CLINICAL THERAPEUTICS/VOL. 2, SUPPL. A, 1979 Fundamentals of Management of the Hypertensive Patient Edward D. Freis, M.D. Senior Medical Investigator, Veterans Administration Hospital, Washington, D.C. ABSTRACT The diagnostic workup in hypertension seeks to identify the few curable forms of the disorder, to indicate those pa- tients who are at increased risk of com- plications, and to reveal those compli- cations that may already have oc- curred. Treatment is based on mod- erate sodium restriction and step-care therapy with antihypertensive agents. The cornerstone of drug therapy is a thiazide diuretic. Other agents, such as methyldopa, are added as required to achieve adequate control of blood pres- sure with a minimum of patient incon- venience. Compliance with therapy is vital, and the establishment of a thera- peutic partnership between physician and patient increases the chance of suc- cessful long-term treatment. INTRODUCTION The emphasis on the diagnostic work- up of the newly diagnosed hypertensive patient has changed in recent years. In the past, the workup was extensive and costly, with the purpose of determining whether the patient had a curable form of hypertension, such as pheochro- mocytoma or primary aldosteronism. However, the number of surgical pro- cedures performed even at such a re- ferral center as the Mayo Clinic’ makes it clear that these curable forms of hy- pertension are extremely rare, ac- counting for perhaps only 1% of the hy- pertension seen in patients over 40. In younger patients these forms are seen more often, but they are still quite un- usual, Today, an elaborate investiga- tion is justified only in the patient who has suggestive clinical evidence of a curable form of hypertension and who is under 40. It is important to realize that surgical treatment, especially in patients over 40, is not particularly suc- cessful. In renovascular hypertension, the most common kind of curable hy- pertension, surgery is generally re- served for patients under age 45, espe- cially those who do not respond to med- ical therapy. Only medical treatment is ordinarily used in patients over 50. The Veterans Administration Coop- erative Study’? and the Public Health Service Hospital Study? have demon- strated the value of effective antihyper- tensive drug therapy in preventing such complications as heart failure, renal failure, dissecting aortic aneurysm, and progression of hypertension to a more severe stage. Elsewhere, there is also suggestive, if not definitive, evidence that treatment may reduce the incidence of myo- cardial infarction and sudden death.56 DIAGNOSTIC WORKUP The purpose of the diagnostic workup is to identify curable forms of hyper- tension and to indicate the severity of the disease and the extent of target organ damage. The workup has been summarized in a risk evaluation record. Obtaining a true blood pressure reading from a patient usually requires taking at least three readings at separate visits, because the stress of an initial examination often causes falsely high readings. In patients who are ner- vous and anxious, it is sometimes de- sirable to have a member of the family record blood pressures at home for two weeks, in order to get a more represen- tative picture: of the patient’s blood pressure. History taking for curable forms of hypertension seeks patient complaints of explosive periodic headaches and pounding of the heart, which suggest pheochromocytoma. Sudden onset of severe hypertension or sudden worsen- ing of mild hypertension suggests reno- vascular hypertension. The patient should also be asked whether he or she has experienced such complications as stroke, myocardial infarction, conges- tive heart failure, angina, dyspnea on mild exertion, or nocturia. Clinical investigations include a chest X-ray, which is not essential but which may show possible pulmonary disease or an enlarged heart. However, an elec- CLINICAL THERAPEUTICS trocardiogram is a better way of identi- fying left ventricular hypertrophy, which is seen with high voltage in the leads over the lateral part of the chest, accompanied by inversion or flattening of the T-waves or sagging of the ST- segments. During clinical examina- tion, the patient’s optic fundi should be inspected for hypertensive changes. Laboratory workup should include a routine blood count and urinalysis, the latter of which may reveal urinary tract infection or other underlying renal dis- eases as shown by cellular or granular casts in the urine or albuminuria. Blood chemistries should include the serum potassium level. A low level of serum potassium, if the patient is not taking a thiazide diuretic, may indicate primary aldosteronism. An_ initial serum potassium and other electrolyte determinations