Patients and Methods  The effects of sodium reduction 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 Three months after the start of intervention, medication was withdrawn.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 follow-up, 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 effective, nonpharmacologic therapy that can lower BP and control hypertension in older individuals.

Sodium reduction is widely advocated as a means to reduce BP and control 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 BP^5-6 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 related to sodium intake should result in a greater BP change in older persons than in younger individuals.⁸ Second, because of the decline in kidney function associated with aging, older individuals may retain sodium to a greater extent than younger persons.⁹ Third, 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.

In view of these considerations, 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 medication-treated hypertension control in older persons with hypertension. The main results of TONE have been published.¹⁰ In brief, TONE demonstrated that a reduced sodium intake and weight loss, alone or combined, could effectively control hypertension. The objectives of this article, which focuses on only the sodium component of TONE, are to examine the following issues: (1) the effects of a reduced sodium intake in subgroups defined by sex, ethnicity, age, and obesity; (2) dose-response relationships; and (3) the effects of a reduced sodium intake on subtypes of the primary outcome variable, dietary intake of other nutrients, and the occurrence of adverse events.

SUBJECTS AND METHODS

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, ie, 3 BPs at each of 3 visits) while taking 1 antihypertensive medication, ie, 1 type of medication whether or not multiple doses were used. Individuals treated with 2 antihypertensive medications were also eligible, if they were successfully weaned from 1 of these medications during the screening phase. Major exclusion criteria were use of antihypertensive medication for conditions other than hypertension (eg, ischemic heart disease), myocardial infarction or stroke within 6 months, angina pectoris, congestive heart failure, serum creatinine level of more than 176.8 µmol/L (>2 mg/dL), blood glucose level of more than 14.4 mmol/L (>260 mg/dL), and self-report of average alcoholic beverage intake of more than 14 drinks per week.

A detailed description of recruitment procedures has been published.¹² In brief, each TONE clinical center implemented site-specific strategies, which included (1) mass mailings of brochures; (2) radio, television, and newspaper advertisements; (3) BP screenings; and (4) enrollment of participants from previous studies. Enrollment began in August 1992 and ended in June 1994.

DATA COLLECTION

Individuals provided a medical history, underwent a physical examination, and had routine laboratory tests to confirm eligibility. TONE data collection visits included 2 screening visits, a randomization visit, drug withdrawal visits (beginning 90 days [±14 days] after the start of intervention), and follow-up visits scheduled every 3 months. For screenees who were taking 2 antihypertensive medications, medication stepdown visits took place after the second screening visit but prior to the randomization visit. Closeout visits occurred between July 1995 and December 1995. The median duration of follow-up was 29 months (maximum of 36 months). During follow-up, 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.

All BP measurements were obtained by trained and certified observers who were masked to intervention assignment. Systolic BP was defined as the appearance of the first Korotkoff sound, and diastolic BP as the point of disappearance of the fifth Korotkoff sound. At each visit, 3 BP measurements were obtained while the participant rested quietly in the seated position. Random-zero sphygmomanometers were used to minimize observer bias.

Twenty-four-hour urine collections were obtained twice prior to randomization and once at the 9-, 18-, and 30-month follow-up visits and at closeout, if this visit did not coincide with 1 of the follow-up visits. Twenty-four-hour dietary recalls were obtained twice prior to randomization and again at the 9- and 12-month follow-up visits and every 6 months thereafter by trained, certified technicians who were masked to intervention assignment. Nutrient calculations were performed using the Minnesota Data System software (food database version 6A; nutrient database version 21), developed by the Nutrition Coordinating Center, University of Minnesota, Minneapolis.¹³ Data from the 24-hour recalls were used to determine macronutrient, micronutrient, and energy intake in randomized groups at baseline and during follow-up.

INTERVENTION

Overweight participants were randomly assigned, in a 2 x 2 factorial design, to 1 of the following 4 groups: (1) combined weight loss and reduced sodium, (2) reduced sodium alone, (3) weight loss alone, or (4) usual lifestyle (UL) control group. Nonoverweight participants were randomly assigned to reduced sodium alone or UL groups. Body mass index values (calculated as weight in kilograms divided by the square of height in meters) of 27.8 for men and 27.3 for women were used as the thresholds to define overweight.¹⁴ This article presents data on participants, both overweight and nonoverweight, who were assigned to the reduced sodium alone or UL group.

