Zestoretic

Untreated and uncontrolled hypertension is a major health problem in the United States. Findings from the Third National Health and Nutrition Examination Survey (NHANES III, phase 2)[1] conducted from 1991 to 1994, suggest that only 53 percent of patients with hypertension are being treated with prescription medication, and only 27 percent have their hypertension under control defined as blood pressure less than 140/90 mm Hg). This was true despite a high level of patient awareness (69 percent) of their condition. Because 24 percent of all adults in the United States, or an estimated 43 million Americans, have hypertension, the findings of NHANES III suggest that over 30 million Americans are at increased risk of cardiovascular disease as a result of uncontrolled hypertension. The risk is even greater in the non-Hispanic black population, where the prevalence of hypertension is estimated to be 32 percent.

Although relatively rare, identification of secondary hypertension is important because it is frequently resistant to usual antihypertensive medications and may be controlled by interventions directed at the underlying cause. The evaluation and treatment of patients with secondary hypertension is beyond the scope of this article. However, the most common forms of secondary hypertension in patients have been recently reviewed.[2-5]

Antihypertensive treatment as generally administered in the United States does not lower blood pressure into the optimal range (less than 120/80 mm Hg), where cardiovascular risk is lowest. Whether more aggressive antihypertensive treatment would improve blood pressure control and reduce the morbidity and mortality associated with cardiovascular disease is an important question that remains unanswered. The first aim of therapy for most patients should be to achieve blood pressure levels of less than 140/90 mm Hg.

The reasons for failure to control blood pressure in the majority of people with hypertension are complex (Table 1).[6] "True" resistant hypertension, defined as hypertension that remains uncontrolled (140/90 mm Hg or higher) despite an optimal two-drug regimen that has had adequate time to work (at least one month since last drug or dosage adjustment) occurs in 10 percent or fewer patients with essential hypertension, and secondary hypertension is even less common.[7] The major causes of uncontrolled hypertension are inadequate therapy, patient noncompliance and inappropriate therapy.

TABLE 1 Reasons for Lack of Responsiveness to Hypertension Therapy

Nonadherence to therapy

* Cost of medication and related care

* Instructions not clear and/or not given to the patient in writing

* Failure of physician to increase or change therapy to achieve blood pressure goals

* Inadequate or no patient education

* Lack of involvement of the patient in the treatment plan

* Side effects of medication

* Organic brain syndrome (e.g., memory deficit)

* Inconvenient dosing schedule

White coat hypertension

Pseudohypertension

Drug-related causes

* Doses too low

* Inappropriate combinations (e.g., two centrally acting adrenergic inhibitors)

* Rapid inactivation (e.g,, hydralazine, oral clonidine [Catapres), captopril [Capoten], acting calcium channel blockers)

* Drug interactions

Glucocorticoids

Mineralocorticoids

NSAIDs

Tyramine and MAO inhibitors

Appetite suppressants

Phenothiazines

Oral contraceptives

Sympathomimetics

Antidepressants

Adrenal steroids

Nasal decongestants

Cocaine

Cyclosporine (Sandimmune, Neoral)

Erythropoietin

Associated conditions

* Increasing obesity

* Alcohol intake greater than 1 oz of ethanol per day

* Sedentary lifestyle

* Sleep apnea

Volume overload

* Inadequate diurectic theraphy

* Excess sodium intake

* Fluid retention from reduction of blood pressure

* Progressive renal damage

Secondary hypertension

* Renal

Renal parenchymal disease

Chronic nephritis

Polycystic kidney disease

Collagen vascular disease

Diabetic nephropathy

Hydronephrosis

Acute glomerulonephritis

Renal vascular disease

Renal transplantation

Renin-secreting tumors

* Endocrine

* Adrenal

Primary aldosteronism

Overproduction of 11 -deoxycorticosterone (DOC), 18-OH-DOC, and other mineralocorticoids

Congenital adrenal hyperplasia

Cushing's syndrome

Pheochromocytoma

* Extra-adrenal chromaffin tumors

* Hyperparathyroidism

* Acromegaly

Pregnancy-induced hypertension

Sleep apnea

Coarctation of the aorta

Neurologic disorders

* Dysautonomia

* Increased intracranial pressure

* Quadriplegia

* Lead poisoning

* Guillain-Barre syndrome

Postoperative hypertension

Isolated systolic hypertension

* Aging, with associated aortic rigidity

* Increased cardiac output

* Thyrotoxicosis

* Anemia

* Aortic valvular insufficiency

Decreased peripheral vascular resistance

* Arteriovenous shunts

* Paget's disease of bone

* Beriberi

NSAIDs = nonsteroidal anti-inflammatory drugs, MAO = monoamine oxidase.