are also useful in eval- uating the changes produced by diu- retic therapy. Serum creatinine and serum urea nitrogen are helpful in identifying unsuspected renal failure and are also useful as baseline mea- surements if a rise is seen in either level during therapy. Pretreatment uric acid levels are also helpful, because gout is common in hypertensive patients. Also, thiazide diuretics may increase uric acid levels. Most patients with elevated serum uric acid levels never develop clinical gout, although frank gout may be precipitated in certain patients. Fasting serum glucose should be measured, with a level of 120 mg or above indicating, to many physicians, the presence of diabetes. Cholesterol and triglyceride levels should also be determined. Hyperglycemia, hyper- cholesterolemia, and hypertriglycerid- emia are known to further increase the EDWARD D. FRLIS risk of myocardial infarction, which is already high in hypertensives because of the hypertension-accelerated athero- sclerosis. Recent evidence suggests that the measurement of high density lipo- proteins is a useful predictor of myo- cardial infarction, the risk of future myocardial infarction being inversely related to the serum concentration of high density lipoproteins.’ The routine measurement of plasma renin levels as part of the diagnostic in- vestigation of the hypertensive patient is a somewhat controversial topic. It has long been known that high renin levels are associated with severe hyper- tension. Recently it has been sug- gested, but not proved, that renin levels are independent indicators of the sev- erity of hypertension, separate from blood pressure, and that a patient with low renin levels will be protected from complications of hypertension. How- ever, other investigators have been un- able to confirm this relationship. Fur- thermore, renin levels may not be the most reliable of tests, particularly when they are not correlated with 24-hour urinary excretion of sodium. [n general, plasma renin levels appear to have little value in evaluating prognosis. It has also been suggested that low- renin hypertensives have high extracel- lular fluid volume and should respond to diuretics, whereas high-renin hyper- tensives should respond to drugs that inhibit secretion of renin. Research may reveal the merit of these hy- potheses, but for the practicing physi- cian the important point is that high blood pressure itself is damaging for the patient and should be controlled by whatever drug or combination of drugs is most effective. There is as yet no sub- stitute for an adequate therapeutic trial. Reduction of Risk Factors Reducing the weight of obese pa- tients is extremely important and may in itself lower blood pressure to normal. The difficulty lies in motivating the pa- tient to lose weight and then maintain a normal weight. Restriction of saturated fats and cholesterol may help to retard the development of atherosclerosis, al- though the evidence is not conclusive. Salt restriction is also helpful. Most patients will not continue on a very low sodium diet, but they may be per- suaded to avoid extremely salty foods and snack foods and not to oversalt their food when cooking or at the table. Patients who smoke cigarettes are advised to stop because of the known link smoking has to coronary disease, for the risk of coronary disease is al- ready above average in these patients. Moderate exercise is encouraged for its general health benefits. Level of Blood Pressure The most important factor in deter- mining a patient’s prognosis is the level of blood pressure. A number of long- term studies, including the Framing- ham study and our VA studies, have shown the relationship between level of blood pressure and degree of risk. The Framingham study, for example, dem- onstrated that hypertensives develop seven times more brain infarctions than normotensives. The risk was propor- tional to the blood pressure through- out its range, increasing 30% for each 10-mm increment in pressure.’ Other Factors Several other factors increase the risk in hypertensive patients and should be evaluated before starting treatment. Age is one factor. The younger the patient, the more likely that hyperten- sion will progress and the shorter will be the life expectancy. Life insurance statistics indicate that the 20-year mor- tality rate for patients with a blood pressure of 150/100 is five times great- er than normal in the age range of 30 to 39 and is twice normal in the age range of 50 to 59.9 Sex is another factor. Men do not tolerate high blood pressure as well as women do. Mortality rates for men are one and one half to two times higher than those for women.!