2018 Korean society of hypertension guidelines for the management of hypertension: part III-hypertension in special situations

It is important to detect white coat HTN [high office blood pressure (BP) but normal out-of-office BP] and masked HTN (normal office BP but high out-of-office BP) using out-of-office BP measurement. White coat effect is more frequently observed in women and older adults. If the diagnosis is not made correctly, it may result in side effects associated with unnecessary medication. Therefore, it is recommended to exclude white coat HTN as much as possible before initiating antihypertensive medication. In patients who are already on medication, it is important to check the effectiveness before adding medication for more aggressive treatment.

For the patients with white coat HTN, lifestyle modifications and regular BP monitoring are recommended. Although there is little evidence, pharmacological treatment as well as lifestyle modifications could be considered when metabolic disturbances and/or subclinical organ damage occurs with white coat HTN [5]. Pharmacological treatment for masked HTN may be beneficial because it has shown a similar cardiovascular (CV) risk profile as sustained HTN [4, 6, 7]. Masked HTN has a higher risk of cardiovascular disease (CVD), thus thorough treatment is considered. There are no clear criteria for the diagnosis of masked HTN and the threshold or reproducibility [8, 9]. However, masked HTN is more common in smokers or in patients with work-related stress and it is observed in about 30% among patients with prehypertension. Special attention should be paid to the patients with metabolic syndrome with high cardiovascular risk, target organ damage, diabetes mellitus (DM), chronic kidney disease (CKD), smokers, heavy drinking, exercise induced hypertension, and occupational stress for the diagnosis and treatment of masked HTN.

Many hypertensive patients have obesity and metabolic abnormalities with alterations of lipid and glucose metabolism. Furthermore, subclinical organ damage is common in these patients. Metabolic syndrome consists of abdominal obesity, dyslipidemia, dysglycemia, and raised BP. The criteria for clinical diagnosis of metabolic syndrome are: 1) abdominal obesity; 2) fasting glucose ≥100 mg/dL (diabetes included); 3) triglycerides ≥150 mg/dL; 4) high-density lipoprotein (HDL)-cholesterol < 40 mg/dL in men and < 50 mg/dL in women; and 5) BP ≥130/85 mmHg [15]. Presence of three or more of these criteria confirms the diagnosis of metabolic syndrome. Abdominal obesity is usually estimated by the measurement of waist circumference. However, cut-off points of waist circumference for abdominal obesity in Korean adults are not established. Cut-off points of waist circumference, which are commonly used, are 1) ≥90 cm in men; ≥80 cm in women (International Obesity Task Force criteria for Asian-Pacific population); and 2) ≥90 cm in men; ≥85 cm in women (Korean adult specific values) [15, 16].

The prevalence of metabolic syndrome has been increased over the last 10 years, as reported in the Korean National Health and Nutritional Survey. The prevalence of metabolic syndrome in Korean aged over 30 years is 30.5% [17]. However, the prevalence of metabolic syndrome is twice as high among the hypertensive patients [18].

In Western countries, people with metabolic syndrome have at 1.5–2-fold higher risk of CV events and death than those without metabolic syndrome and incident diabetes is 5-fold higher in people with metabolic syndrome [19, 20].

In Asian countries, metabolic syndrome had a relative risk of incident diabetes of 3–4, which is a little lower compared to that in Western countries [21, 22]. The most powerful predictor of incident diabetes is hyperglycemia in people with metabolic syndrome. However, metabolic syndrome, even without hyperglycemia, was associated with an increased risk of incident diabetes; the relative risk is 2.4 in Japanese population [22]. In addition to metabolic syndrome, HTN is associated with twice higher risk of incident diabetes [23, 24].

In hypertensive patients with metabolic syndrome, antihypertensive treatment is used to prevent CV morbidity and mortality, while lowering or preventing incident diabetes. Antihypertensive treatment in non-diabetic patients with metabolic syndrome is discussed below, while that treatment for diabetic/CVD patients with metabolic syndrome is discussed in other respective sections of the special situations chapter. Lifestyle modifications, especially weight reduction and regular exercise, are strongly recommended in all hypertensive patients, as they decrease BP, improve metabolic abnormalities, and delay incident diabetes [10, 11].

