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ARTICLES: D. M. Green, A. H. Ropper, R. A. Kronmal, B. M. Psaty, and G. L. Burke Serum potassium level and dietary potassium intake as risk factors for stroke Neurology 2002; 59: 314-320 [Abstract] [Full text] [PDF]

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Serum potassium level and dietary potassium intake as risk factors for stroke

Silvia Di Legge, J David Spence, Arturo Tamayo, and Vladimir Hachinski   (1 April 2003)

Reply to Letter to the Editor

Deborah M Green, Allen H Ropper, Richard A Krommal, Bruce M Psaty and Gregory L Burke for The Cardiovascular Health Study   (26 November 2002)

Serum potassium level and dietary potassium intake as risk factors for stroke

Robert G Hart, Lesly A Pearce   (18 November 2002)

Serum potassium level and dietary potassium intake as risk factors for stroke 1 April 2003
Silvia Di Legge UWO Canada, J David Spence, Arturo Tamayo, and Vladimir Hachinski Send Correspondence to journal: Re: Serum potassium level and dietary potassium intake as risk factors for stroke sdilegge{at}uwo.ca Silvia Di Legge, et al.	Interestingly, Green et al. [1] observed an increased incidence of stroke in the elderly with potassium depletion, after adjustment for vascular risk factors, including hypertension. Detection and management of hypertension remains an unsolved problem: over one half of the population aged 65 or older have hypertension, but fewer than 20% have their blood pressure controlled [2]. The interaction between hypertension, drug effects on ion balance and the risk of stroke is complex; an approach that simplifies this problem is to determine the physiological drivers causing hypertension in the individual patient. Most patients with resistant hypertension have hyperaldosteronism; the key is sorting it out into primary or secondary. Stimulated plasma renin/aldosterone profiling helps determine whether the problem is primary or secondary hyperaldosteronism, but remains underutilized by most physicians initiating antihypertensive treatment. In primary hyperaldosteronism, an excess of adrenocortical hormones may cause low renin hypertension. Adrenocortical hyperplasia is probably more common than Conn's syndrome [3]. Excess aldosterone is responsible per se for salt and water retention and loss of potassium, magnesium and other ions. Patients with low-renin hypertension require diuretics for treatment, but they experience more adverse effects from thiazides because of additional depletion of potassium and other ions. In these cases, a reduction in sodium intake and low-dose thiazides in combination with potassium/magnesium sparing diuretics is more efficacious in preventing potassium depletion. Conversely, angiotensin II antagonists or angiotensin-converting enzyme inhibitors may prevent potassium depletion in patients with secondary hyperaldosteronism, identified by a high renin level. Spence [3] observed that stimulated plasma renin profiling is an efficient way to tailor therapy in patients with resistant hypertension and that adrenocortical hyperplasia is much more common in blacks. A new important cause of low-renin hypertension is a sodium channel polymorphism that accounts for 5% of hypertension in blacks, and is treated specifically with amiloride [4]. In this, and in having low levels of both renin and aldosterone, it resembles Liddle's syndrome. Interestingly, in Green et al study, the highest proportion of African Americans (20%) was observed in the group of patients at increased risk of stroke among those with low serum potassium levels and hypertension, mostly treated with diuretics. Stimulated plasma renin/aldosterone profiling can be done without withdrawing other antihypertensive therapy; using that approach, 15% of patients referred to a hypertension clinic had primary aldosteronism [5]. Thus measuring the renin and aldosterone define three groups of hypertensives, requiring different therapy (Table 1). This approach helps choose the most appropriate treatment for hypertension, and aids with management of potassium depletion from diuretics. References: 1. Green DM, Ropper AH, Kronmal RA, Psaty BM, Burke GL, for the Cardiovascular Health Study. Serum potassium level and dietary potassium intake as risk factors for stroke. Neurology 2002; 59:314-320. 