Randomized trials that changed medical practice

May, 2000

The following list includes those trials that according to the opinion of the members of the Evidence-Based Discussion Group satisfy the following criteria:

    1. demonstrated reversal of the treatment effect (in comparison with previous non-randomized trials)
    2. showed that potentially harmful, very toxic, complicated or expensive treatments were not superior to less harmful and less complicated treatments
    3. resulted in dramatic beneficial effect (e.g. having relative-risk reduction >30%)
    4. provided "an example of the danger of applying pathophysiologic reasoning to therapeutic actions without first testing the hypothesis by means of adequately designed trials".

Although suggested by some members of the group, at this time systematic reviews or meta-analyses are not included in the list.

This is a work in progress and of potentially great importance (it can help us learn about effectiveness of our therapeutic innovative efforts). Please send your comments or information about trials (djulbebm@moffitt.usf.edu) that are not included in the list and that according to your opinion should have been included. In addition, we would welcome inclusion of any new trials that are deemed to meet above criteria.


A similar list was compiled by Fineberg in 1987 (in part cited here) who reviewed 28 "landmark" studies, and found that only 2 had an immediate (1-2 year) impact on practice. (M Ebell):Clinical evaluation: how does it influence medical practice? Fineberg HV Bull Cancer 1987 74:3 333-46

 


Please note that the listed articles have NOT been reviewed; references are included as they were submitted to B. Djulbegovic, who then compiled a list. Therefore, it is possible that some of the papers included do not meet above stated criteria for a "trial that changed our practice."

 


The following individuals have contributed to the list:

Bardri Badrinath, Brian Budenholzer, Mike Campbell, David L. Doggett, Mark Ebell, Peter Ellis, Bruce Guthrie, Janet E. Hiller, Gary Jackson, Richard W Morris, Roy Poses, Steve Simon, Daniel L. Sontheimer, Donald Stanley, Jeffrey A. Tice, Nico van Duijn, Julius Weinberg, Samuel Wiebe, Kenneth S. Yew

 


Cardiology and Thrombosis

Teo KK, Yusuf S, Fuberg CD. Effects of prophylactic anti-arrhythmic drug therapy in acute myocardial infarction. JAMA 1993;270:1589-95

(e.g. prophylactic use of lidocaine (and other anti-arrhytmic drugs?) during myocardial infarction was shown to be more harmful than placebo

(it has been estimated that anti-arrhythmic drugs were causing between 20,000 and 70,000 deaths every year in the USA alone. Moore T. Deadly medicine. New York: Simon and Schuster, 1995, cited in Chalmers I and Lindley R. Double Standards on Informed Consent to Treatment. In: Doyal L, Tobias JS, eds. Informed consent: respecting patients' rights in research, teaching and practice. BMJ Publications, London: 2000)

Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med. 1989;321:406-412

Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH,

Arensberg D, Baker A, Friedman L, Greene HL, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991 Mar 21;324(12):781-8.

("A cardiology professor in 1980 told my fellow students and me that the RCTs I will cite would be unethical because those assigned to the placebo group would be denied "life saving treatment." Thank God (or whoever) that not everyone shared his opinion") (B. Budenholzer)

Epstein AE, Hallstrom AP, Rogers WJ, Liebson PR, Seals AA, Anderson JL et al. Mortality following ventricular arrhythmia suppression by encainide, flecainide, and moricizine after myocardial infarction: the original design concept of the Cardiac Arrhythmia Suppression Trial (CAST). JAMA 1993; 270:2451-2455.

("My favorite example is the CAST study showing that treatment of ventricular ectopy with type I anti-arrhthmics based on the assumption that this would prevent life-threatening arrhthymias actually lead to a higher death rate") (R. Poses)

("showed that class I antiarrhythmics suppressed ventricular extrasystoles but lead to increased total mortality" )(P. Ellis)

Waldo AL, Camm AJ, deRuyter H, Friedman PL, Macneil DJ, Pauls JF, Pitt B, Pratt CM, Schwartz PJ, Veltri EP. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet. 1996;348:7-12

Theroux P, Ouimet H, McCans J, et al. Aspirin, heparin or both to treat unstable angina. N Engl J Med 1988;319:1105-11

Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in oler diabetic patients with isolated systolic hypertension. JAMA. 1996;276:1886-1892

Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998 Aug 19;280(7):605-13.

