Triamterene in the Treatment of Hypertension: More Than Just Potassium Sparing?

H ypertension is the most commonly encountered chronic medical condition in primary care practice and is a major risk factor for stroke and coronary artery disease. For decades, thiazide diuretics have been a recommended first line option for antihypertensive therapy. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended thiazides as first line therapy unless a compelling indication existed for another agent. JNC-8 recommends diuretics as one of four acceptable first line options for non-black patients without chronic kidney disease (other options include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, or calcium channel blockers), and as one of two acceptable options for African American patients without chronic kidney disease (the other option is calcium channel blockers). Hypokalemia frequently results from the administration of thiazide diuretics. This effect is more common with chlorthalidone than hydrochlorothiazide (HCTZ) or indapamide, and occurs in a dose dependent fashion. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), one of the largest trials of antihypertensive therapy (n=33,357), mean potassium levels at 4 years fell 0.2 mEq/L among chlorthalidone treated patients, and potassium fell below 3.5 mEq/L in 8.5% of patients at 4 years (as opposed to 1.9 % of amlodipine treated patients). Hypokalemia, when it occurs, usually appears within the first 2 weeks after initiating diuretic therapy. If hypokalemia occurs, clinicians have the option of beginning potassium chloride replacement therapy (typical doses are 20–40 mEq per day for patients with normal renal function), or beginning a potassium sparing diuretic. Potassium sparing diuretics include triamterene and amiloride (epithelial sodium channel inhibitors) and spironolactone and eplerenone (mineralocorticoid receptor antagonists). The choice of potassium replacement or a potassium-sparing diuretic has been typically left to the discretion of the clinician, as no evidence has suggested that the addition of potassium-sparing diuretics provides additional value in terms of blood pressure lowering or a reduction in cardiovascular events. From the patient perspective, a disadvantage of potassium replacement is the requirement to add either large pills that are often difficult to swallow, or a salty tasting solution to the thiazide. No studies exist of triamterene as monotherapy for the treatment of hypertension. In a recent Cochrane systematic review, authors evaluated the blood pressure lowering effect of potassium-sparing diuretics that block the epithelial sodium channel when given in combination with another antihypertensive agent. Only six trials of 496 patients existed; all six studies were performed in the 1980s. Two trials (n=211) evaluated the incremental benefit of triamterene 50mg per day when added to chlorthalidone at 25 to 50 mg per day. The addition of triamterene provided no incremental reduction in systolic blood pressure (−0.01, 95 % CI −3.63 to 3.61), or diastolic blood pressure (+0.20, 95 % CI −2.01 to 2.41), but total sample sizes were too small to draw any meaningful conclusions. In this issue of JGIM, Tu and colleagues queried a large network electronic medical record system to determine the incremental blood pressure lowering effect of triamterene. They identified 17,291 patients with a diagnosis of hypertension over an 8-year period and divided these patients into those with and without a pharmacy claim for triamterene. Patients who received triamterene were more likely to be female or African American, and less likely to have diabetes, coronary artery disease, congestive heart failure, a history of stroke, or chronic obstructive pulmonary disease. A direct comparison of the blood pressure values in these two groups would be confounded by substantial selection bias due to the nonrandom assignment between the groups. Tu et al. used a novel approach to attempt to correct for limitations inherent in these observational data. They used propensity score matching to estimate the probability that a patient would receive a particular treatment, based on logistic regression that adjusted for 14 clinical characteristics. They then stratified patients into quartiles of estimated propensity and compared the recorded blood pressures for those who had or had not received triamterene. They evaluated separately the impact of adding triamterene to HCTZ or to combinations of drugs that included HCTZ. They present no data on chlorthalidone use; in their network, triamterene was most commonly prescribed as a fixed combination pill with HCTZ (initial dose was HCTZ 25 mg daily and triamterene 37.5 mg daily). Published online September 18, 2015