While previous studies have reported use rates of these agents in the dialysis population, the estimates have varied considerably. In Waves 3 and 4 of the Dialysis Morbidity and Mortality Study (DMMS), which recorded medication use among dialysis patients in 1993, ACE inhibitors were used by 13.9% of incident dialysis patients, β-blockers in 8.5%, and CCBs in 35.0%.¹⁷ Generally higher use rates were reported in both incident and prevalent patients of the DMMS Wave 2 study, which spanned 1996-97: ACE inhibitors were prescribed for 23.6% – 31.6% of individuals ^{18,19, 20}, β-blockers in 19.2% – 25.4% ^18-20 and CCBs in 50.7% – 52.5%.^{18, 20,21}

While these and other ²² studies have examined use of cardioprotective medications to treat hypertension in chronic dialysis patients, no study has specifically examined whether there is substantial geographic variation in care. If there is substantial geographic variability in the use of these agents that cannot be accounted for by differences in underlying comorbidity burden, it could prompt future efforts to uncover the reasons for these differences and might also provide an opportunity to provide more consistent care throughout the U.S. A particularly important subset of patients are Medicaid-eligible individuals, who comprise nearly a third of prevalent dialysis patients²³ and who have not been systematically explored. Since Medicaid-enrolled dialysis patients are more financially disadvantaged and medically-needy, relative to non-Medicaid-enrolled dialysis patients,²⁴ understanding practice patterns in this subgroup has important policy implications for vulnerable publicly-assisted patients’ access to medications. While Medicaid is a joint federal-state program, each state offers prescription benefits with varied degrees of restrictions which may translate into different exposure rates.

To address these gaps in knowledge, we examined Medicaid-enrolled patients with hypertension undergoing long-term dialysis to determine how the use of ACE inhibitors/ARBs, β-blockers, and CCBs was associated with demographic, risk behavior, functional status, comorbidity, dialysis modality, and laboratory factors, and how practice patterns varied by state across the US.

Although residual state-specific programmatic differences probably partially contribute to observed differences in medication use, the unintuitively large variations in care we report may well reflect a lack of consensus regarding optimal hypertension management. Our findings may reflect a therapeutic nihilism about the benefits of these particular agents, given that patients with kidney disease have been systematically excluded from large randomized controlled trials (RCTs) of these agents.³¹ Since few RCTs exist in dialysis patients ^{32, 33}, practitioners must rely in large measure on observational trials, in which the evidence is mixed. For example, for ACE inhibitors, the evidence of a benefit in undifferentiated diaysis patients is far from unanimous³¹, with some studies demonstrating a mortality benefits ^34-37 but several others not.^{17, 38-41} For β-blockers, the one small RCT demonstrating a beneficial effect of these agents studied only in individuals with New York Heart Association Class II or III heart failure.³² Although one large observation study demonstrated a substantial beneficial effect of β-blockers on mortality¹⁷, numerous other studies did not.^{18, 19, 21, 34, 35, 37, 39, 40, 42} Studies of CCBs are also have considerable uncertainty as to their benefits; this class of medicines, which is traditionally considered “less cardioprotective” than ACE inhibitors or β-blockers in the general population, appears to have considerable evidence in support of their benefits for dialysis patients ^{18, 21, 42} but even here, the evidence is far from unequivocal ^{17, 19, 34, 36, 37, 39}.

Our results extend an emerging literature identifying regional differences in the care of chronic dialysis patients. For example, hemodialysis catheter use^{43, 44}, access to kidney transplantation⁴⁵, arteriovenous fistula creation⁴⁶ , and even access to pre-ESRD care⁴⁷ have all been recently found to vary geographically. Our study extends this realm of inquiry into prescriptions for potentially-beneficial antihypertensive medications, and suggest that further research is needed into how to guide use of more consistent, effective therapy in this high-risk population.

Given the lack of evidence demonstrating the putative cardioprotective properties of these agents in dialysis patients, no definitive conclusions about the appropriateness of prescribing patterns can be drawn; only relative, rather than absolute, conclusions can be drawn. However, specific examination of the use of such agents in patients with comorbidities associated with, or those having manifestations of, CVD may reveal insights into additional opportunities to improve care. While diabetics were more likely to be prescribed ACE inhibitors/ARBs than non-diabetics, it was nonetheless the case that only half of such patients were prescribed them. Additionally, diabetics had only slightly more use of β-blockers, which is troubling given the risk of CVD events in such patients. In the case of CHF, it is of interest that ACE inhibitor/ARBs were not prescribed at significantly higher rates, despite what might be as would be expected from other reports,^{1, 48}, suggesting that the additional benefits of ACE inhibitors/ARBs (e.g., ventricular remodeling^49-51) are not being delivered to CHF patients. Even β-blockers, which decrease sympathetic tone⁵² and which are a Class IA recommendation in CHF patients,⁵³ were only slightly more likely to be prescribed in patients with heart failure than without, suggesting that there may be opportunities for improvement of care. Additionally, while individuals with CAD are indeed more likely to receive β-blockers, as reported by other authors^{1, 48}, disease in other vascular beds, as indicated by PVD or a history of a CVA and which may be a marker for undiagnosed CAD^54-56, was not associated with greater use of β-blockers.