(HERS is still controversial but current, and instructive in counterpoint to the overwhelming observational evidence in favor of HRT for CHD prevention.) (J . Tice)

Herrington DM et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl H Med 2000;343:522-9

"Comment:This is another trial that contradicted earlier obsrvational and laboratory studies about favorable effects of estrogen alone or in combination with medroxyprogesterone on coronary artery disease. The authors concluded that "women with heart disease should not use conjugated estrogen, alone or in combination with medroxyprogesterone". Note that data on primary prevention are still not available".

Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).Lancet. 1994 Nov 19;344(8934):1383-9.

("Until 4S I was deeply sceptical about drug treatment for cholesterol. 4S changed that to cautious belief. Equally importantly, for me WOSCOPS reinforced 4S by showing very similar sized effects in a different population. For me, WOSCOPS was more important in making me trust 4S for secondary prevention than in radically changing my practice for primary prevention of heart disease. And then there's been all the rest with a cumulative impact.") (B. Guthrie)

Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.

ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.

Lancet. 1988 Aug 13;2(8607):349-60.

Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999 Jun 12;353(9169):2001-7. Along with The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999 Jan 2;353(9146):9-13.

"Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group." N Engl J Med 1987;316(23):1429-35.

"Long-term effects of intravenous thrombolysis in acute myocardial infarction: final report of the GISSI study. Gruppo Italiano per lo Studio della Streptochi-nasi nell'Infarto Miocardico (GISSI)." Lancet 1987; 2(8564):871-4.

"GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico [see comments]." Lancet 1994;343(8906): 1115-22.

ligation of int. mammary artery as a treatment for coronary artery disease

Fisher LD, Kennedy JW. Randomized surgical clinical trials of coronary artery diseases. Controlled Clin Trials 1982;3:235-258

(cited in: Fineberg HV. Clinical evaluation: how does it influence medical practice. Bull Cancer 1987;74:333-346

(ligation was no better than sham surgery, with small incision in the chest)

"Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group [see comments]." Jama (1991). 265(24): 3255-64.

Colwell, C. W., Jr., D. K. Collis, et al. (1999). "Comparison of enoxaparin and warfarin for the prevention of venous thromboembolic disease after total hip arthroplasty. Evaluation during hospitalization and three months after discharge." J Bone Joint Surg Am 81(7): 932-40.

Leroyer, C., L. Bressollette, et al. (1998). "Early versus delayed introduction of oral vitamin K antagonists in combination with low-molecular-weight heparin in the treatment of deep vein thrombosis. A randomized clinical trial. The ANTENOX Study Group." Haemostasis 28(2): 70-7

Decousus, H., A. Leizorovicz, et al. (1998). "A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prevention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group [see comments]." N Engl J Med 338(7): 409-15.

"Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. ENOXACAN Study Group." Br J Surg 1997;84(8): 1099-103.

Turpie, A. G., M. N. Levine, et al. (1986). "A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery." N Engl J Med 315(15): 925-9.

Planes, A., N. Vochelle, et al. (1988). "Prevention of postoperative venous thrombosis: a randomized trial comparing unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement." Thromb Haemost 60(3): 407-10.

"Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. The Columbus Investigators." N Engl J Med 1997;337(10):657-62.

Barritt DW,Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet 1960;1:1309-1312

A truly historic trial that established efficacy of heparin in the treatment of thrombotic disease. In recent years, the treatment of pulmonary embolism/deep vein thrombosis has been further refined in RCTs (some cited above) demonstrating further benefit of low-molecular weight heparin over unfractionated heparin in several clinical situations. This field has tremendously advanced thanks to RCTs.

Simonneau, G., H. Sors, et al. (1997). "A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l'Embolie Pulmonaire." N Engl J Med 337(10): 663-9.

