The levels of evidence (1 to 4) and the recommendation grades (A to D) are defined at the end of the "Major Recommendations" field.
Summary of Evidence-Based Recommendations for Management of Hypertension*
| Indication |
Recommendation |
Highest Level of Evidence |
Grade |
| Lifestyle modification |
Weight loss (in overweight patients) |
1 |
A |
| Sodium restriction (2.3-3 g/day) |
1 |
A |
| Potassium intake>3.5 g/day |
1 |
A |
| Alcohol restriction <1 oz/day |
2-3 |
B |
| Exercise >30 min/day |
3-4 |
C |
| Type 2 diabetes |
Goal BP <130/80 mm Hg |
2 |
A |
| Goal BP <120/75 mm Hg when severe proteinuria exists |
1 |
A |
| ACEI or ARB as first- or second-line agent |
1 |
A |
| Thiazide diuretic as first- or second-line agent (in low dosage with adequate potassium replacement or sparing) |
1 |
A |
| BB (preferably drugs that block both alpha and beta receptors) as second- or third-line agent |
1 |
A |
| CCB (preferably nondihydropyridine) as second-, third-, or fourth-line agent |
1 |
A |
| Pheochromocytoma |
Alpha-adrenergic blocker as first-line agent, in conjunction with BB or CCB (or both) as needed |
3 |
C |
| Hyperaldosteronism |
Surgical resection for unilateral adenoma |
2 |
B |
| Aldosterone antagonists, ACEI, or ARB for hyperplasia |
2 |
B |
| Low-dose glucocorticoid for GRA |
3 |
C |
| Cushing's syndrome |
Surgical or ablative therapy for adenoma |
1 |
A |
| Medical inhibition of steroid synthesis (especially ketoconazole) in intractable cases |
2 |
B |
| Pregnancy |
All major antihypertensive agents except ACEI/ARB (preferably methyldopa or nifedipine) |
1-2 |
A |
| Magnesium for preeclampsia at high risk for seizures |
1-2 |
A |
*Abbreviations
ACEI = angiotensin-converting enzyme inhibitor
ARB = angiotensin receptor blocker
BB = beta-adrenergic blocking agent
BP = blood pressure
CCB = calcium channel blocker
GRA = glucocorticoid-remediable aldosteronism
Lifestyle Modification
A significant observation is that 30% to 65% of patients with hypertension are obese, a problem frequently compounded by high sodium intake, sedentary lifestyle, and excessive use of alcohol. Therefore, lifestyle modifications directed at correcting these contributing factors may benefit the patient regardless of the primary cause of the hypertension and should have an important, first-line role in any therapy. A moderate weight loss of 5 to 10 kg can have a significant beneficial effect on hypertension in obese patients (grade A, on the basis of multiple well-controlled trials).
The American Association of Clinical Endocrinologists (AACE) recommends restricting daily sodium intake to less than 3 g in patients with uncomplicated hypertension or to as low as 2.3 g in patients with refractory hypertension or multiple risk factors, particularly diabetes mellitus (grade A). Although not all cases of hypertension are related to sodium intake, sodium restriction is an important adjunct to other lifestyle modifications and pharmacologic therapy. Insufficient potassium intake may also be an etiologic factor in hypertension. The AACE recommends a daily potassium intake of at least 3.5 g (in the absence of renal insufficiency), preferably from fresh fruits and vegetables (grade A).
Daily consumption of more than 1 oz of alcohol is associated with elevated levels of BP; even this small quantity may also impair the response to pharmacologic therapy for hypertension. Accordingly, healthy adults should limit alcohol consumption to 2 or fewer average-sized alcoholic drinks per day (grade B, because of the absence of any well-controlled randomized trials).
A favorable inverse relationship has been noted between BP and regular physical activity, independent of body weight. Thus, moderately intense exercise for at least 30 minutes daily is recommended for all adults (grade C, primarily based on observational studies and expert consensus opinion).
Diabetes and Hypertension
Type 2 diabetes mellitus and hypertension are common across all populations and frequently coexist. This relationship is particularly true in African American subjects, among whom up to 14% of adults may have both disorders. Many of the estimated 49 to 69 million adults in the United States with insulin resistance also have hypertension, and a quarter of the patients with type 1 diabetes mellitus have hypertension. Obviously, common pathophysiologic processes are at work, which will influence the effectiveness of all treatments for either disorder. Because of the strong correlation of both diabetes and hypertension with risk of cardiovascular disease (CVD), optimal therapy should address both conditions, while including the common benefits of lifestyle modification.
Because angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are associated with favorable effects on renal function and may improve insulin sensitivity, they are ideal first choices in the treatment of patients with both diabetes and hypertension (grade A). Diuretics have also been shown to be effective in the treatment of hypertension, both alone and in combination therapy, and likely are even more effective in patients with excess sodium intake or impaired sodium excretion. Thiazide diuretics, however, can worsen blood glucose control in patients with diabetes and can increase the likelihood of development of diabetes mellitus in insulin-resistant subjects. Thus, diuretics may have an effective role in the treatment of hypertension in these patients, but they should be used in the lowest effective dosage in conjunction with adequate potassium replacement or the addition of a potassium-sparing agent (grade A).
