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Hypertension - Treatment PHARMACOLOGIC TREATMENT The decision to initiate pharmacologic treatment requires consideration of several factors: the degree of blood pressure elevation, the presence of target organ damage, and the presence of clinical cardiovascular disease or other risk factors.Efficacy Reducing blood pressure with drugs clearly decreases cardiovascular morbidity and mortality. Protection has been demonstrated for stroke, coronary events, heart failure, progression of renal disease, progression to more severe hypertension, and all cause mortality (figure 6). Among older persons, treatment of hypertension has been associated with an even more significant reduction in CHD 120M (figure 7).  These results have been obtained in patients in various countries regardless of sex, age, race, blood pressure level, or socioeconomic status. Therefore, these findings can be generalized with confidence to the entire adult population with high blood pressure. Drug Therapy Considerations Most antihypertensive drugs currently available in the United States are listed in tables 7 and 8. For most patients, a low dose of the initial drug choice should be used, slowly titrating upward at a schedule dependent on the patient’s age, needs, and responses. The optimal formulation should provide 24hour efficacy with a oncedaily dose, with at least 50 percent of the peak effect remaining at the end of the 24 hours. Longacting formulations that provide 24hour efficacy are preferred over shortacting agents for many reasons: (1) adherence is better with oncedaily dosing; (2) for some agents, fewer tablets incur lower cost; (3) control of hypertension is persistent and smooth rather than intermittent; and (4) protection is provided against whatever risk for sudden death, heart attack, and stroke that is due to the abrupt increase of blood pressure after arising from overnight sleep. Agents with a duration of action beyond 24 hours are attractive because many patients inadvertently miss at least one dose of medication each week. Nonetheless, twicedaily dosing may offer similar control at possibly lower cost.   Newly developed formulations provide additional medication choices. For example, combinations of low doses of two agents from different classes have been shown to provide additional antihypertensive efficacy, thereby minimizing the likelihood of dosedependent adverse effects (table 8). Very low doses of a diuretic (e.g., 6.25 mg of hydrochlorothiazide) can potentiate the effect of the other agent without producing adverse metabolic effects. Lowdose combinations with an ACE inhibitor and a nondihydropyridine calcium antagonist may reduce proteinuria more than either drug alone. Combinations of a dihydropyridine calcium antagonist and an ACE inhibitor induce less pedal edema than does the calcium antagonist alone. In some instances, drugs with similar modes of action may provide additive effects, such as metolazone and a loop diuretic in renal failure. ACE inhibitors have been shown to provide beneficial effects in a variety of hypertensionrelated processes including heart failure from systolic dysfunction and nephropathy. The recently introduced angiotensin II receptor blockers produce hemodynamic effects similar to those of ACE inhibitors while avoiding the most common adverse effect, dry cough. However, in the absence of data documenting equal longterm cardiac and renal protection in patients with these conditions, angiotensin II receptor blockers should be used primarily in patients in whom ACE inhibitors are indicated but who are unable to tolerate them. Some antihypertensive agents—such as directacting smoothmuscle vasodilators, central alpha 2 agonists, and peripheral adrenergic antagonists—are not well suited for initial monotherapy because they produce annoying adverse effects in many patients. Reserpine has a uniquely prolonged therapeutic effect and is better tolerated in low doses (0.05 to 0.10 mg per day); however, patients and their families still should be warned about the possibility of depression. The directacting smoothmuscle vasodilators (e.g., hydralazine hydrochloride, minoxidil) often induce reflex sympathetic stimulation of the cardiovascular system and fluid retention. Immediaterelease nifedipine has precipitated ischemic events 124Pr and, in large doses, may increase coronary mortality in patients who have had a myocardial infarction.125M Therefore, this agent should be used only with great caution, if at all. There have been inconsistent reports regarding adverse health effects of shortacting or immediaterelease formulations of nifedipine, diltiazem hydrochloride, and verapamil hydrochloride. Randomized controlled trials are now in progress with longacting types and formulations of calcium antagonists approved for treatment of hypertension. In the meantime, specific recommendations are provided in tables 9 and 10 and figure 8. Special Considerations Special considerations in the selection of initial therapy include demographic characteristics, concomitant diseases that may be beneficially or adversely affected by the antihypertensive agent chosen (table 9), quality of life, cost, and use of other drugs that may lead to drug interactions (table 11). When choosing a certain drug for its favorable effect on comorbidity, clinicians should be aware that reduction of longterm cardiovascular morbidity and mortality may not have been demonstrated.Demographics. Neither sex nor age usually affects responsiveness to various agents. In general, hypertension in African Americans is more responsive to monotherapy with diuretics and calcium antagonists than to betablockers or ACE inhibitors. However, if a betablocker or ACE inhibitor is needed for other therapeutic benefits, differences in efficacy usually can be overcome with reduction of salt intake, higher doses of the drug, or addition of a diuretic.Concomitant Diseases and Therapies. Antihypertensive drugs may worsen some diseases and improve others (table 9). Selection of an antihypertensive agent that also treats a coexisting disease will simplify therapeutic regimens and reduce costs.Quality of Life. Although antihypertensive drugs may cause adverse effects in some patients (table 7), quality of life is maintained and possibly improved by any of the agents recommended for initial therapy.  