Hypertension Treatment & Management

Effective management and treatment of hypertension requires clinicians and patients to work together to balance pharmacologic and nonpharmacologic interventions and prevent target organ damage. ^[3]

The 2016 American Diabetes Association's (ADA's) standards of medical care in diabetes indicate that a majority of patients with diabetes mellitus have hypertension. In patients with type 1 diabetes, nephropathy is often the cause of hypertension, whereas in type 2 diabetes, hypertension is one of a group of related cardiometabolic factors. ^{[70, 71]}  Hypertension remains one of the most common causes of congestive heart failure (CHF). Antihypertensive therapy has been demonstrated to significantly reduce the risk of death from stroke and coronary artery disease.

Other studies have demonstrated that a reduction in blood pressure (BP) may result in improved renal function. Therefore, earlier detection of hypertensive nephrosclerosis (using means to detect microalbuminuria) and aggressive therapeutic interventions (particularly with angiotensin-converting enzyme inhibitor drugs [ACEIs]) may prevent progression to end-stage renal disease. ^[12]

NOTE:  A group was empaneled to write the Eighth Joint National Committee (JNC 8) guideline, but this effort was discontinued by the National Heart, Lung, and Blood Institute (NHLBI). A paper was published in The Journal of the American Medical Association in 2014 that is generally referred to as "JNC 8" but officially, there are no JNC 8 guidelines sanctioned by the NHLBI, nor has JNC 8 been endorsed by the American Heart Association (AHA), American College of Cardiology (ACC), or many other organizations that endorsed JNC 7. 

2017 ACC/AHA guidelines

The 2017 ACC/AHA guidelines eliminate the classification of prehypertension and divides it into two levels ^{[1, 2]} : (1) elevated BP, with a systolic pressure (SBP) between 120 and 129 mm Hg and diastolic pressure (DBP) less than 80 mm Hg, and (2) stage 1 hypertension, with an SBP of 130 to 139 mm Hg or a DBP of 80 to 89 mm Hg.

In adults at increased risk of heart failure (HF), the optimal BP in those with hypertension should be less than 130/80 mm Hg.

Adults with HFrEF (HF with reduced ejection fraction) and hypertension should be prescribed GDMT (guideline-directed management and therapy) titrated to attain a BP of less than 130/80 mm Hg.

Nondihydropyridine calcium channel blockers (CCBs) are not recommended in the treatment of hypertension in adults with HFrEF.

Adults with hypertension and chronic kidney disease (CKD) should be treated to a BP goal of less than 130/80 mm Hg.

After kidney transplantation, it is reasonable to treat patients with hypertension to a BP goal of less than 130/80 mm Hg. After kidney transplantation, it is reasonable to treat patients with hypertension with a calcium antagonist on the basis of improved glomerular filtration rate (GFR) and kidney survival.

Immediate lowering of SBP to lower than 140 mm Hg in adults with spontaneous intracerebral hemorrhage (ICH) who present within 6 hours of the acute event and have an SBP between 150 mm Hg and 220 mm Hg is not of benefit to reduce death or severe disability and can be potentially harmful.

Adults with acute ischemic stroke and elevated BP who are eligible for treatment with intravenous (IV) tissue plasminogen activator (tPA) should have their BP slowly lowered to below 185/110 mm Hg before thrombolytic therapy is initiated.

In adults with an acute ischemic stroke, BP should be less than 185/110 mm Hg before administration of IV tPA and should be maintained below 180/105 mm Hg for at least the first 24 hours after initiating drug therapy.

For adults who experience a stroke or transient ischemic attack (TIA), treatment with a thiazide diuretic, ACEI, or angiotensin receptor blocker (ARB), or combination treatment consisting of a thiazide diuretic plus ACEI, is useful.

In adults with an untreated SBP greater than 130 mm Hg but less than 160 mm Hg or a DBP greater than 80 mm Hg but less than 100 mm Hg, it is reasonable to screen for the presence of white coat hypertension by using either daytime ABPM (ambulatory BP monitoring) or HBPM (home BPM) before diagnosis of hypertension.

In adults with untreated office BPs that are consistently between 120 mm Hg and 129 mm Hg for SBP or between 75 mm Hg and 79 mm Hg for DBP, screening for masked hypertension with home BPM (or ABPM) is reasonable.

In adults with hypertension, screening for primary aldosteronism is recommended in the presence of any of the following concurrent conditions: resistant hypertension, hypokalemia (spontaneous or substantial, if diuretic induced), incidentally discovered adrenal mass, family history of early-onset hypertension, or stroke at a young age (< 40 years).

Adult men and women with elevated BP or hypertension who currently consume alcohol should be advised to drink no more than two and one standard drinks per day, respectively.

Two or more antihypertensive medications are recommended to achieve a BP target of less than 130/80 mm Hg in most adults with hypertension, especially in black adults with hypertension.

Women with hypertension who become pregnant should not be treated with ACEIs, ARBs, or direct renin inhibitors.

Use of BP-lowering medications is recommended for secondary prevention of recurrent cardiovascular disease (CVD) events in patients with clinical CVD and an average SBP of 130 mm Hg or higher or an average DBP of 80 mm Hg or higher, and for primary prevention in adults with an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk of 10% or higher and an average SBP of 130 mm Hg or higher or an average DBP of 80 mm Hg or higher.

Use of BP-lowering medication is recommended for primary prevention of CVD in adults with no history of CVD and with an estimated 10-year ASCVD risk below 10% and an SBP of 140 mm Hg or higher or a DBP of 90 mm Hg or higher.

Adults with an elevated BP or stage 1 hypertension who have an estimated 10-year ASCVD risk below 10% should be managed with nonpharmacologic therapy and have a repeat BP evaluation within 3 to 6 months.

Adults with stage 1 hypertension who have an estimated 10-year ASCVD risk of 10% or higher should be managed initially with a combination of nonpharmacologic and antihypertensive drug therapy and have a repeat BP evaluation in 1 month.

For adults with a very high average BP (eg, SBP ≥180 mm Hg or DBP ≥110 mm Hg), evaluation followed by prompt antihypertensive drug treatment is recommended.

Simultaneous use of an ACE, ARB, and/or renin inhibitor is potentially harmful and is not recommended to treat adults with hypertension.

2017 ACP/AAFP guidelines

The American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) released their guidelines regarding hypertension in adults aged 60 years, including the following ^[72] :

• Clinicians should initiate treatment in patients aged 60 years or older who have persistent SBP at or above 150 mm Hg to achieve a target of less than 150 mm Hg to reduce the risk for stroke, cardiac events, and death.
• If patients 60 years or older have a history of stroke or transient ischemic attack or have high cardiovascular risk, physicians should consider starting or increasing drug therapy to achieve an SBP of less than 140 mm Hg to reduce the risk for stroke and cardiac events.
• Consider initiating or intensifying pharmacologic treatment in some adults aged 60 years or older at high cardiovascular risk based on individualized assessment, to achieve a target SBP of less than 140 mm Hg to reduce the risk for stroke and cardiac events. Factors include comorbidity, medication burden, risk of adverse events, and cost. Generally, increased cardiovascular risk includes known cardiovascular disease, diabetes, or chronic kidney disease with a glomerular filtration rate of less than 45 mL/min/1.73 m ².

Lifestyle modifications

Lifestyle modifications are essential for the prevention of high BP, and these are generally the initial steps in managing hypertension. As the cardiovascular disease risk factors are assessed in individuals with hypertension, pay attention to the lifestyles that favorably affect BP level and reduce overall cardiovascular disease risk. A relatively small reduction in BP may affect the incidence of cardiovascular disease on a population basis. A decrease in BP of 2 mm Hg reduces the risk of stroke by 15% and the risk of coronary artery disease by 6% in a given population. In addition, a prospective study showed a reduction of 5 mm Hg in the nocturnal mean BP and a possibly significant (17%) reduction in future adverse cardiovascular events if at least one antihypertensive medication is taken at bedtime.

In a study that attempted to formulate a predictive model for the risk of prehypertension and hypertension, as well as an estimate of expected benefits from population-based lifestyle modification, investigators reported that the majority of risk factors have a larger role in prehypertension and stage 1 hypertension than in stage 2 hypertension. The investigators derived multistep composite risk scores by assessing significant risk factors in the progression from prehypertension to hypertension, as well as the regression of prehypertension to normal; they indicated that as the number of risk factors included in intervention programs increases, the size of the expected mean risk score decreases. In men, the 5-year predicted cumulative risk for stage 2 hypertension decreased from 23.6% (in the absence of an intervention program) to 14% (with 6-component intervention); the results were similar in women.

