Orthostatic Hypotension in Treated Hypertensive Patients

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1 Orthostatic Hypotension in Treated Hypertensive Patients JESSICA BAROCHINER, J. ALFIE, L. APARICIO, M. RADA, MARGARITA MORALES, PAULA CUFFARO, C. GALARZA, G. WAISMAN Hypertension Section, Internal Medicine Department, Hospital Italiano de Buenos Aires Introduction. Orthostatic hypotension (OH) is a risk factor for morbidity and mortality and one of the causes of non compliance to treatment among medicated hypertensive subjects. Our objective was to assess the prevalence of OH among treated hypertensive patients and its association with clinical characteristics and antihypertensive drug class. Methods. This was a cross-sectional study in which we assessed the prevalence of OH, defined according to the American Autonomic Society and American Academy of Neurology guidelines, among adult treated hypertensive patients who performed a home blood pressure monitoring at our institution. We also determined the prevalence of OH according to age group (< 65, and > 80), antihypertensive drug class, office and home hypertension control status. Results. We included 302 medicated patients in the study. Mean age was 66.6(+13.8), 67% were women. We found a 9.7% global prevalence of OH, which was significantly higher among older individuals (3.6% among patients < 65 years-old, 12.2% in the year-old group and 16.7% among octogenarians, p = 0.02) and those who consumed alpha-blockers (75 vs. 8.5%, p < 0.01). Uncontrolled hypertensive patients at office and/or at home had also a significantly higher prevalence of OH: uncontrolled vs. controlled office blood pressure (BP), 14.3 vs. 6.5%, p = 0.03 and uncontrolled vs. controlled home BP, 15.1 vs. 6.6%, p = Remarkably, 64% of patients with OH had their BP under control when considering office-standing BP. Conclusion. OH is a prevalent entity among treated hypertensive patients and systematic measurement of standing BP should be mandatory in the evaluation of these patients. Key words: Orthostatic hypotension, prevalence, hypertension, medication, home blood pressure monitoring. Orthostatic hypotension (OH) is a phenomenon in which postural hemodynamic homeostasis is not preserved, leading to a significant blood pressure drop [1], which in turn may cause falls, syncope and functional impairment [2][3]. Moreover, in the last years OH has been identified as an independent risk factor for cardiovascular morbidity, including stroke and coronary heart disease, and all-cause mortality [4-9]. On the other hand, hypertension is an agerelated disease [10], expected to increase as worldwide population ages, and previous studies have shown that OH is also related to age [11][12], rendering hypertension management in this expanding group of already fragile elderly individuals more complex. International hypertension guidelines state that hypertension is scantly controlled all over the world and lack of compliance with treatment is a major factor accounting for this phenomenon [13-15]. This could be due in part to adverse effects related to antihypertensive drugs, orthostatic hypotension being one of them [16]. Thus, ascertaining the prevalence of OH among medicated hypertensive patients and establishing associated factors is of capital importance to improve hypertension management. The purpose of this study was to assess the prevalence of orthostatic hypotension among patients under antihypertensive treatment and its association with clinical characteristics and antihypertensive drug classes. MATERIALS AND METHODS Selection of patients This was a cross-sectional study that included hypertensive patients 18 years or older receiving antihypertensive treatment, who came to our institution to perform a Home Blood Pressure Monitoring (HBPM) indicated by their treating physician. All patients that accepted to participate in the study gave written informed consent and completed a questionnaire regarding risk factors (diabetes, smoking status, sedentary lifestyle, family history ROM. J. INTERN. MED., 2012, 50, 3,

