The study cohort was derived from 33,357 ALLHAT participants randomized to C, A, or L (Supplemental Figure S1
). It comprised participants (n
=19,731, 59%) who had normal baseline K+
values (3.5–5.4 mmol/L) and valid year-1 values (2.5–7.0 mmol/L); of these, 1,351 (6.8%) had hypokalemia, 17,982 (91.1%) normokalemia, and 398 (2.0 %) hyperkalemia at year-1. Baseline characteristics were similar between this and the overall ALLHAT cohort (Supplemental Table S1
). In comparison to normokalemic subjects, those who became hypokalemic were more likely to be black, to be women, and to have received antihypertensive medications prior to enrollment; whereas they were less likely to have a history of CHD and/or diabetes, be taking aspirin, or be a past smoker. In addition, persons with hypokalemia tended to have higher baseline SBP and DBP, lower fasting glucose, higher HDL-cholesterol levels and lower triglyceride concentrations than those with normokalemia. Persons who became hyperkalemic by year-1 tended to be older, have lower DBP, have modestly lower eGFR, and were less likely to be in the lipid-lowering trial component than those with normokalemia.
Mean levels of K+
and BP at baseline and by follow-up year are presented in Supplemental Table S1
by serum K+
group. During follow-up, SBP was similar among these groups, while DBP in hypokalemics was slightly higher than those with normal K+
and was lowest in hyperkalemics.
Randomization to C was associated with increased risk of hypokalemia (1185/9159, 12.9%) compared to A (113/5371, 2.1%) and L (53/5201, 1.0%) ( footnote). Severe hypokalemia (K+<3.2 mmol/L) occurred in 277 (3.5%) C participants, 17 (0.3%) A, and 8 (0.2%) L. Overall, participants who developed hypokalemia by year-1 did not experience greater CHD, stroke, or HF than those who remained normokalemic (). The rate for combined CVD was actually lower for hypokalemics compared with normokalemics (HR=0.88), and the result was significantly different for C versus A (p for interaction=0.02; HRC=0.86, HRA=1.48, and ). Total death rates for all hypokalemics exceeded that of normokalemics (HR=1.21, p=0.03) with an absolute risk difference of 2.5% and with significantly different results for L compared with C (p for interaction <0.01; HRC=1.21, p=0.03; HRA=1.60, p=0.06; HRL=3.82, p<0.001). Adjustment for follow-up SBP, DBP, and K+ in Cox PH regression analyses with time-dependent covariates, including fixed covariates previously examined, did not appreciably alter these HRs, slightly increasing the adjusted HR for stroke (1.01 to 1.02), total deaths (1.21 to 1.22), and CVD deaths (1.18 to 1.19) in hypokalemics and, similarly in hyperkalemics, stroke (1.25 to 1.26), death (1.15 to 1.16), and CVD deaths (1.23 to 1.24). The interaction HRs, likewise, did not change appreciably.
Cumulative number of events, 5-year Kaplan-Meier event rates per 100, Cox proportional hazard ratios, corresponding 95% confidence intervals (CI), and p-values for hypokalemia and normal year-1 K+ subgroups within drug groups.*
Table 2 Overall cumulative number of events and 5-year Kaplan-Meier event rates per 100 for the hypokalemic and normal year-1 potassium subgroups.* Also depicted are Cox proportional hazard ratios (HR), corresponding 95% confidence intervals (CI), and p-values (more ...)
Overall mortality in hypokalemics compared with normokalemics comprised an 18% higher risk of CVD death (p=0.20) and a 23% higher risk of non-CVD death (p=.08; ). Mortality from CHD causes accounted for 54% of the CVD deaths but did not differ significantly between hypo- and normokalemic groups (3.99/100 versus 3.78/100; HR=1.32, p=0.11). Notably, mortality from cancer causes, which comprised 52% of non-CVD deaths, was significantly higher in hypokalemics compared with normokalemics (5.48/100 versus 3.74/100; HR=1.52, p<0.01).
There was also heterogeneity between drug groups in several CVD outcomes. Specifically, those assigned to amlodipine who developed hypokalemia, compared with those remaining normokalemic, had significantly increased risk for CHD (HR=2.41), HF (HR=2.19), combined CVD (HR=1.48), and CVD death (HR=2.10). These results for A were significantly different than C, with all interaction p values <0.03. For those assigned to L, there was a significantly increased risk for hypokalemics compared with normokalemics at year-1 for HF (HR=3.10) and CVD death (HR=3.93). These results for L were significantly different than C, with all interaction p values <0.01.
Development of hyperkalemia was far less frequent than hypokalemia (398 vs. 1351) and was more common among L participants (3.6%) than C (1.2%) or A (1.9%). In L participants, those developing hyperkalemia were at increased risk of death (HR=1.49, 1.05–2.12, p=.02) compared with normokalemics (). Overall (), hyperkalemics were at significantly increased risk of combined CVD compared to normokalemics (HR=1.58), but there were no significant interactions with treatment.
Cumulative number of events, 5-year Kaplan-Meier event rates per 100, Cox proportional hazard ratios, corresponding 95% confidence intervals (CI), and p-values for hyperkalemia and normal year-1 potassium subgroups within drug groups.*
Table 4 Overall cumulative number of events and 5-year Kaplan-Meier event rates per 100 for the hyperkalemic and normal year-1 potassium subgroups.* Also depicted are Cox proportional hazard ratios (HR), corresponding 95% confidence intervals (CI), and p-values (more ...)
Potassium supplementation was available (Supplemental Table S2
), and 36% of participants with K+
<3.2 mmol/L at their first follow-up visit (1–3 months after randomization) were reported to be on supplementation at the next visit (within 3 months); 28% of those with a K+
<3.5 mmol/L, and 2% of those with a K+
≥3.5 mmol/L, were on supplementation. These percentages increased by year-4 to 71% of those with K+
<3.2 mmol/L, and 62% of those <3.5 mmol/L. At the year-1, an open-label diuretic was prescribed for 3% of C hypokalemics, 19% of A hypokalemics, and 23% of L hypokalemics. For hyperkalemics, open label ACEI was prescribed for 4% of C, 6% of A, and 3% of L.