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Effects of Reduced Sodium Intake on Hypertension Control in Older Individuals
Results From the Trial of Nonpharmacologic Interventions in the Elderly (TONE)
Lawrence J. Appel, MD, MPH; Mark A. Espeland, PhD; Linda Easter, MS, RD; Alan C. Wilson, PhD; Steven Folmar, PhD; Clifton R. Lacy, MD

Background: Few trials have evaluated the effects of re-

duced sodium intake in older individuals, and no trial has examined the effects in relevant subgroups such as African Americans.
Patients and Methods: The effects of sodium reduc-

tion on blood pressure (BP) and hypertension control were evaluated in 681 patients with hypertension, aged 60 to 80 years, randomly assigned to a reduced sodium intervention or control group. Participants (47% women, 23% African Americans) had systolic BP less than 145 mm Hg and diastolic BP less than 85 mm Hg while taking 1 antihypertensive medication. Three months after the start of intervention, medication was withdrawn. The primary end point was occurrence of an average systolic BP of 150 mm Hg or more, an average diastolic BP of 90 mm Hg or more, the resumption of medication, or a cardiovascular event during follow-up (mean, 27.8 months).
Results: Compared with control, mean urinary sodium

excretion was 40 mmol/d less in the reduced sodium intervention group (P .001); significant reductions in sodium excretion occurred in subgroups defined by sex, race, age, and obesity. Prior to medication withdrawal, mean reductions in systolic and diastolic BPs from the reduced sodium intervention, net of control, were 4.3 mm Hg (P .001) and 2.0 mm Hg (P =.001). During followup, an end point occurred in 59% of reduced sodium and 73% of control group participants (relative hazard ratio=0.68, P .001). In African Americans, the corresponding relative hazard ratio was 0.56 (P = .005); results were similar in other subgroups. In dose-response analyses, end points were progressively less frequent with greater sodium reduction (P for trend=.002).
Conclusion: A reduced sodium intake is a broadly ef-

fective, nonpharmacologic therapy that can lower BP and control hypertension in older individuals. Arch Intern Med. 2001;161:685-693 trol hypertension in older persons,2,3 yet empiric evidence is sparse. Little is known about the ability and willingness of older persons to reduce their sodium intake, the effects of a reduced sodium intake on BP and hypertension control in this population, dose-response relationships, and the effects in relevant subgroups, such as African Americans. Applegate et al4 demonstrated that a multifactorial intervention, consisting of sodium reduction, weight loss, and increased physical activity, can reduce BP in older persons. Otherwise, only a few trials, each with small sample size, have examined the impact of sodium reduction as a means to reduce BP5,6 and control hypertension7 in older persons. In these trials, few, if any, participants were African American. Sodium reduction should be particularly effective in older persons. First, because arterial compliance decreases with age, any change in intravascular volume re-

From the Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Md (Dr Appel); Departments of Public Health Sciences (Dr Espeland), General Clinical Research Center (Ms Easter), and Anthropology (Dr Folmar), Wake Forest University, Winston-Salem, NC; and Division of Cardiovascular Diseases and Hypertension, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick (Drs Wilson and Lacy).

ment with medication are extremely common in the elderly. According to the Third National Health and Nutrition Examination Survey, conducted between 1988 and 1991, the prevalence of hypertension, defined as a systolic blood pressure (BP) of 140 mm Hg or more, a diastolic BP of 90 mm Hg or more, or treatment with medication, exceeds 50% in the civilian, noninstitutionalized population aged 60 years and older.1 In certain subgroups, hypertension is nearly ubiquitous. For example, the prevalence of hypertension among African American women aged 60 to 69 years is 78%. Medication use is also highly prevalent in the elderly, ranging from 31% of Mexican American women with hypertension 70 years and older to 70% of African American women with hypertension 70 years and older. Sodium reduction is widely advocated as a means to reduce BP and con-


YPERTENSION and its treat-



Downloaded from on October 12, 2010 ©2001 American Medical Association. All rights reserved.