Adapted from Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. The Fifth Report of the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1993; 153: 154-83.

Inadequate Therapy

Drug- and Dosage-related Causes

A frequent cause of failure to control blood pressure is the use of inappropriately low dosages of antihypertensive drugs. This error can be avoided if physicians become thoroughly familiar with one or two drugs in each class of antihypertensive medications and follow the manufacturer's recommendations for their use. Doses should be titrated upward until blood pressure is controlled or the maximum recommended dosage is reached, unless the patient experiences dose-related adverse effects. It is then appropriate to add a drug from another class that has additive or synergistic effects with the first drug. Unless the patient has symptoms related to accelerated hypertension, the interval between dose adjustments should be four weeks or more. This amount of time is needed for any dosage of antihypertensive medication to reach its full therapeutic benefit.

The use of inappropriately low dosages of individual antihypertensive drugs inevitably leads to multiple-drug regimens, which reduces compliance. Furthermore, even when optimal drug dosages are administered, polypharmacy is difficult to avoid because blood pressure can be controlled by using one drug in only about 50 percent of patients. Fixed-dose combination therapy is designed to improve patient compliance by decreasing the number of pals that must be taken and reducing the dose-dependent adverse effects of individual components (Table 2).[8] In order to be combined in a single-dose form, federal law requires that each component in the combination must contribute to lowering blood pressure and that the dosage of each component must be such that the combination is safe and effective in a major proportion of the target population (i.e., patients whose hypertension is not easily controlled with a single drug). Most fixed-dose combinations currently available contain one or two diuretics (one for natriuresis, the other for potassium sparing), since diuretics enhance the antihypertensive efficacy of all the other classes of agents (Table 3).[8]

TABLE 2 Advantages of Fixed-Dose Combination Therapy in Patients with Hypertension

Convenience for both patient and physician Improved compliance and simplified titration process Cost is sometimes less than that of individual

components Potentiation of antihypertensive effects

Additive or synergistic effect

Enhanced effect in specific populations

(e.g., combination of diuretics with either ACE

inhibitors or beta-blockers in black patients) Reduction in adverse events through lower dosage

requirements of individual components Attenuation of adverse effects

ACE inhibitors blunting diuretic-induced metabolic

derangements Improved overall antihypertensive effect if the ratio

of components is superior to what is available in

the absence of a fixed-dose combination

ACE = angiotensin converting enyzme.

Reprinted with permission from Sica DA. Fixed-dose combination antihypertensive drugs. Do they have a role in rational therapy? Drugs 1994,48:16-24.

TABLE 3 Fixed-Dose Antihypertensive Combinations

Diuretic-diuretic

Hydrochlorothiazide-triamterene (Dyazide)

Hydrochlorothiazide-amiloride (Moduretic)

Hydrochlorothiazide-spironolactone (Aldactazide) Alpha-adrenergic blocker-diuretic

Prazosin-polythiazide (Minizide)

Beta-adrenergic blocker-diuretic

Bisoprolol-hydrochlorothiazide (Ziac)(*)

Propranolol-hydrochlorothiazide (Inderide,

Inderide LA)

Atenolol-chlorthalidone (Tenoretic)

Timolol-hydrochlorothiazide (Timolide)

ACE inhibitor-diuretic

Captopril-hydrochlorothiazide (Capozide)(dagger)

Benazepril hydrochlorothiazide (Lotensin HCT)

Lisinopril-hydrochlorothiazide (Prinzide, Zestoretic)

Enalapril-hydrochlorothiazide (Vaseretic)

ACE inhibitor-calcium channel blocker

Amlodipine-benazepril (Lotrel)

