Richard L. Byyny

The natural history of medication compliance in a drug trial: Limitations of pill counts

To assess medication compliance over time, we prospectively performed pill counts among 121 ambulatory hypertensive subjects for ⩽ 12 months. Prescribed regimens consisted of pinacidil or hydralazine administered four times a day and of secondary drugs administered up to twice daily. Surreptitious pill counts occurred every 1 to 12 weeks. Among a middle‐aged subject group that had been selected for high rates of compliance, we observed mean compliance rates that approximated 100%. We noted marked intrasubject and intersubject variability for any one medication, between medications, and over time. From baseline blood pressures (±SE) of 155.5 ± 1.9/97.3 ± 1.0 mm Hg, subsequent mean blood pressures varied by compliance subgroup: “hypocompliers” (< 80%), 151.3/91.0 mm Hg; “hypercompliers” (⩾ 120%), 147.6/91.4 mm Hg; and “eucompliers” (80% to 119%), 143.3/88.5 mm Hg (systolic blood pressure: F1,52 = −220.9, NS; diastolic blood pressure: F1,52 = −121.4, NS). We concluded that weekly pill counts indicated marked intersubject and intrasubject variability, obscured by long‐term averages; that compliance lapses appeared to be random; and that excessive medication‐taking was the most consistent with “pill dumping.”

Withdrawal from glucocorticoid therapy.

Glucocorticoids, such as hydrocortisone, cortisone, prednisone, prednisolone and dexamethasone, are commonly used systemically for the treatment of a wide variety of illnesses, including asthma, sa...

Research consent forms: Continued unreadability and increasing length

Consent forms are often long and incomprehensible. The authors studied 88 consecutive research consent forms generated at the Denver Veterans Administration Medical Center, evaluating the reading levels of the forms using the Fry Readability Scale and recording the numbers of lines of text. The mean grade reading level required for comprehension was 13.4 years of schooling. Twenty-two percent of all text passages scored were at the postgraduate level of readability. This difficult readability level has not improved since the forms were last tested in 1982. The mean length of the forms was 84.6 lines. Also found was a 58% increase in the length of forms since 1982, a factor known to impair comprehension. These factors, poor readability and increasing length, may make many consent forms incomprehensible. It is recommended that investigators be brief, use plain English, and write consent forms at appropriate reading levels, and receive training on how to obtain valid consent.

Lack of Efficacy of Hydergine in Patients with Alzheimer's Disease

BACKGROUND There is no effective pharmacologic treatment for Alzheimers disease, the most common dementing illness in the United States. Hydergine, a combination of ergoloid mesylates, is the only approved medication for Alzheimers disease, but despite widespread use its efficacy remains to be established. We conducted a clinical trial of Hydergine-LC, a newer preparation of ergoloid mesylates in the form of a liquid in a capsule (LC) that may have greater bioavailability, to determine its value in patients with Alzheimers disease. METHODS AND RESULTS Eighty older adults with probable Alzheimers disease participated in this double-blind, placebo-controlled trial of Hydergine-LC for 24 weeks. The recommended dose of 1 mg orally three times daily was used. Cognition and behavior were evaluated before and after the trial, and the patients were monitored for adverse effects. The medication was safe and well tolerated. The Hydergine-LC group did not perform better after treatment than the placebo group on any test, and its performance was worse (P less than 0.01 and P less than 0.02, respectively) on one cognitive measure (Wechsler Adult Intelligence Scale Digit Symbol Substitution Task) and on one behavioral scale (the Geriatric Evaluation by Relatives Rating Instrument). CONCLUSIONS Hydergine-LC appears to be ineffective as a treatment for Alzheimers disease.

Short‐Term Effects of Estrogen and Progestin on Blood Pressure of Normotensive Postmenopausal Women

Blood pressure rises in women with increasing age, possibly related to the decrease in production of female hormones that accompanies menopause. Although estrogen or progestin administration alone consistently does not lower blood pressure in postmenopausal women, possible interactions of these two hormones in affecting blood pressure are not well understood. We studied 12 surgically postmenopausal, normotensive women, aged 51 ±2 years (SEM). Treatment for each subject consisted of 1 week each of placebo, estrogen (conjugated equine estrogens, 2.5 mg/day), progestin (medroxyprogesterone acetate, 60 mg/day), and combined estrogen and progestin, given in varied order. At the end of each week, auscultatory blood pressures were measured while patients were seated. Neither estrogen nor progestin alone either increased or decreased blood pressure significantly, whereas combined estrogen and progestin lowered systolic, diastolic, and mean blood pressures 6 to 7 mm Hg (P <.05). Treatment order was unrelated to the change in blood pressure values. The authors suggest that administering progestin with estrogen may be more effective in lowering blood pressure than either hormone alone in postmenopausal women.

