Characteristics of Patients Prescribed Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Blockers, or the Combination at an Urban Medical Center
Ghania Masri, MD; Kristi Bledsoe, PharmD; Carlos Palacio, MD
Abstract
Background: The realization that angiotensin-converting enzyme (ACE) inhibitors do not provide complete blockade of angiotensin II synthesis has resulted in an increased use of combinations of ACE inhibitors and angiotensin receptor blockers (ARBs). This study examines the characteristics of patients in whom this combination was prescribed.
Methods: Seventy-two patients diagnosed with primary hypertension and receiving an ACE inhibitor, an ARB, or their combinations were included. A retrospective review using outcome variables of mean arterial pressure (MAP), and changes between pretreatment MAP and post-treatment MAP were compared between groups. Statistical analysis was performed with SPSS statistical software. Analysis of variance (ANOVA) with Tukey's post hoc analysis was performed on continuous variables. Chi-square analysis was performed on categorical variables. Multivariate linear regression was performed to determine the best predictors of post-treatment MAP.
Results: There were no significant differences between the groups in pre- or post-treatment MAP. Patients on combination therapy with an ACE and ARB agent tended to be on more antihypertensive medications and tended to be diabetic.
Conclusion: All treatment groups had similar blood pressure control and changes in MAP regardless of treatment. These findings suggest that combination ARB and ACE inhibitor therapy is a strategy being used for diabetics with difficult-to-control hypertension, although we cannot determine from our study whether this is primarily for blood pressure control or for renal protection. Whether combining an ACE inhibitor and ARB for blood pressure control alone is supported by the literature may be debatable. Further studies should evaluate the efficacy of such intervention to control hypertension.
Key points:
1. Antihypertensive therapies using ACE inhibitors with ARBs are gaining popularity;
2. This retrospective chart review was completed to examine the characteristics of patients on monotherapy and of patients on combination therapy with ACE inhibitors and ARB agents; and
3. This study suggests a tendency toward combined ARB and ACE inhibitor therapy in patients with diabetes who are on multiple antihypertensive medications.
Introduction
Hypertension plays a major role in the development of cardiovascular disease and increases the risk for cardiovascular events. The renin-angiotensin-aldosterone system (RAAS) is largely responsible for sustained elevated blood pressure and fluid/electrolyte regulation. Angiotensin II levels, regulated by RAAS, have a direct effect on the vasculature. These effects include vasoconstriction, inflammation, endothelial dysfunction, and remodeling. Disorders of the RAAS contribute to the pathophysiology of hypertension, renal dysfunction, and congestive heart failure.[1]
Treatment using angiotensin-converting enzyme (ACE) inhibitors is as safe and effective as treatment with conventional therapies.[2-4] Although these agents are effective, they can be associated with the development of cough and angioedema through the bradykinin system. These adverse reactions led to the use of angiotensin receptor blockers (ARBs) as an alternative treatment. Research has suggested that ACE inhibitors do not provide a complete blockade of angiotensin II synthesis because of alternate, non-ACE pathways. Chymase is found in other tissues, and it participates in the local synthesis of angiotensin II in the heart resulting in hypertrophy of the cardiac muscle.[5,6]
Because of incomplete blockade of the RAAS by ACE inhibitors, the combination of ACE inhibitors and ARBs has become popular. Little data support the use of combination therapy solely for reduction of blood pressure, whereas there are data to support this combination therapy in treatment of congestive heart failure patients and those with diabetic proteinuria.
The Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) study investigated whether combining an ACE inhibitor with an ARB is likely to increase patient benefit.[7] The results indicated that treatment with the combination is more beneficial than therapy with either drug alone in preventing left ventricular remodeling.
The Valsartan in Heart Failure Trial (Val-HeFT) and the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint (ONTARGET) study tested the hypothesis that combination treatment reduced events related to heart failure.[8,9] Data in regard to the benefits of ACE inhibitor/ARB therapy and their synergistic effect on reduction of proteinuria in renal disease have emerged.[10]
Combination use of ACE inhibitor/ARB therapy has become more widespread at Shands Jacksonville Medical Center, Jacksonville, Florida. Practitioners are using the combination to prevent the progression of renal disease and heart failure as well as treatment for uncontrolled primary hypertension.
This study will provide information about dual ACE inhibitor/ARB therapy for the reduction of blood pressure. It compares characteristics of patients with primary hypertension on each agent alone, and patients on combination therapy.