Hypertensive patients should be treated with antihypertensive medication as well as lifestyle modification, but there is no evidence available for the drug treatment in prehypertensive patients [12‐14].

Antihypertensive drugs should lower BP effectively as well as have favorable or neutral effects on insulin sensitivity and metabolic abnormalities. Thus, ACE inhibitors, ARBs, and calcium channel blockers are preferred. Among beta-blockers, vasodilating beta-blockers such as carvedilol and nebivolol can be used as combination therapy with ACE inhibitors/ARBs.

Thiazides and thiazide-like diuretics are avoided as monotherapy or at high doses, but are used as combination therapy or at low doses. High dose diuretics can induce hypokalemia and new onset diabetes, and have unfavorable effects on lipid metabolism. The preferred approach is combination of ACE inhibitors/ARBs with diuretics to minimize their unfavorable effects on glucose and lipid metabolism.

The prevalence of HTN is two-fold in diabetic patients compared to that in the general population, and the occurrence of diabetes is 2.5-fold higher in hypertensive patients [37, 38]. The coexistence of HTN and diabetes causes the progression of CVD, stroke, and renal disease. The high risk of HTN in diabetic patients is related with weight gain, hyperinsulinemia, sympathetic hyperactivity, and salt retention. Additionally, hyperglycemia itself can further increase the risk of HTN by increasing arterial stiffness and progressing atherosclerosis. The nocturnal dipping disappears in diabetic patients, and it is associated with subclinical organ damage such as left ventricular hypertrophy (LVH) and microalbuminuria. In the UK Prospective Diabetes Study (UKPDS)-36, each 10 mmHg decrease in mean systolic blood pressure (SBP) was associated with risk reductions of 12% for any complication related to diabetes, 15% for deaths related to diabetes, 11% for myocardial infarction, and 13% for microvascular complications [39]. Previous studies have shown that appropriate BP control can reduce the incidence of CVD [34, 40‐43].

The recommended target for BP in diabetic patients is < 140/85 mmHg. In previous guidelines, the recommended BP was < 130/80 mmHg or < 140/80 mmHg in diabetic patients [34, 40‐43]. However, recent studies have failed to show any beneficial effect on CV outcome with strict BP control [28, 44]. Due to the beneficial effect of strict BP control in Systolic Blood Pressure Interventional Trial (SPRINT)-eligible patients among Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, BP should be lowered less than 130/80 mmHg in patients with diabetes and CVD [33].

According to a recent meta-analysis, all classes of antihypertensive agents, such as ACE inhibitors, ARBs, calcium channel blockers, beta-blockers and diuretics can be used in diabetic patients [31]. However, ACE inhibitors/ARBs are recommended as first-line antihypertensive therapy in patients with microalbuminuria or proteinuria [32, 34‐36]. The superiority of one antihypertensive class over others is controversial. The choice of a particular class is less significant in practice because two or more antihypertensives should be combined in order to obtain sufficient decrease in BP in most diabetic patients. However, the combination of beta-blockers and thiazide diuretics is not recommended as it could worsen glucose control by increasing insulin resistance. Sodium-glucose co-transporter-2 (SGLT-2) inhibitor can decreased BP, thus it should be used cautiously with antihypertensive medication [45‐47].

The treatment of HTN in older adults reduces the risk of CVD and mortality. The benefit of treatment is also observed with regard to isolated systolic HTN. Accordingly, HTN needs to be actively diagnosed and treated in older adults.

However, the benefit of pharmacological treatment for grade I hypertensive patients older than 80 years remains controversial. Thus, the characteristics of the patient should be considered. The characteristic findings of elderly hypertensive patients are increased SBP and widened pulse pressure due to increased central arterial stiffness. Moreover, atherosclerotic renovascular HTN is commonly observed. Non-dipper, increased daytime BP variability, and orthostatic or postprandial hypotension are also characteristic findings in elderly patients with HTN.

