Cross sectional study to assess the prevalence of resistant hypertension and factors affecting treatment of resistant hypertension

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1 Original article: Cross sectional study to assess the prevalence of resistant hypertension and factors affecting treatment of resistant hypertension 1Dr. Shaylika Chauhan*, 2 Dr. Arundhati Kanbur Kaushalya Medical Foundation and Trust Hospital, Thane (W), Maharashtra, India *Corresponding author drshaylikachauhan@gmail.com Abstract: Introduction: The magnitude of the burden of resistant hypertension needs an increase in awareness, treatment, and control of this condition. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations, so this study was undertaken in 1192 hypertensive patients over a period of two years to assess prevalence and factors affecting treatment of resistant hypertension. Methods: Resistant hypertension was diagnosed by criteria as defined by WHO-ISH guidelines. All patients more than 18 years old, surgical and medical, admitted to the hospital with BP >150/90 and diabetic and chronic renal disease patients with BP >130/80 inspite of taking 3 antihypertensive drugs were diagnosed as resistant hypertension and formed the study cohort. Results: 233 patients out of a total of 1192 hypertensive patients admitted to the hospital in the study period were found to have resistant hypertension. In this study Diuretics was the most commonly used drug class (28.73% of all drugs used).maximum number of patients (54.51%) was taking 3 drugs which were not being taken in fixed dose combinations. Conclusion: Resistant hypertension is a common clinical problem and. LVH, CKD, Obesity, Diabetes are predictors of resistant hypertension which should be adequately treated. Simplified prescribed regimens, longer acting combination drugs, frequent clinical visits, recording of home B.P measurements, multidisciplinary approach can improve compliance. Diuretics in adequate dosage should be utilized to treat resistant hypertension. Keywords: Resistant hypertension, diuretics, diabetes. Introduction: major silent killer. Blood pressure has to be Hypertension prevalence is increasing worldwide controlled as if left untreated half of all hypertensive with 972 million people (333 in economically die of CAD/CHF, about one-third of stroke and onesixth developed and 639 million in economically of renal failure. Patients whose hypertension is developing countries like India suffering from uncontrolled are more likely to have target-organ hypertension). 1 Based on current trends, it is expected damage and a higher long-term cardiovascular risk that non communicable diseases (NCD) like than are patients whose blood pressure is controlled. 2 hypertension will account for 73% of deaths and 60% Thus, hypertension is a major health problem with of the global disease burden by 2020, and will many patients appearing resistant to therapy. account for a major proportion of disease and deaths Resistant hypertension is a common clinical problem in India. 1 Surveys suggest that hypertension may be a faced by both primary care clinicians and specialists. 215

2 The prevalence of resistant hypertension is unknown because of inadequate sample sizes in published studies. However, it is common and is likely to become more common with the aging of the population and with the increasing prevalence of obesity, diabetes mellitus, and chronic kidney disease. A popular meta-analysis, including eight RCTs namely HOPE, SECURE, STOP- Hypertension, STOP - II, TRACE, UKPDS, HOT and Syst-China trials showed Odds ratio reduction of 13% in All causes mortality, 18% in Cardiovascular mortality, 26% in cardiovascular events and 30% in all stroke events. 3 Treatment of high blood pressure also decreases incidence of dementia by 50%, as proved by Syst-Eur trial. 4 There are significant benefits to controlling hypertension however resistant hypertension is not adequately treated. In (ALLHAT ) Antihypertensive and lipid lowering treatment to prevent heart attack study of 14,722 patients above 55 years, 47% remained resistant to therapy 1 year after randomization. 5 In a recent analysis of National Health and Nutrition Examination Survey (NHANES) participants with CKD (Chronic kidney disease) 37% were controlled to less than 130/80 mmhg and only 25% of DM were controlled to less than 140/90 mmhg. 6 LOSARTAN, intervention for end point reduction in hypertension (LIFE) study with controlled hypertension which enrolled HT patients with LVH showed control of 26% which were even lower. 7 Materials and methods A Cross sectional study spanning over a period of 2 years was done from June 2007 to June A total number of 1192 hypertensive patients were admitted in Kaushalya Medical Foundation Trust Hospital, a tertiary care center in Thane, India. Resistant hypertension was diagnosed by criteria as defined by WHO-ISH guidelines. 8 As per WHO-ISH guidelines resistant hypertension is defined as failure of concomitant use of three or more different antihypertensive drugs to lower B.P to less than 150/90 mmhg in patients with classical essential hypertension or to less than 150 mmhg in patients with isolated systolic hypertension or to less than 130/80 mmhg with diabetes and chronic renal disease. 8 Use of diuretics is recommended but not required. Doses of drugs should be optimal but not necessarily maximal. 8 High B.P controlled but with use of 4 or more agents is also considered under resistant hypertension. 8 All the cases, surgical and medical admitted to the hospital with BP >150/90; and diabetic and chronic renal disease patients with BP >130/80 in spite of administering 3 antihypertensive drugs were diagnosed as resistant hypertension and formed the study cohort. Inclusion Criteria: Out of all the hypertensive patients admitted to the hospital, patients fulfilling the following criteria were selected. 1. Adult patients more than 18 years of age were included. 2. Patients with co-morbid factors like DM, COPD, CRF, HT etc. were also included. 216

