TONE

Published

Whelton PK, et al. "Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). TONE Collaborative Research Group". JAMA. 1998. 279(11):839-846.
PubMed • Full text

Clinical Question

Among seniors with hypertension, do non-pharmacologic approaches like sodium reduction and weight loss help in treatment of hypertension?

Bottom Line

Reduced sodium intake and weight loss are associated with improved blood pressure control among adults age 60-80 years with hypertension.

Major Points

Dietary and behavioral interventions have been shown to reduce blood pressure. For example, the DASH diet and the DASH+Low Sodium diet have previously shown efficacy similar to or greater than a single blood pressure agent. In the mid-1990s, evidence was lacking for the role of behavioral, non-pharmacological strategies for reduction of blood pressure among older adults.

Published in 1998, the Trial of Nonpharmacologic Interventions in the Elderly (TONE) randomized 975 adults age 60-80 with hypertension on a single antihypertensive medication or an antihypertensive/diuretic combination pill to usual care or active intervention. Active intervention was 1. Na reduction, 2. weight loss (if overweight), or 3. both (if overweight). All participants attempted to stop their blood pressure medications at 90 days, the vast majority were successful in achieving target BPs without antihypertensives. The primary outcome was a composite outcome of elevated BPs at follow up, need to re-initiate antihypertensive medications, or a cardiovascular event. Those in the intervention arm experienced lower rates of the primary outcome, with similar effects among each of the specific active interventions. TONE supports the role of behavioral interventions like Na reduction and weight loss among seniors with hypertension.

Guidelines

2017 ACC AHA AAPA ABC ACPM AGS APhA ASH ASPC NMA PCNA Hypertension (2017, adapted)

• In adults with elevated BP or hypertension (all COR I, LOE A):
  • Recommend weight loss to lower BP if overweight or obese
  • Recommend DASH diet or a heart-healthy diet facilitating desirable weight
  • Recommend sodium reduction
  • Increased physical activity with a structured exercise program

Design

Some design details are published elsewhere.

• Multicenter, randomized controlled trial
• N=975
  • Active intervention (n=634)
    • Sodium reduction (n=340)
    • Weight loss (n=147; only overweight in this group)
    • Both (n=147; only overweight in this group)
  • Usual care (n=341)
• Setting: 4 US centers
• Enrollment: 1992-1994
• Median follow-up: 29 months
• Analysis: Intention-to-treat
• Primary outcome: Elevated BP at follow-up visits (150/90 over 3 visits, 170/100 over 2 visits, or 190/110 at 1 visit), treatment with antihypertensive medication, or a cardiovascular event during follow-up

Population

Inclusion Criteria

• Community-dwelling men and women age 60-80 years
• Mean SBP <145 mm Hg and DBP <85 mm Hg (3 measurements at each of 3 visits) on one antihypertensive medication
  • Combination non-diuretic antihypertensive+diuretic were considered one medication
• Stable health
• Independence in ADLs
• Presumed capacity to alter diet and physical activity in accordance with the requirements of any TONE interventions

Exclusion Criteria

• Cancer diagnosis or treatment in the prior 5 years, except non-melanoma skin cancer
• Stroke or MI in the prior 6 months
• Active CHD with angina
• HF requiring treatment with specific agents (e.g., ACE-inhibitor)
• AF, 2nd/3rd degree HB unless PPM
• Medications for ventricular arrhythmias
• Clinically-important valvular disease or prior valve replacement
• DM on insulin
• Severe HTN requiring treatment with minoxidil or guanethidine
• Symptomatic PVD
• Psychiatric admission in the prior 5 years or treatment with lithium, a neuroleptic, or MAOI
• Medical treatment for asthma or COPD in the prior 6 months
• Corticosteroid use for >1 month
• Abnormal lab values: Creatinine >2 mg/dL, K > 5.5 mEq/L, Hgb <11 g/dL, blood glucose >260 mg/dL
• BMI <21 (men or women), >33 (men), or >37 (women) kg/m²
• ≥10 lb unintentional weight loss in the prior year

Baseline Characteristics

From the overweight, sodium reduction group, n=144.

• Demographics: Age 66 years, 56% female, 30% African American, 87% HS graduate
• Behaviors: Current smoker 5%, ≥1 drink/week 36%
• Measurements: BMI 31 kg/m², BP 129/72
• Labs: Urinary Na 158 mmol/day, urinary K 58 mmol/day
• Duration of antihypertensives: 12 years

Interventions

• Randomized to a group:
  • Active intervention
    • Sodium reduction - Goal 24h urine Na ≤80 mEq (1800 mg) at 6 mo and maintenance, achieved through behavioral counseling and self-management
    • Weight loss (overweight patients only) - Goal ≥10 lb weight loss at 6 mo and maintenance, achieved through behavioral counseling
    • Both (overweight patients only) - Both sodium reduction and weight loss goals
  • Usual care - Goal no change in urinary Na or weight, quarterly group sessions broadly on general topics for diet, physical activity, and CVD
• At 90 days, antihypertensive drug withdrawal was attempted and maintained if SBP continued <150/90 mm Hg, the follow-up period started at the following visit, approximately 3 months after drug withdrawal attempt
• Overweight was defined as 27.8 (men) and 27.3 (women) kg/m²

Outcomes

Primary Outcomes

Elevated BP at follow-up visits (150/90 over 3 visits, 170/100 over 2 visits, or 190/110 at 1 visit), treatment with antihypertensive medication, or a cardiovascular event during follow-up

The first follow-up visit was about 3 months after attempted antihypertensive withdrawal. Overweight was defined as 27.8 kg/m² for men and 27.3 for women kg/m².

Sodium reduction vs. no sodium reduction: 38% vs. 24% (IRR 0.69; 95% CI 0.59-0.81; P<0.001)

Overweight participants

Na reduction+weight loss vs. usual care: HR 0.47 (95% CI 0.35-0.64; P<0.001)

Na reduction vs. usual care: HR 0.60 (95% CI 0.45-0.80; P<0.001)

Weight loss vs. usual care: HR 0.64 (95% CI 0.49-0.85; P=0.002)

Non-overweight participants

Na reduction alone vs. usual care: HR 0.75 (95% CI 0.59-0.95)

Additional Analyses

Successful withdrawal of antihypertensive medications

86% (usual care) vs. 92.6% (Na reduction only) vs. 93.2% (weight loss only) vs. 93.2% (Na reduction+weight loss)

Subgroup Analysis

For the primary outcome.

Among the 886 patients with successful medication taper

Na reduction+weight loss vs. usual care: HR 0.55 (95% CI 0.41-0.69)

Na reduction vs. usual care: HR 0.68 (95% CI 0.54-0.82)

Weight loss vs. usual care: HR 0.75 (95% CI 0.57-0.93)

Adverse Events

There were no differences between groups in the frequency of the 145 cardiovascular disease events that occurred during follow-up. The distribution of these events can be seen in Table 3 on page 845.

Criticisms

• It is unclear from this trial if a low-sodium diet reduces morbidity and mortality or is safe.
• Weight loss has been found to be associated with some comorbidities, like hip fracture among women ≥65 years in age. It's unclear if weight loss as attained in this trial would be associated with increased hip fractures.
• No assessment of combined medication+lifestyle modifications.
• The definition of overweight (as it is termed in the background paper) and obesity (as it is termed in the main paper in JAMA) does not fit the conventional definition of either condition.
• Not powered to detect a difference in cardiovascular events.

Funding

• NHLBI and NIA at the NIH
• General Clinical Research Center Grant from the National Center for Research Resources at the NIH