Getting to Goal Blood Pressure: Why Reserpine Deserves a Second Look

Abstract

In this editorial, we review data from several hypertension trials in which reserpine therapy was used with good results. We present new data from the Multiple Risk Factor Intervention Trial (MRFIT) that also demonstrate the positive effects of reserpine. We believe that reserpine deserves reconsideration as an effective antihypertensive medication, especially in combination therapy in difficult-to-control hypertensive patients. The prevalence of hypertension in the United States has increased, mainly as a result of the increased prevalence of obesity and the increasing age of the population. At the same time, blood pressure (BP) control rates have improved. For example, data from the National Health and Nutrition Examination Survey (NHANES) indicate that between 1999–2000 and 2003–2004, the prevalence of hypertension increased from 27% to 29%, while BP control rates (BP <140/90 mm Hg) improved from 29% to 37%.1 Recent survey data suggest further improvement in control rates.2 Despite this recent success, BP control rates may still remain below the Healthy People 2010 goal of 50%.3 Reasons for this include not using specific treatment algorithms; lack of careful follow-up; failure to control systolic BP, especially in older patients; and therapeutic inertia (ie, failure to increase the dose of medication or add another medication when BP is not at goal). Until recently, even in the best clinical trials, BP control rates of only 66% to 70% have been achieved,4, 5 although the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial6 reported that with a 2-drug combination as initial therapy, a 73% control rate was achieved in a hypertensive population. One antihypertensive medication that could be used to improve BP control, especially systolic BP, is reserpine, a centrally acting adrenergic antagonist. Its use fell into disfavor years ago, and it has been labeled a relic from the past and an obsolete medication.7, 8 While its use in westernized countries has fallen precipitously in the past decades8, 9 despite its proven efficacy,10-15 reserpine is still used extensively in nonwesternized countries, where health care expenditures are more cost-constrained. In South Africa, for example, it is a second-step hypertension medication after diuretic therapy.10, 16, 17 In India, low-dose reserpine, in combination with diuretics and hydralazine, is used effectively to prevent renal disease.18 Several adverse effects attributed to reserpine in the 1950s and 1960s led to its near demise. These included depression, gastric bleeding, and breast cancer. Early in its use, recommended dosages of reserpine varied from 0.25 mg 3 times a day to as much as 10 mg/d. With the recognition that the half-life of reserpine is several days and that its clinical effect may last even longer, much smaller dosages were recommended (0.05–0.25 mg/d). Studies in which low dosages (0.05–0.1 mg/d) of reserpine are used (usually in combination with diuretics) show that reserpine is well tolerated and that depression develops at rates similar to those seen in the general population.10, 19 At current dosing levels, no increase in gastric acid production or dyspepsia have been reported.13, 20 Last, the reports of increased breast cancer risk associated with reserpine use have been discredited or found to be weak.21-23 The situation of reserpine is analogous in many ways to that of thiazide diuretic therapy. Early in their use, high dosages of diuretics (often up to 200 mg/d) were prescribed. After it became appreciated that these high dosages were associated with higher rates of adverse biochemical effects and little additional antihypertensive efficacy, dosing was reduced. Today, low-dose thiazide diuretics (ie, 12.5–50 mg/d) are the recommended first-step agents in the treatment of hypertension.3 Early hypertension outcome studies, such as the Veterans Administration (VA) Cooperative Studies in the 1960s,24, 25 the Hypertension Detection and Follow-Up Program (HDFP) in the 1970s,26 and MRFIT in the 1980s,27 established that low-dose reserpine therapy was an effective treatment for BP control in hypertension. Further analysis of the MRFIT dataset, presented herein for the first time (Table), indicates that reserpine add-on therapy in men treated with diuretic monotherapy through the first year of the study was more successful in lowering systolic and diastolic BP than medications commonly used as second-step therapy at the time the studies were done (ie, propranolol or methyldopa). Several VA cooperative studies in the 1980s also demonstrated the efficacy of reserpine.13, 14 In the Hypertension in the Elderly VA study, men aged 60 years or older with moderately elevated BP were assigned to varying doses of hydrochlorothiazide therapy. Approximately 40% did not respond to this monotherapy, and second-step medications were added. Results showed equal efficacy of methyldopa, hydralazine, metoprolol, and reserpine and equal duration of action. Measures