9 Third. 18-. In view of these considerations. INTERVENTION Overweight participants were randomly assigned. Major exclusion criteria were use of antihypertensive medication for conditions other than hypertension (eg. Twenty-fourhour dietary recalls were obtained twice prior to randomization and again at the 9. STUDY POPULATION The study population consisted of healthy persons (aged 60-80 years) with systolic BP of less than 145 mm Hg and diastolic BP of less than 85 mm Hg (mean of 9 measurements. certified technicians who were masked to intervention assignment. and diastolic BP as the point of disappearance of the fifth Korotkoff sound. 3 BPs at each of 3 visits) while taking 1 antihypertensive on October 12. Nonoverweight participants were randomly assigned to reduced sodium alone or UL groups. Lung. older individuals may be more willing and able to reduce their sodium intake than younger individuals who have yet to experience the adverse health consequences of elevated BP. For screenees who were taking 2 antihypertensive medications. could effecWWW. angina pectoris. A detailed description of recruitment procedures has been published. in a 2 2 factorial design. 2001 686 Downloaded from www. . and 30-month follow-up visits and at closeout. or (4) usual lifestyle (UL) control group. and had routine laboratory tests to confirm eligibility. ie. 1 type of medication whether or not multiple doses were used. to 1 of the following 4 groups: (1) combined weight loss and reduced sodium. medication stepdown visits took place after the second screening visit but prior to the randomization visit.4 mmol/L ( 260 mg/dL).8 Second. congestive heart failure. and (4) enrollment of participants from previous studies. The median duration of follow-up was 29 months (maximum of 36 months).ARCHINTERNMED. and follow-up visits scheduled every 3 months.SUBJECTS AND METHODS A detailed description of the design and methods of this trial has been published.3 for women were used as the thresholds to define overweight. and self-report of average alcoholic beverage intake of more than 14 drinks per week. This level of sodium intake is slightly below the currently recommended upper limit of 100 mmol/L of sodium per day for the prevention and treatment of hypertension. (3) weight loss alone. ie. older individuals may retain sodium to a greater extent than younger persons.13 Data from the 24-hour recalls were used to determine macronutrient.14 This article presents data on participants. and Blood Institute. DATA COLLECTION Individuals provided a medical history. and energy intake in randomized groups at baseline and during follow-up. because of the decline in kidney function associated with aging. myocardial infarction or stroke within 6 months. Random-zero sphygmomanometers were used to minimize observer bias. Individuals treated with 2 antihypertensive medications were also eligible. 2010 ©2001 American Medical Association. Closeout visits occurred between July 1995 and December 1995. a comprehensive change in diet was not expected. At each visit. (3) BP screenings. drug withdrawal visits (beginning 90 days [±14 days] after the start of intervention). TONE demonstrated that a reduced sodium intake and weight loss. lated to sodium intake should result in a greater BP change in older persons than in younger individuals.12 In brief. as measured by 24-hour urine collections. which included (1) mass mailings of brochures. alone or combined. blood glucose level of more than 14. MAR 12. TONE used intervention techniques derived from experience in clinical trials that achieved BP control through interventions focusing on behavioral change. if they were successfully weaned from 1 of these medications during the screening phase. safety monitoring visits took place whenever a participant’s mean systolic BP was 150 mm Hg or more or diastolic BP was 90 mm Hg or more. micronutrient. Systolic BP was defined as the appearance of the first Korotkoff sound. Body mass index values (calculated as weight in kilograms divided by the square of height in meters) of 27.and 12-month follow-up visits and every 6 months thereafter by trained. Each participant provided written informed consent. All rights reserved. serum creatinine level of more than 176. (2) reduced sodium alone. developed by the Nutrition Coordinating Center. The intervention goal for reduced sodium groups was to achieve and maintain a 24-hour dietary sodium intake of 80 mmol/L or less of sodium.3 Participants were expected to modify only those aspects of their diet that led to a high sodium intake.8 for men and 27. University of Minnesota. nutrient database version 21). 11 The trial protocol was approved by institutional review boards at each participating center and by an external protocol review board appointed by the funding agencies: the National Institute on Aging and the National Heart. 3 BP measurements were obtained while the participant rested quietly in the seated position. To achieve its goal. Minneapolis. who were assigned to the reduced sodium alone or UL group.COM (REPRINTED) ARCH INTERN MED/ VOL 161.8 µmol/L ( 2 mg/dL). All BP measurements were obtained by trained and certified observers who were masked to intervention assignment. TONE data collection visits included 2 screening visits. (2) radio. the Trial of Nonpharmacologic Interventions in the Elderly (TONE) was a randomized trial that tested whether reduced sodium intake and/or weight loss can maintain satisfactory medicationtreated hypertension control in older persons with hypertension. Twenty-four-hour urine collections were obtained twice prior to randomization and once at the 9-. The main results of TONE have been published. underwent a physical examination. if this visit did not coincide with 1 of the follow-up visits.15-17 Social learning theory and behavioral approaches that enhance the understanding of behavior change and the ways to achieve it were incorporated.archinternmed. and newspaper advertisements. both overweight and nonoverweight. each TONE clinical center implemented site-specific strategies. television. Nutrient calculations were performed using the Minnesota Data System software (food database version 6A. Enrollment began in August 1992 and ended in June 1994. During follow-up. ischemic heart disease).10 In brief. a randomization visit.