2. Joffres MR, Ghadirian P, Fodor JG, Petrasovits A, Chockalingam A, Hamet P. Awareness, treatment, and control of hypertension in Canada. Am J Hypert 1997;10:1097-1102. 3. Spence JD. Physiologic tailoring of therapy for resistant hypertension: 20 years' experience with stimulated renin profiling. Am J Hypertension 1999;12:1077-1083. 4. Baker EH, Duggal A, Dong Y, Ireson NJ, Wood M, Markandu ND, MacGregor GA. Amiloride, a specific drug for hypertension in black people with T594M variant? Hypertension 2002;40:13-17. 5. Gallay BJ, Ahmad S, Xu L, Toivola B, Davidson RC. Screening for primary aldosteronism without discontinuing hypertensive medications: plasma aldosterone-renin ratio. Am J Kidney Dis 2001;37:699-705. Table: Tailoring of therapy according to renin/aldosterone profiling Renin (low), Aldosterone (high)for Primary hyperaldosteronism (Adrenocortical hyperplasia or Conn's adenoma), Treatment was spironolactone or eplerinone. Renin (low), Aldosterone (low) for Renal tubular abnormality: Liddle's, Na Channel T594M variant, Treatment was Amiloride. Renin (high), Aldosterone (high) for Renal hypertension: eg renovascular, obstruction, cysts, tumor, etc., Treatment was angiotensin receptor blockers or ACE inhibitors.
Reply to Letter to the Editor 26 November 2002
Deborah M Green University of Hawaii Honolulu Hawaii, Allen H Ropper, Richard A Krommal, Bruce M Psaty and Gregory L Burke for The Cardiovascular Health Study Send Correspondence to journal: Re: Reply to Letter to the Editor dgreen{at}queens.org Deborah M Green, et al.	We appreciate Hart et al. from the SPAF study examining their cohort data in order to compare it with our results. One of our findings was that the small number of diuretic users with lower serum potassium and atrial fibrillation had a 10-fold greater risk of stroke compared with those with higher serum potassium without atrial fibrillation. [1] The SPAF findings do not contradict our findings. They calculate the risk of stroke for those diuretic users with serum potassium levels less than 4.1 meq/L compared with greater than 4.0 meq/L among participants with atrial fibrillation. However, in our study the comparison group was those diuretic users without atrial fibrillation and a serum potassium level greater than 4.0 meq/L. If we restrict our analysis to those with atrial fibrillation, there is a relative risk of 4.7 (p=0.026, 95% confidence interval of 1.2 to 18.2) for a potassium level less than 4.1 compared with greater than 4.0 after adjustments for covariates. These confidence intervals overlap with theirs (RR 1.5, p=0.12, 95% confidence interval 0.9 to 2.4), therefore their results are within sampling error of ours. SPAF study participants were treated with either aspirin or placebo and were more closely monitored than those in CHS, thereby potentially decreasing the relative risk by preventing some strokes in those with low serum potassium. In the CHS only 21% of those with lower potassium and 20% with higher potassium levels were using potassium supplements, compared with 43% and 42% in SPAF. The greater use of potassium supplementation in the SPAF trial may have made it more difficult to detect an effect of low serum potassium on stroke risk. Their results also cannot challenge our overall finding of higher stroke risk associated with lower serum potassium level that we found for all diuretic users with or without atrial fibrillation. Nor do they address our finding of higher stroke risk with low dietary potassium intake among older individuals not taking diuretics. We agree with Hart et al. that no recommendations can be made with regard to diuretic use based on these studies however, we question whether diuretics would be more effective with closer potassium level monitoring and supplementation. We again encourage further prospective studies or reexamination of prior cohort studies to corroborate our findings. References: 1) Green DM, Ropper AH, Kroumal RA, Psaty BM, Burke GL, for The Cardiovascular Health Study. Serum potassium level and dietary potassium intake as risk factors for stroke. Neurology 2002;59:314-320.
Serum potassium level and dietary potassium intake as risk factors for stroke 18 November 2002