3 3. Patients taking more than or equal to 3 antihypertensive drugs with blood pressure more than 150/90 mm Hg. 4. Patients with high B.P controlled but with use of 4 or more agents. 5. Patients with isolated systolic hypertension having systolic blood pressure more than 150 mmhg inspite of taking more than or equal to 3 antihypertensive drugs. 6. Patients with co-morbid conditions like diabetes mellitus, chronic renal disease having a blood pressure of more than 130/80 mm Hg in spite of taking 3 or more antihypertensive drugs. Exclusion Criteria: 1. All pregnant women. 2. Patients less than 18 years of age. 3. Patients who were unaware of the antihypertensive drugs they were taking. 4. Patients who were not admitted to the hospital. 5. Patients with a recent change in antihypertensive medications and their dosage (less than a month). 9 Details of these patients were entered on a proforma. Medically relevant details including the primary condition for which the patient was admitted were noted. Additionally, an obstetric and menstrual history was taken in female patients.blood pressure was measured according to standards set by Indian guidelines for management of hypertension. 10 A detailed drug history was taken with details also taken about drugs which may contribute to prevalence of resistant hypertension. Detailed questions were asked regarding use of antihypertensive drugs and their doses. Patients and their relatives were asked whether the drug was taken regularly and in the dosage prescribed.a brief history and clinical examination was done to assess end organ damage and further investigations were done to assess the patients. Data collected was analyzed using frequency tables, cross tabulations, descriptive tables, pie charts and bar diagrams. Mean values, standard deviation, prevalence was assessed wherever relevant. Statistical tests like binomial test, chi square test were applied and the p value was calculated to know the statistical significance of results obtained. Results and Analysis : A total of 1192 hypertensive patients were admitted to the hospital in the study period. Out of these, 233 (19.54%) patients were found to have resistant hypertension and 959 (80.46%) patients were nonresistant hypertensives. In this study maximum numbers of patients were in the age group of years (27%) followed by 26.6% in the age group of years. Resistant hypertension was least prevalent in patients 18 to 30 years of age. There were 114 female patients (48.9%) and 119 male patients (51.1%) in the study cohort. Percentage of female patients having resistant hypertension was lesser than male patients except in the age group years (50.8% versus 49.2%) and years (55.8% versus 44.2%). (table 1) 126 patients (54%) of the study cohort had a pulse rate of more than 83. In this study Diuretics was the most commonly used drug class (28.73% of all drugs used) followed by Calcium channel blockers (21.79%). Of the total number of 849 drugs used by patients in the study cohort, 244 were diuretics (28.74%). The most commonly used Diuretic was frusemide (Loop diuretic). The most commonly used Calcium channel blocker was amlodipine. (figure 1) 217