Beta-adrenergic blocking agents (BBs) may likewise precipitate or exacerbate type 2 diabetes mellitus. This feature, together with a variety of adverse side effects, seems to make BBs less appealing as first-line agents for treatment of hypertension in patients with either type 2 or type 1 diabetes mellitus (grade A). BBs, however, have proved effective in the management of the ischemic and congestive cardiomyopathies that are more common in patients with diabetes than in those without diabetes. Because the major adverse effects of BBs may be mediated by peripheral vasoconstriction and increasing insulin resistance, the use of the new third-generation BBs (such as nebivolol) or drugs that block both alpha and beta receptors (such as carvedilol) may prove to be particularly beneficial (grade A). These agents cause vasodilatation and an increase in insulin sensitivity.
The use of calcium channel blockers (CCBs) has been associated with both benefits and adverse outcomes in a variety of study populations with diabetes. The nondihydropyridine CCBs (that is, diltiazem and verapamil) may reduce microalbuminuria to an extent comparable to that with the ACEIs, whereas dihydropyridine CCBs may increase it. Increased albuminuria is associated with increased cardiovascular disease (CVD) and chronic kidney disease risk. Although not considered optimal agents for first-line therapy or monotherapy in patients with diabetes, CCBs have proved safe and effective in combination regimens with ACEIs, diuretics, and BBs (grade A).
In general, combination therapy is needed to achieve the stricter BP goals set for most patients with diabetes mellitus. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) recommended achieving systolic BP below 130 mm Hg and diastolic BP below 80 mm Hg in these patients. Although this goal is based largely on level 2 and 3 evidence, the AACE wishes to promote an aggressive approach to the management of hypertension in patients with diabetes and classifies this recommendation as grade A. Systolic and diastolic BP goals at or below 120/75 mm Hg may be even more effective in slowing the progression of renal disease and other cardiovascular and cerebrovascular complications, particularly in the presence of substantial proteinuria (>1 g daily) (grade A).
In light of the plethora of data showing that patients with diabetes have, on average, a 2-fold greater risk of renal disease and a 3-fold greater risk of CVD in comparison with subjects without diabetes, AACE recommends an early aggressive approach in the management of hypertension as part of overall risk factor reduction. In addition to lifestyle modifications, the use of an ACEI or ARB, in conjunction with a low-dose diuretic, a CCB, a third-generation BB, or some combination of these agents, currently seems to be the preferred initial therapeutic regimen for patients with diabetes (grade A).
Endocrine Hypertension
The potential to "cure" someone's hypertension or to avoid a serious complication is of paramount importance but occasionally must be weighed against the costs, particularly the health risks, of attempting to do so. At times, the clinical situation may suggest the likelihood of a secondary cause of hypertension. The index of suspicion for an underlying cause may be raised by the absence of usual accompanying factors (including a family history, gradual onset, obesity, or high salt intake) or by unexpected clinical or laboratory findings before or during treatment (including hypokalemia, azotemia, tachycardia, or refractoriness to treatment). Causes of endocrine hypertension include disorders of the adrenal, thyroid, parathyroid, or pituitary glands or a renin-secreting tumor. The most common of these are of adrenal origin--namely, mineralocorticoid, catecholamine, or glucocorticoid excess. Renal artery stenosis is the main treatable cause of secondary hypertension not of a primary endocrine origin.
Pheochromocytoma is one of the less common but more dramatic and most pursued causes of endocrine hypertension. Most pheochromocytomas are benign, but a substantial percentage may be bilateral or extra-adrenal lesions (paragangliomas). The hypertension may be episodic or sustained. Patients with pheochromocytoma may have a family history of pheochromocytoma or multiple endocrine neoplasia (MEN) syndrome. More commonly, the index of suspicion is raised by episodes of pallor and evidence of orthostatic hypotension accompanying the typical symptoms, such as palpitations, diaphoresis, and headache. The diagnosis requires demonstration of elevated levels of catecholamines or metabolites in the plasma or urine. Sensitivity and specificity considerations should guide the choice of investigatory procedures, including subsequent imaging techniques. Definitive treatment by surgical excision of the tumor cures the hypertension in about 75% of cases. Underlying essential hypertension, progressive renal disease, or an approximately 10% recurrence rate, usually with malignant histologic findings, may prevent complete cure. Preoperative control as well as management of any residual disease (particularly with malignant involvement) is best accomplished with alpha-adrenergic blocking agents and addition, as needed, of BBs or CCBs (or both) (grade C).
Primary hyperaldosteronism may account for up to 15% of patients with hypertension, particularly in middle age. Although hypokalemia and metabolic alkalosis are classic findings, many patients with primary hyperaldosteronism may not display these findings, particularly when adrenal hyperplasia is the cause. The use of the random serum aldosterone/plasma renin activity ratio (ARR) with a sufficiently high cutoff value has facilitated diagnosis at an acceptable cost and low risk. The diagnosis of primary hyperaldosteronism ultimately depends on demonstration of the following findings: (1) hypertension, (2) an elevated ARR, and (3) an elevated serum aldosterone concentration or urinary aldosterone excretion (or both).