"Stroke Prevention in Atrial Fibrillation Study. Final results [see comments]." Circulation 1991;84(2): 527-39.

Flaker, G. C., J. L. Blackshear, et al. (1992). "Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators." J Am Coll Cardiol 20(3): 527-32.

"Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial [see comments]." Lancet 1996;348(9028): 633-8.

 

Endocrinology

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993 Sep 30;329(14):977-86.

 

Infectious Diseases

Warrell DA, Looareesuwan S, Warrell MJ, Kasemsarn P, Intaraprasert R, Bunnag D, Harinasuta T Dexamethasone proves deleterious in cerebral malaria. A double-blind trial in 100 comatose patients.N Engl J Med 1982 Feb 11;306(6):313-9

(The use of steroids in these circumstances was supported by theoretical work, animal studies and case reports. Some might have claimed that the evidence for the use of steroids was "overwhelming" and that the study was unethical! The results showed that steroids were in fact harmful.) (J. Weinberg)

 

Medical Research Council Streptomycin in Tuberculosis Trials Committee. Streptomycin treatment for pulmonary tuberculosis. BMJ 1948; ii: 769-782.

This trial not only established superiority of streptomycin over bed rest (standard treatment at the time), but was first truly randomized trial to be reported. This "1948 watershed" signifies the introduction of randomized controlled trials as one of the most important forms of scientific inquiry ever designed in clinical medicine. (Note that the first trial which allocated patients randomly was one designed to test the efficacy of immunisation against whooping cough, but it was reported three years later in BMJ 1951; i: 1463-1471).

For historical perspectives, see Doll R. Controlled trials: the 1948 watershed. BMJ 1998;317:1217-1220 and a special theme BMJ issue, 31 October 1998 (Volume 317, Issue 7167)

Gastroenterology

Gastric freezing in the treatment of peptic ulcer

Miao LL. Gastric freezing: an example of the evaluation of medical therapy by randomized trials. In: Bunker JP, Barnes, Mosteller F, eds. Costs, risks, and benefits of surgery. Oxford University Press, New York: 1977, pp 198-211

[dramatic results for beneficial effect of gastric surgery in the treatment of peptic ulcers were obtained in uncontrolled studies; RCT demonstrated that surgery was no more successful than less aggressive medical treatments resulting in abandoning this aggressive procedure; cited in: Alman D. What randomized trials and systematic reviews can offer decision makers. Horm Res 1999;51 (suppl 1):36-43]

Riemann, J. F., D. Schilling, et al. (1997). "Cure with omeprazole plus amoxicillin versus long-term ranitidine therapy in Helicobacter pylori-associated peptic ulcer bleeding [see comments]." Gastrointest Endosc 46(4): 299-304.

Graham, D. Y., G. M. Lew, et al. (1992). "Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. A randomized, controlled study [see comments]." Ann Intern Med 116(9): 705-8.

 

Nephrology

Lewis AS, Hunsicker LG, Lan SP, et al. A controlled trial of plasmapharesis therapy in severe lupus nephritis. N Engl J Med 1992; 326:1373-1379.

(Showed that plasmapharesis was ineffective (?detrimental) in the treatment of severe lupus nephritis) (P. Ellis)

 

Oncology.

Bonadonna, G., E. Brusamolino, et al. (1976). "Combination chemotherapy as an adjuvant treatment in operable breast cancer." N Engl J Med 294(8):405-10.

Rossi, A., G. Bonadonna, et al. (1981). "Multimodal treatment in operable breast cancer: five-year results of the CMF programme." Br Med J (Clin Res Ed) 282(6274): 1427-31.

Bonadonna, G., M. Zambetti, et al. (1995). "Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. Ten-year results [see comments]." Jama 273(7):542-7.

Bonadonna, G., P. Valagussa, et al. (1995). "Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node- positive breast cancer: the results of 20 years of follow-up [see comments]." N Engl J Med 332(14): 901-6.

Fisher, B., M. Bauer, et al. (1985). "Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer." N Engl J Med 312(11):665-73.