The non-pharmacological treatment in elderly HTN patients is effective; however, the impact on the patient’s quality of life should be considered [50]. Target SBP for older patients is < 140 mmHg, but orthostatic hypotension should be avoided [51]. Additional studies are required to confirm the target SBP among the frail older patients. The initial dose of the pharmacological treatment is reduced by half in younger patients, and gradually increased. Elderly hypertensive patients without co-morbidities should be treated with ACE inhibitors, ARBs, calcium channel blockers, and diuretics [52‐55]. Beta-blockers do not improve prognosis as much as other drug classes in elderly hypertensive patients. However, beta-blockers would be effective in patients with angina, heart failure, or tachycardia. Combination therapy with two or more drugs should be considered if the BP is not controlled with monotherapy. Patients with co-morbidities require special consideration. It is safe to slowly lower the BP in elderly patients. Complications caused by medication should be monitored when increasing the drug dose. Orthostatic hypotension should be periodically checked by positional BP measurement.

CKD is defined as the presence of kidney injury for > 3 months, with markers of kidney injury being a decrease in estimated glomerular filtration rate (eGFR) (< 60 mL/min/1.73 m²), urinary abnormalities including albuminuria (> 30 mg/day or albumin-to-creatinine ratio > 30 mg/g), hematuria and pyuria, electrolyte disturbances caused by tubular dysfunction, renal structural abnormalities detected by imaging or biopsy procedures, and renal transplants. CKD patients frequently suffer from HTN; hence, the rate of decline in renal function and the incidence of CV complications can be reduced with HTN control [105, 106]. However, we still need to determine the target BP levels, optimal tools to be used in HTN control, and the real benefits and risks associated with treatment [107].

The recent 2017 American College of Cardiology/American Heart Association/American Society of Hypertension guideline recommended a BP target of < 130/80 mmHg in all CKD patients [108]. However, previous major clinical trials failed to show any beneficial effect of strict BP control in non-proteinuric CKD patients. Accordingly, CKD patients without albuminuria are recommended to maintain BP < 140/90 mmHg [109‐111]. On the other hand, randomized controlled trials have suggested that a lower target may be beneficial in proteinuric CKD patients. Thus, we recommend that CKD patients with albuminuria should be treated to maintain SBP < 130 mmHg [30, 112‐114]. BP target levels do not depend on the presence of DM.

Lifestyle modifications should be used as a basic tool for BP control in all hypertensive CKD patients. Although no large scale randomized controlled trials have reported the effects of lifestyle modification on clinical outcomes in CKD patients, the beneficial effects can be inferred from the results reported in previous studies in general populations [115‐121]. The 2011–2014 Korea National Health and Nutrition Examination Survey showed that body mass index (BMI) associated with the risk of CKD [122]. We recommend achieving or maintaining a healthy weight (BMI 20 to 25), lowering salt intake to < 90 mmol (< 2 g) per day of sodium unless contraindicated, undertaking regular exercise compatible with CV health and tolerance, limiting alcohol intake to < 2 standard drinks per day for men and < 1 standard drink per day for women.

Pharmacological treatment in CKD patients includes single or multiple antihypertensive therapies to achieve the target BP. Although any antihypertensive can be used in CKD patients, ACE inhibitors or ARBs have been reported to be renoprotective owing to the reduction in albuminuria and improvement in the rate of decline of the glomerular filtration rate [30, 102‐104]. Thus, we recommend that ACE inhibitors or ARBs should be used in CKD patients with albuminuria. ACE inhibitors or ARBs are preferred in both diabetic and non-diabetic CKD patients with either microalbuminuria (30–300 mg/day) or macroalbuminuria (> 300 mg/day). However, the combination of ACEIs and ARBs in CKD patients are not recommended.