®!! Race is yet another consideration. Hypertension is about twice as preva- lent in the black population as in the white,'? and it is more severe among blacks. Hypertensive heart disease is seen at rates three to seven times greater for blacks of a given age-sex group than for whites of the same age- sex group.'? Indeed, the rate of compli- cations of hypertension is at least dou- ble that seen in whites. Presence of target organ damage at the time of diagnosis greatly increases the risk of further complications, as do hypercholesterolemia and a family history of hypertensive complications. Hypertension aggravates and ac- celerates atherosclerosis, particularly of the coronary and cerebral arteries. Hypercholesterolemia and, to a lesser extent, hypertriglyceridemia, diabetes CLINICAL THERAPEUTICS mellitus, and cigarette smoking are also associated with atherosclerosis of the coronary arteries. When any or all of these factors are present in a patient with hypertension, the risk of myo- cardial infarction or sudden death is considerably increased ,!4 Therapeutic Decisions Regardless of the cause of hyperten- sion, complications result from the elevated blood pressure. The aim of therapy is to lower the blood pressure and keep it at normal or close to nor- mal levels with a minimum of inconve- nience to the patient. The simpler and more convenient the regimen, the more likely the patient will comply with it. The Veterans Administration Coop- erative Study Group on Antihyperten- sive Agents*3!§ showed conclusively that reduction of blood pressure with antihypertensive agents prevented many hypertensive complications such as hemorrhagic stroke, congestive heart failure, accelerated (malignant or pre- malignant) hypertension, renal deteri- oration, dissecting aortic aneurysm, and progression of hypertension from mild to moderate or from moderate to severe forms. The only major complica- tion that did not appear to be pre- vented by treatment was myocardial infarction, The relationship between the physi- cian and the patient is especially impor- tant in successful treatment. If the physician is convinced of the impor- tance of treatment and if the patient is aware of the physician’s concern, then the patient is more likely to stay in treatment. Follow-up visits are an im- portant opportunity for the physician to EDWARD D. FREIS reinforce the patient’s awareness of the need for therapy and the success of the measures used. This can be done by reporting to the patient his lowered pressure, thereby indicating the success of treatment. Step-care therapy is empiric but ef- fective in almost all patients. A thia- zide diuretic is the cornerstone of treat- ment. The choice of a particular agent depends on how conscientious the pa- tient will be in complying with therapy. Age is another consideration. In pa- tients over 60, it is usually wise to begin with a smaller dose of a thiazide than that used in younger patients. Baro- receptor activity is related to the elas- ticity of the carotid artery, and if the walls are relatively stiff, as they often are in older people, then the baro- receptors may be sluggish in responding to postural changes causing orthostatic hypotension. This may result in epi- sodes of dizziness and fainting when the patient arises from a sitting or lying position. In general, older people do not moderate their blood pressure as well as younger people do. Initiating Therapy In patients under the age of 60, | begin therapy with a diuretic. If hydro- chlorothiazide is used, my initial dose is usually 25 mg twice daily. In patients over 60, I initiate therapy with 25 mg of hydrochlorothiazide once a day. The patient returns in one week if the hypertension is fairly severe, in two weeks if the problem is less urgent. If the blood pressure is not controlled at this visit, I double the hydrochloro- thiazide dosage, bringing it to 100 mg per day for the younger patients and to 50 mg per day for those over 60. In both younger and older patients, I prescribe the medication on a b.i.d. schedule. Ordinarily, these are the high- est dosages I use, and they are effective in lowering blood pressure to the de- sired level in about half of all patients. In my experience, older patients tend to respond to smaller doses than younger patients, probably because of their im- paired baroreceptor responses. When the hydrochlorothiazide dose is increased, there may be a propor- tionate increase in dose-related side ef- fects. In these cases, the diuretic must be reduced, and if necessary, a second- step agent can be added. Hydrochlorothiazide is contraindi- cated in anuria and when there is hyper- sensitivity to it or to any other sulfona- mide-derived drugs. It should be used with caution in severe renal disease. In patients with renal disease, thiazides may cause