Phuong-Mai T. Pham
Phuong-Anh T. Pham
Son V. Pham
Cynthia C. Nast
Hai V. Pham
Worldwide trends in blood pressure (BP) from 1975 to 2015 based on pooled analysis of 1,479 population-based measurement studies with 19.1 million participants:
Global age-standardized prevalence of hypertension (HTN), defined as systolic blood pressure (SBP) >140/90 mm Hg, was 24% in men and 20% in women in 2015.
The number of people with HTN has increased by 90% during the four decades studied, presumably due to population growth and aging.
Prevalence of HTN decreased in high-income, increased in low-income countries in South Asia and Sub-Saharan Africa, and remains persistently high in Central and Eastern Europe.
HTN in the United States (Centers for Disease control and Prevention 2020)
Over 100 million have HTN, defined as SBP ≥130 mm Hg or diastolic blood pressure (DBP) ≥80 mm Hg, or are taking antihypertensive medications.
Half of adults with BP ≥140/90 mm Hg who should be taking antihypertensives are not prescribed or taking the medication.
Only about one in four adults have their HTN under control.
HTN costs the United States approximately $131 billion annually, averaged from 2003 to 2014.
Geographic prevalence: HTN is most prevalent in the southeast and eastern urban regions of the United States.
HTN by race: 54% in non-Hispanic black adults, 46% in non-Hispanic white adults, 39% in non-Hispanic Asian adults, and 36% in Hispanic adults
Among those recommended to take antihypertensive medications, BP control is seen in 32% of non-Hispanic white adults, 25% in non-Hispanic black adults, 19% in non-Hispanic Asian adults, and 25% in Hispanic adults.
Standardized office or home BP measuring techniques: (1) no conversation; (2) no exercise, nicotine, or caffeine at least 30 minutes prior; (3) empty bladder; (4)
place correct cuff size on bare arm; (5) support arm at heart level; (6) keep legs uncrossed; (7) support back and feet
For automated oscillometric BP (AOBP) office measurements: after 5-minute rest, average two to five measurements at intervals of 1 to 2 minutes
Variability in BP measurements:
Casual office BP (defined as not following standardized techniques outlined above) is generally 5 to 10 mm Hg higher than standardized office or home BP, AOBP, and awake ambulatory BP.
Out-of-office BP may provide better prediction of kidney disease progression and cardiovascular (CV) events than in-office BP measurements among patients with chronic kidney disease (CKD).
Between-arm BP measurement differences:
Between-arm BP differences of 4 to 5 mm Hg occur in healthy individuals.
Values >10 mm Hg should be considered for vascular assessment.
Values >15 mm Hg is a predictor of prevalent vascular disease and death.
Indications for Ambulatory BP Measurements
Apparent drug resistance (BP not at goal while seemingly being on maximal and optimal drug combination, WCH, noncompliance, proper BP measuring techniques, etc., have not been ruled out.)
Evaluation of nocturnal BP dipper or riser as prognostic factor for target organ damage
Evaluation of BP changes in patients with paroxysmal nocturnal dyspnea and nocturnal angina
Carotid sinus syncope
Safety of withdrawing antihypertensive medications
Assess 24-hour BP control on once-daily medication
Borderline HTN with target organ damage
Evaluation of antihypertensive drug therapy in clinical trials
BP categorization below is based on the average of two or more properly measured readings obtained on at least two separate visits after initial screen.
Adults >18 years of age:
*Pre-HTN category is no longer used.
Stage 1: 130 to 139 mm Hg or DBP 80 to 89 mm Hg
24-hour average > 130/80 mm Hg
Daytime (awake) average > 135/85 mm Hg
Nighttime (asleep) average > 120/70 mm Hg
2017 Hypertension Clinical Practice Guidelines of the American College of Cardiology/American Heart Association (ACC/AHA):
The 2017 Hypertension Clinical Practice Guidelines relies on average BP readings.
Out-of-office BP measurements are recommended to confirm the diagnosis of HTN and titrate BP-lowering medication.
