Hypertension

Hypertension is a multisystem disease whose hallmark is the elevation of blood pressure. Primary hypertension has no apparent cause, constitutes the majority of cases, and is treated with measures to reduce blood pressure. Secondary hypertension does have an abnormality that is causing the elevation in blood pressure, such as a tumor that secretes hormones that raise blood pressure; removing the cause may be curative. Primary hypertension is generally not curable and needs to be managed as a chronic disease.

Classification

Classification of blood pressure for adults

Blood pressure classification	Initial blood pressure mm Hg			Followup recommended
	SBP		DBP
Normal	<120	and	<80	Recheck in 2 years
Prehypertension	120-139	or	80-99	Recheck in 1 year
Stage 1 Hypertension	140-159	or	90-99	Confirm within 2 months
Stage 2 Hypertension	≥ 160	or	≥100	"Evaluate or refer to source of care within 1 month. For those with higher pressures (e.g., >180/110 mmHg), evaluate and treat immediately or within 1 week depending on clinical situation and complications... 2 drug combination for most."
Hypertensive urgency	≥ ~ 180	or	≥ ~ 120 ("without acute target-organ damage")	"usually do not require hospitalization, but they should receive immediate combination oral antihypertensive therapy"
Hypertensive emergency	≥ ~ 180	or	≥ ~ 120 (with "acute target-organ damage")	"require hospitalization and parenteral drug therapy"

Diagnosis

A systematic review by the Rational Clinical Examination has reviewed the research on blood pressure determination.

Ambulatory blood pressure monitoring

Clinical practice guidelines by National Institute for Health and Care Excellence (NICE) recommend routine use of ambulatory monitoring for patients newly found to have high blood pressure readings in clinic. This approach may reduce the cost of care.

Ambulatory may better predict future complications than monitoring the office blood pressure.

Regarding whether the ambulatory pressure should guide treatment, the office pressure may be better.

A randomized controlled trial of comparing ambulatory versus office monitoring was announced but never completed.

Confirmation

If the diastolic pressure is below 110 mm Hg, it should be confirmed on two addition visits as some patients will have a lower blood pressure on repeat measurements. A larger cuff should be used for obese patients.

White coat hypertension

White coat hypertension is a temporary increase in the blood pressure caused by being examined by a medical professional in a clinical environment. If the only measurements being taken are in medical offices, white coat hypertension may cause the appearance of sustained hypertension.

White coast hypertension may not be as important to treat.

Pseudohypertension

Elderly patients may have pseudohypertension due to inability of the blood pressure cuff to compress stiff arteries. Pseudohypertension may be detected by Osler's maneuver.

Excluding secondary hypertension

Causes of secondary hypertension

Cause	Prevalence or effect
Oral contraceptives	1%
Alcohol	6-7 drinks/day may increase BP by 5 mm Hg
Renal artery stenosis	< 1%
Hyperaldosteronism	?
Pheochromocytoma	?
Coarctation of the aorta	?

Since secondary hypertension may be curable, ruling it out is essential. A starting point is listening for an abdominal bruit, especially if it is both systolic and diastolic, may help detect underlying renal artery stenosis.

Among patients with resistant hypertension (blood pressure >140/90 mm Hg despite a three drug regimen, 20% of patients had serum aldosterone and plasma renin activity ratio of more than 65:16 with a aldosterone concentration above 416 pmol/L. However, only 10% of all patients had primary aldosteronism. Half of these patients have a normal serum potassium.

Treatment

Current clinical practice guidelines are:

• 2001 guidelines by National Institute for Health and Clinical Excellence
• 2003 guidelines by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)
• 2007 guidelines by the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).

In addition, drugs for hypertension (antihypertensives) have been reviewed by the Medical Letter.

A systematic review by the Cochrane Collaboration has summarized the benefits of treatment.

Several randomized controlled trials have shown that treating hypertension can reduce morbidity or mortality. These trials include:

• MRC trial
• Hypertension Detection and Follow-up Program
• Treatment of Mild Hypertension Study (TOMHS)
• Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
• Veterans Affairs Cooperative trial
• Losartan Intervention For Endpoint reduction in hypertension study (LIFE)

Treatment goals

Per the JNC7 Guidelines:

• "Treating "most patients" SBP and DBP to targets that are <140/90 mmHg is associated with a decrease in cardiovascular complications.
• In patients with hypertension and diabetes or chronic kidney disease, the BP goal is <130/80 mmHg.