azotemia. Cumulative ef- fects of the drug may develop in pa- tients with impaired renal function. Thiazides should be used with caution in patients with impaired hepatic func- tion or progressive liver disease, since minor alterations of fluid and electro- lyte balance may precipitate hepatic coma. SECOND-STEP AGENTS For patients who do not respond suffi- ciently to a thiazide diuretic, the next step is adding a sympathetic inhibiting agent or a vasodilator to the antihyper- tensive regimen. One can choose a sym- pathetic inhibitor from among those that act centrally, such as clonidine or methyldopa; those that act periph- erally to deplete sympathetic nerve endings of catecholamines, such as hydralazine; those that affect only the alpha-adrenergic portion of the sym- pathetic nervous system, such as prazosin; and those that block only the beta-adrenergic portion, such as pro- pranolol. The centrally acting agents, such as methyldopa, although affecting both alpha- and beta-adrenergic systems, do not usually produce ortho- static hypotension. The agents that af- fect the alpha portion, such as prazosin, are more likely to produce this side ef- fect, and one must be quite careful dur- ing the initial treatment period with such agents. Vasodilators may be suitable for older patients, in whom sympathetic in- hibitors may induce symptoms of pos- tural faintness, weakness, and fatigue. The increased cardiac output seen with some vasodilators may have a benefi- cial effect on the elderly patient’s sense of well being, and if the drug is begun at a low dosage and increased gradually to the therapeutic level, there is seldom any problem of angina occurring. For the patient who has angina, of course, propranolol is probably the most suit- able second-level agent. Reserpine is an effective second-step agent for many patients. Of course, the physician should not prescribe it for pa- tients with mental depression, and ex- treme caution should be used in treat- ing patients with a history of mental de- pression. Electroshock therapy should not be given to patients while on reser- pine, or for seven days after the discon- tinuance of the drug, because severe and even fatal reactions have been re- ported with minimal convulsive elec- troshock therapy. CLINICAL THERAPEUTICS I do not use reserpine in patients with active peptic ulcers or in those with ulcerative colitis. The most commonly seen side effect is nasal stuffiness. Im- potence may occur but is reversible on stopping the drug. At the first sign of depression, the drug must be discon- tinued. Small doses may minimize side effects, and many patients can be con- trolled on as little as 0.1 mg of reserpine daily. Methyldopa is a useful second-step agent in conjunction with a thiazide, and it need be taken only twice a day. In my experience, patients are less like- ly to comply with any regimen that re- quires taking pills more than twice a day. The thiazide-methyldopa com- bination is useful in that the thiazide diuretic, by reducing blood volume, makes the patient more responsive to the antihypertensive effect of methyl- dopa and offsets the sodium retention that may occur with long-term use of methyldopa. When methyldopa is added to a thia- zide regimen, the patient is started at 250 mg twice a day for a total daily dose of 500 mg. If the response is not sufficient, at the next visit the dose is raised to 500 mg twice a day, and in- creased in this manner until a satisfac- tory response is seen or the total daily dose is 2,000 mg. The side effects most often seen are sleepiness and dryness of the mouth, although these tend to les- sen with continued treatment. Impo- tence is sometimes seen with methyl- dopa, but in my experience much less often than with reserpine. I do not use methyldopa in patients with active hepatic disease, such as acute hepatitis and active cirrhosis. I EDWARD D. FREIS also withhold it from patients in whom previous methyldopa therapy has been associated with liver disorders. The great majority, perhaps 95%, of patients can have their hypertension controlled with one or another of the combinations of thiazide plus a sec- ond-step agent. The appropriate com- bination depends on _ blood-pressure response and the occurrence of side ef- fects. It is wiser to seek a two-drug regi- men that is effective than to prescribe a three-drug regimen, because patient convenience is greater with a two-drug regimen, and because the number of side effects is likely to be less with a two-drug regimen than with a three- drug regimen. If the patient does not respond to a particular two-drug com- bination, such as a thiazide plus pro- pranolol, it may be helpful to pick a se- cond drug that is quite different, such as methyldopa. If the patient