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. Author manuscript; available in PMC: 2016 Mar 1.
Published in final edited form as: Am Heart J. 2015 Jan 7;169(3):342–348.e4. doi: 10.1016/j.ahj.2014.11.021

Evaluating the Safety and Efficacy of Sodium-Restricted/Dietary Approaches to Stop Hypertension Diet After Acute Decompensated Heart Failure Hospitalization: Design and Rationale for the Geriatric OUt of hospital Randomized MEal Trial in Heart Failure (GOURMET-HF)

Jeffrey D Wessler 1, Mathew S Maurer 1, Scott S Hummel 2,3
PMCID: PMC4596079  NIHMSID: NIHMS653523  PMID: 25728723

Abstract

Background

Heart Failure (HF) is a major public health problem affecting predominantly older adults. Non-adherence to diet remains a significant contributor to acute decompensated HF (ADHF). The sodium-restricted Dietary Approaches to Stop Hypertension (DASH/SRD) eating plan reduces cardiovascular dysfunction that can lead to ADHF and is consistent with current HF guidelines. We propose that an intervention that promotes adherence to the DASH/SRD by home-delivering meals will be safe and improve health-related quality of life (QOL) in older adults following hospitalization for ADHF.

Methods/Design

This is a three center, randomized, single-blind, controlled trial of 12 weeks duration designed to determine the safety and efficacy of home-delivered DASH/SRD-compliant meals in older adults following discharge from ADHF hospitalization. 66 subjects will be randomized in a 1:1 stratified fashion by gender and left ventricular ejection fraction (< vs. ≥50%). Study subjects will receive either pre-prepared, home-delivered DASH/SRD-compliant meals or usual dietary advice for 4 weeks after hospital discharge. Investigators will be blinded to group assignment, food diaries, and urinary electrolyte measurements until study completion. The primary efficacy endpoint is the change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary scores for health-related QOL from study enrollment to 4 weeks post-discharge. Safety evaluation will focus on hypotension, renal insufficiency, and hyperkalemia. Exploratory endpoints include echocardiography, non-invasive vascular testing, markers of oxidative stress, and salt taste sensitivity.

Conclusion

This randomized controlled trial will test the efficacy, feasibility and safety of 4 weeks of DASH/SRD after ADHF hospitalization. By testing a novel dietary intervention supported by multiple levels of evidence including preliminary data in outpatients with stable HF, we will address a critical evidence gap in the care of older patients with ADHF. If effective and safe, this intervention could be scaled to assess effects on readmission and healthcare costs in older adults following ADHF.

Keywords: Heart failure, sodium restriction, quality of life, dietary intervention

Background

Acute decompensated heart failure (ADHF) is the leading cause of hospitalization in older persons, and expenditures in the U.S. for this diagnosis exceed $15 billion/year.1 Rehospitalizations, the most frequent adverse outcome following ADHF, markedly worsen quality of life (QOL) and result in increased mortality and cost.2 Poor or worsening QOL following ADHF hospitalization is an independent risk factor for mortality and readmission.3 Older patients are at specific risk for persistently poor QOL following ADHF hospitalization, in part due to challenges in managing the complexity of HF self-care.4 While some recent advances have been made in outpatient treatment for HF5 and novel pharmaceutical agents hold promise in ADHF,6 current management strategies have only modestly improved ADHF outcomes.2 Other recent trials of telemedicine7, diuretics8 and newer pharmacologic agents9 have been disappointing, suggesting that outcomes in ADHF patients are driven by mechanisms not addressed by current approaches.