2 204 Jessica Barochiner et al. 2 of cardiovascular disease), history of cardiovascular disease (coronary heart disease, cerebrovascular disease, peripheral artery disease) and antihypertensive drug consumption (class and number). Sedentary lifestyle was defined as physical activity with a frequency <1 times per week; coronary heart disease was defined as a history of myocardial infarction, unstable angina, chronic stable angina or coronary by-pass surgery; cerebrovascular disease was defined as a history of stroke or transient ischemic attack; and peripheral artery disease, as intermittent claudication, abnormal arterial doppler or peripheral revascularization in the lower limbs. Anthropometric and blood pressure measurement We assessed weight, height and waist circumference for all patients and subsequently measured blood pressure (BP) twice in the non-dominant arm, two minutes apart, with a validated automated oscillometric device Omron 705 CP (Omron Corp., Tokyo, Japan), after a five minute rest with the patient in a sitting position, and using an appropriate cuff size according to the arm circumference. We then measured BP with the same device after the patient was standing for two minutes and repeated the reading after two more minutes, always with the arm supported at heart level. Home Blood Pressure Monitoring (HBPM) Patients returned home with the oscillometric device after appropriate training in its use and registered duplicate blood pressure readings (two minutes apart) in the non-dominant arm for four days, in the morning (before breakfast and medication), afternoon and evening. First day-measurements were discarded from analysis. Patients with less than 16 home blood pressure readings were excluded from analysis. Definition of orthostatic hypotension (OH), office and home hypertension control status Orthostatic hypotension was defined as a BP fall from sitting to standing position of >20 mmhg for systolic BP or >10 mmhg for diastolic BP, considering the average of the two readings (at minute 2 and 4). We considered hypertension was under control at office when the average of the two sitting measurements was < 140/90 mmhg; and at home when the average of all measurements (discarding first day) was < 135/85 mmhg. Statistical analysis We determined the prevalence (%) of OH in the study population and compared clinical characteristics of patients with and without OH, using chi-square test for categorical and Student T test for continuous variables. A p-value <0.05 was considered as statistically significant. We also assessed the prevalence of OH by age-group: 65 years-old, years-old and >80 years-old, by antihypertensive drug class, and by hypertension control status at office and at home. RESULTS Among 302 medicated patients included in the study, 13 had insufficient home blood pressure readings, so 289 patients were included in the analysis, 67% women, with an average age of 66.6 (+13.8) years-old. Global prevalence of OH was 9.7%. Patients with OH were significantly older, consumed more antihypertensive drugs and had a higher systolic BP at office and home compared to those without OH (Table I). According to age-group, prevalence of OH was 3.6% among patients younger than 65 yearsold, 12.2% in the year-old group and 16.7% among octogenarians, p = Regarding antihypertensive drug class, prevalence of OH was significantly higher among those treated with alpha-blockers: 75 vs. 8.5%, p < Prevalence of OH was not significantly higher for other antihypertensive drug classes (Fig. 1). Finally, orthostatic systolic BP variation (sitting BP standing BP) showed a significant correlation with office sitting-systolic BP (Fig. 2). Moreover, prevalence of OH was significantly higher in patients with uncontrolled hypertension at office (14.3 vs. 6.5%, p = 0.03) and at home (15.1 vs. 6.6%, p = 0.02) (Fig. 3). Remarkably, although a minority of patients (28.6%) with OH had their hypertension under control considering sitting BP, the proportion of patients with OH that had their hypertension controlled (< 140/90 mmhg at office) increased to 64.3% taking into account standing BP. Interestingly, when we analyzed quintiles of standing systolic blood pressure, 39.3% of patients with OH belonged to the lowest quintile, i.e. standing systolic blood pressure < mmhg (Fig. 4).

3 3 Orthostatic hypotension in treated hypertensive patients 205 Table I Participant characteristics Total With OH Without OH p-value n (%) 289 (100%) 28 (9.7%) 261 (90.3%) Demographic characteristics Women (%) NS Age (+SD) 66.6 (+13.8) 73.8 (+13.4) 65.8 (+13.6) BMI (+SD) 28.4 (4.6) 26.9 (3.9) 28.6 (4.7) NS Waist circumference (+SD) 96.3 (12.4) 93 (9.6) 96.7 (12.7) NS Number of antihypertensive drugs (+SD) 2.1 (0.9) 2.4 (0.9) 2.1 (0.9) Risk factors or history of cardiovascular disease Current smokers (%) NS Diabetes (%) NS Sedentary lifestyle (%) NS History of ischemic Heart disease (%) NS History of cerebrovascular disease (%) NS History of peripheral artery disease (%) NS Family history of cardiovascular disease (%) NS Blood pressure profile Office sitting-systolic BP (mmhg) (+SD) (18.35) (20.63) (17.83) Office sitting-diastolic BP (mmhg) (+SD) (10.39) (11.84) (10.25) NS Office standing systolic BP (mmhg) (+SD) (17.57) (20.27) (17.23) NS Office standing diastolic BP (mmhg) (+SD) (10.28) (10.55) (9.94) <0.001 Orthostatic systolic BP variation (sitting systolic BPstanding 3.41 (9.84) (12.13) 1.89 (8.24) <0.001 systolic BP) (mmhg; +SD) Orthostatic diastolic BP variation (sitting diastolic (6.49) 7.14 (7.39) -2.1 (5.72) <0.001 BP-standing diastolic BP) (mmhg; +SD) Home systolic BP (mmhg; +SD) (14.21) (15.75) (13.88) 0.01 Home diastolic BP (mmhg; +SD) (8.68) (11.21) (8.32) NS BMI: body mass index; BP: blood pressure; NS: non-significant; OH: orthostatic hypotension. Fig. 1. Prevalence of orthostatic hypotension (OH) according to antihypertensive drug class.