Cholesterol level targets

The top 10 key recommendations from the AHA, ACC, and multiple other medical societies for reducing the risk of ASCVD through cholesterol management are summarized below. ^{[73, 74]}

• Emphasize a heart-healthy lifestyle across the life course of all individuals.
• In patients with clinical ASCVD, reduce low-density lipoprotein cholesterol (LDL-C) levels with high-intensity statin therapy or the maximally tolerated statin therapy.
• In individuals with very high-risk ASCVD, use an LDL-C threshold of 70 mg/dL (1.8 mmol/L) to consider the addition of nonstatins to statin therapy.
• In patients with severe primary hypercholesterolemia (LDL-C level ≥190 mg/dL [≥4.9 mmol/L]), without calculating the 10-year ASCVD risk, begin high-intensity statin therapy.
• In patients 40 to 75 years of age with diabetes mellitus and an LDL-C level of ≥70 mg/dL: Start moderate-intensity statin therapy without calculating their 10-year ASCVD risk.
• In patients aged 40 to 75 years evaluated for primary ASCVD prevention: Have a clinician–patient risk discussion before starting statin therapy.
• Assess patient adherence and the percentage response to LDL-C–lowering medications and lifestyle changes with a repeat lipid measurement 4-12 weeks after initiation of statin therapy or dose adjustment; repeat every 3-12 months as needed.

In nondiabetic patients aged 40 to 75 years and with the following characteristics ^{[73, 74]} :

• LDL-C levels ≥70 mg/dL (≥1.8 mmol/L), at a 10-year ASCVD risk of ≥7.5%: Start a moderate-intensity statin if a discussion of treatment options favors statin therapy.

• A 10-year risk of 7.5-19.9% (intermediate risk): Risk-enhancing factors favor initiation of statin therapy.

• LDL-C levels ≥70-189 mg/dL (≥1.8-4.9 mmol/L), at a 10-year ASCVD risk of ≥7.5-19.9%: If a decision about statin therapy is uncertain, consider measuring coronary artery calcium (CAC) levels.

 

The American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) now recommend LDL goals of < 55 mg/dL, < 70 mg/dL, < 100 mg/dL, and < 130 mg/dL for individuals at extreme, very high, high/moderate, and low risk for cardiovascular events, respectively, as outlined below. ^[75]  

Extreme-risk patients: Goals: LDL < 55 mg/dL, non-HDL < 80 mg/dL, apolipoprotein B (apoB) < 70 mg/dL

• Progressive ASCVD, including unstable angina, in patients after achieving an LDL-C < 70 mg/dL

• Established clinical cardiovascular disease in patients with diabetes, chronic kidney disease (CKD) stages 3/4, or heterozygous familial hypercholesterolemia (HeFH)

• History of premature ASCVD (< 55 yr of age in men, < 65 in women)

Very-high-risk patients: Goals: LDL < 70 mg/dL, non-HDL < 80 mg/dL, apoB < 80 mg/dL

• Established or recent hospitalization for acute coronary syndrome; coronary, carotid, or peripheral vascular disease; 10-y risk >20%

• Diabetes or CKD stages 3/4 with one or more risk factors

• HeFH

High-risk patients: Goals: LDL < 100 mg/dL, non-HDL < 130 mg/dL, apoB < 90 mg/dL

• Two or more risk factors and 10-year risk 10-20%

• Diabetes or CKD stages 3/4 with no other risk factors

Moderate-risk patients: Goals: Same goals as high risk

• Two or more risk factors and 10-y risk < 10%

Low-risk patients: Goals: LDL < 130 mg/dL, non-HDL < 160 mg/dL, apoB not relevant

• 0 risk factors

Surgical intervention

Aortorenal bypass using a saphenous vein graft or a hypogastric artery is a revascularization technique for renovascular hypertension that has become much less common since the advent of renal artery angioplasty with stenting. Surgical resection is the treatment of choice for pheochromocytoma and for patients with a unilateral solitary aldosterone-producing adenoma, because hypertension is cured by tumor resection. Of note, patients with benign adenomas may be able to be treated with spironolactone instead of surgery. In patients with fibromuscular renal artery disease, angioplasty has a 60-80% success rate for improvement or cure of hypertension. Another intervention that initially seemed to hold great promise for the treatment of resistant hypertension is renal artery denervation. However, more recent controlled studies have suggested little benefit on BP from percutaneous renal denervation therapy, and ongoing studies are testing this intervention using newer techniques. ^[76]

Consultations

Consultations with a nutritionist and exercise specialist are often helpful in changing lifestyle and initiating weight loss. Consultation with a hypertension specialist is indicated for management of secondary hypertension attributable to a specific cause.

Dietary changes

A number of studies have documented an association between sodium chloride intake and BP. The effect of sodium chloride is particularly important in individuals who are middle-aged to elderly with a family history of hypertension. A moderate reduction in sodium chloride intake can lead to a small reduction in blood pressure. The American Heart Association recommends that the average daily consumption of sodium chloride not exceed 6 g; this may lower BP by 2-8 mm Hg. ^{[8, 77]}

One randomized controlled trial published found that moderate dietary sodium reduction (about 2500 mg Na⁺ or 6 g NaCl per day) added to angiotensin-converting enzyme (ACE) inhibition was more effective than dual blockade (ACE inhibitor [ACEI] and angiotensin II receptor blocker [ARB]) in reducing both proteinuria and BP in nondiabetic patients with modest chronic kidney disease. Furthermore, a low-sodium diet added to dual therapy yielded additional reductions in both BP and proteinuria, emphasizing the beneficial effect of dietary salt reduction in the management of hypertensive patients with renal insufficiency.

The DASH eating plan encompasses a diet rich in fruits, vegetables, and low-fat dairy products and may lower blood pressure by 8-14 mm Hg. The 2011 ADA standard of care supports the DASH diet, with the caution that high-quality studies of diet and exercise to lower blood pressure have not been performed on individuals with diabetes. ^{[71, 78]}

Dietary potassium, calcium, and magnesium consumption have an inverse association with BP. Lower intake of these elements potentiates the effect of sodium on BP. Oral potassium supplementation may lower both systolic and diastolic BP. ^[79] Calcium and magnesium supplementation have elicited small reductions in BP.

In population studies, low levels of alcohol consumption have shown a favorable effect on BP, with reductions of 2-4 mm Hg. However, the consumption of 3 or more drinks per day is associated with elevation of BP. Daily alcohol intake should be restricted to less than 1 oz of ethanol in men and 0.5 oz in women. The 2011 ADA standard supports limiting alcohol consumption in patients with diabetes and hypertension. ^{[71, 78]}

Emerging evidence based on small randomized controlled trials suggests that dark chocolate may lower BP via improved vascular endothelial function and increased formation of nitric oxide. A meta-analysis of 13 randomized controlled trials that compared dark chocolate with placebo confirmed a significant mean SBP reduction of -3.2 mm Hg and DBP reduction of -2 mm Hg in hypertensive and prehypertensive subgroups. ^[80] However, several important questions needs to be answered before dark chocolate can be universally recommended as a lifestyle intervention.

Although many studies implicate a high fructose diet as a contributing factor to the metabolic syndrome and hypertension, a 2012 review of Cochrane database disputed this relationship. ^[81]

Weight loss and exercise

Up to 60% of all individuals with hypertension are more than 20% overweight. The centripetal fat distribution is associated with insulin resistance and hypertension. Even modest weight loss (5%) can lead to reduction in BP and improved insulin sensitivity. Weight reduction may lower blood pressure by 5-20 mm Hg per 10 kg of weight loss in a patient whose weight is more than 10% of ideal body weight.

Regular aerobic physical activity can facilitate weight loss, decrease BP, and reduce the overall risk of cardiovascular disease. Blood pressure may be lowered by 4-9 mm Hg with moderately intense physical activity. ^[5] These activities include brisk walking for 30 minutes a day, 5 days per week. More intense workouts of 20-30 minutes, 3-4 times a week, may also lower BP and have additional health benefits. ^[5]

Blumenthal et al found that in overweight or obese patients with high BP, adding exercise and weight loss to the DASH diet resulted in even larger reductions in BP and cardiovascular biomarkers of risk. ^[82] The trial showed that after 4 months, clinic-measured BP was reduced by 16.1/9.9 mm Hg in patients in the DASH-plus-weight management group; by 11.2/7.5 mm Hg in the DASH-alone group; and by 3.4/3.8 mm Hg in a control group eating a usual diet. Compared with DASH alone, DASH plus weight management also resulted in greater improvement in pulse wave velocity, baroreflex sensitivity, and left ventricular mass. ^[82]

The 2016 and 2017 ADA diabetes standards support increasing physical activity. The recommendations emphasize that exercise is an important part of diabetes management in addition to reducing cardiovascular risk factors, contributing to weight loss, and improving overall well-being. ^{[71, 83]}  Moreover, patients with diabetes and severe hypertension (SBP ≥140 mm Hg or DBP ≥90 mm Hg) at diagnosis or afterward should receive drug therapy along with lifestyle modifications. ^{[71, 83]}

In 2018, the Physical Activity Guidelines Advisory Committee of the US Department of Health and Human Services (HHS) released their key recommendations, including the following ^{[84, 85]} :

• Regular physical activity minimizes excessive weight gain, helps maintain weight within a healthy range, improves bone health, and prevents obesity, even in children as young as 3-5 years.