Materials and Methods
All patients at Shands Jacksonville internal medicine clinic diagnosed with primary hypertension and treated with ACE inhibitors, ARBs, or a combination of the two were considered for enrollment in the study. Exclusion criteria were (1) patients not adherent to treatment as defined by failure to fill prescriptions for more than 1 week from the due date on more than 1 occasion, (2) any patient on therapy with the agent of interest for less than 30 days, and (3) patients on dialysis.
Patients were identified by querying the Shands Jacksonville ambulatory pharmacy database from September 2004 to April 2005. Fifty patients from each treatment group were randomly selected, and only 24 patients from each group were eligible for the study.
Blood pressure values were retrospectively reviewed for visits prior to the start of therapy and after starting therapy with the agent(s) of interest. First pretreatment observation was assessed within 1 week to 3 months before start of therapy. First post-treatment observation was assessed within 1-3 months after start of therapy. Start of therapy was defined as the date when medication(s) of interest first appeared on the pharmacy database. Independent variables included race, sex, smoking status, pretreatment mean arterial pressure (MAP), specified concomitant disease states, and additional antihypertensive(s) used. Outcome variables of post-treatment MAP and change between pretreatment and post-treatment MAP were compared between patients whose regimen included ACE inhibitors or ARBs alone, and patients whose therapy included both agents.
Statistical analysis using SPSS statistical software was performed. P values were calculated using 1-way analysis of variance (ANOVA) for continuous variables and chi-square testing for categorical variables. Pairwise comparisons were done for statistically significant differences with Tukey's post hoc test for continuous variables and chi-square testing for categorical variables. Multivariate linear regression was performed using post-treatment MAP as the dependent variable. Comparability of groups was assessed by comparing age, race, prevalence of congestive heart failure, prevalence of smoking, percentage of diabetics, and percentage of patients on additional antihypertensive medications used according to therapeutic class.
Results
There were no significant differences between the groups in terms of age, ethnicity, and pre- or post-treatment MAP. Each of the 3 groups (ACE inhibitor, ARB, and ACE inhibitor/ARB) achieved a similar reduction or change in MAP (33.7 mm Hg, 37 mm Hg, and 30.9 mm Hg), respectively. Although a majority of the patients in all 3 treatment groups were female, there was a significant difference in the proportion of females between the ACE inhibitor-only and ACE inhibitor/ARB group ( Table ).
The ACE inhibitor/ARB combination group had significantly more diabetic patients on insulin or thiazolidenediones (P < .003). This combination group was on a median of 4 total antihypertensive medications with higher tendency of treatment with thiazide diuretics. The ACE inhibitor treatment group tended to be on only 1 additional antihypertensive agent. ARB-only patients tended to be on a median of 3 total antihypertensive agents.
A main determinant of post-treatment MAP was pretreatment MAP. An interaction existed between pretreatment MAP and number of antihypertensive medications. This interaction suggests that when post-treatment MAP was higher, patients tended to be on more medications. Multivariate linear regression demonstrated that pretreatment MAP and the number of antihypertensive agents were the best predictors of post-treatment MAP
Discussion
The results suggest that the patients on combination therapy were difficult to control, requiring a higher average number of medications. The use of combination therapy may not be superior to therapy with ACE inhibitor or ARB agents alone in controlling blood pressure. Because the combination group was disproportionately diabetic, it is possible that therapy was tailored toward renal protection.
Limitations of this study include its retrospective design and small sample size. Retrospective designs suffer from confounding and selection bias. For example, the patients in this study were predominantly women. This indicates that this is a selected population. Type II error may exist due to underpowering with small sample size. Thus, a positive difference in blood pressure between groups may not be evident. This study demonstrates a need for future studies to evaluate the merit of dual blockade therapy with ACE inhibitors and ARB agents for the treatment of hypertensive patients, such as ONTARGET.[9]
Studies of blockade of the RAAS in patients with type 1 diabetes and diabetic nephropathy, and patients with type 2 diabetes and microalbuminuria, have indicated that ACE inhibitors and ARBs are equally effective in lowering blood pressure and urinary albumin excretion. Short-term studies of dual blockade in diabetics with nephropathy have suggested superior efficacy in lowering albuminuria and blood pressure when compared with treatment with ACE inhibitor alone. No long-term studies of the effects of dual blockade of the RAAS in diabetic nephropathy are available to document renal protection. Thus, dual blockade is not established as a first-line treatment for patients with diabetic nephropathy. However, in patients with uncontrolled albuminuria or hypertension, dual blockade may be helpful in reaching treatment goals.[10]
In summary, our study reinforces the need of combination therapy for treating hypertension. This is in line with the literature on the need for at least 2 agents to achieve blood pressure goal.[11] Given the rising cost of medical treatment, it is important to have evidence-based guidelines prior to implementing high-cost combination blood pressure medication.
