PROJECT SUMMARY Kidney stones affect one in 11 Americans. With related expenditures of $4.5 billion annually, they also pose a tremendous resource burden. In addition, they are not a one-off event with 50% of patients developing a recurrence within five years of their first stone. Thus, interventions that reduce recurrent stones may promote health and have positive economic implications. The use of thiazide diuretics, alkali citrate treatment, or allopurinol—referred to as preventive pharmacological therapy (PPT)—may represent one such intervention. Yet, while current guidelines recommend PPT, it is infrequently used. A recent systematic review funded by the Agency for Healthcare Research & Quality highlighted three gaps in the evidence base for PPT, tempering enthusiasm for it. First, findings from prior studies were driven mainly by intermediate outcomes, but what matters to patients and providers is whether an intervention will prevent future pain episodes that require an emergency department (ED) visit, hospitalization, or surgery. Second, prior studies reported few data on treatment tolerability. Third, the impact that PPT has on future costs in stone formers is largely unknown. If this therapy yields a substantial savings to the healthcare system over the long run, acceptance of it may increase. An obstacle to filling these three gaps has been the availability of data sources with the necessary sample size, clinical granularity, and long-term follow-up for examining the real-world effectiveness of PPT. To overcome this obstacle, we propose a study using innovative linkages of administrative and clinical data. Our proposal has three Specific Aims. Aim 1: To evaluate the impact that PPT has on clinical outcomes. Using the Veterans Health Administration Corporate Data Warehouse and Medicare claims linked with urine chemistry data from Litholink Corporation, we will identify adults with kidney stones, distinguishing patients prescribed thiazides, citrates, or allopurinol from those receiving usual care. We will evaluate ED visit, hospitalization, and surgery rates in these two groups. Aim 2: To examine patient tolerability for PPT. As an assessment of tolerability, we will then measure medication adherence and adverse event rates among patients prescribed thiazides, citrates, or allopurinol. We will examine differences in tolerability across patient subgroups. Aim 3: To determine the healthcare costs associated with PPT use. Finally, we will assess longitudinal payments for patients with kidney stones. We will determine whether variability in these payments exists between patients prescribed PPT versus those receiving usual care. Findings from our study serve to inform the optimal management of kidney stones. To this end, patients will ultimately benefit most from our research.