4 Maximum number of patients (54.51%) were taking 3 drugs. Most of the patients taking 3 drugs were not taking fixed dose combinations. (figure 2) 59.05% of patients taking 3 antihypertensive drugs were taking these drugs as a single drug % of patients taking their 3 antihypertensive drugs were taking 2 of these drugs as a fixed dose pill. 84 patients in all were taking 2 drugs as fixed dose combination medications, 13 patients were taking 4 drugs as fixed dose combination medications (2+2). 3 drugs fixed dose formulations were taken by 2 patients only. (table 2) 66.67% of patients taking 7 drugs were unaware of the dose of their medications. Although some of these drugs were taken as fixed dose pills, number of total antihypertensive drugs required makes it difficult for the patients to remember the dose of antihypertensive medications.26.77% of patients who were taking three antihypertensive drugs were unaware of the doses of these medications. In all 23.17% were unaware of the doses of their antihypertensive medications. (table 3) 82.83% of the study population gave a history of being compliant to their antihypertensive medications. In this study only 40 patients or 17.17% of patients gave a history of noncompliance. (figure 3) 175 patients were taking analgesics which can potentially contribute to prevalence of resistant hypertension. Of these 175 patients 71 patients were on aspirin. 59 patients were taking steroids. (figure 4) 3 women gave history of use of oral contraceptives which can be a contributing factor in presence of resistant hypertension in them. 11 Statistically number of patients not on aspirin (70%) was significantly higher compared to those patients on aspirin (30%). (table 4) Out of 233 patients with resistant hypertension, 81 patients were on statins or statin combinations. Statistically number of patients not on statins (65%) was significantly higher compared to those patients on statins (35%). (table 5) 94 patients (40.3%) of the study cohort had a creatinine of more than 1.5. (table 6)50.64% of the study population gave a history of having diabetes.lipid profile analysis was done in 102 patients. 21.6% of these patients had an abnormal lipid profile as per National Institutes of Health guidelines. 12, In an analysis of Framingham study data, the next strongest predictors after age of lack of systolic blood pressure control were the presence of LVH and obesity (body mass index[bmi] >30 kg/m 2 ) % of all patients with resistant hypertension were overweight (BMI ) and 8.58% patients were obese (class I) ( ). (figure 5) Discussion As a subgroup, patients with resistant hypertension have not been widely studied. The true prevalence of resistant hypertension remains uncertain. 7 While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants as per David Calhoun et al % patients were found to have resistant hypertension in this study. Resistant hypertension is primarily a systolic and age related problem. 14,15 Women are more likely than men to know that they have hypertension, to have it treated, and to have it controlled. 15 Hormone replacement therapy, use of oral contraceptives, menopause make hypertension difficult to control in women. 11,16-17 Women report twice as many adverse 218

5 effects as men. 18 In this study maximum numbers of patients were in the age group of years and percentage of female patients having resistant hypertension was lesser than male patients except in the age group years and years.in the Framingham Heart Study, an average resting heart rate of 83 beats per minute in hypertensive patients was associated with a substantially higher risk of death from a cardiovascular event than patients (54%) of the study cohort had a pulse rate of more than 83.Obese patients do not respond as well as leaner patients to antihypertensive medication. 20 and need progressively higher doses of antihypertensive drugs as the body mass index increases. 21 There are no specific recommendations for treating obese hypertensive patients, though drugs acting on RS may have beneficial effects % of all patients with resistant hypertension were overweight (BMI ) and 8.58% patients were obese (class I) ( ). A strong, graded relation between raised serum cholesterol and coronary artery disease is seen with total cholesterol values above normal % of 102 patients in whom lipid profile was done had an abnormal lipid profile. Angiotensin converting enzyme inhibitor therapy is reported to reduce the increased lipolysis in adipose tissue associated with insulin resistance in hypertensive patients with central obesity. 23 In ALLHAT, diabetes predicted lack of blood pressure control. Pathophysiological effects attributed to insulin resistance that may contribute to worsening hypertension include increased sympathetic nervous activity, vascular smooth muscle cell proliferation, and increased sodium retention % of the study population gave a history of having diabetes.the strongest predictor of treatment resistance was having CKD (Chronic kidney disease) as defined by a serum creatinine of >1.5 in ALLHAT trial patients (40.3%) of the study cohort had a creatinine of more than 1.5. Given their widespread use, nonnarcotic analgesics, including nonsteroidal anti-inflammatory agents (NSAIDs), aspirin, and acetaminophen, are probably the most common offending agents in terms of worsening blood pressure control as per studies carried out by Forman JP et al patients were taking analgesics which can potentially contribute to prevalence of resistant hypertension. Of these 183 patients 71 patients were on aspirin. Aspirin in these patients was being used for its cardioprotective effects but it can contribute to prevalence of resistant hypertension. Analgesics were the most common drugs used which can potentially contribute to prevalence of resistant hypertension (50.72%) and this number is significantly higher than the number of other contributory drugs used. (Referring table 45). Increased use of analgesics in the study cohort can be because of increased prevalence of orthopedic complaints in the elderly age group. Maximum number of patients were in the age group of years followed by years. Sleep apnea affects 2 to 4 percent of middle-aged adults, most of whom are unaware they have this disorder as per Strollo et al. 26 Only 1 patient in our study cohort gave a history of obstructive sleep apnea. Very few patients were evaluated for secondary hypertension. Although relatively rare, identification of secondary hypertension is important because it is frequently resistant to usual antihypertensive medications and 219

