Study design and setting
The study design is a single- center, single arm clinical trial, with an adaptive design of two possible sequential interventions. Focused and individualised dietary counselling to increase potassium intake will be the initial intervention amongst hypertensive individuals with low potassium intake. This study and patient recruitment will take place in a referral hypertension clinic at a tertiary care teaching hospital. Patients with difficult to control hypertension are referred to this clinic, and all patients undergo evaluation of their sodium and potassium intake with a 24 hour urinary collection.
Study population and timeline
In this trial, all patients with low dietary potassium intake will be eligible for enrollment. The study coordinator will screen patient for eligibility and obtain informed consent. Patients known to be at risk for hypokalemia or hyperkalemia will be excluded. The estimated duration for this study is four years.
Inclusion criteria:
(1) Hypertension (either on treatment, any level of BP; or not on treatment with an ambulatory blood pressure monitoring (ABPM) with daytime systolic blood pressure (SBP) > 140 or diastolic blood pressure (DBP) > 90)
(2) Aged 18 and greater
(3) 24 Hour Urine potassium < 60 mmol
Exclusion criteria:
(1) serum potassium < 3.3 or > 5.1 mmol/L
(2) Glomerular filtration rate (GFR) < 45 ml/min/1.73m2
(3) Primary hyperaldosteronism
(4) Pregnancy
(5) Psychiatric disorder which, in the opinion of the investigator, would interfere with the study, or inability to give consent
(6) Severe Liver disease
(7) Metabolic Alkalosis (HCO3 > 32 mmol/L)
(8) Exclude patients who need to be started on renin-angiotensin-aldosterone blockade in the next 3 months
(9) Gastrointestinal Disorder (delayed gastric emptying, dysphagia, gastric/duodenal/oesophageal ulcers)
Interventions
Part 1: Counselling:
All enrolled patients will undergo a 1:1 counselling with a registered dietitian (with possible inclusion of family members, as appropriate). The dietitian will undertake an assessment of the comorbidities (eg. diabetes), dietary intake, dietary habits (eg. eating out, food preparation, socio-cultural aspects) and provide an individually tailored strategy to increase potassium in the diet. Secondly, on a weekly basis, the dietitian will contact the patient by telephone, or electronically (as preferred by the patient) to reinforce the advice and provide support and advice as necessary. Patients who are successful in increasing potassium to desirable levels at 4 weeks (see outcomes below) will continue to have follow up for one more year.
The counselling will be individualised, and focused on addition of food ingredients or items to increase potassium intake, rather than a complete overhaul of the participant lifestyle.
Part 2: Potassium supplementation:
Patients who are not able to successfully increase their potassium intake at 4 weeks with dietary counselling will be enrolled into Stage 2. They will receive oral potassium supplementation in the form of 50 to 100 mmol of potassium citrate (25 to 50 ml of the liquid elixir). This dose of potassium is well tolerated in hypertension (reported adverse events, at < 1% frequency and not different from placebo, are change in bowel habits, belching and flatulence, and abdominal cramps with the current wax matrix–based and microencapsulated or coated microcrystal-containing preparations with extended release characteristics)[9, 19]. There are no reports of hyperkalemia reported in trials using this dose in a similar population[9, 12]. Potassium at this dose and formulation has excellent (> 90%) bioavailability[19]. This dose of potassium also should be effective in increasing urinary potassium to desired levels.
Outcomes
The primary outcome will be a successful increase in potassium intake to > 90 mmol/day as estimated from the 24 hour urinary sample at 4 weeks. The secondary outcomes are persistence of increase in potassium intake (to > 90 mmol/day) at 1 year. For examination of safety, the following outcomes will be specifically examined: hyperkalemia (as defined as a serum potassium > 5.1 mmol/L) at 4 weeks after initiation of dietary counselling, at one and 4 weeks after starting potassium supplements, one week after dose escalation/dispensing, and at 12 months in everyone; and gastrointestinal side effects (change in bowel habits, belching and/or flatulence; abdominal pain or cramps). Additional patient reported adverse effects will also be measured and reported. Serious adverse events will be captured and reported as per regulatory requirements.
Blinding
The trial design is open label, given that behavioural change is difficult to blind. However, numerous safeguards will be in place to minimize actual bias in the data collected.