Physiological and Biochemical Measurements. Some clinicians have found certain physiological and biochemical measurements (e.g., body weight, heart rate, plasma renin activity, hemodynamic measurements) to be helpful in choosing specific therapy.Economic Considerations. The cost of therapy may be a barrier to controlling high blood pressure and should be an important consideration in selecting antihypertensive medication. Generic formulations are acceptable. Nongeneric newer drugs are usually more expensive than diuretics or betablockers. If newer agents eventually prove to be equally effective, then cost should be considered in choosing them for initial therapy; if they prove to be more effective, then cost should be a secondary consideration. Treatment costs include not only the price of drugs but also the expense of routine or special laboratory tests, supplemental therapies, office visits, and time lost from work for visits to physicians’ offices. The costs of medications may be reduced by using combination tablets and generic formulations. Patients should be advised to check prices at different sources. Some larger tablets can be divided, saving money when larger doses cost little more than smaller doses. Some sustainedrelease formulations should not be divided because cutting the tablet eliminates the sustained release function.Managed Care. Because high blood pressure is so common, its management requires a major commitment from clinicians and managed care organizations. This commitment will need to expand even further because the majority of patients with hypertension do not have adequately controlled blood pressure and additional demands will develop from the projected increase in numbers of persons with hypertension due to the aging of the population. However, the cost of managing hypertension is lower overall than the sum of direct and indirect costs that may be avoided by reducing hypertensionassociated heart disease, stroke, and renal failure, especially because these adverse events often lead to expensive hospitalizations, surgical procedures, and highcost technologies. Randomized controlled trials have demonstrated that these reductions occur in a relatively short time and are sustained for years. Managed care programs offer the opportunity for a coordinated approach to care, using various health care professionals and featuring an appropriate frequency of office visits, short waiting times, supportive patient counseling, and controlled formularies. The outcomes of the management of hypertension will need to be monitored, in keeping with the requirements of organizations that monitor quality, such as the Health Plan Employer Data and Information Set (HEDIS). These outcomes may be divided into three categories: immediate (e.g., blood pressure levels, percentage of adherence to therapy), intermediate (e.g., cardiac or renal function, health resource utilization), and longterm (e.g., morbidity and mortality, costeffectiveness). Hypertension specialists may play an important role in providing more costeffective management of high blood pressure by adapting national guidelines for local implementation, providing guidance for new drugs and diagnostic methods, and managing patients with identifiable causes of hypertension, resistance to therapy, or complex concomitant conditions. Drug Interactions. As shown in table 11, some drug interactions may be helpful. For example, diuretics that act on different sites in the nephron, such as furosemide and thiazides, increase natiuresis and diuresis, and certain calcium antagonists reduce the required amount of cyclosporine. Other interactions are deleterious: nonsteroidal antiinflammatory drugs (NSAIDs) may blunt the action of diuretics, betablockers, and ACE inhibitors.Dosage and Followup Therapy for most patients (uncomplicated hypertension, stages 1 and 2) should begin with the lowest dosage listed in table 7 to prevent adverse effects of too great or too abrupt a reduction in blood pressure. If blood pressure remains uncontrolled after 1 to 2 months, the next dosage level should be prescribed. It may take months to control hypertension adequately while avoiding adverse effects of therapy. Most antihypertensive medications can be given once daily, and this should be the goal to improve patient adherence. Home or office blood pressure measurement in the early morning before patients have taken their daily dose is useful to ensure adequate modulation of the surge in blood pressure after arising. Measurements in the late afternoon or evening help monitor control across the day. Treatment goals based on outofoffice measurements should be lower than those based on office recordings.Initial Drug Therapy When the decision has been made to begin antihypertensive therapy (table 5) and if there are no indications for another type of drug, a diuretic or betablocker should be chosen because numerous randomized controlled trials have shown a reduction in morbidity and mortality with these agents (figures 6 and 7).As shown in table 9 and figure 8, there are compelling indications for specific agents in certain clinical conditions, based on outcomes data from RCTs. In other situations where outcomes data are not yet available, there are indications for other agents and the choice should be individualized, using the agent that most closely fits the patient’s needs. If the response to the initial drug choice is inadequate after reaching the full dose, two options for subsequent therapy should be considered (see figure 8 for treatment algorithm):
