Cyclophosphamide is a preferred agent in breast cancer treatment,(1) and hydrochlorothiazide, a drug used to treat hypertension, is one of the most commonly used medications in the United States.(2,3) Pharmacy reference databases such as Micromedex(4) list hydrocholorothiazide and cyclophosphamide as a significant drug-drug-interaction (DDI). However, this claim is supported by one study from 1981, including 14 women receiving breast cancer treatment and also taking a thiazide diuretic for hypertension.(5) This study found that white blood cell counts, assessed weekly, were notably lower in cycles where women were treated with thiazide diuretics versus cycles where the same women were treated with other blood pressure medications (reserpine or propanolol), raising concerns that thiazide diuretics may enhance the myelosuppressive effects of chemotherapy.(5) No studies to date have evaluated clinical outcomes of this potential DDI in a large population of women with breast cancer.

We aimed to estimate associations between concomitant hydrochlorothiazide use and adverse clinical outcomes (neutropenia-related hospitalizations and chemotherapy discontinuation) among older women with breast cancer treated with cyclophosphamide.

In total, 2,136 women initiated adjuvant chemotherapy containing cyclophosphamide for stage I-III breast cancer. Overall, 581 women (27%) were concomitantly exposed to hydrochlorothiazide at adjuvant chemotherapy initation. Patient characteristics were similar among women exposed and unexposed to hydrochlorothiazide (Table 1).

Only 227 (11%) women were hospitalized with a diagnosis code for neutropenia and 447 (21%) discontinued adjuvant chemotherapy before completion (Table 2). Overall, exposure to concomitant hydrochlorothizide was neither associated with neutropenia-related hospitalization (aRR=0.92 (0.70, 1.21)) nor chemotherapy discontinuation (aRR=1.00 (0.96, 1.05)). There was no evidence of effect measure modification by CSF use or age.

Using linked SEER-Medicare data, we observed no association between concomitant hydrochlorothiazide and cyclophosphamide use and either neutropenia-related hospitalization or treatment discontinuation. Our study included 2,136 women and is the largest investigation of this potential DDI to date, in contrast to the study by Orr,(5) which included only 14 patients. The large sample size increased precision of our estimates and provided the opportunity to investigate effect measure modification in key subgroups.

Our study is subject to limitations. First, it is plausible that knowing about the potential DDI, oncologists might recommend discontinuation of hydrocholothiazide in women planning to take or taking cyclophosphamide, leading to exposure misclassification that could attenuate observed associations. In our study, the proportion of women concomitantly exposed to hydrochlorothiazide (27%) is comparable to that of the general population of adults age 65 and over,(2) among whom 20% receive thiazide monotherapy and 11% have combination antihypertensive use, often including hydrochlorothiazide.(2) In addition, we found that 92% of patients had >1 hydrochlorothiazide dispensing following chemotherapy initiation, suggesting continued use of hydrochlorothiazide during treatment. Thus, it does not appear as though oncologists are reacting to the potential DDI. Second, body mass index (BMI) is not available in claims data and could potentially lead to an attenuation in the observed associations, if women with higher BMI are underdosed and are more likely to use hydrochlorothiazide. Third, our data are also limited by the lack of laboratory data, which could provide more direct measures of the outcome of interest, such as absolute neutrophil count. If patient-reported outcomes were available, it would be interesting to examine levels of fatigue or other signs of neutropenia.

A recent working group(7) with expertise in pharmacology, drug information, informatics, and clinical decision support found there was little high quality evidence to support many DDIs, and that compendia and pharmacy database editors do not have a standard guideline or methodology to identify DDIs. The findings from this study could inform pharmacy reference database DDI updates and we suggest reducing the severity level applied to the potential DDI between hydrochlorothiazide and cyclophosphamide.