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, as measured by 24-hour urine collections. 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 Participants were expected to modify only those aspects of their diet that led to a high sodium intake; a comprehensive change in diet was not expected. To achieve its goal, TONE used intervention techniques derived from experience in clinical trials that achieved BP control through interventions focusing on behavioral change.^15-17 Social learning theory and behavioral approaches that enhance the understanding of behavior change and the ways to achieve it were incorporated.

In the reduced sodium group, each person had an introductory individual session with the interventionist assigned to their group. This session occurred within 4 weeks of randomization. Intervention groups, typically consisting of 9 to 12 participants, were then formed in a timely manner so that participants began the reduced sodium program within 45 days after randomization. Each of the TONE interventions consisted of a 4-month "intensive" phase with weekly meetings, a 3-month "extended" phase with biweekly meetings, and a maintenance phase. The interventionist typically was a registered dietitian. The meetings were conducted as group sessions with individual sessions held at every fourth contact.

During the group and individual sessions, interventionists provided information using both centrally and locally prepared materials, motivated participants to make and sustain long-term lifestyle changes, and monitored individual and group progress at frequent intervals. In the process, participants learned about sources of sodium, particularly those foods with a high salt content, and about alternative foods, condiments, and spices. They also learned how to adapt the reduced sodium lifestyle recommendations to their own individual situations, eg, how to select appropriate foods at restaurants.

To enhance follow-up among participants assigned to UL, meetings were held on a regular basis with speakers who led discussions on topics unrelated to BP, cardiovascular disease, or nutrition. To facilitate masking of the data collectors, intervention visits were conducted at separate times and places from data collection visits.

WITHDRAWAL OF ANTIHYPERTENSIVE MEDICATION

Drug withdrawal began 90 days (±14 days) after the first group intervention session. Participants randomized to UL began drug withdrawal at a comparable time. The drug withdrawal process, which was standardized across the 4 clinical centers, used drug-specific tapering regimens. As the medication was tapered, participants were evaluated weekly. After discontinuation of the drug, 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. The rationale for beginning medication withdrawal 90 days after the start of intervention, as opposed to immediately after randomization, was to increase the likelihood of successful drug withdrawal.

OUTCOME VARIABLES

In primary analyses, the outcome variable was a composite end point defined by the need for, or actual resumption of, antihypertensive drug therapy. Specifically, a TONE participant reached a trial end point when any of the following occurred:

• High BP, as indicated by (1) elevated BP measured by TONE BP technicians (at 1 visit, mean diastolic BP 110 mm Hg or systolic BP 190 mm Hg; at 2 visits, mean diastolic BP 100 mm Hg or systolic BP 170 mm Hg; or at 3 visits, mean diastolic BP 90 mm Hg or systolic BP 150 mm Hg), or (2) resumption of antihypertensive medication initiated either by the participant or personal physician for elevated BP measured outside a clinical center.
  
• 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. Participants given medication for non-BP and noncardiovascular conditions, such as migraine headaches and benign prostatic hypertrophy, were censored.
  
• A cardiovascular clinical event (myocardial infarction, angina, congestive heart failure, hypertensive encephalopathy, stroke, or procedure [bypass surgery, angioplasty, endarterectomy]). These clinical events were included as components of the composite end point to reduce the possibility of informative censoring.
  

Medical records were retrieved for all end points occurring outside a TONE visit. An end point committee, masked to intervention assignment, made final decisions concerning the end point status of each participant.

To determine the impact of the interventions on BP, 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. At both times, participants were receiving drug therapy.

