Resistant Hypertension and Associated Comorbidities in a Veterans Affairs Population

ORIGINAL PAPER Resistant and Associated Comorbidities in a Veterans Affairs Population Tushar Acharya, MD; 1,2 Steven Tringali, DO; 1,2 Manmeet Singh, MD; 1,2 Jian Huang, MD 1,2 Primary Care Service, VA Central California Health Care System, Fresno, CA; 1 and Department of Medicine, University of California San Francisco- Fresno Medical Education Program, Fresno, CA 2 Resistant hypertension (RH) is understudied and its reported prevalence varies with study populations. The authors sought to determine its prevalence and association with certain comorbid conditions in a Veterans Affairs population. This cross-sectional study utilized demographic and clinical data from 17,466 patients. Chi-square or t test was used for comparing groups with and without RH. Multivariate logistic regression analysis was used to determine independent associations. Overall, the prevalence of RH was 9%, and 13% of all hypertensive patients met criteria for RH. After adjusting for confounding variables, RH was significantly associated with older age (odds ratio [OR], 1.007), higher body mass index (OR, 1.04), Framingham score (OR, 1.14), and coexisting coronary artery disease, cerebrovascular accident/transient ischemic attack, peripheral vascular disease, congestive heart failure, chronic kidney disease, diabetes mellitus, erectile dysfunction, and metabolic syndrome (OR, 1.3, 1.32, 1.29, 2.88, 2.13, 1.2, 1.12, and 1.2, respectively; all P<.05). Our results indicate a complex interplay of certain comorbid conditions among patients with RH and suggest the need for multifaceted interventions in this high-risk population to prevent cardiovascular events. J Clin Hypertens (Greenwich). 2014;16:741 745. ª 2014 Wiley Periodicals, Inc. Essential hypertension (HTN) is the most prevalent controllable disease in developed countries, affecting more than 25% of the adult population. Its global disease burden is immense, with 62% of strokes, 49% of heart disease, and 7.5 million deaths per year attributed to HTN. 1,2 National Health and Nutrition Examination Survey (NHANES) data show that HTN has become more prevalent in the past decade, with approximately 74.5 million of US adults affected. Even though HTN awareness and treatment are higher among patients older than 60 years, the proportion of patients with controlled blood pressure (BP) in this age group is lower when compared with the young. 3 Multifactorial causes, including financial constraint, cognitive impairment, medication adherence, and polypharmacy, contribute to treatment resistance in the elderly. Resistant HTN (RH) is a relatively common but significantly understudied clinical condition. In 2008, the American Heart Association defined RH as a BP above goal in spite of concurrent use of three antihypertensive agents of different classes ideally including a diuretic and all at optimal doses or BP controlled with four or more antihypertensive medications. 4 Older age, obesity, higher baseline systolic BP, and left ventricular hypertrophy (LVH) have been found to be strong predictors of poor BP control in the Framingham cohort 5 and the Antihypertensive and Lipid-Lowering Address for correspondence: Jian Huang, MD, Clinical Professor of Medicine, VA Central California Health Care System, 2615 East Clinton Avenue, Fresno, CA 93703 E-mail: jian.huang@va.gov Manuscript received: June 15, 2014; revised: August 5, 2014; accepted: August 7, 2014 DOI: 10.1111/jch.12410 Treatment to Prevent Heart Attack Trial (ALLHAT). 6 Target organ damage in the form of LVH and renal dysfunction as well as atherosclerotic disease, diabetes mellitus, and metabolic syndrome are frequently associated comorbid conditions. 