031998 a comparison of sucralfate and ranitidine for

and coagulopathy are the strongest risk factors for Background
clinically important gastrointestinal bleeding.8-11 chanical ventilation are at increased risk for gastro- Randomized trials of prophylaxis against stress ul- intestinal bleeding from stress ulcers. There are con- cers, as compared with no prophylaxis, indicate that flicting data on the effect of histamine H -receptor histamine H -receptor antagonists and antacids pre- antagonists and the cytoprotective agent sucralfate vent clinically important gastrointestinal bleeding.12 on rates of gastrointestinal bleeding, ventilator-asso- Observational studies have suggested, however, that a higher gastric pH is associated with gastric micro- Methods
bial growth,13 tracheobronchial colonization,14 and placebo-controlled trial, we compared sucralfate with nosocomial pneumonia.15 In randomized trials, the the H -receptor antagonist ranitidine for the preven- tion of upper gastrointestinal bleeding in 1200 pa- cytoprotective agent sucralfate, which does not alter tients who required mechanical ventilation. Patients the gastric pH, has been associated with a trend received either nasogastric sucralfate suspension (1 g toward a lower incidence of ventilator-associated every six hours) and an intravenous placebo or intra- pneumonia, both as compared with histamine H - venous ranitidine (50 mg every eight hours) and a receptor antagonists and antacids16 and as compared Results
The patients in the two groups had similar The need to evaluate patients at highest risk for base-line characteristics. Clinically important gastro- both bleeding and pneumonia31 and the need to intestinal bleeding developed in 10 of 596 (1.7 per- blind care givers and research personnel to the treat- cent) of the patients receiving ranitidine, as com- ment assignments, in order to minimize inflated treat- pared with 23 of 604 (3.8 percent) of those receiving ment effects,32 prompted us to evaluate the rates of sucralfate (relative risk, 0.44; 95 percent confidenceinterval, 0.21 to 0.92; Pϭ0.02). In the ranitidine group, clinically important gastrointestinal bleeding, venti- 114 of 596 patients (19.1 percent) had ventilator-asso- lator-associated pneumonia, and mortality in a ran- ciated pneumonia, as compared with 98 of 604 (16.2 domized trial of 1200 patients who required me- percent) in the sucralfate group (relative risk, 1.18; 95 chanical ventilation and who were assigned to receive percent confidence interval, 0.92 to 1.51; Pϭ0.19).
There was no significant difference between thegroups in mortality in the intensive care unit (ICU) (23.5 percent in the ranitidine group and 22.8 percent Enrollment
in the sucralfate group) or the duration of the stay inthe ICU (median, nine days in both groups).
From October 1992 to May 1996, we screened consecutive pa- Conclusions
tients admitted to 16 participating intensive care units (ICUs) toidentify adults who were projected to require mechanical ventila- ing mechanical ventilation, those receiving raniti- tion for at least 48 hours. Criteria for exclusion were a diagnosis dine had a significantly lower rate of clinically impor- of gastrointestinal bleeding or pneumonia on admission, gastrec- tant gastrointestinal bleeding than those treated tomy, a prognosis considered to be hopeless, previous randomiza- with sucralfate. There were no significant differences tion in this or another trial, or receipt of two or more previous in the rates of ventilator-associated pneumonia, the doses of open-label prophylactic therapy. The protocol was ap- duration of the stay in the ICU, or mortality. (N EnglJ Med 1998;338:791-7.)1998, Massachusetts Medical Society.
From McMaster University, Hamilton, Ont. (D.C., G.G., H.F., L.G., A.M.); the University of Toronto, Toronto (J.M.); the University of West- ROPHYLAXIS against stress ulcers has tra- ern Ontario, London (D.L., F.R., A.K.); Dalhousie University, Halifax,N.S. (R.H.); Memorial University, St. John’s, Newf. (S.P.); and Queen’s University, Kingston, Ont. (G.W.) — all in Canada. Address reprint re- vention of upper gastrointestinal bleeding in quests to Dr. Cook at the Department of Medicine, St. Joseph’s Hospital, 50 Charlton Ave., Hamilton, ON L8N 4A6, Canada.
critically ill patients. Recent natural-histo- Other authors were Martin Tweeddale, M.D., University of British Co- ry studies have documented a very low incidence of lumbia, Vancouver; Joe Pagliarello, M.D., University of Ottawa, Ottawa, bleeding,4 however, suggesting that universal pro- Ont.; and Richard Johnston, M.D., University of Alberta, Edmonton.
phylaxis may not be warranted.5-7 Respiratory failure *Other study investigators are listed in the Appendix.