It should be noted that there are occasions when the BP target and the preferred agent mentioned above may be inappropriate. Treatment should be individualized based on the patient’s age, presence of albuminuria and comorbidities. Diabetic or elderly patients need to be questioned about orthostatic dizziness because of the possibility of postural hypotension [123‐125]. ACE inhibitors and ARBs are contraindicated in bilateral renal artery stenosis, and should be used with caution in patients with diffuse atherosclerosis.

The risk of ischemic and hemorrhagic stroke increases proportionally as the BP increases, with HTN being the most common modifiable risk factor in stroke prevention and having the highest attributable risk for stroke in the population. HTN treatment, particularly SBP control, will remarkably reduce the incidence of stroke. For the management of high BP, lifestyle modifications (weight loss, low-fat diet, reduced salt intake, exercise or physical activity, moderation of alcohol intake, and smoking cessation) must routinely precede drug therapy. According to an epidemiologic study, with each increase of 20/10 mmHg from BP level of 115/75 mmHg or higher, deaths from stroke increased at least two-fold. Conversely, a 10/5 mmHg decrease in BP resulted in a 40% decrease in deaths from stroke [61]. In addition, a meta-analysis of clinical studies showed that stroke risk was expected to decrease by about 30–40% by lowering the BP by 10/5 mmHg with drug therapy, regardless of the past history of the patient [63, 126, 127]. For the primary prevention of stroke, it is recommended to maintain the BP < 140/90 mmHg. Although it remains unknown whether a specific drug or class is superior to other antihypertensive drugs in the prevention of stroke, a limited number of reports have shown that calcium channel blockers, ACE inhibitors, or ARBs are superior to beta-blockers [128]. However, for the primary prevention of stroke, it is most important to lower the BP based on an individualized approach for each patient rather than the choice of a specific drug or drug class [129].

Erectile dysfunction is considered to be one of the a CV risk factors associated with poor prognosis [161]. Therefore, risk factors such as DM, dyslipidemia, and smoking should be controlled aggressively, and lifestyle modifications should be recommended to the patients with erectile dysfunction to reduce the CV risk. However, most cases of the erectile dysfunction are not properly diagnosed by doctors and only a minority of patients seeks medical advice. Therefore, more cautious history taking and comprehensive management are required for the improvement of CV prognosis among hypertensive patients with erectile dysfunction [162].

In general, the prevalence of erectile dysfunction associated with antihypertensive medication is reported to be 0–25%, but the prevalence may be affected by underlying conditions such as endothelial dysfunction, and oxidative stress [163]. Erectile dysfunction related to antihypertensive medication is usually observed within 4 weeks. Beta-blockers and diuretics are known to cause erectile dysfunction, and ACE inhibitors and calcium channel blockers are neutral, whereas ARBs are reported to be beneficial [164]. A vasodilating beta-blocker such as carvedilol, nebivolol, and labetalol may be an alternative for hypertensive patients with erectile dysfunction. A phosphodiesterase-5 (PDE5) inhibitor is relatively safe and effective in patients with erectile dysfunction caused by antihypertensive medications, and the additional BP lowering effect is negligible. However, the BP after administration of PDE5 inhibitors should be closely monitored and PDE5 inhibitors must not be co-administered with nitrates [165, 166].

High BP occurring during pregnancy can be divided into four categories: 1) chronic HTN in pregnancy: existing HTN or taking antihypertensive medication before the 20th week of pregnancy; 2) gestational HTN: newly diagnosed HTN after the 20th week of pregnancy in the absence of proteinuria; 3) pre-eclampsia: HTN diagnosed after 20 weeks of pregnancy accompanied by proteinuria (albumin more than 300 mg in 24 h urine or urine albumin/creatinine ratio of 300 mg/g or greater); and 4) pre-eclampsia superimposed on chronic HTN: pre-eclampsia diagnosed in the chronic HTN pregnant women. Based on the BP level, it is classified as mild: 140–149/90–99 mmHg, moderate: 150–159/100–109 mmHg, and severe: 160/110 mmHg or higher.