OUTCOME VARIABLES In primary analyses. WITHDRAWAL OF ANTIHYPERTENSIVE MEDICATION Drug withdrawal began 90 days (±14 days) after the first group intervention session. participants were receiving drug therapy. and 79% of participants were between 60 and 69 years of age. and 43% overweight. •A cardiovascular clinical event (myocardial infarction. 34% college graduates. mean (SD) age was 65. as indicated by (1) elevated BP measured by TONE BP technicians (at 1 visit. tively control hypertension. and spices. angioplasty. Specifically. Of the participants. particularly those foods with a high salt content. differences in change (follow-up minus baseline levels) between the reduced sodium and UL groups were compared using unpaired t tests. or procedure [bypass surgery. were censored. endarterectomy]). a 3-month “extended” phase with biweekly meetings. made final decisions concerning the end point status of each participant. motivated participants to make and sustain long-term lifestyle changes. For continuous outcomes. at 2 visits. age. eg. or at 3 visits. interventionists provided information using both centrally and locally prepared materials. how to select appropriate foods at restaurants. Times were measured from the end of the drug withdrawal process until the occurrence of the end point. To facilitate masking of the data collectors. or during. was to increase the likelihood of successful drug withdrawal. a 2-sided significance level of . KaplanMeier curves were used to portray the distribution of times until failure for each of the study cohorts. meetings were held on a regular basis with speakers who led discussions on topics unrelated to BP. In primary analyses. a TONE participant reached a trial end point when any of the following occurred: •High BP. 2001 687 Downloaded from www. and a maintenance phase. BP and nutrient intake. mean diastolic BP 90 mm Hg or systolic BP 150 mm Hg). as opposed to immediately after randomization. which was standardized across the 4 clinical centers. congestive heart failure. The meetings were conducted as group sessions with individual sessions held at every fourth contact. are to examine the following issues: (1) the effects of a reduced sodium intake in subgroups defined by sex. Each comparison was performed using proportional hazards regression. Each of the TONE interventions consisted of a 4-month “intensive” phase with weekly meetings. participants learned about sources of sodium. change in BP was calculated as the difference between mean BP prior to randomization and BP at the visit when medication withdrawal was first attempted. After discontinuation of the drug. As the medication was tapered. the distributions of times until first occurrence of an end point were compared in participants assigned to the reduced sodium and UL groups. In the process. MAR 12. typically consisting of 9 to 12 participants. These clinical events were included as components of the composite end point to reduce the possibility of informative censoring. During the group and individual sessions. (2) dose-response relationships.6) years. while particiWWW. All rights reserved.COM (REPRINTED) ARCH INTERN MED/ VOL 161. Participants who met an end point criterion prior to. or nutrition. In all analyses. Mean (SD) systolic and diastolic BPs at baseline. used drug-specific tapering regimens.In the reduced sodium group. RESULTS At baseline. drug withdrawal were treated as instantaneous failures. ethnicity. 2010 ©2001 American Medical Association.archinternmed. . intervention visits were conducted at separate times and places from data collection visits. hypertensive encephalopathy. and the occurrence of adverse events. cardiovascular disease. mean diastolic BP 110 mm Hg or systolic BP 190 mm Hg. Intervention groups. and obesity. The drug withdrawal process. At both times. masked to intervention assignment. ANALYSES Analyses were conducted on an intention-to-treat basis. the outcome variable was a composite end point defined by the need for. or actual resumption of. participants were evaluated weekly.ARCHINTERNMED. antihypertensive drug on October 12. •Resumption of antihypertensive medication initiated by either a personal physician or participant for a symptom or condition other than elevated BP or a cardiovascular clinical event. 47% were women. such as migraine headaches and benign prostatic hypertrophy. which focuses on only the sodium component of TONE.8 (4. stroke. each person had an introductory individual session with the interventionist assigned to their group. The rationale for beginning medication withdrawal 90 days after the start of intervention. participants had 3 additional biweekly visits to confirm that their systolic BP remained less than 150 mm Hg and diastolic BP less than 90 mm Hg. Medical records were retrieved for all end points occurring outside a TONE visit. 23% African Americans. Participants given medication for non-BP and noncardiovascular conditions. The interventionist typically was a registered dietitian. To determine the impact of the interventions on BP. eg. To enhance follow-up among participants assigned to UL. They also learned how to adapt the reduced sodium lifestyle recommendations to their own individual situations. Participants randomized to UL began drug withdrawal at a comparable time. The objectives of this article. were then formed in a timely manner so that participants began the reduced sodium program within 45 days after randomization. This session occurred within 4 weeks of randomization. and (3) the effects of a reduced sodium intake on subtypes of the primary outcome variable. and about alternative foods. condiments. dietary intake of other nutrients. angina. and monitored individual and group progress at frequent intervals. An end point committee. or (2) resumption of antihypertensive medication initiated either by the participant or personal physician for elevated BP measured outside a clinical center.05 was considered statistically significant. mean diastolic BP 100 mm Hg or systolic BP 170 mm Hg.