Dietary sodium restriction is associated with reduced risk for ADHF in observational studies,10 and has been described as a ‘cornerstone of HF disease management.’11 However, several randomized studies suggest that this strategy may be ineffective or even harmful in recently discharged ADHF patients.12 Dietary sodium restriction is the most frequently recommended self-care behavior for HF patients,13 and additional understanding of its efficacy and safety is critically important. The provision of ‘therapeutically-designed’ meals cost-effectively improves QOL in otherwise healthy older hypertensives,14 but has not been studied in older adults following ADHF hospitalization, a much more vulnerable population. The principle underlying this proposal is that non-adherence to dietary recommendations is one of the most common preventable causes of ADHF hospitalization, and meal provision following hospital discharge may reduce this risk.15,16

The sodium-restricted/Dietary Approaches to Stop Hypertension (DASH/SRD) eating plan is recommended by current hypertension guidelines and lowers blood pressure (BP) more than sodium restriction alone. In ‘salt-sensitive’ animal models of hypertensive HF, dietary patterns similar to DASH/SRD reduce BP, ventricular and arterial stiffness, and vascular dysfunction by decreasing oxidative stress and inflammation.17 Predictors of a similar phenotype in humans include hypertension, renal insufficiency, diabetes, central obesity, and chronic inflammation, all independent HF risk factors in older adults.18 The DASH/SRD reduces BP and improves vascular function in salt-sensitive humans without HF.19 In older outpatients with hypertension-associated HF, 21 days of DASH/SRD can improve BP, oxidative stress, ventricular diastolic function, ventricular-arterial coupling, and submaximal exercise capacity.20,21

Aims and Hypotheses (Table)

Table.

Aims and Hypotheses for GOURMET-HF

Protocol Term Endpoint
Specific Aim 1: Feasibility and efficacy
    Primary hypothesis Improvement in Health-Related QOL Kansas City Cardiomyopathy Questionnaire
    Feasibility Adherence to DASH/SRD 3-day food diary; urinary electrolytes
Specific Aim 2: Dietary, mechanistic, and safety
    Secondary hypothesis
        Dietary Salt taste affinity reduction Salt taste affinity testing; Food Frequency Questionnaire
    Mechanistic Echocardiography Cardiac chamber dimensions; LV ejection fraction; mitral E:A ratio; Mitral annular tissue
Functional improvement Doppler velocities; Ventricular-arterial coupling; 6 minute hall walk distance
Systemic inflammation and oxidative stress reduction IL-6, hs-CRP, TNF-α, urine F2-isoprostanes; inflammation-related gene response in PBMC
Reduced plasma volume Plasma volume measured by I-131
        Safety Adverse events Death, all-cause hospitalization, new or worsening renal dysfunction, hyperkalemia, symptomatic hypotension, syncope
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QOL, Quality of Life; DASH/SRD, sodium-restricted Dietary Approaches to Stop Hypertension diet ; LV = Left Ventricle; PBMC, peripheral blood mononuclear cells

Aim 1

To assess the feasibility and efficacy of providing DASH/SRD-compliant meals in older adults with hypertension following discharge from a hospital admission for ADHF. Efficacy will be assessed by improvement in health-related QOL and feasibility will be assessed by adherence to DASH/SRD.

Aim 2

To investigate the dietary, mechanistic, and safety effects of DASH/SRD in older adults with hypertension following discharge from a hospital admission for ADHF. Dietary effects will be assessed through salt taste affinity reduction; mechanistic effects will be assessed through echocardiography, functional improvement, systemic inflammation and oxidative stress reduction, and reduction in plasma volume; safety will be assessed through adverse effects including death, all-cause hospitalization, worsening renal function, hyperkalemia, and symptomatic hypotension or syncope.

The primary hypothesis is that providing 4 weeks of home-delivered DASH/SRD-compliant meals will improve health-related QOL in older adults after discharge from hospitalization for ADHF. The primary efficacy endpoint will be the change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary scores for health-related QOL in patients with chronic HF from study enrollment to 4 weeks post-discharge. The KCCQ, a self-administered 23-item instrument, assesses physical limitations, symptoms, self-efficacy, social interference, and overall QOL in HF patients. The KCCQ summary score ranges from 0-100, with higher scores indicating better QOL. The KCCQ summary score independently predicts clinical outcomes such as hospitalization and mortality in outpatients with HF, including those recently hospitalized for ADHF.22 It is a reliable and valid measure in HF patients that is more sensitive to change than other measures of QOL, and is especially responsive in patients with multiple comorbidities.23 A change in KCCQ score of 5 points correlates with changes in clinical status, physical function, and risk of all-cause mortality, cardiovascular death and hospitalization.3,24 Secondary hypotheses are: a) salt taste affinity reduction is greater; b) cardiovascular and sub-maximal functional measures are improved; c) systemic and gene expression markers of systemic inflammation and oxidative stress are reduced, and d) plasma volume is lower in the DASH/SRD group at 4 weeks when compared with the control group.