Generally, there are few controversies regarding drug treatment for BP of > 160/110 mmHg or higher. Previous studies have reported that patients with BP > 150/95 mmHg are more likely to be hospitalized due to incident stroke during the peripartum period [167, 168]. In pregnancy, BP should be controlled below 150/100 mmHg, but it is not recommended to lower DBP below 80 mmHg [169, 170].

Antihypertensive drugs used during pregnancy are methyldopa, labetalol, and nifedipine. Specific drugs are selected in consideration of the drug class previously used, their side effects, and the risk of teratogenicity. Beta-blockers can cause fetal growth retardation, thus they can be used later in the pregnancy. Diuretics should be prescribed cautiously because they can induce volume depletion. ACE inhibitors or ARBs may increase the risk of congenital malformations in pregnancy, it is recommended to replace these drugs before pregnancy or when planning a pregnancy. If a pregnancy is detected during the administration of ACE inhibitors or ARBs, they should be discontinued and replaced promptly. In emergency situations, such as pre-eclampsia, intravenous labetalol is recommended but intravenous nitroprusside or nitroglycerin could be alternatives. After delivery, BP should be controlled below 140/90 mmHg.

Gestational HTN and preeclampsia are associated with an increased risk of developing HTN after delivery and pre-eclampsia is a risk factor for CVD. Patients with a history of pre-eclampsia have about a two-fold risk of ischemic heart disease, stroke, and venous thrombosis and a four-fold risk of developing sustained HTN. Especially in cases of preeclampsia within 32 weeks of gestation, stillbirth, and fetal growth retardation, the risk of HTN increases much more. Thus, active BP control and lifestyle modification even after delivery is strongly recommended for patients with HTN during pregnancy.

In younger populations, women have lower prevalence of HTN than men. But after menopause, the prevalence of HTN in women increases rapidly as reaches the prevalence in men in their 60s and prevalence becomes even higher than that in men in their 70s or 80s. As for age, the increase in pulse pressure is the same between men and women, however, the systolic and diastolic BPs are higher in women after menopause. Care should be taken in the diagnosis of HTN in menopausal women, because white coat HTN occurs more frequently in these women.

After menopause, weight gain, hormonal changes, and psychological changes occur [171]. In particular, the deficiency of estrogen induces menopausal symptoms and CV events [172]. In the past, hormone replacement therapy (HRT) was widely recommended after menopause, but clinical studies found no beneficial effects for CVD or it sometimes worsened, and therefore, HRT is no longer recommended. Because HRT can increase BP, women who have a greater chance of developing HTN need to be carefully observed for a few months [173].

There is no difference in HTN treatment between women and men. Additionally, there is no difference in BP reduction and drug effects between women and men [174]. Oral contraceptives can increase BP in some subjects, and the occurrence of accelerated or malignant HTN is rare. Family history of HTN, past history of HTN during pregnancy, kidney disease, obesity, or oral contraceptive use can increase the risk of BP increase. Therefore, in the early period of oral contraceptive use, BP needs to be carefully monitored, while periodic measurements are recommended thereafter.

Continuous positive airway pressure (CPAP) therapy is effective in improving sleep apnea. However, in studies concerning sleep apnea, CPAP was reported cause a 2–3 mmHg decrease of BP, and the effects differed according to adherence, disease severity, and daytime sleepiness [175‐177, 179].

Vascular disease and its related factors are the major risk factors of dementia, including Alzheimer’s disease [185, 186]. HTN is a major risk factor for ischemic microvascular disease and cerebral white matter disease, which can lead to cognitive dysfunction by damaging the cerebral nerve circuit [187‐189]. It has been reported that Alzheimer’s dementia and other dementia were less likely to develop when systolic BP was well controlled. Furthermore, it was more effective in preventing dementia when treatment was started individuals in their 50s rather than in those treated in their 60s [185, 190]. In most randomized clinical trials, HTN treatment did not have a negative impact on cognitive dysfunction and dementia. However, results from studies have been inconsistent due to lack of study power, insufficient follow-up duration, and inadequate tools for cognitive evaluation [55, 180‐184].