Angiotensin II receptor antagonist-diuretic

Losartan potassium-hydrochlorothiazide (Hyzaar)

Centrally acting adrenergic agonist-diuretic

Methyldopa-chlorothiazide (Aldochlor)

Methyldopa-hydrochlorothiazide (Aldoril)

Clonidine-chlorthalidone (Combipres)

Guanethidine-hydrochlorothiazide (Esimil)

Peripheral-acting antiadrenergic-diuretic

Reserpine-hydrochlorothiazide (Hydropres)

Reserpine-chlorothiazide (Diuril)

Reserpine-hydralazine-hydrochlorothiazide

(Ser-Ap-Es)

Vasodilator-diuretic

Hydralazine-hydrochlorothiazide (Apresazide)

ACE = angiotensin converting enzyme.

(*) the bisoprolol-hydrochlorothiazide combination (Ziac) has been labeled by the U.S. Food and Drug Administration for initial therapy of hypertension.

(dagger) the captopril/thiazide combination (Capozide) has been labeled by the FDA for initial therapy of hypertension.

Adapted with permission from Sica DA. Fixed-dose combination antihypertensive drugs. Do they have a role in rational therapy? Drugs 1994;48.16-24.

Furthermore, a recent study[9] has demonstrated that combination therapies containing a diuretic are more effective than those not containing a diuretic. The new combinations of angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers offer promise, as the ACE inhibitors reduce the peripheral edema that frequently develops with dihydropyridine calcium channel blocker therapy.

Short-acting antihypertensive agents, including not only calcium channel blockers such as capsular nifedipine (Adalat, Procardia) but also oral clonidine (Catapres), hydralazine (Apresoline) and captoprd (Capoten), should generally be avoided because of the need for frequent dosing, leading to noncompliance. In addition, these agents (with the exception of captopril) tend to activate the sympathetic nervous system, resulting in unstable blood pressure control and periods of "rebound hypertension" at the end of the dosing interval.

Patient Factors

Obesity. Obese patients defined as patients with a body mass index greater than 27.8 in men and 27.3 in women) do not respond as well as leaner patients to antdiypertensive medication.[7,10]

Thus, weight reduction is a particularly important adjunct to drug therapy in the obese patient with resistant hypertension. Progressively higher doses of antihypertensive drugs are required to control blood pressure as the body mass index increases.[10] However, even lean patients with hypertension, glucose intolerance and hyperinsulinemia may require higher drug dosages, suggesting that obesity, a sedentary lifestyle, glucose intolerance and insulinemia, all of which are related to insulin resistance, may cause refractory hypertension.[7,10]

Alcohol Abuse. Excess alcohol intake raises blood pressure in both treated and untreated patients with hypertension, and blood pressure either returns to normal or becomes easier to control when alcohol intake ceases.[7,11] Alcohol abuse is also a frequent cause of non-compliance with medications.

Sleep Apnea. Sleep apnea affects 2 to 4 percent of middle-aged adults, most of whom are unaware they have this disorder.[12] Associations between sleep apnea and both diurnal hypertension and morbidity and mortality due to cardiovascular and cerebrovascular causes have been reported.[12,13] The association between sleep apnea and diurnal hypertension is independent of obesity, age and sex, and appears to be related to stimulation of the sympathetic nervous system by repetitive upper-airway closure.[14] A sleep study is indicated in patients with resistant hypertension and other signs and symptoms of sleep apnea, including obesity, large neck size (size 17 or greater in men and size 16 or greater in women), excessive loud snoring, interrupted sleep, daytime somnolence, polycythemia and carbon dioxide retention.[7,12]

Volume Overload

Volume overload, whether related to excess sodium intake or inadequate/inappropriate diuretic treatment, is the most common cause of resistant hypertension in patients who adhere to therapy.[7] All patients with hypertension should be counseled to avoid foods high in sodium and to increase their consumption of fruits, vegetables and low-fat dairy products. These foods contain micronutrients that reduce the pressor effects of concomitant sodium intake. In patients with hypertension and normal renal function, thiazide diuretics are more effective than loop diuretics in lowering blood pressure.[7,15]