4 206 Jessica Barochiner et al. 4 Fig. 2. Correlation between orthostatic systolic blood pressure (BP) variation and office sitting systolic BP. Fig. 3. Prevalence of orthostatic hypotension (OH) according to hypertension control status. Fig. 4. Distribution of patients with orthostatic hypotension (OH) according to standing systolic blood pressure (BP) quintile.

5 5 Orthostatic hypotension in treated hypertensive patients 207 DISCUSSION We found in our study a global 9.7% prevalence of orthostatic hypotension (OH). Patients with OH were significantly older and their hypertension was significantly uncontrolled compared to patients without OH. Regarding antihypertensive drug classes, patients with OH were more frequently receiving alpha-blockers. Several studies have assessed the association between anti-hypertensive drugs and OH, with contrasting results [17-19]. One limitation of our study is that we did not consider subtypes of drugs among classes, for example, second versus first-generation betablockers or different types of diuretics. Although from a pathophysiological point of view it is reasonable to consider all-class diuretics as a common cause of OH, some studies, including this one, have failed to demonstrate this association [17][20]. In our case there was a tendency towards such an association, without reaching statistical significance. This could be due to a low statistical power. OH is a well-known side-effect related to alpha-blockers, especially in older patients, and this was consistent with our findings and with other studies assessing this subject [21][22]. Even though alpha-blockers are not first-line drugs for hypertension treatment, they are usually used in prostatic hyperplasia, a prevalent condition among elder men [23][25]. We failed to find, consistently with other studies [11][18], an association between OH and diabetes, an entity in which autonomic dysfunction has been well documented. One possible explanation is that diabetes was recently diagnosed or was wellcontrolled among our patients. We do not have information on the possible presence of diabetic neuropathy in our population. Another finding of our study was an association between age and OH, which has been previously described, with a significant higher prevalence of OH in elderly and very elderly individuals compared to younger ones [26]. We also found, in accordance with previous studies [12][27], that OH was more often present among patients with uncontrolled hypertension. These two findings underlie the existence of a group of patients who are extremely fragile: on the one hand, they are older and more exposed to medication related sideeffects; on the other hand, they would probably receive more drugs on the basis of office or home sitting-high blood pressure. In has been suggested that physicians need not to be afraid of intensively treating such patients, as a better BP control would reduce the likelihood of developing OH [28]. In our opinion, the finding that OH is more prevalent in sitting uncontrolled hypertensive patients is a strong argument to systematically measure standing BP in all uncontrolled hypertensives, especially older patients. Such a simplistic approach will probably prevent over-medication in vulnerable patients. In support to this opinion, we found in our population that more than 60% of patients with OH had their hypertension under control when considering standing BP. Moreover, more than one third of these patients belonged to the lowest quintile of systolic BP, i.e. standing systolic BP <117.5 mmhg. If only sitting BP is taken into account, a more aggressive treatment would probably worsen OH and its clinical consequences, such as falls, syncope, functional impairment, hospitalizations and cardiovascular morbidity and mortality. Data relating OH and home blood pressure are limited and, in that sense, our study contributes to establish that a similar phenomenon is seen at office and at home: a higher prevalence of office OH in uncontrolled hypertensive subjects. Lack of measurement of standing BP at home constitutes a limitation of our study. Home blood pressure monitoring is becoming a useful and expanding tool to assess hypertension control and has shown to be a better predictor of target organ damage and cardiovascular outcomes than office BP [29][32]. Thus, we feel that prospective studies designed to assess predictive factors of uncontrolled hypertension at home among individuals with OH should be performed in order to assess this issue. In conclusion, OH is a prevalent entity in treated hypertensive patients, especially elderly and very elderly who receive alpha-blockers and those in which hypertension is uncontrolled. Systematic measurement of standing BP should be an essential part of the evaluation of medicated hypertensives. Hipotensiunea arterială ortostatică (htao) este un factor de risc pentru morbiditate şi mortalitate şi una dintre cauzele de neconformitate la tratament, printre subiecţi trataţi cu medicamente hipertensive.