Fisher, B., C. Redmond, et al. (1985). "Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation." N Engl J Med 312(11): 674-81.

Fisher, B., C. Redmond, et al. (1990). "Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16 [see comments]." J Clin Oncol 8(6): 1005-18.

Fisher, B., A. Brown, et al. (1997). "Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18 [see comments]." J Clin Oncol 15(7): 2483-93.

(trials listed above help defined current practice of adjuvant chemotherapy and lumpectomy instead of mastectomy in breast cancer)

Canellos GP, Anderoson JP, Propert KJ, etl. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD vs. MOPP alternating with ABVD. N Engl J Med 1992;327:1478

(trial that defined the current practice of using ABVD as a combination of choice in Hodgin's disease)

Fisher, B., N. Wolmark, et al. (1988). "Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01." J Natl Cancer Inst 80(1): 21-9.

Wolmark, N., H. Rockette, et al. (1999). "Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04." J Clin Oncol 17(11): 3553-9.

(trials that help defined current practice of adjuvant therapy in rectal and colon cancer)

Okawara, G., J. Rusthoven, et al. (1997). "Unresected stage III non-small-cell lung cancer. Provincial Lung Cancer Disease Site Group." Cancer Prev Control 1(3): 249-59.

McKelvey EM, Gottlieb JA, Wislon HE, et el.: Hydroxyadaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer 1976; 38: 1484.

(the key trial that introduced CHOP chemotherapy in the treatment of malignant lymphomas; over next 20 years numerous phase II trials have been introduced claiming superiority of so called second and third chemotherapy regimens; the issue was finally settled in 1993 with publication of RCT showing that CHOP has remained least toxic and equally effective chemo regimen in the treatment of NHL; see below)

Tirelli, U., D. Errante, et al. (1998). "CHOP is the standard regimen in patients > or = 70 years of age with intermediate-grade and high-grade non-Hodgkin's lymphoma: results of a randomized study of the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Study Group." J Clin Oncol 16(1): 27-34.

Fisher, R. I., E. R. Gaynor, et al. (1993). "Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma [see comments]." N Engl J Med 328(14): 1002-6.

(trials that defined the current practice of using CHOP as a combination of choice in NHL in advanced disease)

Miller, T. P., S. Dahlberg, et al. (1998). "Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma [see comments]." N Engl J Med 339(1): 21-6.

(trials that defined the current practice of using CHOP+XRT as a combination of choice in NHL in early stages)

Stadtmauer EA, O'Neill OA, Goldstein LJ et al., Conventional-Dose Chemotherapy Compared with High-Dose Chemotherapy plus Autologous Hematopoietic Stem-Cell Transplantation for Metastatic Breast Cancer. N Engl J Med 2000;342:1069-76.

(this and related trials reported in the abstract form at the ASCO 1999 effected practice of referral in the United States by showing no difference in survival between high-dose and standard treatment arm) (see N Engl J Med 2000;342:1138-1139).

melphalan+prednisone (MP) vs. colchicine in the treatment of amyloidosis

[reversal of the effect; MP in RCT was shown superior to colchicine (N Engl J Med 1997; 336:1202) that was earlier, in non-RCT trial (Am J Med 1987;87:1182), was claimed to be superior to M+P)]

surgery vs. surgery+adjuvant chemoRx in treatment of osteosarcoma
(dramatic beneficial effect of adjuvant chemoRx proving that surgical technique is not sufficient. N Engl J Med 1996;314:1600)

 

Obstetrics and Gynecology

International PHVD Drug Trial Group(1998) International randomised controlled trial of acetazolamide and frusemide in post-haemorrhagic ventricular dilatation in pregnancy. Lancet 352, 433-440

(This trials also "raised severe problems about when to stop a major international trial, where the treatment effect appears opposite to that expected, but when stopping early may reduce the impact of the trial and so make it less likely to change medical practice.) (M.Campbell)

Routine vs selective episiotomy: a randomised controlled trial. Argentine Episiotomy Trial Collaborative Group. Lancet. 1993 Dec 18-25;342(8886-8887):1517-8.