4,7 The exact prevalence of RH is unknown, 4 and the reported prevalence of RH varies with study populations. Veterans are at high risk for uncontrolled BP and its complications. We sought to determine the prevalence of RH and its association with other comorbid conditions in a Veterans Affairs (VA) population. METHODS Patients VA Northern California Healthcare System s institutional review board approved the study protocol. Electronic medical records (EMRs) were reviewed for 17,466 outpatients enrolled at our VA facility for subspecialty care as well as primary care. Demographic information and clinical data on disease diagnoses, laboratory markers, and medication prescription were collected from June 2009 through December 2010 for this cross-sectional study. HTN was defined by International Classification of Diseases, Ninth Revision (ICD-9) code and antihypertensive medication prescription. RH was diagnosed for all hypertensive patients if BP was uncontrolled (>140/90 mm Hg) on three or more, or controlled on four or more agents, including a thiazide diuretic. Individualized data on medication adherence were not available. However, aggregated data on antihypertensive medication adherence as measured by medication possession ratio (MPR) in our VA facility showed an MPR >80% among 90% of the hypertensive patients. The Journal of Clinical Vol 16 No 10 October 2014 741

ICD-9 codes were used for the diagnoses of coronary artery disease (CAD), myocardial infarction (MI), coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), cerebrovascular accident (CVA)/transient ischemic attack (TIA), peripheral vascular disease (PVD), congestive heart failure (CHF), chronic kidney disease (CKD), obstructive sleep apnea (OSA), and erectile dysfunction (ED). Diabetes mellitus (DM) was defined by the ICD-9 code; glycated hemoglobin >6.5%; insulin or oral hypoglycemic agent use; or random blood glucose >200 mg/dl on more than one occasion. Metabolic syndrome (MS) was defined by modified Third Report of the Adult Treatment Panel National Cholesterol Education Program (NCEP-ATP III) criteria; BMI was used instead of waist circumference. Statistical Analysis Student t test or chi-square test was used where appropriate for comparison between the groups with and without RH. A multivariate logistic regression model was used to control for confounders and to calculate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) to determine RH-associated comorbid conditions. Statistical significance was defined as a two-sided P value <.05. In multivariate logistic regression analysis, RH was used as the dependent variable and the independent variables included age; sex; BMI; Framingham score; current alcohol and tobacco use; diagnosis of DM, CAD, CVA/TIA, PVD, CHF, CKD, ED, OSA, depression, anxiety, and posttraumatic stress disorder; and use of nonsteroidal antiinflammatory drugs (NSAIDs), tricyclic antidepressants, and selective serotonin reuptake inhibitors. RESULTS Patient Characteristics and Prevalence of RH The mean age of the study population was 67 years and the average BMI was 29.6. Ninety-six percent of patients were men. The overall prevalence of HTN was 64% and RH was 9% among the study population. Thirteen percent of all hypertensive patients met criteria for RH. Association Between RH and Certain Demographics and Comorbid Conditions Chi-square or t test was used for comparing groups with and without RH. Patients with RH were older, with a mean age of 72.9 years, when compared with the non- RH population. They had significantly higher mean BMI values and higher Framingham scores. The prevalence of certain disease pathologies was higher in the RH group. More patients with RH had a history of MI, PCI, and CABG as well as overall prevalence of CAD. Atherosclerotic disease in other vascular beds, including CVA, TIA, and PVD, was also more prevalent in these patients. Significantly more patients with RH had MS, DM, CHF, CKD, ED, and OSA (Table I). TABLE I. Comparison of Characteristics of Patients With and Without Resistant Resistant (n=1576) No Resistant (n=15,890) P Value Age, y 72.911.0 66.314.1 <.001 BMI, kg/m 2 31.15.8 29.45.9 <.001 Current smoker, % 300 (19) 3560 (22).225 SBP, mm Hg 151.211.5 126.715.5 <.001 DBP, mm Hg 74.812.1 70.410.9 <.001 HR, beats per min 68.713.0 72.813.1 <.001 Framingham score 21.73.3 17.95.4 <.001 MS 1194 (75) 8866 (55) <.001 DM 777 (49) 4099 (25) <.001 CAD 406 (25) 1922 (12) <.001 CHF 318 (20) 715 (4.5) <.001 CVA/TIA 266 (17) 1398 (8.8) <.001 PVD 438 (27) 2097 (13) <.001 CKD 321 (20) 937 (5.9) <.001 ED 476 (30) 3845 (24) <.001 OSA 43 (2.7) 190 (1.2) <.001 Glucose, mg/dl 131.655.3 119.944.3 <.001 Glycated hemoglobin 6.41.37 6.11.27 <.001 Creatinine, mg/dl 1.470.94 1.170.52 <.001 LDL cholesterol, mg/dl 95.233.4 104.134.2 <.001 Statin 929 (59) 6356 (40) <.001 HCTZ 1576 (100) 3178 (20) <.001 ACE inhibitor 1134 (72) 4925 (31) <.001 ARB 