Downloaded from www.nejm.org at UNIVERSITY OF ALBERTA LIBRARY on January 5, 2007 . Copyright 1998 Massachusetts Medical Society. All rights reserved. T h e New E n g l a n d Jo u r n a l o f Me d i c i n e proved by the institutional review boards of all the participating of units transfused minus 2 (i.e., if 4 units of packed cells were centers, and the patients or their proxies gave informed consent.
transfused, the bleeding would be considered clinically importantif the hemoglobin concentration did not rise by at least 2 g per Randomization
Patients were randomly assigned to study groups in blocks of Ventilator-Associated Pneumonia
six, with stratification according to center, by means of a comput-er-generated random-number table prepared at the McMaster Attending intensivists at each center used a modified version of University Methods Center and managed by the ICU study phar- the criteria of the Centers for Disease Control and Prevention macist at each site who administered the coded drugs. All care (CDC)36 to identify patients in whom pneumonia was suspected givers and other research personnel were unaware of the random- on clinical grounds. These criteria were a new radiographic infil- ization schedule and the block size.
trate that had persisted for at least 48 hours (as interpreted bydesignated study radiologists blinded to the patients’ treatment Blinding
assignments) plus at least two of the following: a temperatureabove 38.5°C or below 35.0°C, a leukocyte count of more than The patients, research nurses, and all ICU care givers were un- 10,000 per cubic millimeter or less than 3000 per cubic millime- aware of the treatment assignments for the duration of the study.
ter, purulent sputum, or isolation of pathogenic bacteria from an Therefore, clinicians did not monitor gastric pH. The radiolo- gists, outcome adjudicators, all investigators, and the study statis- Patients in whom ventilator-associated pneumonia was suspect- tician were also blinded until all events had been adjudicated and ed on clinical grounds underwent bronchoalveolar lavage or pro- tected brush-catheter sampling by the study bronchoscopist.37,38Two members of the pneumonia-adjudication committee exam- Drug Preparation, Dispensing, and Administration
ined all relevant clinical and diagnostic documents related to pos- The bags of ranitidine (Zantac, Glaxo Wellcome; prepared by sible cases of pneumonia in duplicate and independently, classify- Baxter) and ranitidine placebo were identical in appearance. The ing patients according to several different methods. One method sucralfate (Sulcrate, Hoechst Marion Roussel) and sucralfate pla- used was the modified CDC criteria described above ; another cebo slurries were identical in color, taste, and consistency. From was the Clinical Pulmonary Infection Score devised by Pugin et coded ranitidine bags and sucralfate bottles stored in each ICU al. (range, 0 to 12, with pneumonia defined by a score of 7 or pharmacy, study pharmacists dispensed either active ranitidine higher). In addition, adjudicators used the criteria of the Mem- (50 mg every eight hours) and sucralfate placebo or active sucral- phis Ventilator-Associated Pneumonia Consensus Conference for fate (1 g every six hours) and ranitidine placebo.
definite ventilator-associated pneumonia (if there was radiograph- Ranitidine was administered in intravenous bolus form, with ic evidence of abscess and a positive needle aspirate, or if there the dose adjusted for renal failure as follows: standard dose, 50 was histologic proof of pneumonia at biopsy or autopsy) and mg every 8 hours; dose for patients with an estimated creatinine probable ventilator-associated pneumonia (if bronchoalveolar la- clearance rate of 25 to 50 ml per minute, 50 mg every 12 hours; vage or protected brush-catheter sampling yielded positive quan- dose for patients with an estimated creatinine clearance rate below titative or semiquantitative cultures, if there was a positive blood 25 ml per minute, 50 mg every 24 hours; and dose for patients culture of an organism found within 48 hours of isolation in the dependent on dialysis, 50 mg every 12 hours. Sucralfate suspen- sputum, if there was a positive pleural-fluid culture of an organ- sion was given through a nasogastric tube or orally. We followed ism found within 48 hours of isolation in the sputum, or if his- all patients until they died or were discharged from the ICU.