P . Because the sex distribution in African Americans differed from that in non–African Americans. sodium reduction was similar in African Americans and non–African Americans. respectively. 24-hour urine collections were provided by 99% of reduced sodium and 97% of UL participants attending these visits. attendance was 91% and 88% of expected in the reduced sodium and UL groups. participants had hypertension for 13 years and had been taking antihypertensive medication for 12 years.001 .4) and 71. respectively. WWW.. 11% a -blocker.COM (REPRINTED) ARCH INTERN MED/ VOL 161.001 *Urinary sodium excretion expressed as millimoles per 24 hours. ‡Within-group difference in reduced sodium group minus within-group difference in usual lifestyle group. respectively.6) −30 (55) −3 (45) −46 (57) −8 (52) −41 (52) 5 (42) −45 (50) −1 (46) −45 (63) −10 (54) Mean (95% CI) P P for Difference in Effect Across Subgroups −40 (−48 to −32) . FOLLOW-UP At the 9-month follow-up visit. pants were taking medication. 97% of reduced sodium and 98% of UL participants provided urine specimens. 2001 688 Downloaded from www.0) −59 (53.3 (7. Sodium reduction tended to be greater in overweight persons than in nonoverweight persons (44 vs 34 mmol/d.0) −7 (53.001 −38 (−48 to −29) . end point status was known in 98% of reduced sodium and UL participants. not applicable. at the 18-month follow-up visit. Mean (SD) 144 (53) 145 (55) 162 (53) 159 (55) 125 (45) 128 (48) 144 (54) 151 (56) 142 (48) 124 (39) 135 (49) 136 (49) 156 (55) 157 (58) Within-Group Change.001 . 97% of reduced sodium and 99% of UL participants provided 24-hour urine collections.24). †For each individual. Of those attending a closeout visit.. At the 9-month follow-up visit.3) mm Hg. 2010 ©2001 American Medical Association. There was no evidence of a substantial imbalance between the reduced sodium and UL groups. Among participants attending the 18-month follow-up visit.1 kg (2. urinary sodium excretion was reduced by 40 mmol/d in the reduced sodium group. −53 (−64 to −41) . differences by sex persisted.5 lb) during follow-up (P . In the 2 age groups (60-69 and 70-80 years). The extent of sodium reduction was less in women than in men (27 vs 53 mmol/d. in part as a result of baseline differences in sodium intake. MAR 12. the reductions in sodium levels were similar.0 (9. within-group changes. the reduced sodium group lost an average of 1. INTERVENTION RESULTS The reduced sodium group achieved and maintained a substantial reduction in sodium on October 12. Mean (SD)† −45 (55.8) −5 (50.001). and 8% another antihypertensive agent.Table 1.archinternmed. Twenty-four-Hour Urinary Sodium Excretion Overall and by Subgroup* Between-Group Difference‡ Group All participants Reduced sodium Usual lifestyle Men Reduced sodium Usual lifestyle Women Reduced sodium Usual lifestyle 60-69 y age group Reduced sodium Usual lifestyle 70-80 y age group Reduced sodium Usual lifestyle Nonoverweight Reduced sodium Usual lifestyle Overweight Reduced sodium Usual lifestyle No. CI indicates confidence interval. however. 27% a calcium channel blocker. more than 40% of reduced sodium participants had an absolute urinary sodium excretion of 80 mmol/d or less in contrast to less than 15% of UL participants.001).ARCHINTERNMED. At the end of follow-up. corresponding attendance was 85% and 83%. Mean (SD) urinary sodium excretion was 161 (54) mmol/d in men and 126 (47) mmol/d in women. P = . 319 320 162 175 157 145 253 250 66 70 184 183 135 137 Baseline. net of UL (P . and 30-month follow-up visits. Closeout visits occurred from 15 to 36 months after randomization.001 −44 (−54 to −35) . 32% of participants were taking a diuretic.001 .001). were 128. average within-group change was the difference between the average of all 24-hour urine collections during follow-up minus the average of 2 baseline 24-hour urine collections. Attendance at the closeout visits was 90% and 93% in the reduced sodium and UL groups.001 . Table 1 displays mean (SD) sodium urinary excretion at baseline.24 −34 (−48 to −20) . Compared with the UL group.96 −46 (−62 to −30) . 18-. ellipses. 22% an angiotensin-converting enzyme inhibitor. All rights reserved. Overall. In these analyses. and between-group differences in sodium excretion. At baseline. On average. we performed sex-stratified analyses (Table 2). . At the 9-. The pattern of findings from 24-hour dietary recalls was similar to that of the 24-hour urinary excretion (data not presented).001 −27 (−39 to −16) .