ANALYSES

Analyses were conducted on an intention-to-treat basis. In primary analyses, the distributions of times until first occurrence of an end point were compared in participants assigned to the reduced sodium and UL groups. Times were measured from the end of the drug withdrawal process until the occurrence of the end point. Participants who met an end point criterion prior to, or during, drug withdrawal were treated as instantaneous failures. Each comparison was performed using proportional hazards regression. Kaplan-Meier curves were used to portray the distribution of times until failure for each of the study cohorts. For continuous outcomes, eg, BP and nutrient intake, differences in change (follow-up minus baseline levels) between the reduced sodium and UL groups were compared using unpaired t tests. In all analyses, a 2-sided significance level of .05 was considered statistically significant.

RESULTS

FOLLOW-UP

At the 9-month follow-up visit, attendance was 91% and 88% of expected in the reduced sodium and UL groups, respectively; at the 18-month follow-up visit, corresponding attendance was 85% and 83%, respectively. At the 9-month follow-up visit, 24-hour urine collections were provided by 99% of reduced sodium and 97% of UL participants attending these visits. Among participants attending the 18-month follow-up visit, 97% of reduced sodium and 99% of UL participants provided 24-hour urine collections. Closeout visits occurred from 15 to 36 months after randomization. Attendance at the closeout visits was 90% and 93% in the reduced sodium and UL groups. Of those attending a closeout visit, 97% of reduced sodium and 98% of UL participants provided urine specimens. At the end of follow-up, end point status was known in 98% of reduced sodium and UL participants.

INTERVENTION RESULTS

The reduced sodium group achieved and maintained a substantial reduction in sodium levels. At the 9-, 18-, and 30-month follow-up visits, 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. Table 1 displays mean (SD) sodium urinary excretion at baseline, within-group changes, and between-group differences in sodium excretion. Overall, urinary sodium excretion was reduced by 40 mmol/d in the reduced sodium group, net of UL (P<.001). The extent of sodium reduction was less in women than in men (27 vs 53 mmol/d; P<.001), in part as a result of baseline differences in sodium intake. In the 2 age groups (60-69 and 70-80 years), the reductions in sodium levels were similar. Sodium reduction tended to be greater in overweight persons than in nonoverweight persons (44 vs 34 mmol/d; P = .24). Because the sex distribution in African Americans differed from that in non–African Americans, we performed sex-stratified analyses (Table 2). In these analyses, sodium reduction was similar in African Americans and non–African Americans; however, differences by sex persisted. The pattern of findings from 24-hour dietary recalls was similar to that of the 24-hour urinary excretion (data not presented). Compared with the UL group, the reduced sodium group lost an average of 1.1 kg (2.5 lb) during follow-up (P<.001).

View this table: [in this window] [in a new window] Table 1. Twenty-four-Hour Urinary Sodium Excretion Overall and by Subgroup*

View this table: [in this window] [in a new window] Table 2. Twenty-four-Hour Urinary Sodium Excretion Stratified by Sex and Race*

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, 3.5 months). In Table 3, the reduced sodium group experienced a mean reduction in systolic BP of 4.3 mm Hg (P<.001) and in diastolic BP of 2.0 mm Hg (P = .001), net of BP change in UL. In all subgroup analyses, the mean reduction in systolic BP in the reduced sodium group was greater than that of the UL group, achieving statistical significance in all but 1 stratum (the 70-80 year age group). Likewise, diastolic BP reductions were consistently greater in the reduced sodium group than in the UL group; however, a few between-group differences did not achieve statistical significance.

View this table: [in this window] [in a new window] Table 3. Systolic and Diastolic Blood Pressure (BP) Overall and by Subgroup*

EFFECTS OF INTERVENTIONS ON HYPERTENSION CONTROL

Of the 448 end points, 334 occurred as a result of elevated BP (of which 203 occurred from measurements in the TONE clinic), 22 as a result of a clinic cardiovascular event, and 92 as a result of participant and personal physician decisions for symptoms and conditions other than elevated BP. The distributions of event subtype in the reduced sodium and UL groups were similar (P = .45, ²₃ test).