tologic examination showed formation of an abscess or consoli-dation with polymorphonuclear-cell infiltration).40 To make a Demographic Characteristics of the Patients
final decision as to whether each patient had ventilator-associatedpneumonia, adjudicators made a summary judgment based on all We documented each patient’s age, sex, admitting diagnosis, available information; disagreement was resolved through discus- location before admission to the ICU, score on the Acute Physi- sion. We determined a priori that the adjudication committee’s ology and Chronic Health Evaluation (APACHE II) scale (range consensus rate of pneumonia would be used for the primary anal- of scores, 0 to 71, with higher scores indicating more severe ysis and that other definitions would be used in the secondary illness),33 and multiple-organ-dysfunction (MOD) score (range, 0 to 24, with higher scores indicating more severe organ dysfunc-tion).34 Statistical Analysis
Since ventilator-associated pneumonia has been considered an Gastrointestinal Bleeding
important potential adverse effect of gastric pH–altering prophy- We monitored patients for signs of overt gastrointestinal hem- laxis against stress ulcers and because previous trials did not ex- orrhage, including hematemesis, nasogastric aspirate containing amine pneumonia as rigorously as gastrointestinal bleeding, we blood or coffee-grounds material, melena, or hematochezia. The designed our trial to have the statistical power to detect a differ- decision to perform endoscopy was left to the discretion of the ence in the rates of pneumonia. On the basis of data published intensive care specialist. Two physicians from the study’s bleeding- through 1991, when our study was designed, we anticipated a 25 adjudication committee examined all relevant clinical and diag- percent incidence of pneumonia and identified a 25 percent re- nostic documents related to possible bleeding episodes in dupli- duction in the risk of pneumonia associated with sucralfate as be- cate and independently, using previously defined criteria.35 We ing plausible and clinically important. This led to the calculation defined clinically important bleeding as overt bleeding plus one of a sample size of 1200 patients as necessary to give the study of the following four features, in the absence of other causes: a 75 percent power to detect such a difference, assuming a two-sid- spontaneous drop of 20 mm Hg or more in the systolic or dia- ed significance test at the 0.05 level. We analyzed all patients in stolic blood pressure within 24 hours after upper gastrointestinal the groups to which they were randomly assigned, according to bleeding; an increase in the pulse rate of 20 beats per minute and the intention-to-treat principle. We compared means using Stu- a decrease in the systolic blood pressure of 10 mm Hg on the pa- dent’s t-test and compared proportions using the chi-square test, tient’s assuming an upright position; a decrease in the hemoglo- with two-tailed P values.41 We used Fisher’s exact test when the bin concentration of at least 2 g per deciliter in 24 hours and the number of data points was small. For the length of the stay in the transfusion of 2 units of packed red cells within 24 hours after ICU, we report data as medians and interquartile ranges.
bleeding; or failure of the hemoglobin concentration (in grams We conducted analyses both with and without adjustment for per deciliter) to increase after transfusion by at least the number the following variables, treated categorically: age (Ͻ65 or у65 Downloaded from www.nejm.org at UNIVERSITY OF ALBERTA LIBRARY on January 5, 2007 . Copyright 1998 Massachusetts Medical Society. All rights reserved. C O M PA R I S O N O F S U C R A L FAT E A N D R A N I T I D I N E TO P R EV E N T U P P E R GAST RO I N T E ST I N A L B L E E D I N G
years), sex, location before admission to the ICU (emergencyroom, operating room, hospital ward, or other ICU), medical or TABLE 1. BASE-LINE CHARACTERISTICS
surgical (elective or emergency) status, APACHE II score (Ͻ25 or у25), MOD score (Ͻ5 or у5), and medical center (of whichthere were 16).42 RANITIDINE
Of 7986 patients admitted to ICUs, 6786 were excluded for the following reasons: mechanical ven- tilation was expected to be needed for less than 48 hours (3754 patients), the prognosis was considered hopeless (481), the patient had pneumonia (988) or gastrointestinal bleeding (432) at admission, gas- trectomy had been performed (41), the patient had previously undergone randomization in this or an- other trial (565), two or more previous doses of open-label prophylaxis had been received (230), the patient had undergone mechanical ventilation in an- other ICU (38), the patient or proxy was unable or unwilling to give informed consent (184), an ad- ministrative error occurred (44), the physician de- clined to have the patient enrolled (14), or another reason (15). Excluded patients were a mean (ϮSD) of 60.8Ϯ15.3 years of age and had a mean APACHE We randomly assigned 1200 patients to the su- cralfate or ranitidine group. Demographic and base- *Plus–minus values are means ϮSD. APACHE II denotes line physiologic characteristics were similar in the the Acute Physiology and Chronic Health Evaluation scale (range of scores, 0 to 71; higher scores indicate more severeillness); MOD denotes multiple-organ dysfunction (range ofscores, 0 to 24; higher scores indicate more severe organ dys- Protocol Violations, Compliance, and Nonstudy
No patient received active drug instead of the as- signed placebo, or vice versa. Of the scheduled dosesof ranitidine and sucralfate, 94.2 percent and 91.7 The results of the analysis in which we adjusted for percent, respectively, were administered. Among pa- other factors were similar (relative risk, 0.45; 95 per- tients who missed doses, the mean number of doses cent confidence interval, 0.22 to 0.92; Pϭ0.03).