Goal BP for everyone is <130/80 mm Hg, except:
Older adults ≥65 years old with HTN and a high burden of comorbidity and limited life expectancy, clinical judgment, patient preference, and a team-based approach to assess risk/benefit are reasonable for decisions regarding intensity of BP-lowering and choice of antihypertensive drugs.
General management regardless of BP level
Promote optimal lifestyle habits
Nonpharmacologic therapy (see Routine Management of HTN section)
Addition of pharmacologic therapy is recommended for
Known atherosclerotic cardiovascular disease (ASCVD) or 10-year risk ≥10%
Diabetes mellitus (DM) type 2, or
For patients with asymptomatic mild or moderate aortic stenosis with normal left ventricular systolic function: BP target of 130-139/70-89 mm Hg is reasonable. A post hoc analysis of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial revealed the lowest all-cause mortality rate for patients in the BP range of 120-139/70-79 mm Hg. All-cause mortality was significantly associated with average SBP < 120 mm Hg and average DBP ≥ 90 mm Hg.
For patients >65 years old, be cautious not to lower DBP <65 mm Hg because this has been suggested to be associated with increased stroke risk.
Types of HTN
White coat hypertension (WCH)
Definition: having home or daytime ambulatory SBP < 130/80 mm Hg but office BP > 130/80 mm Hg after 3 months of diet and lifestyle modification
Prevalence among patients with CKD has been estimated to range from 2% to 41%.
Clinical significance of WCH:
Some studies revealed increased left ventricular mass index compared to individuals with normal BP.
Affected individuals may have impaired diastolic function and higher levels of catecholamines, renin/aldosterone, low-density lipoproteins.
Conversion to sustained HTN occurs in 1% to 5% annually.
Start antihypertensive if office BP is persistently elevated with evidence of target organ damage.
Definition: BP measured in the office is lower than that measured in the out-of-office setting (opposite of WCH).
Prevalence in the general population is estimated at 10% to 20% and higher at 20% to 50%+ in patients with CKD.
A systemic review of published literature from 2000 to 2018 reported similar risks of fatal and nonfatal cardiac and CV events among patients with masked HTN compared with those with sustained HTN (hazard ratio [HR] ˜2.1 vs. 2.3).
Initiate antihypertensive therapy if elevated 24-hour ambulatory BP and evidence of target organ damage.
HTN in both in-office and out-of-office settings
Cuff BP is higher when compared with intra-arterial pressure because of excessive atheromatosis and/or medial hypertrophy in arterial tree.
May be diagnosed by Osler maneuver:
Inflate BP cuff above SBP (detected by loss of pulse with auscultation). Osler maneuver is positive when either brachial or radial artery remains palpable despite loss of pulse by auscultation.
Pseudo-HTN is defined as cuff-measured DBP >10 to 15 mm Hg compared with that of intra-arterial measurement.
Management of BP should be based on intra-arterial value.
Isolated systolic hypertension (ISH)
Isolated diastolic hypertension (IDH)
More common among young men, individuals with sedentary lifestyle, overweight/obesity
Clinical significance of IDH is unclear
Rate of progression or conversion to SDH noted to be 55% in 6.7 years in Framingham Heart Study.
Finland study involving 3,267 healthy men aged 32 to 45 years with untreated IDH had no increase in all-cause mortality.
Cross-sectional analyses of the National Health and Nutrition Examination Survey (NHANES 2013 to 2016) and longitudinal analyses of the Atherosclerosis Risk in Communities Study revealed no significant association between IDH and increased risk for CV outcomes.
Management of IDH
Focus on salt restriction and weight loss, the latter if overweight or obese
Pharmacologic antihypertensive therapy if end-organ damage, that is, proteinuria or left ventricular HTN on electrocardiogram (ECG), or hypothyroidism. Hypothyroidism is associated with BP rise that is more pronounced with DBP than SBP.
BP is not at goal despite optimal doses (optimal dose, defined as >50% of maximal dose recommended for treatment of HTN) of three different appropriate antihypertensive drug classes, ideally one class being a diuretic.
Alternatively, BP is at goal with optimal doses of four appropriate antihypertensive drug classes, ideally once class being a diuretic.
