⚠️ Auto-extracted by Claude on 2026-06-09. Cannot verify against full PDF — paper is closed-access and download failed (no open-access copy located). gap/no-fulltext-access. Core quantitative claims (Na/K ratio p=0.01, Na alone p=0.38, K alone p=0.08, n=2,275, 193 CVD events) are internally consistent with multiple downstream citations (Kong 2025, Neal 2021 discussion) and consistent with the study design as described in the SSaSS trial introduction, but have not been directly confirmed against the primary PDF.
Cook et al. 2009 — TOHP follow-up: Joint effects of sodium and potassium intake
Citation
Cook NR, Obarzanek E, Cutler JA, et al. (Trials of Hypertension Prevention Collaborative Research Group). “Joint Effects of Sodium and Potassium Intake on Subsequent Cardiovascular Disease: The Trials of Hypertension Prevention Follow-up Study.” Archives of Internal Medicine 2009;169(1):32–40. doi:10.1001/archinternmed.2008.523. PMID 19139321.
Background
The Trials of Hypertension Prevention (TOHP) were two randomized trials (TOHP I, 1987–1990; TOHP II, 1990–1995) that tested the effect of lifestyle interventions — including sodium reduction — on blood pressure in adults with high-normal BP. After trial completion, Cook et al. conducted a long-term follow-up study of 2,275 TOHP participants to assess cardiovascular disease outcomes 10–15 years post-trial, examining both sodium and potassium intake as joint predictors.
Study design
Prospective observational follow-up of TOHP I and II trial participants. Post-trial follow-up 10–15 years. Outcome: cardiovascular disease events (n=193 events). Sodium and potassium intake estimated from multiple 24-hour urinary collections obtained during the original trials (gold-standard intake biomarker). Both minerals assessed by quartile and as a ratio (Na excretion / K excretion).
Key findings
| Predictor | Trend across quartiles (p-value) |
|---|---|
| Sodium excretion alone | Nonsignificant upward trend with higher quartiles (p=0.38) |
| Potassium excretion alone | Nonsignificant downward trend with higher quartiles (p=0.08) |
| Na/K excretion ratio | Significant: highest vs lowest quartile → elevated CVD risk (p=0.01) |
The sodium-to-potassium ratio demonstrated the strongest and most statistically significant association with subsequent cardiovascular disease risk. The ratio model provided the best statistical fit among all models tested.
Key conclusion
“A higher sodium to potassium excretion ratio is associated with increased risk of subsequent CVD, with an effect stronger than that of sodium or potassium alone.”
This framing reoriented the sodium field: the relevant dietary metric for cardiovascular risk is the balance of sodium to potassium in the diet, not absolute sodium intake in isolation. This has important practical implications — dietary strategies that simultaneously lower sodium AND raise potassium (such as the DASH diet, the Mediterranean diet with potassium-rich foods, or KCl-partial salt substitutes) are likely more effective than sodium restriction alone because they improve the ratio rather than just one element of it.
Limitations
- Observational follow-up of a trial population selected for high-normal BP; may not generalize to normotensive populations
- 24-hour urine collections were from the original trial period, not contemporaneous with follow-up (intake may have changed post-trial)
- Post-trial contamination: some participants may have continued sodium reduction from the original trial intervention, introducing misclassification
- 193 events in 2,275 participants provides limited statistical power for subgroup analyses
Significance
The Na/K ratio finding from TOHP is the mechanistic/epidemiological anchor for the SSaSS salt-substitute trial (which delivered both effects simultaneously) and for modern dietary guidelines emphasizing the importance of co-delivering potassium alongside sodium restriction. It also explains why observational studies showing “sodium alone → modest or non-significant CVD risk” do not contradict the strong benefit seen with combined Na-restriction + K-repletion strategies.
Relationships
- Context for: neal-2021-ssass-salt-substitute (practical Na/K combined strategy)
- See also: sodium-restriction (companion cation section)