One of the main reasons for resistant hypertension may be a failure to include diuretics in the treatment regimen. In the rush to use newer agents, the use of diuretics has decreased dramatically in the past 10 years despite increasing evidence of their long-term safety and benefical effect. Loop diuretics are necessary to control blood pressure and volume in patients with renal dysfunction (glomerular filtration rate less than 30 mL per minute; serum creatinine approximately 3 to 4 mg per dL [260 to 350 mmol per L]).[7,16] This is a particular problem in patients with progressive hypertension-induced renal damage, as well as in patients with fluid retention either secondary to a reduction in blood pressure or to the effects of other classes of antihypertensive drugs (particularly direct vasodilators and centrally acting adrenergic agents)-. A switch to a loop diuretic may be indicated in these patients.

Nonadherence to Therapy (`Noncompliance')

Failure to follow a prescribed drug regimen has been implicated in approximately 50 percent of patients with resistant hypertension.[7,17-19] Nonadherence to therapy can be attributed to a variety of factors, including cost of medication and related care, inadequate patient education, complex drug regimen, the patient's level of literacy and education, and the adverse side effects of the medication. Nonadherence to therapy should be a primary consideration in the evaluation of all patients with difficult-to-manage hypertension. Clues to nonadherence include frequently missed appointments, failure to manifest the expected biologic effects of prescribed drugs (e.g., slowing of heart rate with use of beta-adrenergic blockers) and alcohol or other substance abuse.[7]

Adherence to antihypertensive treatment can be enhanced by using the strategies outlined in Table 4.[19] The cornerstone of these strategies is the establishment of a good relationship with the patient, and free and open communication about hypertension, its complications and the goals and pitfalls of treatment. In a world where physicians' time is severely limited, educational messages can be delivered by office personnel, written material or video presentations.

TABLE 4 Suggestions for Increasing Patient Compliance with Antihypertensive Therapy

Educate patient about hypertension and the importance of following prescribed

drug regimen Schedule follow-up appointment during office visit and reconfirm by telephone Prescribe the drug regimen least likely to result in adverse effects Choose the least costly regimen likely to be effective Prescribe a once-a-day regimen, if feasible Simplify drug regimen by using a fixed-dose combination product Track attendance Monitor for achievement of blood pressure goal Reward/acknowledge progress toward goal Inquire about compliance obstacles Collaborate with patient in devising new treatment strategies

Adapted with permission from Miller NH, Hill M, Kottke T Ockene IS. The multi-level compliance challenge: recommendations for a call to action. A statement for healthcare professionals. AHA special report. Circulation 1997;95:1085-90.

A positive and supportive approach to treatment combined with the message that an effective, affordable and convenient drug regimen relatively free of side effects can be found for almost every patient yields the best results. The large number of antihypertensive medications now available, including sustained-release preparations and fixed-dose combinations, have made once-a-day dosing and smooth 24-hour control of blood pressure a reality, improving the tolerability of multidrug antihypertensive regimens. Above all, the physician must be convinced that treating to reach a goal blood pressure level of less than 140/90 mm Hg is worthwhile.

Inappropriate Therapy

`White Coat' Hypertension

"White coat" or office hypertension occurs when blood pressure values measured by a health care professional in the office or clinic are significantly elevated compared with blood pressure values measured outside the health care setting (i.e., by ambulatory monitoring or patient self-measurement).[20] White coat hypertension has been reported in 21 to 39 percent of patients with untreated hypertension.[21,22] Prospective studies have not defined the natural history or the mortality and morbidity risks associated with untreated white coat hypertension, but cross-sectional studies[23,24] suggest that, when compared with normotensive patients, patients with white coat hypertension have higher left ventricular mass indices, higher low-density lipoprotein cholesterol and insulin levels, reduced diastolic compliance in the left ventricle, and abnormal elasticity, compliance and stiffness in the large arteries. Thus, white coat hypertension appears not to be a benign condition but perhaps a mild form of essential hypertension associated with increased cardiovascular risk.

White coat hypertension should be suspected in patients who remain resistant to therapy in the absence of target organ damage (retinopathy, renal insufficiency, left ventricular hypertrophy), who manifest symptoms of overmedication (orthostatic symptoms, persistent fatigue) and/or who report home blood pressure values significantly lower than values measured in the office. Because white coat hypertension is so common, all patients with hypertension should be encouraged to obtain home blood pressure values.