The secondary endpoints for this study are divided into three domains: safety, dietary, and mechanistic parameters. Safety will be assessed by tracking adverse events including death, all-cause hospitalization, new or worsening renal dysfunction, hyperkalemia, symptomatic hypotension, or syncope with specific responses to these events detailed below. Dietary endpoints will include long-term DASH/SRD adherence as measured by 3-day food diary, Food Frequency Questionnaire (FFQ), and urinary electrolyte measures at 12 weeks25 as well as salt taste affinity at 4 and 12 weeks.26 Mechanism-related endpoints will include changes from baseline to 4 weeks in BP, noninvasive measures of ventricular function and ventricular-arterial coupling, blood/urine measures of neurohormonal activation, oxidative stress, systemic inflammation, and plasma volume measurements (the latter measured in a subset n=20 at Columbia University Medical Center).

Methods/Design

Trial registration and Funding

This trial is registered at ClinicalTrials.gov (NCT02148679, received 23 May 2014) and is funded by PurFoods, LLC (Des Moines, IA) and the National Institute of Aging (R21 AG047939-01). Dr. Hummel is supported by the National Heart, Lung, and Blood Institute (K23 HL109176) and the University of Michigan's Clinical and Translational Science Award (2UL1TR000433-06), and Dr. Maurer is supported by the National Institute of Aging (K24 AG036778). The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.

General Design

This is a three-center, randomized, single-blind, trial of 12 weeks total duration designed to determine the safety and efficacy of home-delivered DASH/SRD-compliant meals in older adults following discharge from ADHF hospitalization. 66 subjects will be randomized in a 1:1 stratified fashion by gender and left ventricular ejection fraction (< vs. ≥ 50%). Study subjects will receive either pre-prepared, home-delivered DASH/SRD-compliant meals or usual dietary advice for 4 weeks after hospital discharge. The three study sites will be Columbia University Medical Center/NewYork Presbyterian Hospital, the University of Michigan Health System, and the Ann Arbor Veterans Affairs Health System. Investigators will be blinded to group assignment, food diaries, and urinary electrolyte measurements until the completion of the study. See Figure 1 for general study outline.

Figure 1.

Figure 1

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General Study Design

Study Subjects

66 patients aged ≥ 65 years with history of systemic hypertension and ADHF (primary diagnosis for admission or secondary diagnosis after hospitalization for another reason). ADHF will be confirmed by the study physician and require that all four of the following conditions are met: 1) ≥1 symptom of HF (dyspnea, fatigue, orthopnea, paroxysmal nocturnal dyspnea) has worsened from baseline, 2) ≥2 signs of HF (pulmonary congestion on exam and/or chest X-ray, elevated jugular venous pressure, peripheral edema or rapid weight gain, and/or increased B-type natriuretic peptide (BNP; ≥100 pg/ml), 3) change in medical treatment specifically targeting HF (diuretics, vasodilators, and/or neurohormonal modulating agents), and 4) no other cause of the patient's symptoms and signs is apparent.

Patients will be excluded based on the following criteria: persistent hypotension during hospitalization or excessive risk of hypotension from the study diet as judged by the investigators, use of inotropic therapy at hospital discharge, severe valvular heart disease as the primary etiology of HF, uncontrolled hypertension (systolic BP >180 mmHg or diastolic BP >100 mmHg) at discharge, serum potassium >5.0 mmol/L during hospitalization or history of serum potassium >6.0 mmol/L, severe renal insufficiency (estimated glomerular filtration rate, eGFR, <30 ml/min/1.73m2 at discharge), diabetes mellitus type 1 or non-adherence to routine diabetic monitoring, severe anemia (hemoglobin < 9 gm/dl), length of stay <48 hours or >14 days, co-morbidity with expected survival <12 months, active alcohol or substance abuse, and/or a history of persistent noncompliance with treatment recommendations as judged by the investigators.