• In pregnant women, physical activity helps reduce excessive weight gain in pregnancy and helps reduce the risk of developing gestational diabetes and postpartum depression.

• Regular physical activity has been shown to improve cognitive function and to reduce the risk of dementia; falls and fall-related injuries; and cancers of the breast, esophagus, colon, bladder, lung, endometrium, kidney, and stomach. It also helps retard the progression of osteoarthritis, type 2 diabetes, and hypertension.

• Children aged 3-5 years: Should be physically active throughout the day to enhance growth and development.

• Children aged 6-17 years: Sixty minutes or more of moderate-to-vigorous physical activity per day.

• Adults: At least 150-300 minutes per week of moderate-intensity aerobic physical activity, OR 75-150 minutes per week of vigorous-intensity aerobic physical activity, OR an equivalent combination of moderate- and vigorous-intensity aerobic activity; muscle-strengthening activities should be performed on two or more days per week.

• Older adults: Multicomponent physical activity to include balance training, aerobic activity, and muscle-strengthening activity.

• Pregnant and postpartum women: At least 150 minutes of moderate-intensity aerobic activity weekly.

• Adults with chronic conditions or disabilities who are able: Follow key guidelines and perform both aerobic and muscle-strengthening activities.

If lifestyle modifications are insufficient to achieve the goal blood pressure (BP), there are several drug options for the treatment and management of hypertension. Based on the Seventh Report of the Joint National Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the 2010 Institute for Clinical Systems Improvement (ICSI) guideline on the diagnosis and treatment of hypertension recommendations, thiazide diuretics were the preferred initial agents in the absence of compelling indications. ^[5]

However, the updated JNC 8 guidelines no longer recommend only thiazide-type diuretics as the initial therapy in most patients. According to the JNC 8 guidelines, angiotensin-converting enzyme inhibitors [ACEIs] /angiotensin receptor blockers [ARBs], calcium channel blockers [CCBs], and thiazide diuretics are equally efficacious in hypertensive non-black populations, whereas CCBs and thiazide diuretics are favored in black patients with hypertension. ^[10]

Compelling indications may include high-risk conditions that can be direct sequelae of hypertension (heart failure, ischemic heart disease, chronic kidney disease, recurrent stroke) or that are commonly associated with hypertension (diabetes, high coronary disease risk), as well as drug intolerability or contraindications. ^[5] In such compelling cases, another class of drugs should be initiated. An ACEI, ARB, and CCB are all acceptable alternative agents. Beta-blockers are no longer considered first-line therapy for hypertension, but these agents can be used in cases with compelling indications aside from hypertension, such as systolic heart failure. There are several opinions regarding which antihypertensive agents to use initially, because some patients may respond to a therapy that others may not.

The following are drug class recommendations for compelling indications based on various clinical trials ^[5] :

• Heart failure: Diuretic, beta-blocker, ACEI/ARB, aldosterone antagonist

• Following myocardial infarction: Beta-blocker, ACEI

• Diabetes: ACEI/ARB

• Chronic kidney disease: ACEI/ARB

Note that different stages of these diseases may alter their treatment management.

Multiple clinical trials suggest that most antihypertensive drugs provide the same degree of cardiovascular protection for the same level of BP control. Well-designed prospective randomized trials, such as the Swedish Trial in Old Patients with Hypertension (STOP-2), the Nordic Diltiazem (NORDIL) trial, and the Intervention as a Goal in Hypertension Treatment (INSIGHT) trial, have shown that older drugs (eg, diuretics, beta-blockers) and newer antihypertensive agents (eg, ACEIs, CCBs) have similar results.

In addition, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study concluded that there were no differences in primary coronary heart disease outcome or mortality for the thiazide-like diuretic chlorthalidone, the ACEI lisinopril, and the CCB amlodipine. ^[5] In a systematic review and meta-analysis, investigators also determined that in patients with essential hypertension without preexisting renal disease, no significant difference was found between Ras inhibitors and other antihypertensive agents in preventing renal dysfunction.

A post hoc analysis of data from the randomized ACCOMPLISH trial concluded that benazepril plus amlodipine (B+A) was more effective than benazepril plus hydrochlorothiazide (B+H) in reducing cardiovascular events in adults with high-risk stage 2 hypertension and coronary artery disease (CAD). ^{[86, 87]}

In this study, 5314 patients with CAD and 6192 without CAD were given B+A or B+H. Among patients with CAD, the incidence of cardiovascular events was 16% with B+H and 13% with B+A, a hazard reduction of 18% (P = 0.0016). ^{[86, 87]} The composite secondary endpoint of cardiovascular mortality, myocardial infarction, and stroke occurred in significantly fewer B+A patients than B+H patients (5.74% vs 8%; P = 0.033). All-cause mortality was 23% lower in the B+A arm (P = 0.042).

Single agent versus multiagent treatment approach

Over 50% of patients with hypertension will require more than one drug for blood pressure control. ^[7] In stage 1 hypertension, a single agent is generally sufficient to reduce BP, whereas in stage 2, a multidrug approach may be needed. Initiation of 2 antihypertensive agents, either as 2 separate prescriptions or as a fixed-dose combination, should also be considered when BP is more than 20 mm Hg above the systolic goal (or 10 mm Hg above the diastolic goal). ^[5]

Several situations demand the addition of a second drug, because 2 drugs may be used at lower doses to avoid the adverse effects that may occur with higher doses of a single agent. Diuretics generally potentiate the effects of other antihypertensive drugs by minimizing volume expansion. Specifically, the use of a thiazide diuretic in conjunction with a beta-blocker or an ACEI has an additive effect, controlling BP in up to 85% of patients.

The ALTITUDE trial was halted because it was shown that aliskiren can cause adverse events—nonfatal stroke, renal complications, hyperkalemia, and hypotension—when used in combination with an ACEI or an ARB in patients with type 2 diabetes and renal impairment who are at high risk of cardiovascular and renal events.

Hypertension is not only disproportionately high in diabetic individuals, but it also increases the risk of diabetes 2.5 times within 5 years in hypertensive patients. ^[5] In addition, hypertension and diabetes are both risk factors for cardiovascular disease, stroke, progression of renal disease, and diabetic retinopathy. ^[5]

For patients aged 18 years or older with diabetes, the 2013 Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure ("JNC 8") recommends initiating treatment at systolic blood pressure (SBP) levels of 140 mm Hg or greater or at diastolic BP (DBP) levels of 90 mm Hg or greater, and then treat to a goal BP below 140/90 mm Hg. ^{[88, 89]}

The JNC 7 and the 2016 American Diabetes Association (ADA) standard of medical care recommended blood pressure control in diabetic individuals be controlled to 130/80 mm Hg or lower, primarily to prevent or lower the risk of progression from diabetic nephropathy to end-stage renal disease. ^{[5, 71]}

This notion is being challenged by data from the ACCORD trial, which showed that in patients with type 2 diabetes, targeting an SBP of less than 120 mm Hg compared with less than 140 mm Hg did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. ^[90] A total of 4733 patients with type 2 diabetes were randomly assigned to intensive therapy or standard therapy, with a mean SBP of 119.3 mm Hg in the intensive group and 133.5 mm Hg in the standard group. No difference was observed in terms of primary outcome (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) and no difference was noted in annual rates of death from any cause.

However, annual rates of stroke, a prespecified secondary outcome, were significantly reduced in the intensive therapy group (0.32% vs 0.53%). Serious adverse events attributed to antihypertensive treatment was significantly greater in the intensive therapy group (3.3% vs 1.3%). Thus, other than a minor decrease in stroke rate, intensive BP control in diabetes did not improve outcome and was associated with a greater rate of serious adverse events.

In general, patients with diabetes type 1 or type 2 and hypertension have shown clinical improvement with diuretics, angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers, angiotensin receptor blockers (ARBs), and calcium antagonists. ^[5] Most studies, however, have shown superiority of ACEIs or ARBs over calcium antagonists in diabetic patients. A notable exception is the ACCOMPLISH trial, which showed that, in patients at high risk for cardiovascular events, the combination of benazepril (an ACEI) and amlodipine (a CCB), was superior to the combination of benazepril plus hydrochlorothiazide (a thiazide diuretic). ^[91] About 60% of the patient cohort had diabetes.