236 (15) 795 (5) <.001 b-blocker 1056 (67) 3178 (20) <.001 CCB 835 (53) 1906 (12) <.001 Nitrate 94 (6) 317 (2) <.001 Hydralazine 63 (4) 64 (0.4) <.001 Spironolactone 79 (5) 159 (1) <.001 Clonidine 63 (4) 127 (0.8) <.001 NSAIDs 1071 (68) 10487 (66).39 TCA 58 (3.7) 604 (3.8).46 SSRI 236 (15) 2542 (16).40 Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; CAD, coronary artery disease; CCB, calcium channel blocker; CHF, congestive heart failure; CKD, chronic kidney disease; CVA/TIA, cerebrovascular accident/transient ischemic attack; DBP, diastolic blood pressure; DM, diabetes mellitus; ED, erectile dysfunction; HCTZ, hydrochlorothiazide; HR, heart rate; LDL, low-density lipoprotein cholesterol; MS, metabolic syndrome; NSAIDs, nonsteroidal anti-inflammatory drugs; OSA, obstructive sleep apnea; PVD, peripheral vascular disease; statin, HMG-CoA reductase inhibitor; SBP, systolic blood pressure; SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressant. Categoric variables are expressed as number (percentage) and continuous variables are expressed as meanstandard deviation. P values are based on chi-square test for categorical and Student t test for continuous variables. Adjusting for confounding factors, including demographics, certain comorbid conditions and medications, multivariate logistic regression analysis did not change the significant association of RH with older age (OR, 742 The Journal of Clinical Vol 16 No 10 October 2014

TABLE II. Binary Multivariate Logistic Regression Analysis for Individual Associations of Resistant 1.007; 95% CI, 1.001 1.014; P=.033), higher BMI (OR, 1.042; 95% CI, 1.031 1.053; P<.001), and higher Framingham score (OR, 1.141; 95% CI, 1.119 1.164; P<.001). The multivariate logistic regression analysis also revealed that some of the comorbid disease processes remained significantly associated with RH. These were MS (OR, 1.204; 95% CI, 1.038 1.398; P=.014), DM (OR, 1.203; 95% CI, 1.056 1.370; P=.005), CAD (OR, 1.304; 95% CI, 1.134 1.5; P<.001), CHF (OR, 2.881; 95% CI, 2.443 3.397; P<.001), CVA/TIA (OR, 1.315; 95% CI, 1.124 1.538; P=.001), PVD (OR, 1.287; 95% CI, 1.124 1.475; P<.001), CKD (OR, 2.128; 95% CI, 1.824 2.483; P<.001), and ED (OR, 1.123; 95% CI, 1.082 1.382; P=.001) (Table II). DISCUSSION Odds Ratio 95% Confidence Interval Age 1.007 1.001 1.014 BMI 1.042 1.031 1.053 Framingham score 1.141 1.119 1.164 MS 1.204 1.038 1.398 DM 1.203 1.056 1.370 CAD 1.304 1.134 1.500 CHF 2.881 2.443 3.397 CVA/TIA 1.315 1.124 1.538 PVD 1.287 1.124 1.475 CKD 2.128 1.824 2.483 ED 1.123 1.082 1.382 Abbreviations: BMI, body mass index; CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; CVA/TIA, cerebrovascular accident/transient ischemic attack; DM, diabetes mellitus; ED, erectile dysfunction; MS, metabolic syndrome; PVD, peripheral vascular disease. Odds ratios represented in tabular format are derived from multivariate logistic regression analysis comparing different characteristics between patients with and without resistant hypertension and are not comparable between variables. Prevalence In this study, we found the prevalence of RH to be 9%. Of all veterans seen at the primary care clinic, 64% had HTN. Among hypertensive patients, 13% qualified as having RH. Our findings fell within the general range of what has been reported in the literature. According to NHANES data, the prevalence of RH among US hypertensive population was estimated at 8.9% and among those being treated at 12.8%. 8 Five percent of the patients seen in the primary care setting and up to 50% seen by nephrology specialists have been reported to have treatment resistance. 9 Approximately 11% to 18% of patients seen in tertiary care clinics may have RH. 10,11 Clinical trials have reported a higher rate of resistance to antihypertensive therapy. In the large HTN intervention trial ALLHAT, at the completion of 5 years of follow-up, 27% of patients were taking 3 or more antihypertensive medications. 