BP not controlled despite being on ≥5 drugs including a diuretic.
Apparent (drug)-resistant HTN
Dippers and risers
Dippers are individuals who experience a physiologic nocturnal fall in BP of >10% compared with daytime BP.
It has been suggested that nondippers or risers, particularly in association with elevated absolute nighttime BP, may predict end-organ damage and adverse CV events.
The proportion of dippers decreases with increasing CKD stage.
The proportion of risers increases with increasing CKD stage.
END-ORGAN DAMAGE OF HTN
Acute hypertensive nephropathy associated with hypertensive emergencies
Hematuria, acute kidney injury (AKI)
Direct endothelial damage, ischemic injury, microangiopathic hemolytic anemia causing obstruction of interlobular arteries
Histopathology (Fig. 5.1)
Fibrinoid necrosis of small arterioles (pink, amorphous fibrinoid materials within vessel wall due to necrosis) and “onion skinning” of small renal arteries. “Onion skinning” is used to describe hyperplastic arteriosclerosis with thickened concentric smooth muscle cell layer with thickened, duplicated basement membrane and narrowed lumen. In malignant HTN, these hyperplastic changes may be accompanied by fibrinoid necrosis of the arterial intima and media.
Chronic hypertensive nephropathy
Slowly progressive kidney injury with relatively bland urine, mild albuminuria
End-stage kidney disease (ESKD) due solely to HTN is uncommon due to the relative preservation of glomerular injury until advanced stage, except for genetically susceptible subpopulation such as African Americans or those who suffer from frequent hypertensive emergency episodes and associated acute hypertensive nephrosclerosis. The relative glomerular sparing is consistent with the minimal albuminuria associated with chronic hypertensive nephropathy.
Slowly progressive thickening and sclerosis of renal resistance vessels with relative sparing of glomerular capillaries. Ischemic glomerular loss occurs slowly over decades.
Acute cardiac complications associated with hypertensive emergencies
Acute coronary syndrome, acute myocardial infarction (MI)
Acute left ventricular dysfunction, acute heart failure (HF)
Acute aortic dissection (see Hypertensive Emergencies section)
Chronic cardiac complications
Left ventricular hypertrophy (LVH) that increases the risk of MI, HF, ventricular arrhythmias, sudden cardiac death
Ischemic stroke, intracerebral or subarachnoid hemorrhage
Ischemic stroke, vascular dementia
Lacunar infarctions, microhemorrhages, and focal or diffuse white matter lesions may be seen in early hypertensive microangiopathic complications.
Evaluation of HTN
Routine evaluation in patients with HTN
Recommended tests: lipid profile, kidney function, urinalysis, fasting blood glucose, hemoglobin A1C, complete blood count, ECG, thyroid-stimulating hormone
Optional tests: echocardiogram, uric acid, urine albumin-to-creatinine ratio
Clinical clues that should prompt evaluation for secondary HTN
Presence of signs/symptoms related to specific hypertensive conditions
Unprovoked (absence of diuretic use) or severe hypokalemia (mineralocorticoid excess)
Evaluation of Suspected Secondary HTN
Check for proper BP measurement techniques
Check for volume overload
Presence of obesity
Review drug induced and related causes:
Inappropriate antihypertensive medication combinations (e.g., using several vasodilators in a patient with increased heart rate without a β-blocker [BB], using multiple sympatholytic drugs without any vasodilator, or using multiple drugs with reflex salt-retention but without a diuretic)
Nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors
Cyclosporine (CSA) and tacrolimus
Antidepressants (monoamine oxidase [MAO] inhibitors)
Erythropoiesis-stimulating agents (reduced nitric oxide [NO] synthesis, increased entholin-1)
Vascular endothelial growth factor (VEGF) inhibitors, such as sunitinib (downregulate NO expression)
Selected over-the-counter dietary supplements and medicines:
Sympathomimetics (decongestants, anorectics)
Ephedra, ma huang, bitter orange
Licorice (including some chewing tobacco)
Common drinks/recreational drugs:
Caffeine (small and transient increase in BP)
Excess alcohol intake
Cocaine, amphetamines, methamphetamines, other illicit drugs
Routine Management of HTN (ACC/AHA 2019)
Best proven nonpharmacologic interventions for prevention and treatment of HTN
Target ideal body weight or aim for a weight loss of at least 1 kg
SBP may reduce by 1 mm Hg/kg weight loss.