Figure 1 displays the distribution of end point times after completion of medication withdrawal by intervention group. Beginning with completion of medication withdrawal and continuing throughout follow-up, the proportion who remained end point free in the reduced sodium group exceeded that of the UL group. After 30 months of follow-up (after drug withdrawal), the proportion without an end point was 36% in the reduced sodium group and 21% in the UL group. The relative hazard ratios associated with assignment to reduced sodium vs UL were 0.68 (95% confidence interval [CI], 0.56-0.82; P<.001) and 0.69 (95% CI, 0.57-0.84; P<.001, adjusting for weight change). In analyses restricted to end points defined by elevated BP in any setting (Figure 2), 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 corresponding relative hazard ratio was 0.67 (95% CI, 0.54-0.83; P<.001). In analyses restricted to end points defined by an elevated BP as measured in a TONE clinic, the relative hazard ratio remained virtually identical, ie, 0.62 (95% CI, 0.47-0.82; P<.001).

View larger version (18K): [in this window] [in a new window] Figure 1. Proportion of participants who remained free of a trial end point (elevated blood pressure, resumption of medication, and cardiovascular events) during follow-up.

View larger version (18K): [in this window] [in a new window] Figure 2. Proportion of participants who remained free of elevated blood pressure during follow-up. Cardiovascular events were censored.

In dose-response analyses that assessed the risk of an end point by quintiles of change in urinary sodium excretion (Figure 3), the relative hazard ratio decreased with greater reductions in urinary sodium excretion (P for trend = .002). The risk of an end point was unrelated to baseline dietary sodium intake or excretion (data not presented).

View larger version (12K): [in this window] [in a new window] Figure 3. Relative hazard ratio (with 95% confidence interval) of a trial end point by quintile of change in urinary sodium excretion (observational analyses, n = 639). The cut points for the quintiles are as follows: +19, -9, -35, and -70 mmol/d.

In subgroups defined by sex, ethnicity, age group, and weight (Table 4), results were similar to overall findings. For instance, in African Americans, the relative hazard ratio associated with assignment to reduced sodium vs UL was 0.56 (95% CI, 0.37-0.84; P = .005). The relative hazard ratio by class of withdrawn medication was 0.62 (95% CI, 0.42-0.92; P = .02) for diuretic users, 0.61 (95% CI, 0.42-0.92; P = .02) for calcium channel blocker users, 0.50 (95% CI, 0.40-0.94; P = .02) for angiotensin-converting enzyme inhibitor users, 1.66 (95% CI, 0.79-3.50; P = .18) for ß-blocker users, and 1.53 (95% CI, 0.62-3.80; P = .36) for users of other antihypertensive medications (all adjusted for sex, ethnicity, age, weight, and change in urine sodium excretion).

View this table: [in this window] [in a new window] Table 4. Relative Hazard Ratio for End Points Associated With Assignment to Reduced Sodium Intervention vs Usual Lifestyle Control Group

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, P = .16), the occurrence of cardiovascular events was similar in the 2 groups (Table 5). Headache occurred less frequently in the reduced sodium group compared with the UL group (35 vs 54 individuals, P = .04); otherwise, the occurrence of adverse symptoms was similar in the 2 groups. Compared with the UL group, intake of total energy, dietary fat, saturated fat, monounsaturated fat, iron, calcium, thiamin, and riboflavin declined in the reduced sodium group, while intake of potassium and magnesium increased (each P<.05; Table 6).

View this table: [in this window] [in a new window] Table 5. Number of Individuals Reporting Cardiovascular and Other Adverse Events (and Total Number of Events) During Follow-up by Randomized Group*

View this table: [in this window] [in a new window] Table 6. Daily Nutrient Intake*

COMMENT

The reduction in sodium intake observed in this trial had a substantial impact on BP, despite the fact that mean baseline BP, while participants were taking medication, was within the nonhypertensive range. Specifically, from a mean baseline BP of 128/71 mm Hg, a reduced sodium intake lowered systolic and diastolic BPs by 4.3 and 2.0 mm Hg, respectively. The extent of sodium reduction at 3 months after randomization (before drug withdrawal) is not known, because the first 24-hour urine collection was obtained 9 months after randomization (about 6 months after drug withdrawal). Nonetheless, if the average 40-mmol/d reduction in sodium intake occurred by 3 months, then the BP reduction observed in TONE is similar to that expected, ie, 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.¹⁸ TONE did not assess the impact of sodium reduction in persons with high BP. However, it is likely that the extent of BP reduction would be greater than that observed in this trial.

