-ered fully. A disappointing rate of only 4% ofthe patients fulfilled the inclusion criteria.To estimate the number of patients whowould have benefited from intravenousthrombolysis we excluded the patients whoeither recovered fully and had no functionaldisability after completed rehabilitation orwho died during hospital stay. Berwaerts et alargue that these patients should have beenincluded as the outcomes for them wouldhave been unknown at the time of drugadministration. We believe, however, that itwas justified to exclude them from the analy-sis of the number of patients who would actu-ally benefit from alteplase treatment. None ofthese patients would have benefited fromtreatment because they either had a completerecovery without thrombolysis or they died.As the NINDS trial shows, alteplase treatmenthas no effect on overall mortality.The results of our study in combinationwith the arguments offered by Hoffmanshould raise serious questions about theapproval of intravenous thrombolysis inpatients with acute stroke. The possible, butnot proved, marginal benefit of intravenousthrombolysis in a very small number ofpatients (1 out of 160 patients in our simula-tion model) should be considered incontrast to the marked benefit of treatmentand rehabilitation of unselected patients inspecialised stroke units,2–5 regardless of theirage, sex, severity of stroke, and comorbidity.Economic resources are limited and shouldbe used where they benefit most patients inthe most effective way—in this case byproviding early, intensive rehabilitation to allpatients in dedicated stroke units.Henrik Stig Jørgensen consultantDepartment of Neurology, Bispebjerg Hospital,Bispebjerg bakke 23, DK-2400 Copenhagen, NV,Denmark1 National Institute of Neurological Disorders and Strokert-PA Stroke Study Group. Tissue plasminogen activatorfor acute ischemic stroke. N Engl Med J 1995;333:1581-7.2 The Stroke Unit Trialists’ Collaboration. Collaborative sys-tematic review of the randomised trials of organised in-patient (stroke unit) care after stroke. BMJ1997;315:1151-9.3 Jørgensen HS, Nakayama H, Raaschou HO, Larsen K,Hübbe P, Olsen TS. The effect of a stroke unit: reducesmortality, discharge to nursing home, length of hospitalstay and cost. A community-based study. Stroke 1995;26:1178-82.4 Jørgensen HS, Kammersgaard LP, Nakayama H, RaaschouHO, Larsen K, Hübbe P, et al. Treatment and rehabilitationon a stroke unit improves 5-year survival. A community-based study. Stroke 1999;30:930-3.5 Jørgensen HS, Kammersgaard LP, Houth JG, NakayamaH, Raaschou HO, Larsen K, et al. Who benefits from treat-ment and rehabilitation on a stroke unit? A community-based study. Stroke 2000;31;434-9.Intention to treat analysis isrelated to methodologicalqualityEditor—In their survey of all randomisedcontrolled trials published in 1997 in fourmajor medical journals, Hollis and Campbellfound that only 48% of the reports explicitlymentioned intention to treat analysis.1 In aconsiderable proportion it was insufficientlydescribed and sometimes inadequatelyapplied. Their results are confirmed by ourassessment of all randomised controlled trialspublished between 1993 and 1995 in thesame four journals.2 In addition to our assess-ment of ethical issues, we calculated theproportion of randomised controlled trialsreporting intention to treat analysis inaccordance with different descriptive andmethodological characteristics.In our review of 608 randomisedcontrolled trials, we found that 290 of thetrials (47.7%) explicitly mentioned that theyapplied the principle of intention to treatanalysis. The reporting of this issueincreased slightly between 1993 and 1995(although the increase was not significant).Trials with a greater number of participantsand those funded by the pharmaceuticalindustry were more likely to report theapplication of the intention to treat princi-ple (table). In the multivariable logisticregression analysis, when we controlled forthe general characteristics previouslydescribed, we found that trials with survivalof patients as the principal outcome wereLetters1007BMJ VOLUME 320 8 APRIL 2000 bmj.commore frequently reported to follow theintention to treat principle. In addition,those randomised controlled trials that gaveno information about sample size were lesslikely to report the use of this principle(table). Randomised controlled trials notreporting the number of withdrawals orlosses to follow up and those not reportinginformation about compliance with treat-ment were also less likely to report theintention to treat principle, although theseresults were not significant.Our data support the relation between ahigher methodological quality of the trialsand the reporting of the intention to treatanalysis. Our results reinforce the conclu-sions of Hollis and Campbell that the appli-cation of this principle still needs toimprove because it seems that there hasbeen no improvement between 1993 and1997.1 A joint effort of editors and research-ers is needed to meet the CONSORTguidelines3 and the authors’ recommenda-tions favouring intention to treat analysis.1A better quality of reporting will help read-ers to assess the design, conduct, and analy-sis of randomised controlled trials morecritically.Miguel Ruiz-Canela assistant professorDepartment of Biomedical Humanities andDepartment of Epidemiology and Public Health,School of Medicine, University of Navarra, E 31080Pamplona, Spainmcanela@unav.esMiguel Angel Martínez-González acting