Adopt DASH-like eating plan:
Encourage diet rich in fruits, vegetables, whole grains, low-fat dairy products with reduced saturated and total fat
SBP may reduce by 8 to 14 mm Hg.
<1,500 mg/d; aim for ≥1,000 mg/d reduction in most adults
SBP may reduce by 2 to 8 mm Hg.
Increase potassium intake:
3,500 to 5,000 mg/d unless patient has problems with hyperkalemia
SBP may reduce by 4 to 5 mm Hg.
Regular aerobic, dynamic resistance, or isometric resistance activity, for example, 30-minute brisk walk daily, most days of week, or 150-min/wk
SBP may reduce by 4 to 9 mm Hg.
Moderation of alcohol consumption:
<2 drinks daily in most men, <1 drink daily in women and lightweight persons
SBP may reduce by 2 to 4 mm Hg.
For overall CV risk reduction, stop smoking.
Initiate pharmacologic therapy
See indications outlined in BP Goals section.
Pharmacologic Therapy for HTN
Initiating pharmacologic therapy
Initial drug selection depends on underlying conditions, “compelling indications” (e.g., ACEI/ARB for systolic HF, post-MI, α-blockers for benign prostate hypertrophy, BBs for essential tremors, hyperthyroidism, migraine, atrial fibrillation/flutter with rapid ventricular rates, angina, mineralocorticoid receptor antagonist for hyperaldosteronism, thiazide diuretics for Gordon syndrome or osteoporosis, amiloride for Liddle syndrome).
Mainstay therapy for adults with or at risk for CVD includes BBs and/or ACEI or ARB, with subsequent addition of CCB and/or thiazide or thiazide-like diuretics as needed. Loop diuretics should be reserved for severe HF or severe CKD. Mineralocorticoid-receptor antagonists (MRAs), such as spironolactone or eplerenone, may be considered in ischemic HF or resistant HTN.
If there is no “compelling indication” for drug selection, first-line antihypertensive drugs include thiazide diuretics, CCBs, ACEIs, or ARBs. (The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT] did not show any difference in coronary heart disease or nonfatal MI and stroke between CCB, ACEI, or thiazide diuretics.)
For drug-naïve patients with SBP > 20/10 mm Hg above goal, two-drug therapy should be initiated.
Notes regarding thiazide diuretics
Clinically available thiazide and thiazide-like diuretics include hydrochlorothiazide (HCTZ), chlorthalidone (CTDN), and indapamide (INDAP).
The longer duration of diuretic and antihypertensive action of CTDN and INDAP compared with HCTZ may confer better nighttime BP control: HCTZ (<24 hours), CTDN (24 to 72 hours), INDAP (24 hours+ and 32 hours+ for immediate-release and sustained-release forms, respectively).
2015 meta-analysis involving 14 randomized controlled trials (RCTs) comparing HCTZ versus CTDN and INDAP:
No differences in metabolic adverse effects were detected.
2.5-mg INDAP reduced stroke by 29% and all CV events by 23% in the Post Stroke Antihypertensive Treatment Study. Perindopril-INDAP combination also reduced CV events in two other placebo-controlled trials.
In an observational cohort study, CTDN was associated with lower LVH compared to HCTZ. In another observational cohort analysis (n = 12,866), the percentage risk reduction in CV events from CTDN versus HCTZ was 21%. In network meta-analyses of randomized trials (n = 50,946), CTDN conferred a 25% risk reduction in congestive heart failure (CHF) and CV events compared with HCTZ.
Bottom line: CTDN and INDAP reduce SBP more than HCTZ and confer ˜21% risk reduction in CHF and CV events compared with HCTZ.
Protection against fracture: The use of thiazide and thiazide-like diuretics has been shown to confer long-term protection against fracture compared to the use of other antihypertensive agents.