has impaired renal function, it may be useful to substitute furosemide for the thiazide diuretic in order to achieve sufficient reduction in volume. For the fraction of hypertensive pa- tients who still do not respond, despite adequate diuresis and compliance, referral to a teaching center special- izing in resistant hypertension is the alternative. Combination Therapy Combination therapy offers impor- tant advantages to both patient and physician. The most important benefit is that the convenience of combination therapy improves patient compliance with the antihypertensive regimen. Also, the cost of the medication may be lower. Of course, it is essential that the physician titrate the individual drugs first and then determine whether there is a convenient combination of the agents employed. Management Problems Patients with coexisting diseases such as diabetes, various cardiovascular problems, and renal disorders present some difficulties in management. In the case of diabetes, physicians are sometimes reluctant to prescribe thia- zides for fear of worsening the hyper- glycemia. Thiazides may worsen glu- cose tolerance to some extent and may elevate blood sugar. However, in terms of preventing complications, it is prob- ably more important to control the hypertension than to control the blood sugar. Therapy should aim to control the hypertension first, which is often difficult to accomplish without a di- uretic. If the blood sugar rises some- what, treatment can be directed to- wards that. Beta-adrenergic blocking agents, of course, should not be used in insulin-dependent diabetics because they may disguise the symptoms of in- sulin shock. The patient with cerebral vascular disease, who may have some senile changes, with difficulty in remember- ing recent events and in locating him- self in time and place, probably should be treated cautiously because the men- tal symptoms may be made worse. Pro- pranolol should probably be avoided in these patients since they may already be suffering from the effects of decreased cardiac output. A thiazide in small doses plus a vasodilator such as hydra- lazine, if a second drug is needed, may be the best of therapeutic choices. In the patient who has had a stroke, the situation is similar. One does not want to decrease cardiac output, but such a patient may have severe hyper- tension that requires several agents for control, The patient who has had a sub- arachnoid hemorrhage should be in- vestigated to determine whether he has a surgically correctable aneurysm, but of course his blood pressure should be controlled first. Congestive heart failure is usually not seen in any patient who is receiving adequate antihypertensive therapy that includes a diuretic. If congestive heart failure appears, it suggests that the treatment is inadequate, either in terms of diuresis or in terms of blood pres- sure control. In the VA cooperative study, no patients under treatment for hypertension developed congestive heart failure. It was only seen in the control group. For patients who have had conges- tive heart failure in the past, it is impor- tant to make sure they are receiving adequate amounts of a diuretic and that their renal function is not impaired. If it is, they should be given furosemide. Good control of blood pressure is es- sential to preventing a recurrence of the congestive heart failure. In my opinion, patients who have had myocardial infarctions in the past three months probably should not re- ceive propranolol or hydralazine be- cause of the risk of precipitating heart failure. Patients whose myocardial in- farcts occurred more than three months previously can probably be treated in the same way as any other hyperten- sives. Patients who have second-degree or CLINICAL THERAPEUTICS greater heart block should not be given propranolol and probably not reserpine either. Both drugs tend to depress heart rates even further. In atrial fibrillation, it is very diffi- cult to obtain a true blood pressure reading, but there are no contraindica- tions to any of the drugs discussed. In patients with angina, reducing the blood pressure often benefits the an- gina. A thiazide plus propranolol is usually effective therapy. Beta-adrenergic blockers should not, of course, be used in patients with a history of asthma, and it may be wise to avoid their use in patients with chronic obstructive pulmonary disease, since there is often an asthmatic component present. Patients with impaired kidney func- tion are difficult to treat because they are so resistant to drugs. They do not respond sufficiently to thiazide diu- retics possibly because their glomeru- lar filtration rates are so low. I have found that thiazide diuretics lose their effectiveness when the glomerular