Patient preferences may vary based on the requirement for laboratory monitoring with thiazide-type medications. As this is a Reviewed, New-added recommendation, the Work Group systematically reviewed evidence related to this recommendation.[137,142-144] The Work Group s confidence in the quality of the evidence is moderate. The body of evidence had some limitations including an assumption of class effect between all thiazide-type diuretics, inconsistent results across different composite outcomes, and an age cut-off that did not match the primary study evidence.[137,142-144] Other considerations regarding this recommendation included the benefits, primarily in the composite cardiovascular outcome, outweighing the potential harm of adverse events, which was insignificant compared to other therapies. Patient values and preferences were somewhat varied. Thus, the Work Group decided upon a Weak for recommendation. More research is needed into the comparative effectiveness of different medications in the thiazide-type diuretic class. Recommendation 26. We recommend against more than one of the following three drug classes together in the same patient: angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or direct renin inhibitors. (Strong against | Not Reviewed, Not Changed) Discussion Despite the potential for additional blood pressure reduction with combination therapy of agents that act at the renin-angiotensin system (ACEIs, ARBs, and direct renin inhibitors [DRIs]), data from clinical trials have reported an increased risk for harm (including hypotensive symptoms, kidney dysfunction or acute kidney injury events, or hyperkalemia) without long-term cardiovascular or kidney outcome benefit in patients treated with combination therapy with any two of these three classes compared to monotherapy.[145-147] Although these trials primarily studied high-risk patients (those with at least one of the following conditions: vascular disease, diabetes, CKD, or diabetic nephropathy), the majority of patients either had a diagnosis of HTN or were being treated with antihypertensive medications.