of cognitive-behavioral effects, such as depression, diminished cognitive abilities, and changes in activities of daily living, did not differ between the groups; however, reported adverse effects and withdrawal due to drug intolerance were higher with methyldopa. There were no reported adverse effects that were increased with reserpine, but postural dizziness and headache were reduced with reserpine. In addition, serum cholesterol levels decreased the most among reserpine users (−16 mg/dL). The most recent clinical hypertension trial to report on the use of reserpine was the Systolic Hypertension in the Elderly Program (SHEP).28 This study in more than 4700 adults aged 60 years or older was the first to demonstrate the efficacy of low-dose antihypertensive medication in preventing stroke (by 35%) and cardiovascular events (by 32%) in people with isolated systolic hypertension (defined as systolic BP >160 mm Hg and diastolic BP <90 mm Hg). The active treatment group (n=2365) received a low dosage of chlorthalidone (12.5–25.0 mg/d) with a step up to atenolol (25.0–50.0 mg/d) or reserpine (0.05–0.10 mg/d), if needed. During the 4.5 years of average follow-up, 32% of the active treatment group (n=757) received atenolol add-on therapy over an average exposure period of 2 years, and 8% (n=193) received reserpine over a mean exposure period of 1.7 years.29 For reserpine, the relative risk (vs nonuse of reserpine) and 95% confidence intervals were 0.65 (0.26–1.59) for mortality, 0.27 (0.04–2.26) for stroke, 0.93 (0.29–2.96) for coronary heart disease events, and 0.55 (0.20–1.49) for cardiovascular disease events. While none of these findings was statistically significant (owing to small numbers of participants and events), all the risk ratios are consistently <1. Moreover, all these values are considerably lower than those associated with atenolol use (0.84 [0.54–1.30], 1.34 [0.80–2.28], 1.04 [0.58–1.87], and 1.07 [0.71–1.61], respectively), a medication still in wide use. These results are similar to those of MRFIT. Given the new results from MRFIT and the results of the VA Cooperative trial and SHEP, it would appear that reserpine still has a role in the management of hypertension. The question arises: how should it be used? It is now commonly accepted practice to initiate antihypertensive therapy with 2 antihypertensive medications in persons with stage 2 hypertension. The most common combination is a diuretic with either an angiotensin converting enzyme (ACE) inhibitor/angiotensin II receptor blocker (ARB) or a calcium channel blocker (CCB). In many cases, especially in older persons and those with diabetes and obesity, 2 medications are not completely effective and ≥3 medications may be required. This was the experience in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).30 In the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study31 in high-risk diabetic individuals, the intensive BP intervention arm begins treatment with 2-drug antihypertensive therapy with the anticipation that more drugs will be needed to control systolic BP <120 mm Hg. Persons with diabetes usually are obese. When obesity is centrally distributed, insulin resistance is present, and with it the metabolic syndrome. It has been estimated that among US adults aged 60 years or older, ≈65% have hypertension32 and ≈40% have the metabolic syndrome.33 One consequence of insulin resistance is increased sympathetic tone.34 This initiates or sustains increased vascular resistance and with it elevated BP. In these obese individuals, blockade of increased sympathetic tone with reserpine, through reduction of peripheral and central noradrenaline stores, may have a salutary effect in BP control. Combining a diuretic, which decreases the excess fluid volume associated with the metabolic syndrome, and an ACE inhibitor/ARB or CCB, which protects endothelial function and/or decreases vascular resistance, represents an effective treatment plan for the clinician in BP management. This is in keeping with the growing awareness that combination therapy is an effective means of treatment,35 but more may have to be done in some patients. The use of reserpine, an additional option, may provide for improvement in management in these individuals. Reserpine is an effective BP-lowering agent. It is most effective in the elderly and the obese, often when systolic BP is the limiting goal BP measure. It has a very long duration of action (days) and may therefore be helpful in partially adherent patients. At present, there are no pharmaceutical advocates for the use of reserpine or a clinical trial to test its effects on clinical outcomes. It will only be at the behest of the medical community that consideration be given for the use of low-dosage reserpine (0.05–0.10 mg once daily, often at bedtime) to better control BP. In most patients, reserpine's role may be as a relatively inexpensive third- or fourth-step drug. While the exact place for its use can be debated, we believe it deserves strong consideration when better BP control is required.