Two or more antihypertensive drugs at maximal doses should be used to achieve optimal BP targets in patients with diabetes and hypertension. ^[71] Either an ACEI or an ARB is usually required in patients with diabetes and hypertension. If the patient cannot tolerate one class of drugs, the other should be tried. If needed to achieve BP goals, a thiazide diuretic is indicated for those patients with an estimated GFR of 30 mL/min/1.73 m² or greater, and a loop diuretic is indicated for those with an estimated GFR of less than 30 mL/min/1.73 m². Regardless of which antihypertensive drugs are used, kidney function and serum potassium levels should be monitored. ^[71]

In a subgroup analysis from the TRINITY study (TRI ple therapy with olmesartan medoxomil, amlodipine, and hydrochlorothiazide in hyperteN sive patienT s studY), Chrysant et al reported that in patients with hypertension and diabetes, triple-combination drug therapy resulted in greater BP reductions and BP-goal achievement (< 130/80 mm Hg) than dual-combination drug therapy. The triple-combination regimen consisted of olmesartan medoxomil, 40 mg; amlodipine besilate, 10 mg; and hydrochlorothiazide, 25 mg.

Ruggenenti et al found that in patients with type 2 diabetes who have hypertension, combined manidipine and delapril therapy helped improve health in patients with cardiovascular disease, retinopathy, and neuropathy, as well as stabilized insulin sensitivity. ^[92] However, neither of these agents are available in the US.

A randomized, placebo-controlled study of 119 patients demonstrated that adding spironolactone to existing treatment in patients with resistant hypertension and diabetes mellitus significantly lowered blood pressure. Systolic and diastolic blood pressure were each significantly reduced in the spironolactone group and unchanged in the placebo group at 4 months. ^[93]

In a study that evaluated BP pattern changes during the development of hypertension in patients with or without diabetes mellitus using data from the Mexico City Diabetes Study (MCDS) and the Framingham Offspring Study (FOS), investigators found that although baseline diabetes mellitus was a significant predictor of incident hypertension, baseline hypertension was an independent predictor of incident diabetes mellitus. They indicated that development of hypertension and diabetes mellitus track each other over time; transition from normotension to hypertension was characterized by a sharp increase in BP values; and insulin resistance was not only a common feature of prediabetes and prehypertension, but it was also an antecedent of progression to the two respective disease states. ^[94]

2017 ADA guidelines

The ADA released updated guidelines in 2017, as follows ^[83] :

Blood pressure should be measured at every routine clinical care visit. Patients found to have an elevated blood pressure (≥140/90 mm Hg) should have blood pressure confirmed using multiple readings, including measurements on a separate day, to diagnose hypertension.

All hypertensive patients with diabetes should have home blood pressure monitored to identify white coat hypertension.

Orthostatic measurement of blood pressure should be performed during initial evaluation of hypertension and periodically at follow-up, or when symptoms of orthostatic hypotension are present, and regularly if orthostatic hypotension has been diagnosed.

Most patients with diabetes and hypertension should be treated to a systolic blood pressure goal of < 140 mm Hg and a diastolic blood pressure goal of < 90 mm Hg.

Lower systolic and diastolic blood pressure targets, such as < 130/80 mm Hg, may be appropriate for individuals at high risk of cardiovascular disease if they can be achieved without undue treatment burden.

For patients with systolic blood pressure >120 mm Hg or diastolic blood pressure >80 mm Hg, lifestyle intervention consists of weight loss if overweight or obese; a Dietary Approaches to Stop Hypertension (DASH)-style dietary pattern, including reduced sodium and increased potassium intake; increased fruit and vegetable consumption; moderation of alcohol intake; and increased physical activity.

Patients with confirmed office-based blood pressure ≥140/90 mm Hg should, in addition to lifestyle therapy, have timely titration of pharmacologic therapy to achieve blood pressure goals.

Patients with confirmed office-based blood pressure ≥160/100 mm Hg should, in addition to lifestyle therapy, have prompt initiation and timely titration of 2 drugs or a single-pill combination of drugs demonstrated to reduce cardiovascular events in patients with diabetes.

Treatment for hypertension should include drug classes demonstrated to reduce cardiovascular events in patients with diabetes: ACEIs, ARBs, thiazide-like diuretics, or dihydropyridine calcium channel blockers. Multiple-drug therapy is generally required to achieve blood pressure targets (but not a combination of ACEIs and ARBs).

An ACEI or ARB, at the maximum tolerated dose indicated for blood pressure treatment, is the recommended first-line treatment for hypertension in patients with diabetes and urine albumin-to-creatinine ratio ≥300 mg/g creatinine or 30–299 mg/g creatinine. If one class is not tolerated, the other should be substituted.

For patients treated with an ACEI, ARB, or diuretic, serum creatinine/estimated glomerular filtration rate and serum potassium levels should be monitored.

Pregnant women with diabetes and preexisting hypertension or mild gestational hypertension with systolic blood pressure < 160 mm Hg, diastolic blood pressure < 105 mm Hg, and no evidence of end-organ damage do not need to be treated with pharmacologic antihypertensive therapy.

In pregnant patients with diabetes and preexisting hypertension who are treated with antihypertensive therapy, systolic or diastolic blood pressure targets of 120–160/80–105 mm Hg are suggested in the interest of optimizing long-term maternal health and fetal growth.

Hypertensive emergencies are characterized by severe elevations in blood pressure (BP) (>180/120 mm Hg) associated with acute end-organ damage. ^[5] Examples include hypertensive encephalopathy, intracerebral hemorrhage, acute myocardial infarction, acute left ventricular failure with pulmonary edema, aortic dissection, unstable angina pectoris, eclampsia, ^[5] or posterior reversible encephalopathy syndrome (PRES) (a condition characterized by headache, altered mental status, visual disturbances, and seizures). ^[56] Patients with hypertensive emergencies should be monitored and managed in an intensive care unit. ^{[33, 95]}

The primary goal of the physician is to determine which patients with acute hypertension are exhibiting symptoms of end-organ damage and require immediate intravenous parenteral antihypertensive therapy. That is, the fundamental principle in determining the necessary emergent care of the hypertensive patient is the presence or absence of end-organ dysfunction.

Initial treatment goals are to reduce the mean arterial BP by no more than 25% within minutes to 1 hour. If the patient is stable, reduce the BP to 160/100-110 mm Hg within the next 2-6 hours. ^[5] Several parenteral and oral therapies can be used to treat hypertensive emergencies, such as nitroprusside sodium, hydralazine, nicardipine, fenoldopam, nitroglycerin, or enalaprilat. Other agents that may be used include labetalol, esmolol, and phentolamine. ^[5] Avoid using short-acting nifedipine in the initial treatment of this condition because of the risk of rapid, unpredictable hypotension and the possibility of precipitating ischemic events. ^[5] Once the patient’s condition is stabilized, the patient’s BP may be gradually reduced over the next 24-48 hours.

Exceptions to the above recommendation include the following ^[5] :

• Patients with an ischemic stroke (currently, no clear evidence exists for immediate antihypertensive treatment)

• Patients with aortic dissection (their systolic BP should be lowered to < 100 mm Hg, if tolerated)

• Patients in whom BP is lowered to allow thrombolytic therapy (eg, stroke patients)

Approximately 3-45% of adult patients presenting to an emergency department have at least one increased BP during their stay in the ED, but only a small percentage of patients will require emergency treatment. However, medical therapy and close follow-up are necessary in patients who present to the ED with acutely elevated BPs (systolic BP >200 mm Hg or diastolic BP >120 mm Hg) that remain significantly elevated until discharge. ^[96]

Guidelines recommendations

The 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommendations for hypertensive crises and emergencies include the following ^[1] :

• Admit adults with a hypertensive emergency to an ICU for continuous monitoring of BP and target organ damage, as well as for parenteral administration of an appropriate medication.
• For adults with a compelling condition (ie, aortic dissection, severe preeclampsia or eclampsia, or pheochromocytoma crisis), lower SBP to below 140 mm Hg during the first hour and to below 120 mm Hg in aortic dissection.
• For adults without a compelling condition, reduce the SBP to a maximum of 25% within the first hour; then, if the patient is clinically stable, lower the BP to 160/100 -110 mm Hg over the next 2-6 hours, and then cautiously to normal over the following 24-48 hours.

For further information, see the Medscape Drugs & Diseases article Hypertensive Emergencies in Emergency Medicine.