Blinded assessment of outcomes:
The primary outcome in this trial is a change in potassium intake, as measured by 24 hour urinary potassium. This is an objective measure however, and the laboratory personnel measuring the values will not be aware of which intervention is ongoing when they perform the measurement.
Ascertainment and Follow-up plan:
In order to minimize ascertainment bias, all patients, irrespective of the group, will have similar measurement schedule. Nevertheless, we will study the frequency of loss to follow-up and reasons thereof.
Measurements
The dietary intake of potassium will be assessed using 24 hour collection of urine. There is a very close relationship overall between urinary potassium excretion and dietary potassium intake. There is a circadian variation[20] (more potassium excretion in the day than at night) which will be overcome with a 24 hour urine collection. Twenty four hour urinary sodium and creatinine (to assess for accuracy of collection) will also be measured for all participants at baseline, 4 weeks and 52 weeks (end of study). In addition, participants who enrol into Stage 2 may have additional 24 hour urinary collection at 9 weeks and 14 weeks after initiation of the potassium supplement/dose escalation. Blood will also be collected at the same time points for measurement of kidney function and electrolytes (creatinine, sodium, potassium, total CO2, chloride). As an additional safety measure, serum potassium will be measured one week after starting potassium supplementation, one week after dose escalation and one week post each re-dispensing visit. Blood pressure will be measured using automated oscillometric measurements and 24 hour ambulatory monitoring. Additional assessment of adherence to supplement (apart from 24 hour urine measures) will be made on the basis of returned pills/bottles. Patients satisfaction will be assessed using a simple 3 question survey (see supplementary material).
Sample size and analytical plan
The study goal is to estimate the success rate of the dietary intervention, as well as the success rate of the two-stage approach. Dietary counselling alone will not exceed this degree of increase which was seen with supervised intake and meal provision, but there are no robust data to support an estimate of its effect. However, potassium supplementation at the dose proposed would very likely result in achieved potassium intake of > 90 mmol/day in all participants. A sample size of 100 participants will allow us to able to estimate both success rates to within a margin of error of at most 5%. At 4 weeks, there should be little loss to follow up; however we estimate this to be about 20% to be conservative. Thus this trial will enrol 120 participants.
The primary outcome is a simple proportion of the participants who are able to achieve an increase in potassium intake. Secondary outcomes of the proportion of participants with persistent adequate potassium intake at 52 weeks, and safety outcomes, will also be reported as proportions. For the secondary outcomes of change in sodium, potassium and blood pressure, mean differences will be calculated and reported, and a paired t-test will be used to compare for statistical significance. There will be no interim analysis.
The proportions will be summarized as absolute numbers and percentages. Continuous outcomes will be reported as mean (and 95% confidence intervals). A p value of < 0.05 will be used for the paired comparisons of the continuous outcomes (i.e. secondary outcomes of change in sodium, potassium and blood pressure).
Access to medical records and study data will be limited to authorized personnel listed on the study delegation log or permitted by the study agreement. Access to electronic data will be password protected and auditable, electronic data will be stored on a hospital network with firewall and security back-up measure in place, and paper copies of the study data will be stored securely in locked cabinets and in locked offices.
Adverse events
The qualified investigator will follow adverse events with start dates occurring any time after informed consent is obtained until 7 days (for non-serious adverse events) or 30 days (for severe adverse events) after the last day of study participation. At each study visit, the investigator (or designee) will inquire about the occurrence of adverse events (AE)/serious adverse events (SAEs) since the last visit and record in participant research record and case report form. Events will be followed for outcome information until resolution or stabilization.
Data Safety Monitoring Board
This study will be monitored by an independent Data Safety Monitoring Board (DSMB), consisting of a Clinical Epidemiologist, a Nephrologist, and a Biostatistician. The DSMB will be immediately informed of any SAEs which may potentially be related to the study intervention. Other SAEs will be reviewed during regular DSMB meetings. Interim reports, prepared by the data management team for the study, for review by the DSMB will include data on recruitment, compliance, adverse effects, baseline comparability and treatment comparisons. An agreed upon review package which contains the appropriate data summary by treatment will be provided by the study statistician for the purposes of these reviews.