Identifying the specific cause of primary hyperaldosteronism can be difficult but should be pursued. Distinguishing between aldosterone-producing adenoma (unilateral or bilateral) and bilateral adrenal hyperplasia may be particularly difficult, necessitating one or more imaging techniques or selective adrenal vein sampling. Although a laparoscopic surgical procedure is increasingly available and usually the treatment of choice for a unilateral adenoma, medical therapy is preferred for bilateral adrenal hyperplasia (grade B). In patients with glucocorticoid-remediable aldosteronism (GRA), low doses of a glucocorticoid may provide effective treatment after exclusion of Cushing's disease or ectopic production of corticotropin (adrenocorticotropic hormone or ACTH) (grade C).
Cushing's syndrome is perhaps most frequently suspected as a cause of secondary hypertension and, at the same time, is one of the most elusive diagnoses to make. Many pseudo-Cushing's states have been identified, and because definitive treatment is almost always surgical, considerable care must be exercised to arrive at an accurate diagnosis. Unfortunately, in many cases, this diagnostic difficulty may result in substantial expense, including referral to a tertiary or even quaternary center at times, particularly if corticotropin-releasing hormone (CRH) stimulation and inferior petrosal sinus sampling are necessary.
Identification of Cushing's syndrome, at least in the earlier stages, necessitates an increased index of suspicion among the myriad of patients with similar phenotypic features, including centripetal obesity, hirsutism, and striae. New-onset glucose intolerance and hypertension may be the earliest features of the syndrome. Difficult-to-control hypertension, hypokalemia, and perhaps hyperpigmentation may be the only presenting manifestations when ectopic ACTH production is the initiating abnormality.
The cause of hypertension in most patients with Cushing's syndrome is unclear but likely multifactorial, including increased catecholamine sensitivity and some mineralocorticoid effect of cortisol. Accordingly, no one class or combination of antihypertensive agents tends to be routinely effective at controlling BP, and treatment should include elimination of the pathologic hormone production, usually by surgical intervention (grade A). In otherwise inoperable or intractable cases, ketoconazole and mitotane have been used with some success (grade B). Even after effective management of excess cortisolemia, however, up to 33% of patients with the endogenous syndrome have persistent systolic hypertension and 75% have persistent diastolic hypertension. As in the other foregoing causes of secondary hypertension discussed, residual or recurrent hypertension should be appreciably easier to manage after effective treatment of the endocrine pathologic condition.
Pregnancy-associated hypertension involves at least 3 different categories of patients, as discussed subsequently in the original guideline document. Even when the hormonal milieu of pregnancy is primarily etiologic, termination of the pregnancy is usually not a preferred option for treatment. Although the need to treat mild hypertension (<140/90 mm Hg) during pregnancy remains a matter of debate, the immediate treatment of severe hypertension (>170/110 mm Hg) clearly improves both maternal and fetal outcomes, and most authorities agree that treating moderate hypertension is also beneficial, at least to the mother. Methyldopa or CCBs, particularly nifedipine, are thought to be the most suitable antihypertensive agents for use during pregnancy, but BBs and other classes of antihypertensive drugs, except ACEIs and ARBs, can be used safely in accordance with the experience of the treating physician. Magnesium sulfate is superior to other agents in reducing recurrent eclamptic seizures and is recommended for preeclampsia at high risk for seizures. The levels of evidence for all the aforementioned recommendations warrant a grade A classification.
Definitions
Levels of Evidence
- Well-controlled, generalizable, randomized trial
Adequately powered
Well-controlled multicenter trial
Large meta-analysis with quality ratings
All-or-none evidence
- Randomized controlled trial--limited body of data
Well-conducted prospective cohort study
Well-conducted meta-analysis of cohort studies
- Methodologically flawed randomized clinical trials
Observational studies
Case series or case reports
Conflicting evidence with weight of evidence supporting the recommendation
- Expert consensus
Expert opinion based on experience
"Theory-driven conclusions"
"Unproven claims"
Recommendation Grades
- Homogeneous evidence from multiple well-designed randomized controlled trials with sufficient statistical power
Homogeneous evidence from multiple well-designed cohort controlled trials with sufficient statistical power
>1 conclusive level 1 publications demonstrating benefit >> outweighs risk
- Evidence from at least one large well-designed clinical trial, cohort or case-controlled analytic study, or meta-analysis
No conclusive level 1 publication; >1 conclusive level 2 publications demonstrating benefit >> outweighs risk
- Evidence based on clinical experience, descriptive studies, or expert consensus opinion
No conclusive level 1 or 2 publication; >1 conclusive level 3 publications demonstrating benefit >> outweighs risk
No conclusive risk at all and no conclusive benefit demonstrated by evidence
- Not rated
No conclusive level 1, 2, or 3 publication demonstrating benefit >> outweighs risk
Conclusive level 1, 2, or 3 publication demonstrating risk >> outweighs benefit