Intervention

Study food will be designed and prepared by PurFoods, LLC (Des Moines, IA) in consultation with research dietitians at the University of Michigan and Columbia University. Study patients randomized to food delivery will select from an available menu of meal options that adhere to nutritional targets as above. Study food will be pre-packaged for storage with preparation (typically microwave heating) to be completed at home by the subject, and will be delivered every 1 to 2 weeks under the direction of PurFoods.

The study diet will have goal daily sodium intake of 1500 mg/2100 kilocalories27 and energy intake to maintain lean body mass while meeting DASH diet nutritional targets.28 In patients with eGFR 45-60 ml/min/1.73m2 and serum potassium >4.5 mmol/L at hospital discharge and in patients with eGFR <45 ml/min/1.73m2, the potassium content of the DASH/SRD will be reduced to 3000 mg/d as recommended by the National Kidney Foundation.29 The potassium content will also be reduced to 3000 mg/d in patients prescribed potassium-sparing diuretics (e.g. spironolactone) with serum potassium greater than 4.5 mmol/L at hospital discharge, regardless of renal function.

Upon study enrollment, both groups will receive a standardized pamphlet containing instructions on following a 2000 mg/d sodium restriction, the standard discharge recommendation at the three enrolling centers; the recommendations in this material are also generally consistent with the DASH diet pattern. In both groups, study personnel will solicit and answer questions related to dietary concerns at the safety visit and during scripted telephone calls at weeks 2 and 3. Specific dietary consumption will be assessed by 3-day food diaries and urinary sodium and potassium during weeks 1 and 4 post-discharge.

Procedures

In total, subjects will have the following number of procedures (see Figure 2 for study timeline): Up to 4 physical examinations; Up to 4 blood draws for assessment of renal function, electrolyte levels, and hemoglobin/hematocrits; 4 urine collections for urinary studies (3× 24-hour collections, 1× spot urine); 4 salt affinity taste strip tests; up to 5 supine/standing brachial blood pressure and pulse rate measurements (done at each visit); 3 ECGs; 2 two-dimensional (2D) echocardiograms; 2 non-invasive arterial tonometry tests; 3 six-minute walk tests; 4 Quality of Life Questionnaires; up to 3 Food Frequency/food diary questionnaires.

Figure 2.

Figure 2

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Study Procedures Timeline

A description of the procedures follows

Medical history and brief physical exam

Demographic information, medical and food allergy history, medications, height, weight, vitals including supine and standing blood pressure, and a HF-focused physical examination will be obtained and recorded.

Blood tests

Total blood volume ~140ml, to be obtained in intervals at baseline, 1, and 4 weeks. Screening: basic metabolic panel, liver function test, lipid panel, hematocrit, BNP, troponin I; Safety: basic metabolic panel, cystatin C, phosphorus; Efficacy: BNP, lipid panel, IL-6, hs-CRP, TNF-α. In addition, blood will be collected in PaxGene tubes at hospital discharge and 4 weeks post-discharge. These samples will be analyzed with real-time PCR to explore inflammation-related gene response in peripheral blood mononuclear cells (Open Array Human Inflammation Panel, Applied Biosystems, Foster City, CA). At the Columbia site, 2 additional blood samples will be collected for the analysis of blood volume components (i.e. plasma and red cell volume);

Urine Tests

24-hour urine specimens will be obtained at baseline, 4, and 12 weeks and will be used to measure sodium, potassium, creatinine, protein, aldosterone, and F2-isoprostanes.

Salt taste threshold testing

Salsave test strips (Advantech Toyo Co., Fukuoka, Japan) will be used to evaluate a patient's salt taste threshold. In this method 7 test strips containing salt (NaCl) concentrations ranging from 0 to 1.6 mg/cm2 make up each set. Each test strip is sequentially placed on the tongue, and the strip whose salt concentration is detected determines the salt taste threshold.30

Six-minute walk test

The six minute walk test will be conducted as described by Guyatt.31 The total distance walked after six minutes to the nearest meter will be recorded as well as patient's symptoms (angina, dyspnea, fatigue, dizziness).