The European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) 2007 guidelines add to diabetes and chronic kidney disease that tight control (<130/80 mmHg) is needed for patients with:

• stroke
• myocardial infarction
• proteinuria

Mild hypertension may not warrant treatment. "Antihypertensive drugs used in the treatment of adults (primary prevention) with mild hypertension (systolic BP 140-159 mmHg and/or diastolic BP 90-99 mmHg) have not been shown to reduce mortality or morbidity in RCTs" according to a meta-analysis by the Cochrane Collaboration. In a meta-analysis of randomized controlled trials of patients with mild hypertension, the relative risk ratio of pharmacotherapy, as compared to placebo, for mortality was 0.85 and the relative risk reduction was 15.0%. This finding did not reach statistical significance Similarly, intensive blood-pressure control ("a mean arterial pressure of 92 is lower than the traditional blood-pressure target of 130/80 mm Hg") had no effect on progression of chronic kidney disease according to a randomized controlled trial.

Recent trials present alternative evidence:

• An industry-sponsored, unblinded randomized controlled trial suggests benefit from treating any patient with a cardiac risk to a goal systolic pressure of 130 mm Hg. The HOPE trial reported similar results. Although 39% of HOPE patients had diabetes, the benefit occurred in patients with and without diabetes.

J-curve

Overly aggressive treatment of hypertension may be harmful due to the "j-curve" effect. It is not clear if this is due to excessive reduction in systolic pressure or low diastolic pressure after treatment or due to general bad health rather than treatment.

According to the HOT randomized controlled trial, the nadir of the j-curve must be below 80 mm Hg.

Non-drug treatment

• See also salt and health
• Exercise
• Lifestyle modification

Initial medication

Clinical practice guidelines have tried to make blanket recommendations for all patients:

• "Thiazide-type diuretics for most" patients are recommended by the JNC7 clinical practice guidelines. Chlorthalidone may be the best choice based on the Multiple Risk Factor Intervention Trial and other studies. In the MRFIT trial, the clinics that predominantly used chlorthalidone reported lower mortality than the clinics using hydrochlorothiazide (5% versus 7%).
• "First-line low-dose thiazides reduce all morbidity and mortality outcomes. First-line ACE inhibitors and calcium channel blockers may be similarly effective but the evidence is less robust. First-line high-dose thiazides and first-line beta-blockers are inferior to first-line low-dose thiazides" according to the Cochrane Collaboration.
• ß-blockers
  • ß-blockers are the preferred initial medication for patients with coronary heart disease according to a systematic review.
  • "ß-blockers, especially in combination with a thiazide diuretic, should not be used in patients with the metabolic syndrome or at high risk of incident diabetes" is noted by the European ESH/ESC clinical practice guidelines. The ESH/ESC guidelines cite the LIFE and ASCOT trials. Unlike the ALLHAT study, both of these trials were in largely anglo populations, supported by industry, and at the same institution. All patients in the LIFE trial had left ventricular hypertrophy (LVH). Based on these two trials, a meta-analysis has concluded that beta blockers should not be the first choice treatment.
• For Stage 2 Hypertension (SBP ≥ 160 or DBP≥100) consider starting two medications for more effect.

Refinements in selection

Selected trials comparing initial medications

Trial	Patients			Intervention	Result
	Race	BMI	Age (mean)
ALLHAT 2002	47% anglo	30	70	Chlorthalidone	Diuretics (chlorthalidone) better than calcium channel blockers and angiotensin-converting enzyme inhibitors
ANBP2 2003	95% anglo	27	72	Hydrochlorothiazide	Diuretics (hydrochlorothiazide) not as good angiotensin-converting enzyme inhibitors
ACCOMPLISH 2008	84% anglo	31	68	Hydrochlorothiazide	Diuretics (hydrochlorothiazide) not as good as calcium channel blockers

Several randomized controlled trials have compared initial medications for hypertension. As summarized in the table, the disparate results may be due to racial and gender differences in responses to medications.

Should renin levels guide decisions?

Predicting response to anti-hypertensives based on demographics

Category name	demographics	Comments	Best anti-hypertensive categories
High renin demographic	less than 50 years old, anglo	salt-sensitive; diuretic responsive	diuretics, calcium channel blockers
Low renin demographic	more than 50 years old, non-anglo*		ace-inhibitors, ß-blockers
* Obesity and female are also associated with low renin.

Some authors have proposed that either the renin level or the renin level indexed to urinary sodium excretion in 24 hours.

Efficacy of different drugs. From Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

However, the Veterans Affairs Cooperative trial suggests the initial drug may be better selected based on the patient's age, race, and gender. The patient's demographic roughly corresponds with their renin profile, but is more predictive than the renin profile. The molecular basis is being determined. In the Veterans Affairs Cooperative, among the high renin demographic (young whites), diuretics had similar efficacy to placebo; whereas in the low renin demographic (older blacks), the ace-inhibitors had similar efficacy to placebo in the Veterans Affairs Cooperative Study Group on Antihypertensive Agents (see figure). Similarly, a meta-analysis has concluded that beta-blockers are a good first choice for younger patients, but not for older patients.