46 −1.3) −0. 3.7 (−3.2 to −0.9 (9.0) 70.4 (−3. 2001 689 Downloaded from www.9) . Mean (SD)† −26 (64) −1 (48) −32 (51) −4 (43) −55 (44) −14 (48) −60 (54) −6 (54) Mean (95% CI) P P for Difference in Effect Across Subgroups −25 (−47 to −3) .2 to −1.9 to −3.6 (8.1) −0.1 (7.2 (7.8 (7. ‡Within-group difference in reduced sodium group minus within-group difference in usual lifestyle group.8) −1.7 (11. average within-group change was the difference between the average of all 24-hour urine collections during follow-up minus the average of 2 baseline 24-hour urine collections.3) Between-Group Difference‡ Mean (95% CI) Diastolic BP.1) 70. ‡Within-group difference in reduced sodium group minus within-group difference in usual lifestyle group.4 (6.archinternmed.007 . .4) .46 −54 (−67 to −42) .7 (7.9 (10.4) .5) 127.3) −0.6) 71.83 −28 (−41 to −15) .3) 127.0) 126.7 (8.9 to 1.1) −0.4 (−6.6) 72.6) .0 (−3.6 (11. MAR 12.5 to −2.7) 71. mm Hg Within-Group BP Change.1) 0.2 (11. Mean (SD) 128.8 (7. Twenty-four-Hour Urinary Sodium Excretion Stratified by Sex and Race* Between-Group Difference‡ Group African American women Reduced sodium Usual lifestyle Non–African American women Reduced sodium Usual lifestyle African American men Reduced sodium Usual lifestyle Non–African American men Reduced sodium Usual lifestyle No.0 to −2.7) −3.1 (7.2 (9.3) −2.7 (7.5) −3.4 to 2.2) −0. 317 296 162 163 155 133 66 76 251 220 251 230 66 66 135 123 182 173 Baseline BP.001 −5. Mean (SD) 129 (49) 123 (41) 123 (43) 131 (51) 158 (60) 157 (47) 163 (52) 160 (56) Within-Group Change.9 to 0. average within-group change was the difference between BP prior to drug withdrawal minus baseline BP.001).001) and in diastolic BP of 2. In Table 3.5 (9.4) −2. All rights reserved.0 (8.COM (REPRINTED) ARCH INTERN MED/ VOL 161.3 (7.001 −2.3 (7.03 .25 −4.3 (9.0 (−6. 2010 ©2001 American Medical Association.1) 71. †For each individual.0) −0.4 (11.5) −5.3 (8.8) −2.4) 129.1 (7.3 (6.2) 126.3) −0. mm Hg Within-Group BP Change.2 (9.002 −1.001 *Urinary sodium excretion expressed as millimoles per 24 hours.0) 72.3 (−3.6) . CI indicates confidence interval.6) 129.8 (9.7 (9.4 (7.6 (11.0) .3) 126. Mean (SD)† −2.2 (7.5) .0 (−5.7) −0.14 −5.5) 71.1) Between-Group Difference‡ Mean (95% CI) Group All participants Reduced sodium Usual lifestyle Men Reduced sodium Usual lifestyle Women Reduced sodium Usual lifestyle African American Reduced sodium Usual lifestyle Non–African American Reduced sodium Usual lifestyle 60-69 year age group Reduced sodium Usual lifestyle 70-80 year age group Reduced sodium Usual lifestyle Overweight Reduced sodium Usual lifestyle Nonoverweight Reduced sodium Usual lifestyle No.5 months). Mean (SD)† −4. 49 56 108 89 20 21 142 154 Baseline.7) on October 12.9 (−7.8 (10.5) .2 (7.8) −0.0 (−8.6) .4) 68.6 (7.5 (9.001 −2.6 (11.4 (9.7 to 0.4) 128.3 (7.2 (6.1 to 0.001 −41 (−69 to −13) .6) 128.0 to −0.004 *CI indicates confidence interval.01 −5.0 to −0.6) 127.6) −0.5 to −0.001 −2.001 −1.6) 128.7 (10.2) P Baseline BP.001 −1.5) 127. In all subgroup analyses.0) . Systolic and Diastolic Blood Pressure (BP) Overall and by Subgroup* Systolic BP.3)† −0.4) 72.4) 129.2 (10.9) −4.1 (11.9 to −2.3) .4 to −1.9 (9. Table 3.6 (11.6 (7. EFFECTS OF INTERVENTIONS ON BP The effect of the reduced sodium intervention on BP was assessed by comparing the change in BP from baseline with BP at the visit prior to medication withdrawal (mean interval.001 −2. Mean (SD) 71.0) . †For each individual.5 (−5.2 (9.Table 2.0) −2.0 (8.0 mm Hg (P=.2 (10.7) −0.9) 125.2 (7.8) .02 −1.1 (10.0) −2.6 (7.2 (−7.3) P −4.2 (8.3) 127.3 mm Hg (P .8) .7 (8.4 (9. the reduced sodium group experienced a mean reduction in systolic BP of 4.6 (6.7) 127.7) .ARCHINTERNMED.4) 71.2 to −1.6) .9 (−5.3 to −0.8) −2.2) 68.2 (6.4 (9.7 (6.5) .2 (−3.4) −5.7 (7.2 (9.7) −4.4 (10.1 (9.1) .5) 71.5) −0.2 (7.0) −1.4 (7.2) 71.3 (8.9 (−6.9 (11.6 (−4.7) 128.2) 72. net of BP change in UL.8 (10.2) −4.4 (7.2 to −2.4 (7.8) 71.005 −2.002 −3.7 (−3. the mean reduction in systolic BP in the reduced soWWW.6) 0.02 −4.0) −1.2 (7.2) −0.2 (8.8) −1.3 (−6.1 (−3.1) 1.09 −3.9 (8.