Ambulatory monitoring and blood pressure self-measurement are also helpful in patients with apparent drug resistance, episodic hypertension or autonomic dysfunction, and in patients with hypotensive symptoms who take antihypertensive medications. Extensive evidence indicates that ambulatory blood pressure values or blood pressure self-measurement correlates more closely than office blood pressure values with target organ damage.[25] Although treatment guidelines have not been defined for white coat hypertension, careful follow-up and antihypertensive treatment are indicated, particularly in patients developing signs of target organ damage.[24]

Once white coat hypertension is diagnosed, accurate home blood pressure values are the best guide for therapy. To maximize accuracy, the patient should be encouraged to obtain a quality arm or wrist (not finger) cuff device. The patient should initially bring the device to the office to ensure that he or she knows how to use it properly and to have its accuracy validated against a calibrated mercury sphygmomanometer.

Pseudohypertension

Pseudohypertension is a falsely elevated blood pressure obtained by indirect cuff measurement secondary to loss of arterial compliance, necessitating increased cuff pressure in order to compress the underlying artery.[26] Loss of arterial compliance is usually secondary to atherosclerosis, occurring most commonly in the elderly. The Systolic Hypertension in the Elderly Program (SHEP)[27] study group determined that 7 percent of the elderly screened had pseudohypertension. Diagnosing hypertension when the patient actually has pseudohypertension can lead to overmedication of the patient. Pseudohypertension should be suspected in elderly patients whose blood pressures remain elevated despite therapy, who have little or no evidence of target organ damage or who manifest symptoms of overmedication.

Diagnosis of pseudohypertension is problematic. The Osler maneuver, in which the radial or brachial artery remains palpable when the blood pressure cuff is inflated above the auscultated systolic pressure, has been advocated as a screening test for pseudohypertension,[28] but its diagnostic value has been questioned.[29] A definitive diagnosis of pseudo-hypertension requires direct measurement of intra-arterial blood pressure but, since this is a hazardous procedure, blood pressure may be measured by using an automatic infrasonic or plethysmographic device (2300 Finapres blood pressure monitor. Ohmeda, Ohmeda Drive, P.O. Box 7550, Madison, WI 53707; telephone: 800-345-2700-7550), with, recording from a finger as an alternative.[30]

REFERENCES

[1.] The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413-46.

[2.] Greco BA, Breyer JA. The natural history of renal artery stenosis: who should be evaluated for suspected ischemic nephropathy? Semin Nephrol 1996;16:2-11.

[3.] Pickering TG, Mann SJ. Renovascular hypertension: medical evaluation and nonsurgical treatment. In: Laragh JH, Brenner BM, eds. Hypertension: pathophysiology, diagnosis, and management. 2d ed. New York: Raven, 1995:2039-54.

[4.] Manger WM, Gifford RW Pheochromocytoma: a clinical overview. In: Laragh JH, Brenner BM, eds. Hypertension: pathophysiology, diagnosis, and management. 2d ed. New York: Raven, 1995:2225-44.

[5.] Bravo EL. Primary aidosteronism. issues in diagnosis and management. Endocrinol Metab Clin North Am 1994;23:271-83.

[6.] The Fifth Report of the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1993;153:154-83.

[7.] Setaro JF, Black HR. Refractory hypertension. N Engl J Med 1992;327:543-7.

[8.] Sica DA. Fixed-dose combination antihypertensive drugs. Do they have a role in rational therapy? Drugs 1994;48:16-24.

[9.] Materson BJ, Reda DJ, Cushman WC, Henderson WG. Results of combination anti-hypertensive therapy after failure of each of the components. Department of Veterans Affairs Cooperative Study Group on Anti-hypertensive Agents. J Hum Hypertens 1995;9:791-6.

[10.] Modan M, Almog S, Fuchs Z, Chetrit A, Lusky A, Halkin H. Obesity, glucose intolerance, hyperinsulinemia, and response to antihypertensive drugs. Hypertension 1991;17:565-73.