Use of thiazide diuretics in CKD: CTDN has been shown to remain effective in reducing SBP by 19 to 20 mm Hg even in patients with advanced CKD G4. Continuation of thiazide diuretics rather than switching to loop diuretics may be appropriate in a stable patient if volume overload is not a concern. Loop diuretic switch is reasonable in the case of resistant HTN and/or volume overload.
The use of low-dose MRA (e.g., aldosterone)
Confers additional benefits in CV outcomes in patients with New York Heart Association (NYHA) classes III and IV HF or decreased left ventricular ejection fraction after an MI.
Recommended to be used concurrently with thiazide diuretics to offset hypokalemia
May lower BP regardless of serum aldosterone levels
BP-lowering effect has been shown to be more pronounced in patients with suppressed plasma renin activity (PRA).
May reduce BP even in hemodialysis patients
Recommended to be added in resistant HTN: spironolactone 25 to 50 mg daily. Anglo-Scandinavian Cardiac Outcomes Trial revealed that the addition of spironolactone at median dose of 25 mg daily in addition to 2.9 other antihypertensive medications lead to a fall in BP of 21.9/9.5 mm Hg at 1.3-year follow-up. Optimum Treatment of Drug-Resistant Hypertension Study revealed the addition of spironolactone at 25 to 50 mg every day (qd) over a 12-week treatment period reduced SBP by 8.7 mm Hg on average compared to placebo.
Adverse effects: hyperkalemia, metabolic acidosis
Specific drug contraindications
Special Considerations in Pharmacologic Therapy of HTN
Use of ACEI or ARB should be considered for the following
Nondiabetics with HTN and albuminuria ≥30 mg/d
Direct renin inhibitor (DRI) combination with ACEI and ARB
Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) Trial
Combination therapy consisting of losartan and aliskiren was minimally beneficial compared to lone losartan therapy in patients with DM type 2 with urine albumin-to-creatinine ratio >300 mg/g.
Combination therapy was associated with higher rate of hyperkalemia (4.7% vs. 17%).
Aliskiren in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial
Combination therapy with aliskiren and either an ACEI or ARB in patients with diabetic kidney disease reduced proteinuria and SBP by 1 to 2 mm Hg compared with placebo group receiving either ACEI or ARB alone.
25% greater stroke rate and more frequent hyperkalemia were observed with combination therapy.
Weight and antihypertensive therapy
The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic HTN (ACCOMPLISH) trial suggests the preferential addition of a CCB over a diuretic to an ACEI in normal weight patients in terms of CV outcome (i.e., [CCB + ACEI] is better than [diuretic + ACEI] in normal weight patients). In obese high-risk hypertensive patients, the choice of adding either a diuretic or CCB to an ACEI is less important.
The difference in outcome was thought to be due to the difference in pathogenesis of HTN in normal versus obese patients. Lean individuals may have more prominent renin and sympathetic nervous system (SNS) activities with their HTN and are thus more sensitive to diuretics, which could further stimulate renin-angiotensin-aldosterone system (RAAS).
Antihypertensive therapy based on PRA: “renin profiling”
PRA > 0.65 ng/mL/h (typically seen in younger Caucasians) may have HTN associated with vasoconstriction and respond well to ACEI, ARB, or BBs.
PRA < 0.65 ng/mL/h (typically seen in African Americans, Afro-Caribbeans, and older Caucasians) may indicate volume expansion-related HTN and may respond well to diuretics and CCB.
A 2016 pilot study comparing the effectiveness of adding aldosterone antagonist (AA) versus administering renin-guided therapy (RGT) outlined above to patients with resistant HTN revealed fewer additional medications required for RGT versus AA to achieve the same antihypertensive effect.
Considerations for BP management in African Americans
Considerations for BP management in the elderly
Available data do not show cognitive decline in elderly patients who achieve target BP with the use of antihypertensive therapy (Hispanic Community Health Study/Study of Latinos). However, women with uncontrolled BP despite being treated with antihypertensive medications may have an associated cognitive decline (Women’s Health Initiative Memory Study).