In the design, analysis, and presentation of main trial results, the primary outcome variable included clinical, potentially BP-related events (eg, stroke and myocardial infarction) as well as resumption of medication initiated by either the participant or personal physician for reasons other than elevated BP. 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. This decision tends to inflate the number of end points and might obscure differences between groups. It is illustrative that in subsidiary analyses, restricted to the 334 events that were related only to elevated BP, the main trial findings persist.

In TONE, there was no evidence of an adverse impact of the reduced sodium intervention on the occurrence of cardiovascular events. In fact, there was a tendency toward fewer cardiovascular events in the reduced sodium intervention group compared with the UL group, primarily as a result of fewer instances of angina. In terms of adverse symptoms reported by participants, there were significantly fewer reports of headaches in the reduced sodium intervention group. No other adverse symptom achieved statistical significance. The reduced sodium intervention did have an impact on several aspects of diet. For most nutrients, eg, total energy, fat, and potassium, the changes were favorable. In a few instances, such as a reduced intake of calcium, the changes were potentially deleterious. Whether this reduction in calcium intake is clinically relevant is unclear, because a reduced intake of sodium has opposite effects on bone demineralization.¹⁹ Hence, the net impact on bone mineral density is uncertain. Overall, TONE results reaffirm the safety of moderate dietary sodium reduction.²⁰

Findings from this trial have important public health and clinical implications. Because hypertension is common in the elderly and because sodium reduction can substantially reduce BP, population-based and individualized efforts to reduce sodium intake are appropriate. The elderly often live and/or dine in common settings (eg, community centers, senior centers, or nursing homes). As such, institutional changes in food preparation can provide an efficient means to reduce BP in broad populations. While TONE participants were able to achieve modest reductions in sodium intake through careful selection of food products, the availability of low-sodium foods was limited. To facilitate easy access to such items, food manufacturers should minimize the addition of sodium and should use alternative seasonings for flavor.

Successful sodium reduction will require individualized counseling as a routine component of hypertension management. Unfortunately, Medicare, the primary insurer of older persons in the United States, does not cover nutrition therapy for most outpatient conditions such as hypertension. The TONE trial provides convincing evidence that individualized counseling can reduce BP and control hypertension. Such evidence supports current efforts to expand Medicare coverage of nutrition services.²¹

From a clinical perspective, TONE results indicate that sodium reduction can control hypertension in a sizeable proportion of medication-controlled patients with hypertension. Before clinicians attempt medication withdrawal, candidate patients must be committed to reducing their sodium intake, ideally in the setting of a supervised counseling program. Furthermore, regular BP monitoring is warranted because many individuals will require resumption of drug therapy. In another article from the TONE study, patients with recently diagnosed and well-controlled hypertension were most likely to be successful at medication withdrawal.²² Still, physicians may decide to promote sodium reduction without medication withdrawal; in this setting, a reduced sodium intake can substantially lower BP and presumably decrease the risk of atherosclerotic cardiovascular events.

In summary, a reduced sodium intake is a broadly effective, nonpharmacologic therapy that lowers BP and controls hypertension in older individuals. Our results, in combination with the high prevalence of hypertension and its treatment with medication in the elderly, argue for substantial efforts to reduce sodium intake in older persons.

This work was supported by grants HL02642, HL43641, HL48642, and HL60197 from the National Heart, Lung, and Blood Institute; AG09799, AG09771, and AG09773 from the National Institute on Aging; and RR00722 from the National Center for Research Resources of the National Institutes of Health.

We thank the trial participants and the entire TONE Collaborative Research Group.

Corresponding author and reprints: Lawrence J. Appel, MD, MPH, Johns Hopkins University, 2024 E Monument St, Suite 2-645, Baltimore, MD 21205-2223 (e-mail: lappel{at}jhmi.edu).