001).53 (95% CI. the relative hazard ratio associated with assignment to reduced sodium vs UL was 0. P=. P=. 0. dium group was greater than that of the UL group.36) for users of other antihypertensive medications (all adjusted for sex.67 (95% CI.477 ∗ ∗ 0.623.92.280 0.0 0.42-0. OTHER EFFECTS OF THE INTERVENTIONS Except for a tendency toward less angina in the reduced sodium group compared with the UL group (9 vs 17 individuals. EFFECTS OF INTERVENTIONS ON HYPERTENSION CONTROL Of the 448 end points.92.66 (95% CI.362 0. 23 test). ethnicity.6 0.82.270 0 (3) 6 (9) 12 (15) 18 (21) 24 (27) 30 (33) Months After Drug Withdrawal (Months After Randomization) Figure 2.818 0. results were similar to overall findings.494 ∗ ∗ 0.1 0.47-0.8 0.6 0.3 0. P .357 ∗ ∗ 0.61 (95% CI.596 0.16).84. 0. Figure 3. the relative hazard ratio decreased with greater reductions in urinary sodium excretion (P for trend=. In analyses restricted to end points defined by an elevated BP as measured in a TONE clinic.505 0. 0.614 Relative Hazard Ratio ∗ ∗ 0. weight. In subgroups defined by sex.449 0.8 ∗ Usual Lifestyle Reduced Sodium 1.57-0. the proportion without elevated BP was 43% in the reduced sodium group and 27% in the UL group at the end of follow-up. The relative hazard ratio by class of withdrawn medication was 0.005).40-0. and −70 mmol/d. Proportion of participants who remained free of elevated blood pressure during follow-up. 2010 ©2001 American Medical Association.50 (95% CI. ie.82. Cardiovascular events were censored.4 1.0 0.397 0.5 0. Relative hazard ratio (with 95% confidence interval) of a trial end point by quintile of change in urinary sodium excretion (observational analyses. 0. −9.002). n=639).02) for diuretic users. Proportion of participants who remained free of a trial end point (elevated blood pressure.209 0 (3) 6 (9) 12 (15) 18 (21) 24 (27) 30 (33) Months After Drug Withdrawal (Months After Randomization) Quintile of Change in Urinary Sodium Excretion (Median Change.83.4 0. The distributions of event subtype in the reduced sodium and UL groups were similar (P=.5 0.432 ∗ ∗ 0. Beginning with completion of medication withdrawal and continuing throughout follow-up. 334 occurred as a result of elevated BP (of which 203 occurred from measurements in the TONE clinic). .archinternmed.68 (95% confidence interval [CI].6 0. Figure 1 displays the distribution of end point times after completion of medication withdrawal by intervention group. % 0.002 Free of End Point. 0.1. The cut points for the quintiles are as follows: +19. P=.42-0. For instance. and cardiovascular events) during on October 12. ethnicity.80. After 30 months of follow-up (after drug withdrawal). 0.793. 0. 0.02) for angiotensinconverting enzyme inhibitor users.560. Likewise.712 0. P=.3 0.001.527 ∗ 0. 1. The risk of an end point was unrelated to baseline dietary sodium intake or excretion (data not presented). the proportion who remained end point free in the reduced sodium group exceeded that of the UL group.9 0.4 0. 22 as a result of a clinic cardiovascular event. and 1.347 0.001). MAR 12.7 0. 0.1 0.611 ∗ ∗ 0. mmol/d) Figure 1.7 0.001) and 0. The corresponding relative hazard ratio was 0.2 0. P = .745 1.9 ∗ 0. 1. the relative hazard ratio remained virtually identical. diastolic BP reductions were consistently greater in the reduced sodium group than in the UL group.0 0.94. and change in urine sodium excretion).8 0. 2001 690 Downloaded from www. 0. The relative hazard ratios associated with assignment to reduced sodium vs UL were 0.900 ∗ 0.69 (95% CI. P=. Headache ocWWW.18) for -blocker users.4 0.471 ∗ ∗ 0. the pro- portion without an end point was 36% in the reduced sodium group and 21% in the UL group.COM (REPRINTED) ARCH INTERN MED/ VOL 161.37-0. the occurrence of cardiovascular events was similar in the 2 groups (Table 5). resumption of medication. however. a few between-group differences did not achieve statistical significance.567 ∗ ∗ 0.2 1st (+41) 2nd (+3) 3rd (–22) 4th (–51) 5th (–93) 0.926 Usual Lifestyle Reduced Sodium Free of End Point. achieving statistical significance in all but 1 stratum (the 70-80 year age group). −35. age. adjusting for weight change).62 (95% CI.56 (95% CI.45. 0. % 0.84.50. and 92 as a result of participant and personal physician decisions for symptoms and conditions other than elevated BP.408 ∗ ∗ 0. P .2 P for Trend = . P .2 0. P =.ARCHINTERNMED.0 0. In dose-response analyses that assessed the risk of an end point by quintiles of change in urinary sodium excretion (Figure 3). In analyses restricted to end points defined by elevated BP in any setting (Figure 2). in African Americans. 0. age group.0 ∗ ∗ 0. P .02) for calcium channel blocker users.54-0.62 (95% CI. and weight (Table 4). 0. All rights reserved.