fil- tration rate falls to about 30% of nor- mal, The serum creatinine level is then usually in the range of 4 to 6. At this point one must prescribe furosemide, because this diuretic remains active in the presence of renal failure, although higher than usual doses may be re- quired. The drug also does not decrease renal blood flow and glomerular filtra- tion rate in the majority of cases. As the sodium is removed by the loop diu- retics, blood volume and blood pres- sure fall, but there is a rise in the blood urea nitrogen (BUN) and creatinine. In my opinion, this reflects merely a hemodynamic change and does not in- dicate increased renat damage. The EDWARD D. FREIS BUN and creatinine usually return to near-pretreatment levels in a month or two despite continued treatment. Final- ly, if the patient does not respond to furosemide and the creatinine rises to the range of 10 to 15, it will be neces- sary to put the patient on hemo- dialysis. Patients with impaired kidney func- tion can rarely be controlled with a single drug. Besides a diuretic, a help- ful second-step drug is methyldopa. Because it is excreted primarily by the kidney, it is not excreted as rapidly as normal in the patient with impaired kidney function. Therefore, when the blood pressure starts to respond, the dosage should be reduced somewhat be- cause of this cumulative effect. In my experience, patients with renal failure’ respond better to methyldopa than to REFERENCES I. Tucker, R.M. and Labarthe, D.R. (1977): Frequency of surgical treat- ment for hypertension in adults at the Mayo Clinic from 1973 through 1975. Mayo Clin. Proc. 52, 549. 2. Veterans Administration Coopera- tive Study Group on Antihyperten- sive Agents (1967): Effects of treat- ment on morbidity in hypertension: Results in patients with diastolic blood pressures averaging 115 through 129 mmHg. J. Am. Med. Assoc. 202, 1028. 3. Veterans Administration Coopera- tive Study Group on Antihyperten- sive Agents (1970): Effects of treat- most second-step drugs now available. CONCLUSIONS Step-care therapy provides effective treatment of hypertension for most pa- tients. A thiazide diuretic is the basis of therapy, and the addition of one or more agents, such as methyldopa, will almost always control those who do not respond to a diuretic alone. When the agents have been titrated to suit the pa- tient’s individual needs, it may be ap- propriate to employ a combination agent (if the doses match those of the available combinations) as both an economy and to improve compliance. Cooperation and interaction between physician and patient are essential for successful therapy. ment on morbidity in hypertension: IT. Results in patients with diastolic blood pressures averaging 90 through 114 mmHg. J. Am. Med. Assoc. 213, 1143. ° 4. U.S. Public Health Service Hospitals Cooperative Study Group, Smith, W.M., Chairman (1977): Treatment of mild hypertension. Results of a 10- year intervention trial. Circ. Res. 40 (Suppl. 1}, 98. 5. Ahlmark, G., Saetre, H. and Kars- gren, M. (1974): Reduction of sudden deaths after myocardial infarction. Lancet 2, 1563. 6. Green, K.G. (1975): Improvement in prognosis of myocardial infarction by long-term beta-adrenoreceptor block- ade using practolol. Br. Med. J. 3, 735. Gordon, T., Castelli, W.P., Hjort- land, M.C., Kannel, W.B. and Dawber, T.R. (1977): High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am. J. Med. 62, 707-714, Kannel, W.B., Dawber, T.R., Sorlie, P. and Wolf, P.A. (1976): Compo- nents of blood pressure and risk of atherothrombotic brain infarction: The Framingham Study. Stroke 7, 327, Build and Blood Pressure Study (1959): Volume 1. Society of Ac- tuaries, Chicago. Sokolow, M. and Perloff, D. (1961): The prognosis of essential hyperten- sion treated conservatively. Circula- tion 23, 697. Bechgaard, P. (1946): Arterial hyper- tension: A follow-up study of one CLINICAL THERAPEUTICS thousand hypertonics. Acta Med. Scand. Suppl. 172, 3. United States Public Health Service (1966): Hypertension and hyperten- sive heart disease in adults: United States 1960-62. Series 11, Number 13. National Center for Health Statis- tics, Washington. Stamler, J. (1975): Epidemiology of hypertension: Achievements and chal- lenges. In: Hypertension: A Practical Approach, p. 30. Editor: M. Moser. Little, Brown & Co., Boston. Truett, J., Cornfield, J. and Kannel, W.B. (1967): A multivariable analysis of the risk of coronary heart disease in Framingham. J. Chronic Dis. 20, 511. Veterans Administration Cooperative Study Group on Antihypertensive Agents (1972): Effects of treatment on morbidity in hypertension: III. Influence of age, diastolic pressure, and prior cardiovascular disease; further analysis of side effects. Cir- culation 45, 991.