missed was 2.3 (median, 3; interquartile range, 2 to Seventeen patients underwent upper gastrointesti- 3) for ranitidine and 2.9 (median, 4; interquartile nal endoscopy; additional diagnostic tests included laparotomy (in four), angiography (three), sigmoid- Fourteen patients in the ranitidine group (2.3 per- oscopy (three), and red-cell scanning (one); two pa- cent) and 16 in the sucralfate group (2.6 percent) re- tients were examined at autopsy. One patient in the ceived an additional drug as prophylaxis against sucralfate group had bleeding from a gastroduodenal stress ulcers outside of the study protocol (Pϭ0.74).
anastomosis, and another in the same group had Most patients received enteral nutrition (70.3 per- bleeding from an aortic graft–enteric fistula. The cent and 71.8 percent, respectively; Pϭ0.55). Enter- source of bleeding was unclear for 8 patients in the al feeding was started a median of three days (in- ranitidine group and for 11 patients in the sucralfate terquartile range, two to four) after admission to group. Table 2 lists the 14 patients who had bleeding from gastric, esophageal, or duodenal erosions ordiscrete ulcers along with their study group, indica- Gastrointestinal Bleeding
tion of bleeding, and diagnostic tests or procedures In the ranitidine group, 10 of 596 patients (1.7 (Table 2). Post hoc subgroup analysis of patients percent) had clinically important gastrointestinal with documented esophageal, gastric, or duodenal bleeding, as compared with 23 of 604 (3.8 percent) ulcers or erosions generated results consistent with in the sucralfate group (relative risk, 0.44; 95 percent our main findings (relative risk of bleeding in the confidence interval, 0.21 to 0.92; Pϭ0.02); the ab- ranitidine group as compared with the sucralfate solute reduction in the risk of bleeding was 2.1 per- group, 0.41; 95 percent confidence interval, 0.13 to cent (95 percent confidence interval, 0.29 to 3.97).
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range, 5 to 15) in the ranitidine group and 9 days Among 596 patients receiving ranitidine, 114 (interquartile range, 5 to 17) in the sucralfate group (19.1 percent) had ventilator-associated pneumonia, (Pϭ0.27). The duration of intubation was 7 days as compared with 98 of 604 (16.2 percent) in the (interquartile range, 4 to 13) in the ranitidine group sucralfate group (relative risk, 1.18; 95 percent con- and 8 days (interquartile range, 4 to 15) in the su- fidence interval, 0.92 to 1.51; Pϭ0.19); the abso- lute difference in risk was 2.9 percent (95 percent Mortality in the ICU
confidence interval, Ϫ1.4 to 7.2). Results of the ad-justed analysis were similar (relative risk, 1.14; 95 Mortality in the ICU was similar among patients percent confidence interval, 0.91 to 1.44; Pϭ0.26).
receiving ranitidine (140 of 596 [23.5 percent]) and Table 3 presents the rates of pneumonia when dif- those receiving sucralfate (138 of 604 [22.8 per- ferent diagnostic criteria were used. As the defini- cent]; relative risk, 1.03; 95 percent confidence in- tion of pneumonia became more strict, the overall rate decreased, although the difference between thetwo groups persisted. Table 4 shows the organisms DISCUSSION
isolated from endotracheal aspirates from patients We found that patients receiving ranitidine had a with pneumonia. There was no significant difference significantly lower risk of gastrointestinal bleeding in the types of isolates between the groups.