Arterial tonometry

Central end-systolic BP and carotid-femoral pulse wave velocity will be non-invasively obtained at the radial artery with a Sphygmocor tonometer (AtCor Medical, Itasca, IL) as described.32 Carotid-femoral pulse wave velocity, a measure of central arterial stiffness, will also be obtained.

2D echocardiography

Using a commercially available GE Vivid-9 echocardiography system or equivalent, a complete 2D imaging protocol will be performed. Cardiac chamber dimensions, left ventricular (LV) ejection fraction, mitral inflow velocities (E:A ratio), deceleration time of early filling velocity and LV isovolumic relaxation time, and mitral annular tissue Doppler velocities (e’, a’, s’) will be measured as per published procedures.33 Speckle-tracking analysis will be performed on short-axis and 4-chamber views to derive radial, circumferential, and longitudinal strain and strain rate. Arterial and single-beat end-systolic ventricular elastance and Parametrized Diastolic Formalism analyses will be performed as previously described.34

Plasma volume measurement

Twenty five microcuries of 131I labeled albumin (Megatope, IsoTex Diagnostics, Inc., TX) will be injected from a prefilled syringe provided by Daxor Corporation. A 20 gauge butterfly needle will be placed in an antecubital arm vein for venous blood sampling. 5 cc of blood will be collected before isotope injection, and at 12, 18, 24, 30 and 36 minutes after isotope injection (total 30 cc). Specimens will be analyzed with an automated system (BVA100 Blood Volume Analyzer, Daxor Corp., NY).35

QOL questionnaires

The KCCQ is a self-administered, 23-item questionnaire developed to describe health-related QOL in HF patients. It quantifies disease-specific physical limitations, symptoms, self-efficacy, social interference and quality of life with well-defined psychometric properties.23 The 12-item Short-Form Survey (SF-12), previously validated in HF patients,36 and the Visual Analog Scale will be administered to investigate the effects of home food delivery on general quality of life.

Dietary assessment

The Block Food Frequency Questionnaire will be used to analyze nutrient intake, and subjects’ responses at baseline and 12 weeks will be scored for adherence to DASH/SRD.25 Three-day food diaries will be performed during weeks 1, 4, and 12 post-discharge. The Dietary Sodium Restriction Questionnaire (DSRQ) was developed and validated in HF patients to assess patient-specific barriers to following low sodium diet recommendations.37 We will administer a modified version that also investigates barriers to following the DASH dietary pattern (e.g. fruit and vegetable, fiber intakes).

Statistical Approach

In a large ADHF clinical trial, marked gains in QOL occurred during hospitalization but smaller gains were noted following hospital discharge (mean KCCQ scores among survivors: 32±19 upon admission, 53±22 at 1 week post-discharge, 58±24 at 24 weeks).38 Prior studies have shown a change in KCCQ scores from 60±22 to 75±17 over a 6-month dietary intervention,39 and from 64±23 to 70±25 over 1-2 years for patients with good adherence to HF self-care recommendations compared to poor adherence.40 While KCCQ scores vary across groups of patients, they are reproducible over time within stable individuals (e.g., in 811 stable HF patients, the intra-class coefficient of serial KCCQ over three months was 0.89)23 and highly responsive to clinical change. We will use paired t-testing to compare within-group change in KCCQ summary score (ΔKCCQ) between hospital discharge and week 4, and two-sample t-testing to compare between-group ΔKCCQ at these two time points (primary endpoint). Randomizing 33 patients in the DASH/SRD and control arms (conservatively anticipating three post-discharge deaths or dropouts in each group for a total of 30 analyzed in each arm)41 and assuming SD of ΔKCCQ = 8, this study will have 80% power to detect a between-group ΔKCCQ difference of 5 points. Analysis will be by intention to treat, regardless of the location and status of the patient at the end of the intervention (i.e., QOL questionnaires will be administered even if the patient is currently rehospitalized and not currently consuming study food).

