1. In post-hoc analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), use of thiazide diuretic chlorthalidone in patients with hypertension was associated with lower risk of fracture hospitalizations compared to calcium channel blocker (amlodipine) and ACE-inhibitor (lisinopril).
2. This further adds to the evidence that a thiazide diuretic should be the first medication used in patients with hypertension.
Evidence Rating Level: 2 (Good)
Study Rundown: Hypertension and fragility fractures are two common age-related conditions that are often associated, and hypertension remains a risk factor for fractures. In observational studies, therapy for hypertension has been shown to reduce fracture risk, specifically when using thiazide diuretics and beta-blockers. The observed effects have not been studied in a randomized controlled trial. This study sought to analyze data from the ALLHAT trial comparing chlorthalidone, amlodipine, and lisinopril both during the trial period and during the post-trial follow-up with regards to hospitalizations for hip or pelvic fractures.
For the in-trial cohort, patients on chlorthalidone had a lower risk of fracture compared to those on lisinopril or amlodipine. In the cohort which included five years of post-trial follow-up, there was no significant benefits of chlorthalidone compared with the other two medications, although there was a trend towards lower fracture risk with chlorthalidone. While the strength of the study was in the initial design of the trial, this was a post-hoc analysis which can introduce bias. Variables important for fracture risk were not included in the original study and may not have been balanced in the study groups. Also, one-third of patients in the original trial were excluded due to lack of available data on fractures.
In-Depth [post hoc analysis]: This study is a post-hoc analysis of the ALLHAT trial, a randomized, double blind, controlled study evaluating first line treatment of hypertension with either thiazide diuretic, calcium channel blocker, or ACE-inhibitor. The trial was conducted from 1994 to 2002 with post-trial follow-up ending in 2006. Patients were included if they were over the age of 55, had a blood pressure of at least 140 mm Hg systolic or 90 mm Hg diastolic with additional risk factors for coronary artery disease. Notably, patients with prior myocardial infarction, stroke, angina, heart failure or kidney disease were excluded. Hospitalizations for hip and pelvic fractures were obtained through records from Medicare and Veterans Affairs databases. One-third of study participants were excluded due to lack of fracture data.
For the in-trial cohort, 16,622 participants were included, of whom 307 had hip fractures and 34 had pelvic fractures. Compared to either amlodipine or lisinopril, chlorthalidone had a lower risk of fracture (HR 0.79; 95% CI 0.63-0.98). This trend was maintained in comparison to lisinopril (HR 0.75; 95% CI 0.58-0.98), however chlorthalidone and amlodipine were not statistically different (HR 0.82; 95% CI 0.63-1.08). Analysis including post trial follow-up demonstrated no statistically significant difference between the three agents, though the trend was towards lower risk of fractures among patients on chlorthalidone (HR 0.85; 95% CI 0.70-1.02).
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