Klein MC, Gauthier RJ, Jorgensen SH, Robbins JM, Kaczorowski J, Johnson B, Corriveau M, Westreich R, Waghorn K, Gelfand MM, et al. Does episiotomy prevent perineal trauma and pelvic floor relaxation? [published erratum appears in Online J Curr Clin Trials 1992 Sep 12;Doc No 20:[54 words; 1 paragraphs]. Online J Curr Clin Trials. 1992 Jul 1;Doc No 10:[6019 words; 65 paragraphs].

( We thought we were doing such good, now it appears that we may have been increasing the chance of tears rather than decreasing.) (G. Jackson )

use of DES to prevent miscarriages in pregnant women

Chalmers TC. The impact of controlled trials on the practice of medicine. Mt Sinai J Med 1974;41:753-759

(outcomes were worse in DES treated group compared to control; this is considered as classic example of the danger of introducing chemotherapy based on pathophysiologic rationale instead of empiric testing ) (cited in: Fineberg HV. Clinical evaluation: how does it influence medical practice. Bull Cancer 1987;74:333-346)

ACTOBAT Study Group. Australian collaborative trial of antenatal thyrotropin-releasing hormone (ACTOBAT) for prevention of neonatal respiratory disease Lancet, 1995; 345:877-882.

("In our study - which was large and had an intention to treat analysis we not only showed no benefit of antenatal TRH but also an indication of adverse effects in the group excluded in prior analyses".(JE Hiller)

A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia"  Lucas MJ, Leveno KJ, Cunningham FG.  N Eng J Med 1995 Jul 27; 333(4):201-5

"Proved magnesium was superior for prevention of eclampsia, and changed opinions, as witnessed by number of editorials in journals following publication.  Magnesium was largely preferred in the US, but phenytoin was preferred in Europe (particularly the U.K.) prior to this study."(D. Sontheimer)

Folate And Neural Tube Defect

Czeizel E, Dudas I. [Prevention of the first occurrence of anencephaly and spina bifida with periconceptional multivitamin supplementation]. Orv Hetil 1994;135:2313-7

 

Ophtalmology

Optic nerve decompressive surgery for nonarteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. The Ischemic Optic Neuropathy Decompression Trial Research Group [see comments]. JAMA 1995; 273: 625-632

This is "another RCT that changed medical (surgical) practice. Optic nerve decompression was a favoured and widespread treatment prior to this trial which proved its uselessness and potential harmfulness" (S. Wiebe)

Neurology

Extracranial/Intracranial bypass surgery for stroke prevention in symptomatic atherosclerotic stroke. This common surgical procedure was abandoned after the RCT demonstrating no benefit (The EC/IC Bypass Study Group. Failure of Extracranial-Intracranial Arterial Bypass to Reduce the Risk of Ischemic Stroke. N.Engl.J.Med. 1985; 313: 1191-1200.)

 

Also of interest:

"A peculiar category is the 'tomato effect'', in fact a type 4 error. The example - as far as I can recall it - is the efficacy of gold injections in R.A. based on a infectious theory. When that infectious theory was proven wrong, the gold therapy was abandonned and with that the real efficacy of that therapy, untill the efficacy of gold was rediscovered, and proven in properly designed studies." (Nico van Duijn)

The tomato effect. rejection of highly effacious therapies. Goodwin JS, Goodwin JM. JAMA 1984; 251: 2387-90.

Warlow, C. and J. Wardlaw (1997). "The drug trials that have influenced our clinical practice in acute ischaemic stroke." Thromb Haemost 78(1): 558-61.

"The best example I can think of is ECMO. It was so successful and so rapidly adopted that there was a lot of debate about whether a randomized trial would be ethical.

A rather technical discussion of "adaptive randomization" (an approach that tried to overcome some of the ethical problems with studying a therapy like ECMO) appears in Ware JH "Investigating Therapies of Potentially Great Benefit: ECMO" Statistical Science (November 1989) 4(4):298-317" (S. Simon)

 

____________________

Send all comments regarding this list to:

Benjamin Djulbegovic at

djulbebm@moffitt.usf.edu