Frequency and Profiles of Drug Combinations Constituting the Triple Whammy in Japan: An Analysis of a Patient Estimation Database

“Triple whammy” prescriptions, combining non-steroidal anti-inflammatory drugs (NSAIDs), renin–angiotensin system (RAS) inhibitors, and diuretics, increase acute kidney injury (AKI) risk. To clarify the frequency and profiles of these prescriptions and identify vulnerable populations, we analyzed the AHI partners database to estimate the number of individuals prescribed these three drug classes. In the single-agent analysis, loxoprofen was the most commonly prescribed NSAID (66.3%), olmesartan (19.4%) and telmisartan (15.9%) were the predominant RAS inhibitors, and furosemide (19.6%) and spironolactone (16.0%) were the most frequently used diuretics. Dual-drug combinations showed patterns consistent with the single-agent results for NSAIDs and diuretics. By contrast, sacubitril/valsartan was the most common RAS inhibitor when combined with diuretics, frequently utilized for heart failure management. In triple whammy prescriptions, NSAIDs and diuretics patterns mirrored those of single-agents. The annual number of triple whammy prescriptions showed a statistically significant downward trend over the study period by the Mann–Kendall trend test (p = 0.048). Notably, sacubitril/valsartan was the leading RAS inhibitor (46/199 patients, 23%), showing a higher proportion than its single-agent use (7.4%). Heart failure patients prescribed these two causative drugs are highly vulnerable to “triple whammy” prescriptions. Awareness of inadvertent NSAID additions is warranted to mitigate potential AKI risks.