79 . despite the fact that mean baseline BP. approximately half of the estimated 10– and 4–mm Hg declines in systolic and diastolic BPs from a 100-mmol/d sodium reduction in persons 60 to 69 years of age. the primary outcome variable included clinical.99 . analysis. In fact..16 .69 . intake of total energy.005 .COM (REPRINTED) ARCH INTERN MED/ VOL 161. This large randomized controlled trial demonstrated that free-living. In dose-response analyses.64 (0.60 (0.80 *CI indicates confidence interval. and presentation of main trial results. It is illustrative that in subsidiary analyses. the main trial findings persist.68) 0.ARCHINTERNMED. The extent of sodium reduction at 3 months after randomization (before drug withdrawal) is not known. was within the nonhypertensive range. while participants were taking medication. data not applicable.56 (0. saturated fat. thiamin. of Individuals (No. these data indicate that a modest reduction in sodium intake is a feasible and broadly effective nonpharmacologic therapy in older persons. and riboflavin declined in the reduced sodium group.50 to 1.001 . perhaps as a result of small sample size. ie.27 . WWW.14 . y 60-69 70-80 Weight status Not overweight Overweight Relative Hazard Ratio (95% CI) 0. 2010 ©2001 American Medical Association. However. Specifically.88 . the effects of the intervention on BP and end points in the age group 70 to 80 years did not achieve statistical significance. No other adverse symptom achieved statistical significance.14) 0.83) 0.002 .62 . progressively greater reductions in sodium intake were associated with a reduced risk of a trial end point. P=. .34 .. restricted to the 334 events that were related only to elevated BP.archinternmed. iron.66 ( on October 12.24 . monounsaturated fat. of Events) Type of Adverse Event Cardiovascular event Stroke Transient ischemic attack Myocardial infarction Arrhythmia Congestive heart failure Angina Other Any cardiovascular event Other adverse events Excessive weight loss Physical injury from exercise Palpitations Nonischemic chest pain Dizziness Edema Excessive weight gain Headache Other Any adverse event Reduced Sodium 1 (1) 7 (8) 2 (2) 6 (6) 2 (4) 9 (10) 12 (13) 36 (44) 0 (0) 1 (1) 7 (9) 20 (22) 24 (29) 14 (15) 2 (2) 35 (36) 66 (86) 169 (244) Usual Lifestyle 2 (2) 7 (8) 4 (4) 3 (4) 1 (1) 17 (19) 19 (19) 46 (57) 0 (0) 0 (0) 11 (13) 17 (18) 15 (17) 21 (22) 3 (3) 54 (63) 55 (66) 176 (259) Group All participants Sex Men Women Ethnicity African American Other Age group. In TONE.94) 0.01 . there was no evidence of an adverse impact of the reduced sodium intervention on the occurrence of cardiovascular events. All rights reserved.56 to 0. from a mean baseline BP of 128/71 mm Hg.58 to 0.001 . potentially BP-related events (eg. there was a tendency toward fewer cardiovascular events in the reduced sodium intervention group compared with the UL group..18 . because the first 24-hour urine collection was obtained 9 months after randomization (about 6 months after drug withdrawal). the occurrence of adverse symptoms was similar in the 2 groups.56 to 0. primarily as a result of fewer instances of angina.68 (0. Number of Individuals Reporting Cardiovascular and Other Adverse Events (and Total Number of Events) During Follow-up by Randomized Group* No. The rationale for this decision was to minimize the potential for informative censoring that otherwise might occur in this trial of older persons had the end point been restricted to only elevated BP. In aggregate.82) 0.Table 4. calcium. it is likely that the extent of BP reduction would be greater than that observed in this trial. .0 mm Hg.54 to 0. older people with hypertension can reduce their sodium intake and that a reduced sodium intake can lower BP and the need for antihypertensive drug therapy.99 .75 (0.84) 0. there were significantly fewer reports of headaches in the reduced sodium intervention group. In the design.05. while intake of potassium and magnesium increased (each P .001 .99 .30 .41 Table 5.70 .02 .18 TONE did not assess the impact of sodium reduction in persons with high BP.80) P* . and weight status. COMMENT *Fisher exact tests comparing numbers of individuals reporting events. Table 6). curred less frequently in the reduced sodium group compared with the UL group (35 vs 54 individuals.. then the BP reduction observed in TONE is similar to that expected.99 . Relative Hazard Ratio for End Points Associated With Assignment to Reduced Sodium Intervention vs Usual Lifestyle Control Group P for Intervention Effect Within P for Group Interaction† .72 (0.96) 0. This decision tends to inflate the number of end points and might obscure differences between groups. Nonetheless. if the average 40-mmol/d reduction in sodium intake occurred by 3 months. MAR 12. Compared with the UL group.04). The effects were consistent in subgroups defined by sex.75 (0.49 to 0. stroke and myocardial infarction) as well as resumption of medication initiated by either the participant or personal physician for reasons other than elevated BP.82) 0.27 . In terms of adverse symptoms reported by participants. The reduction in sodium intake observed in this trial had a substantial impact on BP.45 to 0. otherwise. 2001 691 Downloaded from www.58 to 0. ellipses.001 .37 to 0. a reduced sodium intake lowered systolic and diastolic BPs by 4. However. . respectively.04 . †P for difference in intervention effect across subgroups.47 . dietary fat. ethnicity.72 (0.99 .3 and 2. The reduced sodium intervention did have an impact on several aspects of diet.