6 may be controlled by interventions directed at the underlying cause. Volume overload, whether related to excess sodium intake or inadequate/ inappropriate diuretic treatment, is the most common cause of resistant hypertension in patients who adhere to therapy as per Setaro JF et al. 21 A recent study has demonstrated that combination therapies containing a diuretic are more effective than those not containing a diuretic as per Materson et al. 27 In this study also Diuretics was the most commonly used drug class followed by Calcium channel blockers. Of the total number of 849 drugs used by patients in the study cohort, 244 were diuretics (28.73%). Application of binomial test shows that that there is a highly significant difference between use of diuretics (28.73%) and other nondiuretic antihypertensives (71.27%) (Referring table 34) indicating that diuretics are underutilized to treat resistant hypertension. Sica et al 28 suggested that given the outcome benefit demonstrated with chlorthalidone and its superior efficacy compared with hydrochlorothiazide, chlorthalidone should be preferentially used in patients with resistant hypertension. There is underutilization of long acting diuretics like chlorthalidone in this study. Consistent with reports of a high prevalence of primary aldosteronism in patients with resistant hypertension, some patients may benefit from adding mineralocorticoid receptor antagonists (MRAs) to their antihypertensive regimens as per Nishizaka et al patients were using spironolactone in this study. Mineralocorticoid receptor antagonists like spironolactone and amiloride which are particularly useful in patients with resistant hypertension are underutilized. CVD risk should be addressed at the same time as reduction of BP to goal level by use of aspirins and statins as per Arya SN et al 30 in patients with resistant hypertension. Our study shows that number of patients prescribed aspirin (30%) and statins (35%) is significantly low in the study cohort. (Referring table 47, 49). As per Fine LJ et al 31 lack of knowledge of treatment guidelines, underestimation of cardiovascular (CV) risk, and the use of spurious reasons to avoid intensification of therapy, such as the physician s perception that the patient will not accept more medications, is related to clinician s failure to intensify treatment which can contribute to prevalence of resistant hypertension. In our study there is a highly significant difference between the number of patients taking 7, 6, 5, 4 and 3 antihypertensive drugs. Number of patients taking 3 drugs (54.51%) is much higher than the number of patients taking 7 drugs (1.29%). (Referring table 35, 36, figure 10). This could be due to clinical inertia on the part of health care providers to initiate or intensify therapy. Basile J et al 32 suggested that more number of patients should be encouraged to take combination medications as it improves compliance. Maximum number of patients in this study were not taking their antihypertensives in fixed dose combinations. Advantages of fixed dose combinations are improved compliance and simplified titration process, lesser cost, potentiation of antihypertensive effects, reduction in adverse events, attenuation of adverse effects (ACE inhibitors blunting diuretic-induced 220