Other quantitative measures will be summarized with descriptive statistics and graphical representations of variance, then evaluated with t-testing as above. Correlation and regression techniques will be used to explore physiological relationships (e.g., the relationship between plasma volume and oxidative stress).

This study is not intended or powered to determine the impact of providing DASH/SRD on HF readmissions. However, we will explore 30-day and 90-day all-cause readmissions using logistic regression and Poisson regression methods (with count data days out of the hospital and alive within the interval), adjusted for a previously validated risk model that includes KCCQ summary score as the strongest predictor.38

Data and safety monitoring

A data monitoring committee (DMC) composed of two independent clinicians and one statistician will be established to evaluate safety. Adverse events will be recorded from the day of the first study related procedure and reported on a monthly basis to the IRB and DMC; serious adverse events will be recorded until 30 days after the patient's last study visit, and reported to the IRB and DMC within 24 hours of knowledge of the event. The trial will be stopped for harm if there is in the judgment of the DMC, a large disparity in serious events in the DASH/SRD study arm. The Principal Investigators at each site and their study personnel will collect and manage the data provided to the DMC.

Renal function and electrolytes will be assessed at baseline and 1 week post-discharge during a safety visit, during which targeted physical examination for volume status will allow adjustment of diuretics by the investigators as clinically indicated. The dietary intervention will be stopped in any patient who develops new or worsened renal impairment as defined by eGFR decrease of ≥50%, hyperkalemia (K >5.7 mmol/L), syncope, or other serious adverse event deemed by the investigators to be related to study participation. Note that study participants with recent ADHF hospitalization are inherently at high risk for rehospitalization and mortality (combined ~25% over the 4-week intervention period of the study, ~35% over the total 12-week term of the study) regardless of study participation. Patients randomized to food delivery will have delivery suspended if hospitalized; food delivery will be resumed after hospital discharge if the investigators have not determined contraindications to continued participation (e.g. hypotension, hyperkalemia).

Other design considerations/limitations

Our trial design does not adjust for habitual baseline variation in sodium intake. As in many North American hospitals, all ADHF inpatients at the three trial sites receive a 2000 mg/day sodium-restricted diet while hospitalized.42 This standardized intervention prior to randomization should minimize the impact of pre-hospitalization diets on our findings. The 1500 mg/d sodium threshold for the study diet was selected to match current American Heart Association recommendations, and is supported by our pilot study in which meals with 1500mg/d sodium were provided to older HF outpatients without adjustment for baseline dietary practices.20,21 We acknowledge that the effects of meal home-delivery on QOL may be challenging to separate from the effects specifically related to the DASH/SRD. In addition to the KCCQ we will obtain the SF-12, a well-validated measure of general QOL,36 in order to evaluate changes in QOL related to food delivery alone.

Conclusion

The purpose of this randomized controlled trial is to test the efficacy and safety of 4 weeks of DASH/SRD after ADHF hospitalization. Hypothesized mechanisms of DASH/SRD benefits include improvements in ventricular function, ventricular-arterial coupling, and reduced plasma volume as well as reductions in systemic oxidative stress and inflammation and a shift in salt taste affinity. By testing a novel dietary intervention supported by multiple levels of evidence including preliminary data in outpatients with stable HF, we will address a critical evidence gap in the care of older patients with ADHF. If effective and safe, this intervention could then be scaled to assess effects on readmission and healthcare costs in older adults following ADHF hospitalization.

Highlights.

  • Older ADHF patients may have difficulty with self-care and are often rehospitalized

  • This trial tests home-delivered DASH/SRD meals post-ADHF discharge in older adults

  • The primary study outcome is health-related quality of life

  • Feasibility outcomes include safety and dietary adherence

  • Exploratory endpoints include plasma volume and oxidative stress

Acknowledgments

The authors gratefully acknowledge the assistance of Wahida Karmally, MS, RD, CDE (Columbia University), Theresa Han-Markey, MS, RD, and Debra Peterman, RD (University of Michigan).

Footnotes

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