chairJokin de Irala-Estévez associate professorDepartment of Epidemiology and Public Health,School of Medicine, University of Navarra1 Hollis S, Campbell F. What is meant by intention to treatanalysis? Survey of published randomised controlled trials.BMJ 1999;319:670-4. (11 November.)2 Ruiz-Canela M, Martínez-González MA, Gómez Gracia E,Fernández-Crehuet Navajas J. Informed consent andapproval by institutional review board in published clinicaltrials. N Engl J Med 1999;340:1114-5. (Erratum N Engl JMed 1999;341:460.)3 Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I,et al. Improving the quality of reporting of randomizedcontrolled trials. The CONSORT statement. JAMA1996;276:637-9.Using anticoagulation oraspirin to prevent strokeResearch was methodologically flawedEditor—The paper by Hellemons et al isnot justified in concluding that aspirin is theprophylactic choice in primary care foratrial fibrillation, if there is no clearindication for full anticoagulation.1The study is methodologically flawed. Asclinicians, we ask ourselves: “Which patientin atrial fibrillation should be given anti-coagulants?” This is a statistical questionabout the risks and benefits of aspirin orwarfarin for that individual patient.In the power calculation Hellemons et alasked whether low anticoagulation (inter-national normalised ratio 1.1-1.6) or aspirinshould be used—but this is the wrongquestion. The choice should have beenbetween aspirin and standard anticoagula-tion (INR 2.5-3.5). The increased incidenceof major intracranial bleeding in the aspiringroup compared with the anticoagulatedgroups (0.75% per patient year v 0.35%)calls into question the sagacity of using onetailed statistical tests.As the study was underpowered, thequestion of whether standard anticoagula-tion or aspirin was better in preventingmajor cerebral infarction cannot beanswered. Although there is a trend towardsfull anticoagulation (hazard ratio 0.67), the95% confidence intervals are so wide (0.11to 4.1) that the result is meaningless.The arbitrary exclusion from standardanticoagulation of all people who were 78years or older also undermines the study, foralthough it may have reduced the complica-tion rate from anticoagulation, it will havealso reduced the potential benefit.This paper highlights the problems inreporting “negative” or “no difference” stud-ies. It has failed to show “no difference”between standard anticoagulation and aspi-rin prophylaxis in atrial fibrillation, asclinically important differences could wellexist within the confidence limits. The studyadds little to previous work that doesdemonstrate benefit from anticoagulation2and may be misinterpreted as an excuse forReporting of intention to treat analysis in published clinical trials (1993-5)Total NoNo (%)reportingintention totreatCrude odds ratio fornot reporting the useof intention to treat(95% CI)Logistic regressionmultivariable modeladjusted odds ratio(95% CI)Odds ratio (95% CI)adjusted fordescriptivecharacteristicsAll sample 608 290 (47.7)Descriptive characteristics of the trialsJournal:N Engl J Med 219 122 (55.7) 1 1JAMA 81 37 (45.7) 1.50 (0.90 to 2.50) 1.64 (0.92 to 2.92)BMJ 105 44 (41.9) 1.74 (1.09 to 2.79) 1.80 (0.96 to 3.39)Lancet 203 87 (42.9) 1.68 (1.14 to 2.46) 1.54 (0.95 to 2.50)Year of publication:1995 211 108 (51.2) 1 11994 195 92 (47.2) 1.17 (0.79 to 1.73) 1.20 (0.78 to 1.86)1993 202 90 (44.6) 1.30 (0.89 to 1.92) 1.14 (0.73 to 1.77)Country of authors:Europe (except UnitedKingdom)164 86 (52.4) 1 1United Kingdom 127 61 (48.0) 1.19 (0.75 to 1.90) 0.90 (0.52 to 1.55)United States 240 120 (50.0) 1.10 (0.74 to 1.64) 1.24 (0.75 to 2.07)Other 77 23 (29.9) 2.59 (1.45 to 4.60) 2.59 (1.38 to 4.85)Main specialty of authors:Medical specialties 432 213 (49.3) 1 1Surgery ormedical-surgical106 45 (42.5) 1.32 (0.86 to 2.02) 1.23 (0.76 to 1.99)Intensive or emergencycare37 18 (48.6) 1.03 (0.52 to 2.01) 1.08 (0.51 to 2.29)Public health 16 7 (43.8) 1.25 (0.46 to 3.42) 1.60 (0.54 to 4.74)Other 17 7 (41.2) 1.39 (0.52 to 3.72) 1.29 (0.44 to 3.82)Number of participating subjects:>500 171 109 (63.7) 1 151 to 500 322 167 (51.9) 1.63 (1.11 to 2.39) 1.68 (1.12 to 2.53)<50 115 14 (12.2) 12.66 (6.68 to 24.10) 12.43 (6.24 to 24.36)Source of funding:Pharmaceutical industry 206 129 (62.6) 1 1Public agency 165 73 (44.2) 2.11 (1.39 to 3.20) 2.11 (1.34 to 3.34)Other 126 52 (41.3) 2.38 (1.52 to 3.75) 2.01 (1.22 to 3.30)Not reported 111 36 (32.4) 3.49 (2.14 to 5.68) 2.35 (1.34 to 4.10)Methodological characteristics of the trialsOutcome:Survival 142 104 (73.2) 1 1Other 466 186 (39.9) 4.12 (2.72 to 6.24) 2.86 (1.77 to 4.60)Sample size estimation:Shown 281 167 (59.4) 1 1Not shown 327 123 (37.6) 2.43 (1.75 to 3.37) 2.28 (1.55 to 3.37)Compliance with treatment:Stated 532 261 (49.1) 1 1Not stated 76 29 (38.2) 1.56 (0.95 to 2.56) 1.71 (0.98 to 2.99)Reporting follow up or withdrawals:Reporting the number ofpatients withdrawn or lostto follow up194 100 (51.5) 1 1Not giving informationabout number of patientslost to follow up414 190 (45.9) 1.25 (0.89 to 1.76) 1.45 (0.98 to 2.14)A higher odds ratio means a higher probability of not reporting the use of the intention to treat principle.Letters1008 BMJ VOLUME 320 8 APRIL 2000 bmj.com

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Intention to treat analysis is related to methodological quality

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Universidad de Navarra

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