In patients who are pregnant, the goal of antihypertensive treatment is to minimize the risk of maternal cardiovascular or cerebrovascular events. Hypertensive disorders—categorized as chronic hypertension, preeclampsia, chronic hypertension with superimposed preeclampsia, gestational hypertension, and transient hypertension (see Table 3, below)— may contribute to maternal, fetal, or neonatal morbidity and mortality, particularly in the first trimester. ^[5]

Table 3. Hypertensive Disorders in Pregnancy (Open Table in a new window)

In normal pregnancy, women’s mean arterial pressure (MAP) drops 10-15 mm Hg over the first half of pregnancy. Most women with mild chronic hypertension (ie, systolic BP 140-160 mm Hg, diastolic BP 90-100 mm Hg) have a similar decrease in BP and may not require any medication during this period. Conversely, diastolic BP greater than 110 mm Hg has been associated with an increased risk of placental abruption and intrauterine growth restriction, and systolic BP greater than 160 mm Hg increases the risk of maternal intracerebral hemorrhage.

Lifestyle modifications are generally sufficient for the management of pregnant women with stage 1 hypertension who are at low risk for cardiovascular complications during pregnancy. ^[4] Restrictions to lifestyle modifications may include aerobic exercise (theoretical increased preeclampsia risk from inadequate placental blood flow) and weight reduction, even in obese pregnant women. Reduction of sodium intake and avoidance of tobacco and alcohol use are similar to those for individuals with primary hypertension. ^[5]

Although the primary risk of chronic hypertension in pregnancy is development of superimposed preeclampsia, no evidence suggests that pharmacologic treatment of mild hypertension reduces the incidence of preeclampsia in this population.

Antihypertensive therapy should be started in pregnant women if the systolic BP is greater than 160 mm Hg or the diastolic BP is greater than 100-105 mm Hg. The goal of pharmacologic treatment should be a diastolic BP of less than 100-105 mm Hg and a systolic BP of less than 160 mm Hg.

Women who have preexisting end-organ damage from chronic hypertension or who have previously required multidrug therapy for BP control should have a lower threshold for starting antihypertensive medication (ie, >139/89 mm Hg) and a lower target BP (< 140/90 mm Hg). The JNC 7 recommendations are to continue antihypertensive medication as needed to control BP and to reinstate antihypertensive therapy when the SBP is 150-160 mm Hg or the DBP is 100-110 mm Hg.

Selection of antihypertensive medication

Although reducing maternal risk is the goal of treating chronic hypertension in pregnancy, it is fetal safety that largely directs the choice of antihypertensive agent. Methyldopa is generally the preferred first-line agent because of its safety profile. ^[5] Other drugs that may be considered include labetalol, beta-blockers, and diuretics. Data are limited regarding the use of clonidine and calcium antagonists in pregnant women with chronic hypertension; however, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor (ARB) antagonists should be avoided because of the risk of fetal toxicity and death. ^[5]

For further information, see the Medscape Drugs & Diseases articles Hypertension and Pregnancy, Preeclampsia, and Eclampsia.

According to Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), pediatric hypertension is defined as high blood pressure (BP) that persists on repeated measurements, at the 95th percentile or higher for age, height, and sex. ^[5] More cases of chronic hypertension are seen in children who are obese, have inactive lifestyles, or have a family history of hypertension or cardiovascular disease. ^[5]

Guidelines recommendations

The 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines updated their definitions of BP categories and stages. ^[97]

In children up to age 13 years, BP categories and stages are defined as follows:

• Normal BP: Below 90th percentile
• Elevated BP: From the 90th percentile or higher to less than the 95th percentile or 120/80 mm Hg to below the 95th percentile (whichever is lower) 
• Stage 1 hypertension: From the 95th percentile or higher to less than the 95th percentile plus 12 mm Hg, or 130/80 to 139/89 mm Hg (whichever is lower) 
• Stage 2 hypertension: The 95th percentile or higher plus 12 mm Hg, or 140/90 mm Hg or higher (whichever is lower)

In children aged 13 years or older, BP categories and stages are defined as follows:

• Normal BP: SBP Less than 120 mm Hg and DBP less than 80 mm Hg (ie, < 120/< 80 mm Hg)
• Elevated BP: 120/below 80 mm Hg to 129/below 89 mm Hg (ie, 120/< 80 to 129/< 80 mm Hg)
• Stage 1 hypertension: 130/80 to 139/89 mm Hg
• Stage 2 hypertension: At 140/90 mm Hg or higher (≥140/90 mm Hg)

The 2017 American Academy of Pediatrics (AAP) recommendations include the following ^[97] :

• Measure BP yearly in all children and adolescents aged 3 years and older.
• Evaluate BP in all children and adolescents aged 3 years and older at every healthcare visit if they are obese, are taking medications known to increase BP, have renal disease, or a history of aortic arch obstruction or coarctation, or diabetes.
• Trained clinicians in the office setting should make a hypertension diagnosis children or adolescents in the presence of auscultatory-confirmed BP readings at or over the 95th percentile for age and height at three separate visits.
• Perform ambulatory BP monitoring (ABPM) to confirm hypertension in children and adolescents with elevated BP measurements for 1 year or longer or with stage 1 hypertension over three clinic visits.
• Perform ABPM in children and adolescents with suspected white coat syndrome; the diagnosis is based on a mean systolic BP (SBP) and diastolic BP below the 95th percentile and an SBP and DBP load less than 25%.
• Children and adolescents aged 6 years and older do not need to undergo extensive evaluation for secondary causes of hypertension if there is a family history of hypertension, they are overweight/obese, and/or do not have a history or physical examination findings suggestive of a secondary cause of hypertension.
• In children and adolescents undergoing evaluation for high BP, obtain a perinatal history, appropriate nutritional history, physical activity history, psychosocial history, and family history, as well as perform a physical examination to identify findings suggestive of secondary causes of HTN.
• At the time when pharmacologic therapy for hypertension is being considered, perform echocardiography to evaluate for cardiac target organ damage (LV mass, geometry, and function).
• Hypertensive children and adolescents being evaluated for left ventricular hypertrophy (LVH) should not undergo electrocardiography.
• LVH should be defined as an LV mass greater than 51 g/m ² (males and females) for children and adolescents older than age 8 years and defined by an LV mass greater than 115 g/body surface area (BSA) (boys) or more than 95 g/BSA (girls).
• Screening Doppler renal ultrasonography may be used to assess for potential renal artery stenosis (RAS) in normal weight children and adolescents age 8 years and older with suspected renovascular hypertension
• Routine testing for microalbuminuria is not recommended for children and adolescents primary hypertension.
• Nonpharmacologic and pharmacologic treatment goals in children and adolescents diagnosed with hypertension should be a reduction in SBP and DBP to below the 90th percentile and less than 130/80 mm Hg in adolescents aged 13 years and older.
• Failure of lifestyle modifications in hypertensive children and adolescents (especially those with LVH on echocardiography, symptomatic hypertension, or stage 2 hypertension without a clearly modifiable factor) should prompt initiation of pharmacotherapy with an angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), long-acting calcium channel blocker (CCB), or thiazide diuretic.
• Evaluate children and adolescents with chronic kidney disease (CKD) for hypertension at each medical encounter. In the presence of both CKD and hypertension, treat to lower the 24-hour mean arterial pressure (MAP) below the 50th percentile by ABPM. Regardless of apparent BP control with office measures, assess BP by ABPM at least yearly to screen for masked hypertension in children and adolescents with both CKD and hypertension.
• Evaluate for proteinuria in children and adolescents with both CKD and hypertension. If all three conditions are present, treat with an ACEI or ARB.
• Evaluate children and adolescents with type 1 or 2 diabetes for hypertension at each medical encounter. Treat if the BP is at or over the 95th percentile or more than 130/80 mm Hg in adolescents aged 13 years and older.

Lifestyle interventions should be initiated in all hypertensive children. When lifestyle modifications are inadequate for BP control or are unsuccessful in patients with more elevated BP, pharmacologic therapy must be considered. ^[5]  In general, the selection of antihypertensive agents in children is similar to that in adults, but the doses are smaller and must be closely titrated. Extreme cautions are necessary with antihypertensive therapy in sexually active teenage girls and in those who are pregnant; ACEI and ARBs should not be used.

Continuous IV infusions are the most appropriate initial therapy in acutely ill infants with severe hypertension. The advantages of IV infusions are numerous; the most important advantage is the ability to quickly increase or decrease the rate of infusion to achieve the desired BP. As in patients of any age with malignant hypertension, care must be taken to avoid too rapid a reduction in BP, so as to avoid cerebral ischemia and hemorrhage. Premature infants, in particular, are already at increased risk because of the immaturity of their periventricular circulation. Because of the paucity of available data regarding the use of these agents in newborns, the choice of agent depends on the individual clinician’s experience.

In a large study that evaluated the incidence of hypertension, associated risk factors, and the use of antihypertensive drugs in the neonatal intensive care unit (NICU) setting, the risk for hypertension was found to be greatest in neonates with a high severity of illness assessment, extracorporeal membrane oxygenation (ECMO), coexisting renal disorder, and renal failure. ^[98] Nearly 58% of infants received antihypertensive therapy, with a median duration of 10 days, and 45% received more than one agent. The most common antihypertensive drugs were vasodilators (64.2% of hypertensive neonates), followed by ACEIs (50.8%), calcium channel blockers (24%), and alpha- and beta-blockers (18.4%). ^[98]

For further information, see the Medscape Drugs & Diseases article Pediatric Hypertension.