More recently, plasma renin activity was found to predict response to adrenergic beta-antagonists versus diuretics better than using demographic predictors.

Race, gender, and age demographic may partly predict frequency of drug toxicity to different anti-hypertensive medications.

Contraindications

There are contraindications to each of the four major classes, even when other indicators suggest a particular class might be best for the hypertensive patients:

• Beta-blockers: asthma, bradycardia and heart block
• Diuretics: metabolic syndrome, hypokalemia
• ACE inhibitors: pregnancy
• Calcium channel blockers: constipation, irritable bowel syndrome

Comorbidities

Given that the antihypertensive is likely to be a lifelong treatment, selection also may be guided by other chronic diseases of the patient.

• Beta-blockers: reduce benign essential tremor; may prevent migraine
• Diuretics: heart failure
• ACE inhibitors: protective of the kidneys, as in diabetes
• Calcium channel blockers: also may prevent migraine; may relieve neuropathic pain

Labile hypertension

While labile hypertension may be due to a pheochromocytoma, it may be due to baroreflex failure. This can be treated with clonidine 0.3 to 2.4 mg orally total per day.

Resistant hypertension

Blood pressure may be difficult to treat, especially in older patients. A third of cases may be due to white coat hypertension. Clinical practice guidelines from the American Heart Association (AHA) address the management of resistant hypertension.

Physiology

Resistant hypertension is characterized by volume expansion and abnormalities of the renin-angiotensin system with high aldosterone and cortisol with low renin levels in the plasma in spite of many patients taking thiazide diuretics.{ This suggests that high corticotropin may contribute, in some cases due to an abnormal cytochrome P-450 3A5 allele that may reduce metabolism of cortisol and corticosterone (a precursor of aldosterone). Resistant hypertension is also associated with insulin resistance.

Evaluation

The AHA defines resistant hypertension as "blood pressure that remains above goal in spite of the concurrent use of 3 antihypertensive agents of different classes."

First, 'pseudoresistance' should be considered:

• Medication noncompliance
• Inadequate prescribing by the health care provider may be the most common cause of persistent hypertension.
• White coat hypertension, pseudohypertension and other problems of measurement.

Next, secondary hypertension should be considered:

• Renal artery stenosis may be the cause of as much as 30% of cases of truly resistant hypertension.
• Primary aldosteronism underlies about 10% of cases of resistant hypertension.
• Obstructive sleep apnea

Treatment

A low sodium (50 mmol or 1150 mg of sodium) diet may help.

The AHA recommends that one of the three medicines use for hypertension should be a diuretic.

"Three drugs at half standard dose in combination" may be better than one drug at standard dose according to a systematic review.

In an unblinded, uncontrolled extension of the ASCOT randomized controlled trial, spironolactone 25-50 mg per day as a fourth medication reduced the blood pressure by 21.9/9.5. This result was not affected by whether one of the first three medications included a diuretic. A second study study, also uncontrolled, corroborated the role of spironolactone. In this study, 54% of patients were African-American, 45% had primary hyperaldosteronism.

Catheter-based renal sympathetic denervation has been studied for resistant hypertension.

Hypertensive emergency

Treatment must be from a critical care perspective. While the blood pressure must be lowered quickly to avoid end-stage organ failure or crises such as cerebral hemorrhage, lowering it too quickly may create a different end-stage organ failure through decreased perfusion. "Treat the patient, not the number".

Diabetes

Randomized controlled trials of treating hypertension in patients with diabetes mellitus type 2

Trial	Population	Intervention	Comparison	Outcome	Comments
ACCORD 2010	4,733 patients	Systolic pressure goal of less than 120 mm Hg for 4.7 years	Systolic pressure goal of less than 140 mm Hg	Mortality	Insignificantly increased
ADVANCE 2007	11,140 patients	Fixed combination of perindopril and indapamide that achieved blood pressure of 136/73 for 4.3 years	Achieved blood pressure of 130/73	Mortality	Significantly reduced

Geriatrics

Treatment of hypertension in the geriatrics is effective.

However, treatment of patients over age 80 is not clear. A randomized controlled trial included in this meta-analysis found that treating patients aged 80 years or older for two years who have a systolic pressure over 160 mm hg (the average entry pressure was 173/91 mm Hg) and treating to 150/80 mm Hg reduced morbidity. In this trial, the average seated blood pressure at the end of the study in the treatment group was 143/78.

The Cochrane Collaboration has also performed a meta-analysis of this topic and concluded "treating healthy persons (60 years or older) with moderate to severe systolic and/or diastolic hypertension reduces all cause mortality and cardiovascular morbidity and mortality. The decrease in all cause mortality was limited to persons 60 to 80 years of age."

See also

• Salt and health