7 metabolic derangements) as suggested by Sica DA et al. 33 Table 38 shows that the number of patients taking their antihypertensive drugs as single drugs is significantly higher than the number of patients taking their antihypertensive drugs in fixed dose combinations. Failure to follow a prescribed drug regimen has been implicated in approximately 50 percent of patients with resistant hypertension as per Setaro et al 21 and Miller NH et al. 34 In this study only 40 patients or 17.17% of patients gave a history of noncompliance which was significantly lower than the number of patients who gave a history of being compliant to their antihypertensive medications (82.83%). (Referring table 42). On enquiry most of the patients said that they were compliant, there was no subjective method to test this. Electronic means for compiling ambulatory patient s drug dosing histories have now made it both technically and economically feasible to distinguish clearly between noncompliers and non-responders however since such devices weren t used in this study population compliance cannot be objectively assessed. Patients were not aware of the drugs or the doses that they were taking. For this study written prescriptions were relied upon, but still doses of drugs were not available in some cases. In all 23.17% were unaware of the doses of their antihypertensive medications in this study which was significantly lower than the number of patients who said that they were aware of the doses of their medications. (Referring table 40). This could be due to the fact that predominantly educated and patients belonging to higher socioeconomic class present to this hospital. Conclusion : Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists and efforts should be made to optimize its management. LVH, CKD, Obesity, Diabetes are predictors of resistant hypertension and should be adequately treated. Secondary hypertension should be ruled out in patients with Refractory hypertension. Several classes of pharmacological agents which can increase blood pressure and contribute to treatment resistance should be avoided. Simplified prescribed regimens, longer acting combination drugs, frequent clinical visits with involvement of family members, recording of home B.P measurements, multidisciplinary approach involving nutritionists, pharmacists, and nurses and checking physiological makers of therapy can improve compliance. Diuretics in adequate dosage should be utilized to treat resistant hypertension. The patients of resistant hypertension are at many times higher risk of CVD and they should be started on aspirin and statins Indian Journal of Basic & Applied Medical Research Is Now with IC Value:

8 Tables and content: Table 1: Sex and Age group cross tabulation. Age group (Years) Percentage out of total female resistant hypertensive patients Percentage out of total male resistant hypertensive patients Percentage out of total resistant hypertensive patients F M < % 2.50% 1.70% % 5.00% 3.90% % 14.30% 13.30% % 26.10% 27.00% % 26.90% 26.60% % 19.30% 22.30% % 5.90% 5.20% Total % % % Indian Journal of Basic & Applied Medical Research Is Now Officially listed in HIFA & CABI, UK 222

9 Percentage of total drugs taken Percentage of Drug Classes Taken Figure 1: Percentage of drug classes of anti-hypertensive medications being taken by patients with resistant hypertension. Percentage of Antihypertensive Drugs Percentage drugs6 drugs 5 drugs 4 drugs 3 drugs Figure 2:Percentage of antihypertensive drugs being used in patients with Resistant hypertension. 223

10 Table 2: Use of fixed dose combination antihypertensive drugs out of total number of antihypertensive drugs in this study population No of antihypertensives being taken by the patient No of patients taking 2 antihypertensive drugs as fixed dose pill No of patients taking 4 antihypertensive drugs in combination (2 +2) drugs No of patients taking 3 antihypertensive drugs as fixed dose pill No of patients taking their antihypertensives as single drugs 7 drugs drugs drugs drugs drugs Total Table 3: Number and percentage of patients with resistant hypertension unaware of the doses of their antihypertensive medications. No of drugs Number of patients unaware of dose Total number of patients Percentage of patients unaware of dose 7 drugs drugs drugs drugs drugs Total

11 Number of cases Compliant and Non-compliant Cases and Percentage Number Percentage Figure 3: Total number and percentage of compliant and noncompliant cases. Patients Taking Drugs Contributing to Resistant Hypertension Number of patients Figure 4: Patients taking drugs contributing to resistant hypertension 225

12 Table 4: Comparison ofthe number of patients taking aspirin and those not taking aspirin in the study cohort. Number of patients Observed Proportion Test Proportion P value( by binomial test) Aspirin or aspirin (a) +dipyridamole used Not on aspirin (Significant) Total Table 5: Comparison of number of patients on statins and those not on statins in the study cohort. Number of patients Observed Proportion Test Proportion P value (by binomial test) Statins used (a) Statins not used (Significant) Table 6: Comparison of resistant hypertensive patients with a creatinine of <=1.5 or >1.5. Creatinine Number of patients Observed Proportion Test Proportion P value (by binomial patients) <= (a) > (Significant)

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