2017 ACP/AAFP guidelines

The American College of Physicians (ACP) and American Academy of Family Physicians (AAFP) released updated guidelines on the pharmacologic treatment of hypertension in adults aged 60 years and older in January 2017. ^{[72, 99]}  A few of their recommendations are outlined below.

Clinicians should initiate treatment in patients aged 60 years or older who have persistent systolic blood pressure (SBP) at or above 150 mm Hg to achieve a target of below 150 mm Hg to reduce the risk for stroke, cardiac events, and death.

If patients 60 years or older have a history of stroke or transient ischemic attack or have a high cardiovascular risk, physicians should consider starting or increasing drug therapy to achieve an SBP of less than 140 mm Hg to reduce the risk for stroke and cardiac events.

Consider initiating or intensifying pharmacologic treatment in some adults aged 60 years or older at high cardiovascular risk based on an individualized assessment, to achieve a target SBP of below 140 mm Hg to reduce the risk of stroke or cardiac events. Factors include comorbidity, medication burden, risk of adverse events, and cost. Generally, an increased cardiovascular risk includes known cardiovascular disease, diabetes, or chronic kidney disease with a glomerular filtration rate (GFR) of less than 45 mL/min/1.73 m².

2014 "JNC 8" guidelines

The Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) recommends for patients aged 60 years or older, initiate therapy in those who have SBP levels at 150 mm Hg or greater or whose diastolic BP levels are 90 mm Hg or greater and to treat to below those thresholds. ^{[88, 89]} These guideline recommendations are based on the results of several trials demonstrating a lack of benefit for a more stringent SBP goal than 140 mm Hg. ^{[100, 101]} However, more recently, this has been challenged by results of the Systolic Blood Pressure Intervention Trial (SPRINT) study, particularly a prespecified subgroup analysis in elderly patients older than 75 years who exhibited reduced overall mortality with an SBP target less than 120 mm Hg rather than 140 mm Hg. ^[102] Although the results of the SPRINT substudy are intriguing, more research will be necessary to determine the optimal BP targets in the elderly, particularly those with diabetes or prior stroke, who were excluded from the SPRINT trial.

The classic trials for treatment of isolated systolic hypertension in the elderly are the Systolic Hypertension in the Elderly Program (SHEP) ^[103] and the Systolic Hypertension in Europe (Syst-EUR) ^[104] studies. Systolic pressure continues to rise progressively throughout life, reaching the highest levels in later stages of life. By the age of 60 years, of those with hypertension, about two thirds have isolated systolic hypertension, and by the age of 75 years, nearly all hypertensive patients have systolic hypertension, of which three quarters of cases are isolated hypertension. ^[5] Furthermore, severe arteriosclerosis may lead to pseudohypertension. Isolated hypertension results in low cardiac output because of the decreased stroke volume and high peripheral resistance. This may reduce glomerular filtration further, which is why low activity of renal angiotensin aldosterone cascade is encountered in elderly individuals who are hypertensive.

Despite low plasma renin activity (PRA), blood pressure responds well to angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapy. Low doses of diuretics may also be effective. Thiazide-type diuretics may be particularly beneficial for patients aged 55 years or older with hypertension or CVD risk factors and for patients aged 60 years or older with isolated systolic hypertension. ^[7] The SHEP trial found that chlorthalidone stepped-care therapy for 4.5 years was associated with a longer life expectancy at 22-year follow-up in patients with isolated systolic hypertension. ^[103] The Syst-Eur trial used a study design and sample size similar to those of the SHEP trial, in which treatment with the CCB nitrendipine resulted in significant reduction in stroke and overall CVD events. ^[104]

Calcium antagonists are quite useful because of their strong antihypertensive effects. Often, combining 2 drugs at a lower dose may be preferable to using a single drug at a high dose, because of the potential for adverse effects with the higher dose. Beta-blockers may not be as effective as other first-line agents in patients aged 60 years and older, especially for stroke prevention, and should probably be used when other indications are present, such as heart failure, previous myocardial infarction, and angina. ^[7]

Elderly patients should also be encouraged to lose weight if necessary, be more physically active, reduce their salt intake, and avoid excessive alcohol intake. ^[5]

 

For black patients, relative to non-Hispanic white persons, hypertension is more common and more severe, develops earlier, results in more clinical sequelae, and is associated with other comorbidities (eg, cardiovascular risk factors). ^[5] As with all prehypertensive and hypertensive patients, weight and sodium reduction (eg, DASH diet) can be effective for BP control.

The Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure ("JNC 8") recommends initiating therapy with a thiazide-type diuretic or calcium channel blocker (CCB) in black patients with hypertension. ^{[88, 89]} In addition, regardless of race or diabetes status, in patients 18 years or older with CKD, initial or add-on therapy should consist of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) but not both (ie, do not use an ACEI and an ARB in the same patient). ^{[88, 89]}

Beta-blocker, ACEI, or ARB monotherapy in black patients may be less effective for BP reduction than in white patients. ^[5] In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), thiazide-type diuretics or CCBs were more effective than ACEIs in black patients. However, combination therapy with a diuretic and agents of the other drug classes eliminated the differences in BP reduction between racial groups. ^[5] In general, therapy is initiated at the lowest recommended dose of the selected agent; then, it is titrated upward, or another drug is added to reach the goal BP. ^[7]

In one study, Weinberger et al reported that the combination of aliskiren and amlodipine, a calcium channel blocker, was more effective than amlodipine alone in treating black patients with stage 2 hypertension and obesity or metabolic syndrome. ^[105] However, in December 2011, Novartis, the manufacturer of aliskiren, terminated the ALTITUDE study because of an increased incidence of adverse events (nonfatal stroke, renal complications, hyperkalemia, hypotension) when aliskiren was added to ACEI or ARB therapy. The study involved patients with type 2 diabetes and renal impairment at high risk for cardiovascular and renal events.

Hypertension, especially stage 2 hypertension, can affect the retina, choroid, and optic nerve, as well as increase intraocular pressure (IOP). ^[5] In hypertensive retinopathy, the most common finding is generalized or focal narrowing of the retinal arterioles; occlusion or leakage of the retinal vessels may occur with acute or advanced hypertension. Hypertensive choroidopathy most commonly manifests in young patients with acute elevated blood pressure (BP), such as that which occurs in eclampsia or pheochromocytoma. ^[5]

Treatment of ocular hypertension varies. Depending on the severity of the ocular hypertension, management may include observation or initiation of antihypertensive therapy. In general, pharmacologic treatment is initiated in patients who have an increased risk of developing glaucoma.

Blood pressure control may result in regression of signs of hypertensive retinopathy, but spontaneous resolution may also be possible. ^[54] Among the issues that still need to be clarified are the following:

• Whether antihypertensive agents with potential direct beneficial microvascular effects (eg, angiotensin-converting enzyme inhibitors [ACEIs]) would reduce the damage of retinopathy beyond the reduction caused by lowered blood pressure

• Whether the specific reduction of hypertensive retinopathy also leads to reduction in cardiovascular disease morbidity and mortality

• Whether established risk-reducing interventions in targeted persons with hypertensive retinopathy would lead to additional advantages, as compared to the use of strategies without regard to retinal findings

In the presence of hypertensive optic neuropathy, a rapid reduction of BP may pose a risk of worsening ischemic damage to the optic nerve. The optic nerve demonstrates autoregulation, so there is an adjustment in perfusion based on BP. A precipitous reduction in BP will reduce perfusion to the optic nerve and central nervous system as a result of their autoregulatory changes, resulting in infarction of the optic nerve head and, potentially, acute ischemic neurologic lesions of the CNS.

For further information, see the Medscape Drugs & Diseases article Ocular Hypertension.

The goals of therapy for renovascular hypertension (RVHT) are maintenance of normal blood pressure (BP) and prevention of end-stage renal disease (ESRD). The therapeutic options include medical therapy, percutaneous transluminal renal angioplasty (PTRA) and stenting, and surgical revascularization. These options must be individualized, because no randomized studies document the superiority of one option over another.

It is important to note that the presence of renal artery stenosis or fibromuscular dysplasias are not always associated with renovascular hypertension. In addition, the potential benefits of percutaneous interventions are not proven. A trial by Bianchi et al failed to show improvement in systolic blood pressure, serum creatinine, renal events, mortality, or vascular events in patients with renal artery stenosis who underwent percutaneous renal artery intervention. ^[12]

In a study focusing on patients with atherosclerotic renal artery stenosis, data suggested that revascularization therapy should be confined to patients who have renal ischemia with viable underlying renal function, because they will experience the greatest clinical benefit. The indications for surgery or angioplasty include an inability to control BP while on a medical regimen, the need to preserve renal function, and intolerable effects of medical therapy.