Intensive vs. Standard Ambulatory Blood Pressure Lowering to Lessen Functional Decline in the Elderly (INFINITY) trial: Among elderly patients with HTN, intensive lowering of ambulatory SBP reduced the development of subcortical white matter disease and nonfatal CV events but did not improve mobility or cognitive function.
Caution with frail, institutionalized elderly: BP lowering to < 130/80 mm Hg with the use of two or more antihypertensive agents in older nursing home residents is associated with increased mortality rates (Treatment with Multiple Blood Pressure Medications, Achieved Blood Pressure, and Mortality in Older Nursing Home Residents Study)
Other drug considerations in HTN
Sodium-glucose cotransporter 2 (SGLT2)
Valsartan/sacubitril as an antihypertensive agent
Although the combination drug has been shown to confer greater antihypertensive effect compared to ARB alone in elderly patients in a 2019 meta-analysis, safety and efficacy data for its use as an antihypertensive agent in RCTs are lacking. Recommendation for its use as an antihypertensive agent has not been made at the time of this writing.
Summary of Systolic Blood Pressure Intervention Trial (SPRINT)
Multicenter RCT of intensive versus standard BP control
9,361 persons with SBP ≥ 130 mm Hg with CVD risks but without DM were enrolled and randomized to SBP control <120 mm Hg (intensive) or <140 mm Hg (control)
Inclusion: age ≥ 50 years with SBP ≥ 130 mm Hg and ≥1 of the following: history of CVD, CKD G3, intermediate to high risk for CVD other than stroke, or age ≥75 years
Primary composite outcome was MI, other acute coronary syndromes, HF, or death from CV causes.
At 3.26 mean follow-up years, nondiabetic adults, age ≥50 years at increased CVD risk or with CKD with intense BP control had a 25% reduction in primary combined CV outcome and 27% reduction in mortality.
Hypotensive and syncopal episodes and electrolyte disturbances, but not injurious falls, were more common in the intensive group.
Benefit of intensive BP treatment appeared to be less for women compared with men.
Individuals with CKD at enrollment
Individuals age ≥ 75 years
Relative HR of primary CVD outcome and all-cause mortality were lower with marginal significance in the intensive group.
There was no difference in kidney outcome, defined as ≥50% decline in eGFR from baseline or reaching ESKD. Degree of albuminuria, but not incident albuminuria, was lower in the intensive group.
Individuals age ≥ 75 years old at enrollment:
Rates of all-cause mortality (HR 0.67) as well as fatal and nonfatal major CV events were lower in the intensive group.
Kidney outcome defined above was higher in the intensive group but statistical significance was not reached due to low event numbers.
No difference in serious adverse events
PRIMARY (ESSENTIAL) HYPERTENSION
Pathogenesis of primary HTN
Increased sympathetic activity and responsiveness
Increased angiotensin II (AII) activity and mineralocorticoid excess
Risks of primary HTN
Genetics: twofold risk if both parents have HTN
Reduced nephron mass due to immature birth, intrauterine developmental abnormality (e.g., maternal drug use, malnutrition), and postnatal disturbances (e.g., malnutrition, infections)
Black ethnicity (more common and severe compared to non-blacks)
Lifestyle associated: high salt intake, excess alcohol consumption, physical inactivity, vitamin D deficiency. Fructose intake, thus far, not proven to increase HTN risk.
Metabolic: dyslipidemia, independent of obesity
Diagnosis of primary HTN
Rule out WCH
Rule out ingestions of medications/substances that can cause HTN (i.e., caffeine, tobacco smoking, amphetamines, cocaine, sympathomimetics, etc.)
Rule out secondary causes as per risks, signs/symptoms. See Secondary Causes of HTN section.
Full history and physical examination
Laboratory studies: See Evaluation of HTN section.
Management of primary HTN
See Routine Management of HTN section.
Indications for evaluation of secondary HTN
Not controlled on an appropriate combination of three antihypertensive agents of different classes, one of which is a diuretic or
Controlled on an appropriate combination of four antihypertensive agents of different classes, one of which is a diuretic.
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