This study showed that more than 1 in 10 older long-stay patients in VA nursing homes had potentially inappropriate prescribing of primarily renally cleared medications when evidence-based, consensus-derived criteria were used. This is considerably less than the 42% rate of prescribing problems found in 456 patients prescribed 1 of 20 primarily renally cleared drugs reported in the study by Papaioannou et al9
in 4 long-term care facilities in 3 Canadian cities. It is also less than the 46% of 56 patients with a prescribing problem involving 1 of 27 medications from 2 nursing homes in Georgia.10
We suspect that our study findings represent the lower bounds of prescribing problems with primarily renally cleared medications for older nursing home patients for several reasons. First, our sample was restricted to those with adequate (ie, not dialysis-dependent) or stable (no recent change between 2 serum creatinine values) renal function, which reduced the at risk pool for prescribing problems. Moreover, we applied a consensus list of oral-dosing guidelines for 21 primarily renally cleared medications, and of these, only 7 were part of the Rahimi et al10
(2008) list. Only 5 were in the study from Papaioannou et al.9
This discrepancy suggests that many of the drugs rated as being inappropriately prescribed (eg, angiotensin-converting enzyme inhibitors) in the Rahimi et al10
and Papaioannou et al9
studies may have contributed to an overestimation of the prescribing problem. Finally, our lower rate may in part be attributable to the availability of an electronic medical record system in the VA nursing homes, which allows for the easy retrieval of information necessary for the calculation of CrCl (eg, age, weight, and recent serum creatinine values) and the use of a collaborative practice model between on-site pharmacists and prescribers in many VA nursing homes.
It is of interest that both our study and the study by Papaioannou et al9
reported that ranitidine and glyburide were among the most common drugs with prescribing problems. It is well known that histamine 2 blockers such as ranitidine, when given in higher doses than necessary, can lead to problems with cognitive impairment in older adults.27
Glyburide has been associated with an increased risk of severe hypoglycemia compared with other sulfonylureas.28–30
In addition, renal insufficiency, advanced age, dose, concomitant medications, and the initiation of therapy are well-known predisposing factors to hypoglycemia with sulfonylureas.29,31
Given the increased risk of hypoglycemia, especially in the elderly and those with renal impairment, VA Pharmacy Benefits Management Services recommends the use of glipizide instead of glyburide in patients with an estimated creatinine clearance less than 50 mL/min who require a sulfonylurea for control of their diabetes and is actively working with providers to decrease glyburide use in this patient population.
This study also identified that advancing age was associated with an increased risk of inappropriate dosing of renally cleared drugs. This finding is consistent with results from the study by Papaioannou et al9
and underscores the need for health professionals to be aware that a serum creatinine within the laboratory reference range (ie, “normal”) does not necessarily reflect normal renal function in elders because of age-related changes in lean muscle mass and turnover. We also found, as did Papaioannou et al,9
that the risk of inappropriately prescribing of these renally cleared medications decreases as weight increases. One possible explanation for this finding is that estimated creatinine clearance is often overestimated in obese individuals. Alternatively, it is possible that doses for obese individuals are given greater scrutiny. Last, an increased risk of inappropriate prescribing in those with multiple comorbidities is clinically sensible and consistent with previous studies of suboptimal prescribing in older veterans cared for in other clinical care settings.32,33
What should clinicians do about these findings? First, CrClr should be estimated using the Cockcroft-Gault equation for all older nursing home patients being prescribed these target drugs. The rationale is that to date most pharmacokinetic studies of drugs that are primarily renally cleared used the Cockcroft-Gault equation.13,34
Although the use of actual body weight is recommended for most patients, one might consider substituting lean body weight (LBWmale = 9270 * total body weight/6680 + 216 * BMI; LBWfemale = 9270 * total body weight/8780 + 244 * BMI) as suggested by Demirovic et al,35
for those who are morbidly obese because actual body weight will overestimate creatinine clearance in these patients. It is also important to note that clinical laboratories are beginning to use the new serum creatinine assay, which results in creatinine values that are 5% less and leads to higher estimated creatinine clearances. To address this, one group of authors recently suggested the use of a revised Cockcroft-Gault equation14
(changes italicized): eCrClr = 140 − age*weight/68
* serum creatinine. However, this approach has not yet been validated in pharmacokinetic studies of drugs that are primarily renally cleared.
Second, until more convincing data are available, clinicians who provide care for older patients should reject the recent recommendations from the Food and Drug Administration (FDA), the National Kidney Disease Education Program (NKDEP), and the National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) that the MDRD can be used in place of the Cockcroft-Gault for dosing renally cleared medications.34,36
These recommendations are based primarily on one cross-sectional study involving 5504 participants from 6 research and 4 clinical sites.37
The study objective was to determine the concordance between kidney function and dosing recommendations for 15 drugs as per eGFR via MDRD corrected for body surface area (BSA) and eCrClr via CG with measured GFR via I-125 iothalmate clearance. Study investigators found that the MDRD had better concordance than CG with measured (mGFR) kidney function. They also found that the MDRD had better concordance than the CG with dosing recommendations determined by mGFR. However, it must be noted that there are numerous limitations precluding the application of these study findings to elderly patients including the following: (1) only 13% of the sample was 65 years or older, and no information was provided separately for those 85 or older or frail; (2) GFR was measured using a method that is not used routinely in clinical practice; (3) eGFR reported by laboratories is not routinely corrected by BSA and has not been validated; (4) no drugs to avoid were included (eg, glyburide < 50 mL/min); and (5) the study conducted a data simulation and not a pharmacokinetic study.38
This latter point is important after considering the findings of a pharmacokinetic study of gentamicin, a narrow therapeutic range primarily renally cleared medication, in 68 older inpatients from Australia.39
Study investigators found that the MDRD equation overestimated gentamicin clearance by 29% as opposed to the Cockcroft-Gault equation, which underestimated gentamicin clearance by 10%. This discordance was even more pronounced in those 80 or older where the bias for the MDRD was 69% higher and the Cockcroft-Gault equation was 4% lower.39
Using the MDRD may therefore result in an overestimation of renal function and could lead to potentially inappropriate dosing and associated adverse drug events. Therefore, at the present time, we would recommend that clinicians use the Cockcroft-Gault equation to estimate kidney function and consult pharmacotherapy references for dosing guidelines for primarily renally cleared medications.17,18,40
This study has potential limitations. The study sample included mostly older male patients, whereas in most non-VA nursing homes, most patients are older females. The use of some medications may be different in VA versus non-VA settings, but these renally cleared drugs are commonly used in the elderly. Also, renal function was estimated and not directly measured. However, the collection of 24 hours of urine output is often impractical in older frail nursing home patients. As a result, most practitioners rely on calculated estimates of renal function in clinical practice.
Despite the potential limitations listed previously, we conclude that prescribing problems with primarily renally cleared medications were common. Future studies should focus on developing and assessing the impact of computerized provider order entry, combined with clinical decision support systems, on improving the prescribing of primarily renally cleared medications and associated patient outcomes such as adverse drug reactions.