With the advent of noninvasive techniques, aortal renal bypass using a saphenous vein or hypogastric artery is not commonly employed for revascularization. PTRA can be an effective treatment for hypertension and the preservation of renal function in a subset of patients. PTRA may be the initial choice in younger patients with fibromuscular lesions amenable to balloon angioplasty. Renal artery stenting of osteal lesions has been associated with improved long-term patency.

Medical therapy is required in the preoperative phase of interventional therapy. Medical therapy is also indicated for high-risk individuals and for older patients who have easily controlled hypertension. The specific population that will benefit from these techniques has yet to be clearly defined.

Angiotensin-converting enzyme inhibitors (ACEIs) are effective in patients with unilateral renal artery stenosis; however, ACEIs need to be avoided in patients with bilateral renal artery stenosis or stenosis of a solitary kidney. A diuretic can be combined with an ACEI. Because of their glomerular vasodilatory effect, calcium antagonists are effective in renal artery stenosis and do not compromise renal function.

For most patients with RVHT, with the exception of persons with fibromuscular dysplasia, it is unclear whether revascularization will be beneficial. Fibromuscular dysplasia responds well to angioplasty. The causes of renovascular hypertension include atherosclerosis, fibromuscular dysplasia, coarctation of the aorta, embolic renal artery occlusion, aneurysm of the renal artery, and diffuse arteritis. Additionally, causes of diffuse bilateral renal ischemia (eg, accelerated hypertension, vasculitis, hepatitis B, and IV drug abuse) may also lead to hypertension.

For further information, see the Medscape Drugs & Diseases article Renovascular Hypertension.

Resistant hypertension is defined as uncontrolled blood pressure (BP) (previously ≥140/90 mm Hg; ≥130/90 mm Hg per the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines ^[1] ) despite treatment with antihypertensive agents of three or more different classes, of which one is a diuretic, ^{[42, 106]} or controlled BP on a four-drug regimen. Data suggest that the addition of low-dose spironolactone provides significant additive BP reduction in both black patients and white patients who have resistant hypertension, with or without primary hyperaldosteronism. ^[107] However, ambulatory BP is normal in more than one third of patients with resistant hypertension, stressing the importance of monitoring patients to achieve correct diagnosis and management. ^[108] Patients should also be monitored for medication nonadherence, ^[106] which has been reported to be as high as 66% in those with resistant hypertension. ^[109] At-risk patients should also be tested for occult obstructive sleep apnea.

2018 AHA updated guidelines

Three important points emphasized in the 2018 updated AHA guidelines on resistant hypertension include (1) routine queries about patients' sleep patterns, as poor sleep duration and quality can interfere with blood control (BP) control; (2) lifestyle modifications (eg, low-sodium diet, weight loss, exercise, ≥6 hours of uninterrupted sleep each night; and (3) considering a change in antihypertensive agents from hydrochlorothiazide to chlorthalidone or indapamide if an above-goal BP persists despite adherence to a three-drug regimen and an optimal lifestyle (if the BP remains elevated despite the drug change, consider adding spironolactone as a fourth agent. Be extra vigilant if the estimated glomerular filtrate rate [eGFR] is < 30 mL/min/1.73 m²). ^{[42, 110]}  Clinicians should also assess and ensure optimal medication adherence in patients with resistant hypertension.

If the patient's BP is still not at target despite the above steps, the AHA suggests the following steps on the basis of expert opinion, and emphasizes they should be tailored to the patient ^[42] :

1. Unless the patient's heart rate is below 70 bpm, add a beta-blocker such as metoprolol succinate or bisoprolol, or a combined alpha-beta-blocker such as labetalol or carvedilol. If a beta-blocker is contraindicated, a central alpha-agonist such as a clonidine patch weekly or guanfacine at bedtime may be considered; if these agents are not tolerated, once-daily diltiazem may be considered. If the patient's BP is still not at target, then:

2. Add hydralazine 25 mg three times daily and uptitrate to the maximum dose. Concomitant use of a beta-blocker and a diuretic is required. If a patient has congestive heart failure and reduced ejection fraction, administer hydralazine on a background of isosorbide mononitrate 30 mg daily (max: 90 mg daily). If the patient's BP is still not at target, then:

3. Substitute minoxidil 2.5 mg two to three times daily for hydralazine and uptitrate. Concomitant use of a beta-blocker and a loop diuretic is required. If the patient's BP is still not at target, then:

4. Consider referring the patient to a hypertension specialist and/or for clinical trials.

 

There was initial enthusiasm for catheter-based renal sympathetic denervation in the treatment of resistant hypertension based on several early studies that compared renal denervation to standard medical treatment. Originally published as a small, 45-patient proof-of-principle and safety study in 2009, ^[111] a follow-up nonrandomized study with 153 patients (Symplicity HTN-1) conducted in Australia, Europe, and the United States showed that this technique lowered BP for an extended period of up to 2 years in patients with resistant hypertension (defined here as a SBP >160 mm Hg and taking more than three antihypertensive drugs, including a diuretic). ^[112] Postprocedure office BPs were reduced by 20/10 mm Hg, 24/11 mm Hg, 25/11 mm Hg, 23/11 mm Hg, 26/14 mm Hg, and 32/14 mmHg at 1, 3, 6, 12, 18, and 24 months, respectively. The complication rate was 3% and consisted of three groin pseudoaneurysms and one renal artery dissection, all managed without further sequelae.

Subsequently, an open-label prospective, randomized study conducted in 24 centers in Europe, Australia, and New Zealand (Symplicity HTN-2) confirmed the safety and efficacy of this treatment in 106 patients randomized to renal denervation with previous treatment (n = 52) or to previous treatment alone (n = 54). ^[113] At 6 months, renal denervation resulted in a reduction in SBP of 10 mm Hg or more in 84% of patients, compared to 35% of controls. No serious procedure-related or device-related complications occurred.

Of note, these earlier studies were unblinded and did not include a sham procedure as a control. The first single-blind, randomized, sham-controlled trial of renal denervation therapy, SYMPLICITY HTN-3, failed to demonstrate a significant difference in office-based BP measurements after 6 months. ^[114] Although recruitment for ongoing studies of renal denervation in the United States were halted based on these results, a number of new studies that attempt to address shortcomings in SYMPLICITY HTN-3 by utilizing modifications such as bipolar electrode catheters and denervation of the main renal arteries along with distal branches and accessory arteries are recruiting patients. ^[76]

Additional experimental therapies for resistant hypertension include iliac artery-vein fistulas and baroreceptor activation treatment (BAT) by an implantable stimulator. ^{[109, 115]}

Causes of resistant hypertension

Causes of resistant hypertension include improper BP measurement, volume overload, drug-induced or other causes, and associated conditions such as obesity or excessive alcohol intake.

Improper BP measurement

Improper BP measurement may result in falsely high readings, such as when the wrong-sized cuff is used, when patients have heavily calcified or arteriosclerotic brachial arteries, or in cases of white-coat hypertension (observed in 20-30% of patients ^[63] ).

In one study, investigators determined that a true diagnosis of resistant hypertension with ambulatory BP monitoring (ABPM) is associated with a more severe degree of vascular dysfunction (versus white-coat resistant hypertension), as measured by hyperemia-induced forearm vasodilation (HIFV) and serum biomarkers. ^[116] However, there is no direct association between BP levels and other types of abnormalities in vascular function (eg, compliance). ^[116]

Falsely high readings due to white-coat hypertension may be avoided by having patients rest before the measurement, by having a nurse check the blood pressure, or by arranging to have the blood pressure monitored at home. Development of hypotensive symptoms with the patient on medication is an indication of this type of hypertension. White-coat hypertension can also be evaluated by the use of a 24-hour ambulatory monitor.

Inadequate treatment and patient nonadherence

Inadequate treatment is common in cases of resistant hypertension ^[5] ; in several published series, this has been described as the most common cause of resistant hypertension. Patients may not be on an effective drug or drug dose, or concomitant volume expansion may occur as a side effect of the drug.

Nonadherence with medical therapy ^{[42, 117]} or dietary modifications (eg, salt restriction) may play a role in causing resistant hypertension. Address noncompliance with extensive patient education, simplification of the drug regimen, use of fixed-dose combinations, and use of drugs with the fewest adverse effects.