than patients receiving sucralfate (relative risk, 0.44;95 percent confidence interval, 0.21 to 0.92). This Duration of Patients’ Stay in the ICU
finding appears to contrast with the results of a re- All patients were included in the analysis. The me- cent meta-analysis, which suggested that the drugs’ dian length of the ICU stay was 9 days (interquartile effect on bleeding was equivalent (relative risk, 0.95; TABLE 2. EROSIVE OR ULCERATIVE CONDITIONS AFFECTING THE ESOPHAGUS, STOMACH, OR DUODENUM
Sucralfate group
Ranitidine group
*The 14 patients listed are those who had clinically important gastrointestinal bleeding with erosions or ulcers of the †Clinically important bleeding was defined as overt bleeding plus one of the following four features, in the absence of other causes: (1) a spontaneous drop of 20 mm Hg or more in the systolic or diastolic blood pressure within 24 hoursafter upper gastrointestinal bleeding; (2) an increase in the pulse rate of 20 beats per minute and a decrease in the systolicblood pressure of 10 mm Hg on the patient’s assuming an upright position; (3) a decrease in the hemoglobin concen-tration of at least 2 g per deciliter in 24 hours and the transfusion of 2 units of packed red cells within 24 hours afterbleeding; or (4) failure of the hemoglobin concentration (in grams per deciliter) to increase after transfusion by at leastthe number of units transfused minus 2 (i.e., if 4 units of packed cells were transfused, the bleeding would be consideredclinically important if the hemoglobin concentration did not rise by at least 2 g per deciliter).
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(95% CI)†
*CI denotes confidence interval, adjudication rate the consensus of the study’s pneumonia-adjudi- cation committee, CDC the modified criteria of the Centers for Disease Control and Prevention,36clinical suspicion a Clinical Pulmonary Infection Score у7 (range of scores, 0 to 12),39 probablepneumonia probable ventilator-associated pneumonia according to the criteria of the Memphis Con-sensus Conference,40 and definite pneumonia definite ventilator-associated pneumonia according tothe same criteria.40 †The absolute percent difference shown is the rate in the ranitidine group minus that in the su- 95 percent confidence interval, 0.17 to 5.36)12;however, the confidence limits around these two es- TABLE 4. ORGANISMS ASSOCIATED WITH VENTILATOR-
timates overlap widely, and the difference could be ASSOCIATED PNEUMONIA IN THE STUDY PATIENTS.* attributable to chance. We found no significant dif-ference in the incidence of pneumonia between pa- RANITIDINE
tients receiving an H -receptor antagonist and those ORGANISM
receiving sucralfate (relative risk, 1.18; 95 percentconfidence interval, 0.92 to 1.51), a finding that is consistent with pooled data from previous random- ized trials (relative risk, 1.19; 95 percent confidence The strengths of our trial include the measures taken to conceal the patients’ treatment assignments; the blinding of care givers, research personnel, and analysts; the high rates of compliance; the adjudica- tion of outcomes according to rigorous criteria; and the examination of the relation between prophylaxis and the incidence of ventilator-associated pneumo- nia defined according to a variety of criteria, given the absence of a well-accepted reference standard.
Our study was limited by uncertainty about the causes of gastrointestinal bleeding; even in patients whose condition was stable enough for them to un- *Organisms shown are those isolated from endotracheal dergo endoscopy or other diagnostic tests, a site of aspirates from patients with ventilator-associated pneumonia; bleeding could not always be identified. The source the total number of organisms is more than the number ofpatients because several patients had more than one isolate.
of bleeding remained unknown for 19 of 33 pa-tients. Moreover, although our sample was large, theconfidence intervals around key estimates were wide.