Although we limited our analysis to patients with hypertension, the high prevalence of hypertension in the dialysis population means that we found comparable overall use rates of these drugs compared to other studies of chronic dialysis patients. ACE inhibitors/ARBs were prescribed in 48.7% of these hypertensive individuals, similar to the 39-49% use of ACE inhibitors reported in other studies. This is more than the 23.1% – 25.5% of undifferentiated individuals reported by others to be on ACE inhibitors alone during the 1990’s^{18, 20, 21} but identical to privately insured USRDS patients(48.7%) in 2002.²² These rates were also generally comparable to analyses based on Dialysis Clinics, Inc.(DCI) patients (43.8%)⁵⁷ as well as DOPPS II data from 2002-04 (38.9%).¹ Use of β-blockers, at 54.5%, was consistently higher than in older reports (17.8-19.3%^{18, 20, 21}) as well as in more contemporary findings from USRDS (39.0%)²² and DOPPS II (26.4%) data.¹ CCBs were prescribed to 48.6% of individuals, a rate in the middle of the range (40-55%) from other studies.^{1, 18, 20, 21, 57, 58} Slight discrepancies in estimates across reports are likely to be the result of differing use rates of other classes of agents and sample inclusion criteria, the most important of which is the definition and prevalence of hypertension.

One of the restrictions we did not explicitly model, which is employed by many states’ Medicaid programs and which could have affected our results, are the state-specific limitations on the numbers of prescriptions per month. There were thirteen states that reportedly had monthly caps ³⁰; however, in our analyses of raw claims, we have found that these caps were not strictly enforced. In general, the purported limits range from three to eight prescriptions per month, though some apply only to brand-name drugs and some states allow for overrides of the policy. For instance, our own state, Kansas, purportedly has a limit of five brand- name medications per month, but pharmacists can easily electronically override the limit at the point of sale. Details of which states actually enforced such policies are not readily available, but clearly persons on dialysis who resided in states with caps were routinely able to exceed them to some degree.

It is important to consider several limitations in this study. First, we studied only dually-eligible prevalent chronic dialysis patients. By virtue of having Medicaid, the patients we studied probably represented the neediest patients, and compared to the general chronic dialysis population, are more likely to be female and non-Caucasian, have functional limitations and engage in risk behaviors, and be on in-center hemodialysis.²⁴ Although this somewhat decreases our ability to generalize findings to the US dialysis population as a whole, dually-eligible patients are in many ways reflective of growing trends in dialysis patients, such as the increase in females, Hispanics, individuals with functional limitations, and in those on in-center HD. Second, we relied on the CMS-2728 dialysis intake form to determine comorbidities, including hypertension. While this source is suboptimal compared to more rigorous approaches⁵⁹, it has been shown to have good sensitivity and specificity for most major comorbidities⁶⁰ and it seems it seems unlikely that use of this form would substantially undermine our primary finding, namely that of substantial geographic variability, which is an issue worthy of future detailed study. An important limitation is that, like most observational studies, we do not have actual data on blood pressure readings, so we are unable to determine if patients were indeed hypertensive over time. However, while patients may have acquired hypertension after the initiation of dialysis, it is unlikely that it would have resolved after starting it. As such, our findings may be a conservative estimate of the population who may potentially benefit from selecting medications with putative cardioprotective properties. Additionally, we do not examine use of all classes of antihypertensives. However, our goal was not study antihypertensive treatment as a whole, but rather whether and how medications with ostensible cardioprotective properties vary geographically in their prescription patterns, and, by extension, whether geographic variation exists in whether prescribers appear to believe such medications provide benefits for CVD outcomes. While a strength of our study is our use of prescription medication records, rather than chart abstraction,^{61, 62} to determine that patients had been actively filled at least one prescription medication during the observation window, the presence of a claim for medication dispensation is of course not equivalent to consumption, which is difficult and costly to quantify.

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