1. Objectives

To evaluate the effects of potassium supplementation in adults with primary hypertension

2. How studies were identified

The following databases were searched:

• CENTRAL (The Cochrane Library 2004, Issue 1)
• MEDLINE (to 2004)
• EMBASE (to 2003)
• Science Citation Index (to 2003)
• ISI Proceedings (to 2003)
• CAB abstracts (to July 2005)
• ClinicalTrials.gov
• Current Controlled Trials

Reference lists were screened and general Internet searches were also conducted

3. Criteria for including studies in the review

3.1 Study type

Randomized controlled trials, including both parallel and crossover designs, with an intervention period of at least eight weeks

3.2 Study participants

Adults over 18 years of age with elevated blood pressure, defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥85 mmHg, without a known primary cause

(Studies enrolling pregnant women were excluded as were studies including participants whose anti-hypertensive medication varied during the course of the trial)

3.3 Interventions

Oral potassium supplementation or dietary interventions only manipulating potassium intake compared to placebo, no intervention, or usual diet

3.4 Primary outcomes

• All-cause mortality
• Coronary heart disease events (fatal or non-fatal myocardial infarction, excluding heart failure and if possible angina)
• Cerebrovascular events (fatal or non-fatal strokes, excluding transient ischaemic attacks if possible)
• Systolic and diastolic blood pressure at end of follow-up

Secondary outcomes included total withdrawal from treatment, withdrawals due to adverse events, any adverse effects reported, serum potassium level at end of follow-up

4. Main results

4.1 Included studies

Five randomized controlled trials, enrolling 425 participants, were included in this review

• Three trials were of parallel design, one was a crossover trial, and one was a 2x2 factorial design comparing low sodium, high potassium, low sodium-high potassium, and usual diets
• Duration of follow-up ranged from eight to 16 weeks
• Mean blood pressure at baseline was 151/95 mmHg; systolic blood pressure ranged from 145 to 174 mmHg and diastolic blood pressure ranged from 92 to 100 mmHg
• Four trials compared oral potassium supplements (48 to 120 mmol/day) to a placebo control, and one trial compared dietary advice to increase potassium intake to usual diet
• Participants were predominantly male (75%), mean age was 50 years, and ethnicity was reported in two trials (61% Caucasian)

4.2 Study settings

• Australia, Germany, Italy, Kenya, and the USA
• Blood pressure was measured in study clinics with the patients supine or seated

4.3 Study settings

How the data were analysed
For the factorial trial, the potassium treatment group was aggregated over high potassium and low sodium-high potassium diets, while usual diet was aggregated over normal and low sodium diets. Results from all included trials were pooled in meta-analyses stratified by parallel or crossover design; these were then combined in an overall meta-analysis if they did not exhibit heterogeneity. Mean differences (MD) between the treatment and control groups and 95% confidence intervals (CI) were calculated. The following subgroup analyses were planned:

• By dose of potassium in the treatment arm: >100 mmol/day and ≤100 mmol/day
• By participants’ mean baseline blood pressure: >145/95 mmHg and ≤145/95 mmHg

Sensitivity analyses were also performed excluding trials in which the following were not reported: (i) adequate allocation concealment and, (ii) blinding of participants, treatment providers and outcome assessors.

Results
All-cause mortality, cardiovascular events and cerebrovascular events
None of the included studies reported on deaths, or on cardiovascular or cerebrovascular events.

Blood pressure
Pooled analysis of the parallel trials revealed a non-statistically significant reduction in both systolic (MD -14.5 mmHg, 95% CI [-31.2 to 2.2], p=0.089) and diastolic blood pressure (MD -7.5 mmHg, 95% CI [-16.1 to 1.1], p=0.086) in the treatment group relative to the control group (4 trials/386 participants). Including the crossover trial did not alter the results materially, with an MD in systolic blood pressure of -11.25 mmHg (95% CI [-25.18 to 2.68], p=0.11) and in diastolic blood pressure of -5.03 mmHg (95% CI [-12.47 to 2.42], p=0.19). Heterogeneity was high in all of these analyses (I²≥99%).

Subgroup and sensitivity analyses
Little difference was observed between the effects of potassium in trials with lower (≤145/95 mmHg) or higher baseline blood pressure (>145/95 mmHg). However, a greater reduction in blood pressure was observed in trials administering lower doses of potassium (≤100 mmol/day) than trials with higher doses (>100 mmol/day), and in lower dose trials treatment effects were statistically significant (MD systolic blood pressure -26.89 mmHg, 95% CI [-51.19 to -2.19], p=0.033; and MD diastolic blood pressure -14.33 mmHg, 95% CI [-20.60 to -8.06], p<0.00001; 2 trials). Sensitivity analysis restricted to the two trials judged to be of high quality found a non-significant reduction in systolic and diastolic blood pressure among those randomized to potassium treatment.

Adverse effects
In pooled analysis of the three parallel trials that reported on rate of withdrawal, no statistically significant difference was found between treatment and control groups. Adverse gastrointestinal effects (stomach pain and flatulence) were reported to be more frequent in the treatment group in one study, although withdrawal due to adverse effects was statistically significantly higher in the control group.

Additional outcomes
Final serum potassium was higher among those treated with potassium (MD 0.20 mmol/L, 95% CI [0.02 to 0.38], p=0.034; 2 trials).

5. Additional author observations*

Heterogeneity was substantial in meta-analyses and was not explained by differences in baseline blood pressure. Although further subgroup analysis suggested that trials administering a lower dose of potassium achieved a statistically significant and greater reduction in blood pressure, this result should be interpreted with caution, as it may be a chance finding due to multiplicity. Only two of the five included trials were judged to be of high quality, and when restricted to these studies, meta-analysis still displayed a high degree of heterogeneity (I²=87%). The observed heterogeneity may be a result of differing baseline dietary potassium or sodium intakes, or other unreported characteristics of the populations studied.

While this review does not show that increasing oral potassium intake reduces blood pressure in adults with primary hypertension, further placebo-controlled randomised trials are required to clarify this finding given the substantial heterogeneity observed in pooled analyses and low quality of included trials overall. Future trials should be of high quality, enrol a large number of participants, have follow-up durations adequate to detect meaningful long-term effects, and effects should be reported in relation to the ethnicity of participants and their baseline dietary intake of potassium and sodium.