6 208 Jessica Barochiner et al. 6 Obiectivul nostru a fost de a evalua prevalenţa în rândul pacienţilor trataţi cu medicamente hipertensive şi asocierea lor cu caracteristicile clinice şi clasa de medicament antihipertensiv. Metode. Acesta a fost un studiu transversal în care am evaluat prevalenţa hipotensiunii arteriale ortostatice, definite conform Societăţii Americane şi Academiei Americane de Neurologie, liniile directoare, printre pacienţi adulţi trataţi cu medicamente hipertensive în care presiunea arterială a fost monitorizată acasă şi în instituţia noastră. Am stabilit, de asemenea, prevalenţa hipotensiunii ortostatice în funcţie de grupa de vârstă ( <65, şi >80), clasa de medicamente antihipertensive; la birou şi acasă; hipertensiune statutul de control. Rezultate. Am inclus 302 de pacienţi, cu medicaţie în studiu. Vârsta medie a fost de 66.6 (13.8), 67% dintre pacienţi au fost femei. Am găsit o prevalenţă de 9.7 la nivel mondial a hipotensiunii ortostatice, care a fost semnificativ mai mare în rândul persoanelor mai în vârstă (3.6% în rândul pacienţilor cu vârsta de sub 65 de ani; 12.2% la pacienţii cu vârste cuprinse între de ani, şi de 16.7% în rândul pacienţilor cu vârsta peste 80 ani; p = 0.02 şi cei care au consumat alfablocante (75 faţă de 8.5%, p < 0.01). Pacienţii hipertensivi cu TA necontrolată, la birou şi/sau la domiciliu au avut, de asemenea, o prevalenţă semnificativ mai mare de hipotensiune ortostatică necontrolată faţă de tensiunea arterială controlată de la birou, de 14.3 faţă de 6.5%, p = 0.03 şi acasă tensiunea arterială ortostatică necontrolată faţă de tensiunea arterială controlată, de 15.1 faţă de 6.6%, p = De remarcat că 64% dintre pacienţii cu hipotensiune arterială ortostatică au avut la birou tensiune arterială sub control. Concluzie. Hipotensiunea arterială ortostatică este o entitate răspândită printre pacienţii hipertensivi trataţi şi măsurarea sistematică a tensiunii arteriale ar trebui să fie obligatorie în evaluarea acestor pacienţi. Corresponding author: Dr. Jessica Barochiner Postal address: Juan D. Perón 4190 (C1181ACH) Buenos Aires, Argentina. Phone number: (5411) Fax number: (5411) address: jessica.barochiner@hospitalitaliano.org.ar REFERENCES 1. SMITH JJ, PORTH CM, ERICKSON M. Hemodynamic response to the upright posture. J Clin Pharmacol 34: , KARIO K, TOBIN JN, WOLFSON LI, WHIPPLE R, DERBY CA, SINGH D, et al. Lower standing systolic blood pressure as a predictor of falls in the elderly: a community-based prospective study. J Am Coll Cardiol 38: , HEITTERACHI E, LORD SR, MEYERKORT P, MCCLOSKEY I, FITZPATRICK R. Blood pressure changes on upright tilting predict falls in older people. Age Ageing 31: , EIGENBRODT ML, ROSE KM, COUPER DJ, ARNETT DK, SMITH R, JONES D. Orthostatic hypotension as a risk factor for stroke: the Atherosclerosis Risk in Communities (ARIC) study, Stroke 31: , ROSE KM, TYROLER HA, NARDO CJ, ARNETT DK, LIGHT KC, ROSAMOND W et al. Orthostatic hypotension and the incidence of coronary heart disease: the Atherosclerosis Risk in Communities study. Am J Hypertens 13: , BENVENUTO LJ, KRAKOFF LR. Morbidity and mortality of orthostatic hypotension:implications for management of cardiovascular disease. Am J Hypertens 24(2):135-44, MASAKI KH, SCHATZ IJ, BURCHFIEL CM, SHARP DS, CHIU D, FOLEY D et al. Orthostatic hypotension predicts mortality in elderly men: the Honolulu Heart Program. Circulation 98: , ROSE KM, EIGENBRODT ML, BIGA RL, COUPER DJ, LIGHT KC, SHARRETT AR et al. Orthostatic hypotension predicts mortality in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 114: , FEDOROWSKI A, STAVENOW L, HEDBLAD B, BERGLUND G, NILSSON PM, MELANDER O. Orthostatic hypotension predicts all-cause mortality and coronary events in middle-aged individuals (the Malmo Preventive Project). Eur Heart J 31:85 91, LEWINGTON S, CLARKE R, QIZILBACH N PETO R, COLLINS R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Prospective Studies Collaborative. Lancet 360: , 2002.

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