Limited data suggest better compliance with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) than with some of the other antihypertensive medications. ^[118]

Extracellular volume expansion

Extracellular volume expansion may contribute to the inability to lower systemic BP. The volume expansion may occur because of renal insufficiency or because of sodium retention due to treatment with vasodilators, a high-salt diet, or insufficient dosing of a diuretic. This condition can be treated with more aggressive diuretic therapy until clinical signs of extracellular volume depletion (eg, orthostatic hypotension) develop. The JNC 7 recommends a thiazide-type diuretic for the majority of hypertensive patients but notes that patients with a decreased GFR or who are in heart failure often require therapy with a loop diuretic. ^[5]

Vasoactive substances

Resistant hypertension may be encountered in patients who are ingesting vasoactive substances despite taking antihypertensive drugs regularly. Salt and alcohol are common examples; others include cocaine, amphetamines, anabolic steroids, oral contraceptives, cyclosporine, antidepressants, and nonsteroidal anti-inflammatory drugs.

Excluding secondary causes

Whenever confronted with resistant hypertension, try to exclude any secondary causes of hypertension. A reevaluation of the patient’s history, physical examination, and laboratory results may provide clues to secondary hypertension (eg, renal parenchymal disease, renal artery stenosis, primary hyperaldosteronism, obstructive sleep apnea, pheochromocytoma/paraganglioma, Cushing syndrome, coarctation of the aorta). ^[42] Primary hyperaldosteronism is estimated to have a prevalence of 20% in this population. ^[119]

Obstructive sleep apnea is also associated with resistant hypertension, with 85% of patients with resistant hypertension having an elevated apnea/hypopnea index. A study by Pedrosa et al also found that two good predictors of sleep apnea in patients older than 50 years with resistant hypertension is a large neck circumference and snoring. ^[120]

However, treatment with CPAP may reduce BP in patients with resistant hypertension and sleep apnea. In the Spanish open-label, randomized HIPARCO trial, 98 patients with obstructive sleep apnea (OSA) and resistant hypertension who were treated with 12 weeks of continuous positive airway pressure (CPAP) had significantly improved 24-hour mean and diastolic blood pressure (BP) measurements, as compared to BP in 96 patients who did not receive CPAP therapy. ^{[121, 122]} Reductions in 24-hour mean and diastolic BP in the CPAP group were 3.1 mm Hg and 3.2 mm Hg, respectively, but there was no change in 24-hour systolic BP. However, a per-protocol analysis showed reductions in 24-hour mean BP (4.4 mm Hg) and diastolic BP (4.1 mm Hg) and a significant decrease in 24-hour systolic BP (4.9 mm Hg). ^{[121, 122]}

In addition, 35.9% of those on CPAP therapy showed improvements in their nocturnal BP pattern (ie, ≥10% decrease in average nighttime vs average daytime BP), as compared to 21.6% in the control group. There was also a significant correlation between duration of CPAP use and the reduction in BP levels. ^{[121, 122]}

Pseudohypertension in an overestimation of intra-arterial pressure by cuff blood pressure (BP) measurement. This may be observed in elderly individuals who have thickened, calcified arteries, as the cuff has relatively more difficulty compressing such arteries; much higher cuff pressure may be required to occlude a thickened brachial artery. The diastolic BP may also be overestimated.

Consider pseudohypertension in situations in which no organ damage occurs despite markedly high BP measurements, when patients develop hypotensive symptoms on medications, and when calcification of the brachial artery is observed on radiologic examination. Direct measurement of intra-arterial pressure may be required in this setting.

Following suspicion of pheochromocytoma (labile, elevated blood pressure [BP]; paroxysmal hypertension with headache palpitations, pallor, perspiration), ^[5] the presence of a tumor should be confirmed biochemically by measuring urine and plasma concentrations of catecholamine or their metabolites. Keep in mind that catecholamine testing is subject to an increased rate of false positives, which can be due to medication effects or measurement conditions. In most situations, computed tomography scanning or magnetic resonance imaging may be used to localize the tumor in the abdomen. In the absence of abdominal imaging, nuclear scan with metaiodobenzylguanidine (MIBG) may further help with the localization. Positron emission tomography (PET) scanning and octreotide scanning may also be used.

Surgical resection is the treatment of choice for pheochromocytoma, because hypertension is cured by tumor resection. In the preoperative phase, nonspecific alpha-adrenergic blockade is indicated with phenoxybenzamine, and following adequate alpha-adrenergic blockade, beta-adrenergic blockade is added if excess tachycardia is present. These patients are often volume contracted and require saline or sodium tablets. Catecholamine production can be reduced further by metyrosine.

For adrenal pheochromocytoma, laparoscopic adrenalectomy is becoming the procedure of choice in suitable patients. Follow-up 24-hour urinary excretion studies of catecholamines should be performed 2 weeks following surgery (and periodically thereafter) to detect recurrence, metastases, or development of second primary lesion.

For further information, see the Medscape Drugs & Diseases article Pheochromocytoma.

The prevalence of primary hyperaldosteronism increases with the severity of hypertension, being 2% in stage 1 and 20% in resistant hypertension. ^[119] Hypokalemia (an unprovoked or an exaggerated hypokalemic response to a thiazide) and metabolic alkalosis are important clues to the presence of primary hyperaldosteronism. However, these are relatively late manifestations; in a large subset of patients, the serum potassium concentration and bicarbonate are within the reference range, and additional screening testing is needed in patients with high index of suspicion for primary hyperaldosteronism.

Measurement of the ratio of plasma aldosterone to renin activity ratio is the best initial screening test for primary hyperaldosteronism. A ratio of over 20-30 suggests that primary hyperaldosteronism may be present. Some labs require a minimum plasma aldosterone level of 12 ng/dL.

The diagnosis of primary hyperaldosteronism can be confirmed by the determination of the aldosterone excretion rate in a 24-hour urine following IV or oral salt loading (ie, urinary aldosterone excretion rate greater than 12-14 μg/24 hours, with urine sodium at least 200 mEq/24 hours). Saline suppression testing can also be used to confirm the diagnosis.

The appropriate therapy depends on the cause of excessive aldosterone production. A CT scan with dynamic protocol may help localize an adrenal mass, indicating adrenal adenoma, which may be a nonsecreting incidentaloma or a hypersecreting adenoma. If the results of the CT scan are inconclusive, adrenal venous sampling for aldosterone and cortisol levels should be performed.

Medical therapy is indicated in patients with adrenal hyperplasia, patients with adenoma who are poor surgical risks, and patients with bilateral adenomas. These patients are best treated with sustained salt and water depletion. Hydrochlorothiazide or furosemide in combination with either spironolactone or amiloride corrects hypokalemia and normalizes the blood pressure. Some patients may require the addition of a vasodilator or a beta-blocker for better control of hypertension.

Adrenal adenomas may be resected via a laparoscopic procedure. Surgical resection often leads to the control of blood pressure and the reversal of biochemical abnormalities. These patients may develop hypoaldosteronism during the postoperative follow-up period and require supplementation with fludrocortisone.

For further information, see the Medscape Drugs & Diseases article Hyperaldosteronism.

Various interventions can be implemented to improve BP control in patients with hypertension or to treat uncontrolled hypertension. These interventions include the following:

• Self-monitoring

• Educational interventions directed to the patient

• Educational interventions directed to the health professional

• Nurse or pharmacist care

• Organizational interventions that aim to improve the delivery of care

• Appointment reminder systems

The Cochrane Collaboration has shown that these interventions are associated with large net BP reductions and that health professional (nurse or pharmacist)–led care may be a promising way of delivering care. A study by Pezzin et al found that extensive patient education, coupled with nurse-led monitoring and feedback, resulted in significant improvements in 3-month BP control and secondary BP outcomes in high-risk black patients with stage 2 hypertension. ^[123] Cochrane recommendations include the recommendation that family practices and community-based clinics have an organized system of regular follow-up and review of their patients with hypertension. A randomized trial found that systolic BP decreased in individuals with poor BP control at baseline with use of home BP management consisting of nurse-administered behavioral management and nurse-administered and physician-administered medication management. ^[124]

Antihypertensive drug therapy should be implemented by means of a vigorous stepped care approach when patients do not reach target BP levels.

A comprehensive strategy for reduction of mortality and morbidity associated with hypertension must include prevention strategies, earlier detection, and adequate treatment. Ideally, a population strategy should be used to lower BP in the community. More intensive efforts are required to lower blood pressure in high-risk population groups, which include individuals with a family history of hypertension, black ancestry, obesity, excessive sodium consumption, physical inactivity, and/or alcohol consumption. Even a small reduction in BP confers significant health benefits. A reduction of 2 mm Hg in diastolic BP is estimated to decrease the risk of stroke by 15% and the risk of coronary heart disease by 6%.

Prevention of hypertension may be achieved by the following interventions:

• Weight control

• Increased physical activity

• Moderated sodium and alcohol intake

• Increased potassium intake

• A diet rich in fruits and vegetables and low-fat meat, fish, and dairy products