04 Baseline 1646 ± 32 58.4 −0.Table 6.3 −35 ± 20 −0.19 Hence.27 290.02 ± 0.77 ± 0.9 ± 8.8 2633 ± 55 277.004 .0 to 2.2 (−4.50 .com on October 12.4 ± 8.26 294.1 −50 ± 49 −16.4 1124 ± 23 10. multiply by 4.2) 8.5 0. food manufacturers should minimize the addition of sodium and should use alternative seasonings for flavor. the changes were potentially deleterious. Such evidence supports current efforts to expand Medicare coverage of nutrition services.8 ± 5.6 −1.10 .05 3.2 ± 0.5 1.31 . The elderly often live and/or dine in common settings (eg.00 ± 0.4 ± 0.8 (−3. §To convert kilocalories to kilojoules.1 (−2. .12 (−0.5 1. the changes were favorable. the pri- mary insurer of older persons in the United States.6 to 11.26 .4 1. average within-group change was the difference between the average of all 24-hour dietary recalls during follow-up minus the average of 2 baseline 24-hour dietary recalls.8 to −1.48 ± 0.05 0.20 Findings from this trial have important public health and clinical implications.0 to 0.4 19. µg E. or nursing homes). Our results.27 −9.9 ± 4. µg Thiamin.27 2.92 .0 to 0.2 ± 0. population-based and individualized efforts to reduce sodium intake are appropriate. mg Riboflavin. the net impact on bone mineral density is uncertain.9 −1. mg Baseline 1810 ± 31.3 (−1. As such.4 (−4. Before clinicians attempt medication withdrawal. fat. mg Folate.1 110 ± 65 6.2 1032 ± 22 9.3 ± 0.5 −3.2 (−11.5 to 0.9 to 20. in combination with the high prevalence of hypertenWWW.19 8.1 ± 1. The TONE trial provides convincing evidence that individualized counseling can reduce BP and control hypertension.4 242.11 ± 0.02 .02 . Overall.003 . All rights reserved.03 −0.8 ± 0.1 13.2 ± 1.22 −1.2 ± 17.0 ± 0. While TONE participants were able to achieve modest reductions in sodium intake through careful selection of food products.6 ± 4.0 ± 0.3 17 ± 67 −0.2 (−0.8 (−10. because a reduced intake of sodium has opposite effects on bone demineralization.5 ± 0.6) −0.32 ± 0.84 .6 23.19 8.0 ± 18.9 ± 1.29 ± 0.02) −0.7 ± 0. Because hypertension is common in the elderly and because sodium reduction can substantially reduce BP.30 ± 0.0 to −0.19 ± 0. in each randomized group.16 ± 0.002 .3 (−5. Whether this reduction in calcium intake is clinically relevant is unclear. candidate patients must be committed to reducing their sodium intake.5) −19 (−203 to 165) 0. nonpharmacologic therapy that lowers BP and controls hypertension in older individuals.2 ± 0. community centers.3 1141 ± 61 1.8 ± 0. Nutrient intake from supplements not included.8 ± 8.0 to −0.3 −0.7 ± 5.03 4. Unfortunately.49 ± 0. physicians may decide to promote sodium reduction without medication withdrawal.04 Between-Group Difference‡ Mean (95% CI) −119 (−197 to −41) −5.1 ± 6.22 Still.4 224.6 ± 0.9 ± 0.6 20.4 ± 1. TONE results reaffirm the safety of moderate dietary sodium reduction.8 ± 17.4 640.8 ± 4.72 ± 0.8) −71 (−119 to −23) −27 (−84 to 30) −0.2) 160 (25 to 295) 24 (8 to 39) −2.98 . mean ± SE within-group change.4 732. and mean (95% confidence interval [CI]) between-group differences.03 ± 0.8 ± 1.9 62.4 −71.66 ± 0.002 . µg C.4 −8 ± 2 −0.35 .5 ± 8.4 66. ‡Within-group difference in reduced sodium group minus within-group difference in usual lifestyle group.5) 12 (−11 to 35) −0.5) −2.21 From a clinical perspective. kcal§ Macronutrients. Furthermore.9 ± 4.4 −1.4 (−1.1 ± 18.21 .26 Within-Group Change† −115 ± 2. total energy.20 −0.184.7 ± 0.4 −1.1 to −1.03 −0. 2001 692 Downloaded from www.05 −0. ideally in the setting of a supervised counseling program.7 ± 4.5 −0. a reduced sodium intake is a broadly effective.ARCHINTERNMED.6 12. patients with recently diagnosed and well-controlled hypertension were most likely to be successful at medication withdrawal.0 (−0.3 (−1.8 to 1.64 ± 0. the availability of low-sodium foods was limited. µg B6.21 126.1 ± 0. data are available for 315 to 341 participants.5 ± 0.6 13.4) −0.5 −2.1 15.3 −0.002 *Data are given as mean ± SE baseline.8 ± 0.8 −7.6 22.1) −1. and potassium. in this setting.3 (−3.3 to −0.04 Usual Lifestyle Within-Group Change† 4 ± 28 −2.3 −2 ± 66 0.6 4.archinternmed.22 6. mg Niacin.81 ± 0.8 2733 ± 55 284.5 −0.001 . TONE results indicate that sodium reduction can control hypertension in a sizeable proportion of medication-controlled patients with hypertension.8) −2.COM (REPRINTED) ARCH INTERN MED/ VOL 161.1 ± 1.9 ± 0.1) P . To facilitate easy access to such items.9 ± 4.3 1133 ± 61 1.1 (−0.20 ± 0.03 20. institutional changes in food preparation can provide an efficient means to reduce BP in broad populations.22 to −0.82 ± 0. regular BP monitoring is warranted because many individuals will require resumption of drug therapy.009 . In summary.4 (−1.66 ± 0.5 −1.5 −3.51 .2) −0. mg D. mg B12. Daily Nutrient Intake* Reduced Sodium Nutrient Intake/24 h Total energy.54 ± 0.3 ± 3.6 1. g Total fat Saturated fat Monounsaturated fat Polyunsaturated fat Protein Carbohydrates Minerals.03 20.6 18. MAR 12.1 ± 0.5 ± 1. eg.19 ± 0.3 ± 0. does not cover nutrition therapy for most outpatient conditions such as hypertension.8 ± 1. Successful sodium reduction will require individualized counseling as a routine component of hypertension management.35 ± 0. Medicare. senior centers.4) −1.1 to 0.20 −0.21 119.9 ± 0.008 .2 ± 0.05 ± 0. such as a reduced intake of calcium. a reduced sodium intake can substantially lower BP and presumably decrease the risk of atherosclerotic cardiovascular events.1 to 0.3 ± 0. 2010 ©2001 American Medical Association.6 4.6 −0.2 ± 0.2 ± 4.5) 0.51 .6 −1.18 .0) −0.8 ± 6.4 −0. mg Potassium Magnesium Iron Calcium Phosphorus Zinc Vitamins A. For most nutrients.45 . In a few instances.3 to 0. †For each nutrient.4 −0.4 −1.14 ± 0. In another article from the TONE study.

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