Robert G Hart University of Texas Health Science Center San Antonia TX, Lesly A Pearce Send Correspondence to journal: Re: Serum potassium level and dietary potassium intake as risk factors for stroke HARTR{at}uthscsa.edu Robert G Hart, et al.	Green et al. from the Cardiovascular Health Study report an increased stroke risk among 24 elderly patients with atrial fibrillation who used diuretics and whose serum potassium levels were <4.0 mEq/L. [1] As proposed by these investigators, we examined this finding in a larger cohort of participants in the Stroke Prevention in Atrial Fibrillation trials. [2] Excluding those with prior stroke/TIA, there were 584 atrial fibrillation patients who were not anticoagulated, who were receiving diuretics, and whose serum potassium was recorded at study entry. Among diuretic users, serum potassium level was not significantly predictive of stroke when analyzed as a continuous variable (p=0.5). However, the stroke rate was 5.1% per year for the 190 diuretic users whose serum potassium was <4.0 mEq/L vs. 2.7% per year for the remaining 394 patients (unadjusted relative risk = 1.9, p=0.05). Among 72 additional patients with prior stroke/TIA who were receiving diuretics (such patients were excluded by Green et al.), there was a trend for decreased stroke with serum potassium levels of <4.0 mEq/L (unadjusted relative risk = 0.4, p=0.07). Among atrial fibrillation patients not receiving diuretics (n = 1189), serum potassium levels were not related to stroke risk (p=0.9 for serum potassium dichotomized at < 4.0, p = 0.4 if continuous). To further explore potential mechanisms underlying the association between serum potassium levels of <4.0 mEq/L and stroke in diuretic users, the frequency of risk factors for stroke in atrial fibrillation patients was compared according to the serum potassium level [2]: those with lower serum potassium levels had more stroke risk factors. (Table) The observed stroke rate among atrial fibrillation patients using diuretics with low serum potassium levels was only modestly, and not significantly, increased over that predicted by concomitant risk factors. (Table) [2] considering all 11 patients without a prior stroke/TIA and adjusting for risk factors (age, sex, hypertension, and systolic BP>160 mmHg), a serum potassium level <4.0 mEQ/L among diuretic users was not independently associated with stroke (relative risk+1.5, 95% CI 0.9-2.4;p=0.12). These analyses confirm the association between serum potassium levels <4.0 mEq/L and stroke risk among atrial fibrillation patients taking diuretics. However, at least part of the increased risk is explained by comorbid conditions, rather than due to a direct effect of low serum potassium, itself. Consequently, it is uncertain whether avoiding diuretic agents or whether treatment of low serum potassium levels would reduce stroke in these patients. References 1. Green DM, Ropper AH, Kronmal RA, Psaty BM, Burke GL for the Cardiovascular Health Study. Serum potassium level and dietary potassium intake as risk factors for stroke. Neurology 2002; 59: 314-320. 2. Hart RG, Pearce LA, McBride R, Rothbart RM, Asinger RW. Factors associated with stroke during aspirin therapy in atrial fibrillation: Analysis of 2012 participants in the SPAF I-III trials. Stroke 1999;30: 1223-1229. - Table. Diuretic Users with Atrial Fibrillation: Patient Features* First figure represents Potassium < 4.0 mEq/L N = 190. Second figure represents Potassium > 4.0 mEq/L N = 394. Third figure is p. Age, yrs (mean) 71 70 0.88 Women (%) 38 34 0.39 Systolic blood pressure, mmHg (mean) 142 137 0.005 Systolic blood pressure >160 (%) 15 9 0.03 Hypertension (%) 81 74 0.08 Diabetes (%) 20 24 0.24 Recent heart failure (%) 17 20 0.48 Estimated GFR# (mean)(cc/min) 73 73 0.99 Furosemide use (%),n = 366 48 66 0.001 Thiazide use (%), n = 366 49 31 0.001 ACEinhibitoruse(%),n = 340 35 46 0.06 Potassium supplement (%) 43 42 0.86 Predicted stroke rate** 3.9 3.6 (%/yr) Observed stroke rate 5.1(3.2,8.1) 2.7 (1.7,4.1) (%/yr) (95%CI) *Participants without prior stroke or TIA. GFR = glomerular filtration rate, ACE = angiotension converting enzyme. # Estimated according to the formula: GFR = [(140 - age(yrs)) x weight (kg)] / [72 x serum creatinine (mg/dL)]. For women, multiply by 0.85. ** Modelled on the frequency of risk factors for stroke in atrial fibrillation patients (2); patients with prior thromboembolism excluded.