6 A higher occurrence of RH in treatment trials may be explained by the enrollment of older patients at higher cardiovascular risk. 12 Age Following the trend of HTN in general, RH is almost universally more prevalent in the elderly. With a mean age of 64 years, 13 veterans are at high risk for uncontrolled BP and its complications. Not surprisingly, we found that patients with RH were significantly older, with a mean age of 72.9 years when compared with 66.3 years in the non-rh group. This significant association of RH with age is probably a product of arterial stiffening, impaired baroreceptor function, endothelial dysfunction, and oxidative and inflammatory stress accumulated over time. As the population ages, treatment resistance is also expected to rise. Obesity Unlike age, controllable correlates of RH such as obesity are potential targets to help reduce eventual end-organ damage. Obesity is on the rise at an alarming rate and is increasingly affecting the younger population. Continuation of this trend in the United States can be a major setback to efforts for HTN control. Obesity predisposes to treatment resistance 14,15 by activation of reninangiotensin-aldosterone axis and sympathetic overstimulation. 16 We found more obese patients in the RH group. This is consistent with results of previous studies including ALLHAT. Framingham Risk Score Framingham score takes age, sex, BP, cholesterol, and smoking history into account to provide a composite 10-year coronary heart disease risk assessment. 17 An analysis of NHANES data recently published showed a risk score of more than 20% to be independently associated with apparent treatment-resistant HTN. 18 We found a similar correlation between RH and Framingham score. Patients with RH had a mean risk score of 21.7%, whereas those without RH had a score of 19.7%. However, because of our large sample size, this statistically significant relative difference of 14% between the two groups may represent only a trend. Diabetes Mellitus DM and HTN frequently coexist. It has been reported that as many as three or four antihypertensive agents may be required to adequately control BP in patients with diabetes. 19 Presence of DM predicted poor BP control in ALLHAT patients. 6 Consistently, in our study, more patients in the RH group had comorbid DM. Insulin resistance may partially be responsible for this correlation. The Journal of Clinical Vol 16 No 10 October 2014 743

Metabolic Syndrome Obesity, insulin resistance, dyslipidemia, and HTN comprise MS, which is another predictor of cardiovascular mortality. 20 Detrimental effects of increased aldosterone levels have been implicated in the etiology of MS and RH by impairing pancreatic beta cell function, reducing insulin sensitivity, and causing endothelial dysfunction. 7 CAD, CHF, and CVA HTN, as the foremost risk factor for CAD and CVA, is responsible for the majority of cardiovascular morbidity and mortality in the United States. It is also the leading cause of CHF, either directly causing hypertensive heart disease or indirectly contributing to ischemic cardiomyopathy. A large retrospective cohort study with a mean follow-up of 3.8 years, found significantly higher combined outcomes of death, MI, CHF, CVA, and CKD in RH patients, with a hazard ratio of 1.47. 21 RH patients in the Reduction of Atherothrombosis for Continued Health (REACH) registry had a higher composite outcome of cardiovascular death, MI, or CVA at 4 years, with a hazard ratio of 1.11. They also had higher risk of CVA and number of hospitalizations for CHF. 22 Accounting for different study design, we found CAD, CHF, and CVA/TIA to be more prevalent in patients with RH when compared with those without RH, with ORs of 1.30, 2.88, and 1.32, respectively. Chronic Kidney Disease CKD is a common complication in patients with HTN and DM. Renal dysfunction causes increased sodium and water retention. These patients frequently have fluid overload, which, in turn, makes BP control difficult. Persistently elevated BP causes nephrosclerosis, leading to further kidney damage and perpetuating a vicious cycle. Prevalence of HTN varies inversely with glomerular filtration rate. Adequate BP control slows the progression of glomerular filtration rate decline in patients with proteinuria. 23 However, achieving this target is a significant challenge. Only 27% of patients with CKD had BP below the therapeutic target of 140/ 90 mm Hg in the NHANES data subanalysis. 24 Around 15% of nondiabetic patients with CKD had treatment resistance in a cross-sectional study. 