Previous randomized trials indicate that H -recep- group in this trial (3.8 percent) approximates the 3.7 tor antagonists substantially lower the incidence of percent incidence observed among untreated pa- overt and clinically important bleeding as compared tients receiving mechanical ventilation in our natu- with no prophylaxis.12 Our findings show that rates ral-history study.11 Previous trials comparing sucral- of bleeding are lower among patients given H - fate with no prophylaxis have found a significantly receptor antagonists than among those given su- lower rate of overt bleeding with sucralfate23,29,43,44; cralfate. The incidence of bleeding in the sucralfate however, in the single trial from which data on clin- Downloaded from www.nejm.org at UNIVERSITY OF ALBERTA LIBRARY on January 5, 2007 . Copyright 1998 Massachusetts Medical Society. All rights reserved. T h e New E n g l a n d Jo u r n a l o f Me d i c i n e ically important bleeding events could easily be ex- Supported by the Medical Research Council of Canada and Hoechst tracted,29 1 of 30 patients in the control group and Marion Roussel. Drugs were supplied by Glaxo Wellcome, Baxter, andHoechst Marion Roussel. Dr. Cook is a Career Scientist of the Ontario 1 of 24 patients in the sucralfate group had clinically important bleeding. Given all this evidence, it isplausible that sucralfate has no effect on clinically We are indebted to the members of the Canadian Critical Care Trials Group for their help, particularly the research nurses who par- ticipated in this study, and to Drs. Thomas Todd, Thomas Noseworthy, Although we found no significant difference in Timothy Winton, and Michael Tryba for their support and advice. the rates of pneumonia between the two groups, therelative risk suggests a trend toward a lower rate of APPENDIX
pneumonia among patients receiving sucralfate. It is In addition to the authors, the study investigators and institutions were possible that sucralfate appears to have a small pro- as follows: B. Plumstead and L. Frighetto, Vancouver General Hospital,Vancouver, B.C.; T. Noseworthy, E. Konopad, S. Bishop, M.L. Derko, and tective effect against pneumonia because stress-ulcer K. Horon, Royal Alexandra Hospital, Edmonton, Alta.; D. Stollery, M.
prophylactic medications that increase the gastric Goers, and R. Jarman, Grey Nun’s Hospital, Edmonton, Alta.; D. Roberts, pH themselves increase the incidence of pneumonia.
T. Ostrusniuk, and J. Studney, Winnipeg Health Sciences Center, Win-nipeg, Man.; T. Winton, D. Foster, D. Baptiste, M. Steinberg, and M. Lee, This contention is supported by direct comparisons Toronto Hospital, General Division, Toronto; G. Darling, M. Culham, and of trials of H -receptor antagonists with no prophy- V. Bobiwash, Wellesley Hospital, Toronto; M. Lefcoe (study radiologist), D. McCormack (study bronchoscopist), L. McCarthy, and C. Gawlik, Lon- laxis, which show a trend toward higher rates of don Health Sciences Center (Victoria Campus), London, Ont.; S. Lang- pneumonia among the patients receiving H -recep- don, M. Johnson, and C. Charters, London Health Sciences Center (Uni- tor antagonists (odds ratio, 1.25; 95 percent confi- versity Campus), London, Ont.; M.K. Scott and S. Jansen, St. Joseph’sHealth Center, London, Ont.; E. McDonald, T. Dinh, and S. Toner, St.
dence interval, 0.78 to 2.00).12 Furthermore, the Joseph’s Hospital, Hamilton, Ont.; S. Salama, Henderson Hospital, Hamil- relative effects of sucralfate and no prophylaxis ton, Ont.; A. Taite and P. Newman, Kingston General Hospital, Kingston, against stress ulcers on the incidence of pneumonia Ont.; M. Loewen, Ottawa Civic Hospital, Ottawa, Ont.; D. Gibbons, G.
Leaman, and G. Gibbons, Health Sciences Center, St. John’s, Newf.; P.
is unclear. Among the 226 patients enrolled in two Roy, M. Coffin, and H. Lummis, Victoria General Hospital, Halifax, N.S.; randomized trials, there was a trend toward a higher Methods Center — P. Austin and S. Troyan (project coordinators), L. Buck-ingham (data-base manager), and S. Duchesne (data entry); Adjudication incidence of pneumonia among those receiving su- Committees — D. Heyland, A. Freitag, K. Gough, M. Meade, A. Sarabia, cralfate than among those given no prophylaxis (odds M. Turner, H. Devitt, B. Guslits, M. Heule, R. Jaeschke, and J. Lang.
ratio, 2.11; 95 percent confidence interval, 0.82 to REFERENCES
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