HighRisk Patients Although similar general approaches are advocated for all patients with hypertension, modifications may be needed for those with stage 3 hypertension, those in risk group C, or those at especially high risk for a coronary event or stroke (table 5). Drug therapy should begin with minimal delay. Although some patients may respond adequately to a single drug, it is often necessary to add a second or third agent after a short interval if control is not achieved. The intervals between changes in the regimen should be decreased, and the maximum dose of some drugs may be increased. In some patients, it may be necessary to start treatment with more than one agent. Patients with average SBP of 200 mm Hg or greater and average DBP of 120 mm Hg or greater require more immediate therapy and, if symptomatic target organ damage is present, may require hospitalization.StepDown Therapy An effort to decrease the dosage and number of antihypertensive drugs should be considered after hypertension has been controlled effectively for at least 1 year. The reduction should be made in a deliberate, slow, and progressive manner. Stepdown therapy is more often successful in patients who also are making lifestyle modifications. Patients whose drugs have been discontinued should have scheduled followup visits because blood pressure usually rises again to hypertensive levels, sometimes months or years after discontinuance, especially in the absence of sustained improvements in lifestyle.  J-curve Hypothesis Concerns have been raised that lowering DBP too much may increase the risk for coronary events by lowering diastolic perfusion pressure in the coronary circulation—the socalled J-curve hypothesis. The J-curve also has been detected in the placebo group of clinical trials of older persons with hypertension. The J-curve concern may be more relevant to patients with both hypertension and preexisting coronary disease and to those with pulse pressure greater than 60 mm Hg. On the other hand, data support a progressive reduction in both cerebrovascular disease and renal disease with even greater reductions in blood pressure. All available evidence supports the value of the reduction of DBP and SBP at all ages to the levels achieved in clinical trials—usually DBP to below 90 mm Hg and SBP to below 140 mm Hg in patients with isolated systolic hypertension. In trials of persons with isolated systolic hypertension, no increase in cardiovascular morbidity and mortality was observed, despite further reductions of DBP.CONSIDERATIONS FOR ADHERENCE TO THERAPY Poor adherence to antihypertensive therapy remains a major therapeutic challenge contributing to the lack of adequate control in more than twothirds of patients with hypertension. As attempts to improve adherence are made, patients have the right and responsibility to be active and well-informed participants in their own care and to achieve maximal physical and emotional well-being. Health care professionals have the responsibility to provide patients with complete and accurate information about their health status, allowing patients the opportunity to participate in their care and to achieve goal blood pressure.Followup Visits Achieving and maintaining target blood pressure often requires continuing encouragement for lifestyle modification and medication adjustment. Most patients should be seen within 1 to 2 months after the initiation of therapy to determine the adequacy of hypertension control, the degree of patient adherence, and the presence of adverse effects. Associated medical problems— including target organ damage, other major risk factors, and laboratory test abnormalities—also play a part in determining the frequency of patient followup. Visits to other members of the health care team may provide opportunities for more frequent followup. Once blood pressure is stabilized, followup at 3 to 6month intervals (depending on patient status) is generally appropriate. In some patients, particularly older persons and those with orthostatic symptoms, monitoring should include blood pressure measurement in the seated position and, to recognize postural hypotension, after standing quietly for 2 to 5 minutes.Strategies for Improving Adherence to Therapy and Control of High Blood Pressure Various strategies may improve adherence significantly (table 13). The choice and application of specific strategies depend on individual patient characteristics, and health care providers are not expected to apply all of them at any one time or to all patients. In particular, pharmacists should be encouraged to monitor patients’ use of medications, to provide information about potential adverse effects, and to avoid drug interactions. Nursemanaged clinics offer attractive opportunities to improve adherence and outcomes. The services of other members of the health care team, such as those who provide counseling in nutrition or exercise, should be used.Resistant Hypertension Hypertension should be considered resistant if blood pressure cannot be reduced to below 140/90 mm Hg in patients who are adhering to an adequate and appropriate tripledrug regimen that includes a diuretic, with all three drugs prescribed in near maximal doses. For older patients with isolated systolic hypertension, resistance is defined as failure of an adequate triple-drug regimen to reduce SBP to below 160 mm Hg. Of the various causes of true resistance listed in table 12, one of the most common is volume overload due to inadequate diuretic therapy. Frequently, a cause for resistance can be recognized and overcome. However, if goal blood pressure cannot be achieved without intolerable adverse effects, even suboptimal reduction of blood pressure contributes to decreased morbidity and mortality. Patients who have resistant hypertension or who are unable to tolerate antihypertensive therapy may benefit from referral to a hypertension specialist. |
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