25 We found CKD to be almost four times more common in RH patients (20.4% vs 5.9%), with an OR of 2.13. A strong association exists between the two conditions with complex reciprocal interaction. Peripheral Vascular Disease PVD results from atherosclerosis in the extremities. HTN is a known risk factor and has been associated with PVD in several large population-based reports including the Framingham Offspring Study, 26 the Atherosclerosis Risk in Communities (ARIC) study, and subanalysis of the NHANES data. 27 We found a similar correlation. Erectile Dysfunction Endothelial dysfunction and atherosclerosis have also been cited as the underlying pathology for ED. 28 In a large managed care claims database, more than 40% of patients with ED had a concomitant diagnosis of HTN, 29 and another cross-sectional study suggested that BP control was associated with a lower prevalence of ED. This association was independent of age and cardiovascular disease. 30 Thus, it is not surprising that we found a statistically significant correlation between RH and ED. To our knowledge, this is the first report of such an association between ED and RH. Obstructive Sleep Apnea OSA is an important reversible risk factor for secondary HTN. Excessive sympathetic drive in these patients has been attributed as the cause. 31 Moreover, OSA severity correlates with poor response to antihypertensive medications. In a study of 41 participants with RH undergoing sleep study, an 83% correlation was found between RH and OSA. 32 In our study, 2.7% of the RH population had OSA in comparison to 1.2% of non-rh patients, a significant difference by chi-square test (Table I). This association, however, was not statistically significant in the subsequent multivariate logistic regression analysis. This may represent underreporting of OSA in our EMR as we exclusively used ICD codes for OSA diagnosis. Nevertheless, higher prevalence of OSA in patients with RH deserves special diagnostic considerations and treatment strategies. Limitations There are several limitations to our study. First, this cross-sectional study is designed to suggest association only and does not assess causality. Second, data on patient adherence to medications were not retrievable for this study with relatively large samples. Nonadherent patients frequently have elevated BP at primary care visits and often receive a prescription for additional antihypertensive agents. Third, elevated BP readings from a single clinic visit caused by inappropriate measurement techniques and white-coat effect could contribute to inaccurate diagnosis. Fourth, some widely used over-the-counter drugs, especially NSAIDs and decongestants, can lead to elevated BP. Similarly, excessive consumption of caffeine and alcohol and use of illicit drugs can also lead to difficult-to-control HTN. Using available data, we made an effort to adjust for some of these confounding factors by multivariate logistic regression analysis, although a few other variables, such as use of over-the-counter NSAIDs and decongestants and illicit drugs, were either incomplete or unavailable in our EMR. Fifth, the retrospective nature of the study with use of ICD-9 codes for defining disease status leads to underdiagnosis of certain diseases. Lastly, the patients in this study were predominantly men and the findings should thus be generalized with caution. 744 The Journal of Clinical Vol 16 No 10 October 2014

CONCLUSIONS Overall prevalence of RH in this study fell in the range reported in the general population. We found certain cardiovascular and metabolic diseases and conditions with target organ damage to be significantly more prevalent in patients with RH. Acknowledgment and disclosure: We would like to thank Dr Jocelyn Fong and Mr Sean McFarland for their assistance with data collection and verification and Dr Ronna Mallios for her assistance with data analysis. The authors report no specific funding in relation to this research and no conflict of interest to disclose. Contributors: Dr Huang was the principal investigator of this study, supervised its conduct and data collection and analysis, and was primarily responsible for the writing of this paper. Dr Acharya was responsible for data verification and organization and the draft of the manuscript. Dr Tringali was responsible for verification of data analysis and manuscript revision. Dr Singh assisted in the draft of this manuscript. 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