[11.] Puddey IB, Beilin LJ, Vandongen R. Regular alcohol use raises blood pressure in treated hypertensive subjects. A randomised controlled trial. Lancet 1987;1(8534):647-51.

[12.] Strollo PJ Jr, Rogers RM. Obstructive sleep apnea. N Eng J Med 1996;334:99-104.

[13.] Hla KM, Young TB, Bidwell T, Palta M, Skatrud JB, Dempsey J. Sleep apnea and hypertension. A population-based study. Ann Intern Med 1994;120:382-8.

[14.] Fletcher EC. The relationship between systemic hypertension and obstructive sleep apnea: facts and theory. Am J Med 1995;98:118-28.

[15.] Ram CV, Garrett BN, Kaplan NM. Moderate sodium restriction and various diuretics in the treatment of hypertension. Arch Intern Med 1981;141:1015-9.

[16.] National High Blood Pressure Education Program Working Group report on hypertension and chronic renal failure. Arch intern Med 1991;151:1280-7.

[17.] Sackett DL, Haynes RB, Gibson ES, Hackett BC, Taylor DW, Roberts RS, et al. Randomised clinical trial of strategies for improving medication compliance in primary hypertension. Lancet 1975;1(7918):1205-7.

[18.] Management of patient compliance in the treatment of hypertension. Report of the NHLBI Working Group. Hypertension 1982;4:415-23.

[19.] Miller NH, Hill M, Kottke T, Ockene IS. The multilevel compliance challenge: recommendations for a call to action. A statement for healthcare professionals. AHA special report. Circulation 1997;95:1085-90.

[20.] Pickering TG. Clinical applications of ambulatory blood pressure monitoring: the while coat syndrome. Clin Invest Med 1991;14:212-7.

[21.] Pickering TG, James GD, Boddie C, Harshfield GA, Blank S, Laragh JH. How common is white coat hypertension? JAMA 1988;259:225-8.

[22.] Lerman CE, Brody DS, Hui T, Lazaro C, Smith DG, Blum MJ. The white-coat hypertension response: prevalence and predictors. J Gen intern Med 1989;4:226-31.

[23.] Weber MA, Neutel JM, Smith DH, Graettinger WF. Diagnosis of mild hypertension by ambulatory blood pressure monitoring. Circulation 1994;90:2291-8.

[24.] Glen SK, Elliott HL, Curzio JL, Lees KR, Reid JL. White-coat hypertension as a cause of cardiovascular dysfunction. Lancet 1996;348:654-7.

[25.] Appel LJ, Stason WB. Ambulatory blood pressure monitoring and blood pressure self-measurement in the diagnosis and management of hypertension. Ann Intern Med 1993;118:867-82.

[26.] Taguchi JT, Suwangool P. "Pipe-stem" brachial arteries. A cause of pseudohypertension. JAMA 1974;228:733.

[27.] Wright JC, Looney SW. Prevalence of positive Osler's manoeuver in 3387 persons screened for the Systolic Hypertension in the Elderly Program (SHEP). J Hum Hypertens 1997;11:285-9.

[28.] Messerli FH, Ventura HO, Amodeo C. Osler's maneuver and pseudohypertension. N Engl J Med 1985;312:1548-51.

[29.] Zuschke CA, PettyjJohn FS. Pseudohypertension. South Med J 1995;88:1185-90.

[30.] Anzal M, Palmer AJ, Starr J, Bulpitt CJ. The prevalence of pseudohypertension in the elderly. J Hum Hypertens 1996;10:409-11.

The Authors

SUZANNE OPARIL, M.D., is professor of medicine and director of the Vascular Biology and Hypertension Program in the Division of Cardiovascular Disease at the University of Alabama School of Medicine, Birmingham. She received a medical degree from Columbia University College of Physicians and Surgeons, New York City. Dr. Oparil completed an internship and was an assistant resident in medicine at Presbyterian Hospital, New York City, and was a senior assistant resident in medicine at Massachusetts General Hospital, Boston.

DAVID A. CALHOUN, M.D., is assistant professor of medicine at the University of Alabama School of Medicine. He received a medical degree from the University of Virginia School of Medicine, Charlottesville, and completed an internship and residency in medicine at the University of Alabama School of Medicine

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