The antihypertensive efficacy of hydrochlorothiazide is not prostacyclin dependent

We tested the hypothesis that vascular prostacyclin synthesis is stimulated by hydrochlorothiazide and could account for some of the drugs antihypertensive effect. We studied 13 patients with mild essential hypertension in a randomized, double‐blind design to assess the effects of indomethacin on hydrochlorothiazides ability to lower blood pressure, alter body weight, stimulate plasma renin activity, and modulate vascular prostacyclin biosynthesis as assessed by the urinary excretion of the major enzymatically produced metabolite of prostacyclin, 2,3‐dinor‐6‐keto‐prostaglandin F1α (PGF1α), measured by GC/MS. Administration of hydrochlorothiazide, 50 mg daily for 2 weeks, was associated with a significant decrease in both systolic and diastolic blood pressure in both supine (systolic, 148 ± 3 to 136 ± 3 mm Hg; diastolic, 97 ± 2 to 94 ± 3 mm Hg) and upright (systolic, 151 ± 4 to 131 ± 2 mm Hg; diastolic, 103 ± 2 to 97 ± 3 mm Hg) positions. Hydrochlorothiazide administration resulted in a 1 kg weight loss and stimulation of plasma renin activity from 1.7 ± 0.4 to 5.3 ± 1.1 ng angiotensin I/ml/hr. However, the urinary excretion of 2,3‐dinor‐6‐keto‐PGF1α was unchanged after administration of hydrochlorothiazide (86 ± 13/ng/gm creatinine during placebo, 74 ± 13 ng/gm during week 1 of hydrochlorothiazide, and 70 ± 9 ng/gm during week 2 of the drug). Administration of indomethacin, 50 mg twice a day, resulted in greater than 60% inhibition of 2,3‐dinor‐6‐keto‐PGF1α excretion but did not affect the antihypertensive response to hydrochlorothiazide. Indomethacin did not oppose the diuretic effect of hydrochlorothiazide as assessed by weight loss but did attenuate the rise in plasma renin activity. Our data demonstrate that the blood pressure‐lowering effect of a thiazide diuretic does not require enhanced prostacyclin synthesis and the cyclooxygenase inhibitor indomethacin does not antagonize the antihypertensive efficacy of hydrochlorothiazide.

Selective and nonselective β‐blockade of the peripheral circulation

The effects of selective β1‐ as compared to nonselective β‐adrenergic blocking drugs on the peripheral circulation have not been adequately investigated. Ten healthy subjects received placebo for 1 wk followed by 4 wk of either propranolol or metoprolol in equivalent but increasing doses each week. Subjects then crossed over to the other sequence of placebo and drug. Measurements of calf blood flow, mean blood pressure, and calculation of calf vascular resistance were obtained at rest, after three loads of supine exercise on a bicycle ergometer, and during isoproterenol infusion testing. At the doses chosen, both β‐adrenergic blocking drugs induced equivalent decreases in exercise heart rate. Metoprolol lowered resting and exercise mean blood pressure at most doses, whereas propranolol had less of an effect on this variable. Neither drug altered resting or exercise calf blood flow or vascular resistance. More isoproterenol was required to increase the heart rate and decrease the vascular resistance during treatment with propranolol than with metoprolol. We conclude that in normotensive subjects metoprolol is somewhat more effective than propranolol in lowering mean arterial pressure during exercise when the drugs are given at doses equivalent in effects on exercise heart rate. Neither drug has a deleterious effect on calf blood flow or vascular resistance. Despite this, a marked separation between the vascular β2‐adrenergie –blocking effects of these drugs can be demonstrated with an isoproterenol infusion indicating β2‐adrenergic–receptor sparing by metoprolol.

The hypotensive action of captopril and enalapril is not prostacyclin dependent.

Angiotensin converting enzyme inhibitors have been proposed to have a prostaglandin‐dependent component to their hypotensive action. The aim of this study was to assess whether the structurally dissimilar angiotensin converting enzyme inhibitors captopril and enalapril stimulate the synthesis of prostacyclin, whether their hypotensive action is blunted by indomethacin, and whether these biochemical or physiologic parameters differ for the two drugs, in white subjects with essential hypertension. Twelve patients were enrolled and 11 finished the study. The study consisted of a double blind, randomized, double‐crossover design. All patients received either placebo or 50 mg indomethacin twice a day for 3 weeks; after 1 week of placebo or indomethacin either 50 mg captopril or 10 mg enalapril twice a day was added and continued for 2 weeks. Each patient received every possible combination. Neither captopril nor enalapril stimulated prostacyclin production as determined by measurement of the urinary excretion rate of its main enzymatic metabolite, 2,3‐dinor‐6‐keto‐prostaglandinF1α. Although indomethacin reduced the urinary excretion of the enzymatic metabolite of prostacyclin by more than 50%, it did not influence the hypotensive effect of captopril or enalapril. We conclude that neither captopril nor enalapril have a significant prostacyclin‐dependent component to their hypotensive action.

Epidemiology of Hypertension in the Elderly

SummaryEpidemiological studies confirm that hypertension, particularly systolic hypertension, is a major cardiovascular and cerebrovascular risk factor in the elderly. Clinical trials convincingly demonstrate the benefits of treating both diastolic hypertension in persons up to age 80 years, and isolated systolic hypertension in persons over age 60. The European Working Party on Hypertension in the Elderly (EWPHE) trial showed that reducing elevated blood pressure resulted in a 27% reduction in overall cardiovascular mortality, as well as significant reductions in severe congestive heart failure, strokes and deaths from myocardial infarction. The Systolic Hypertension in the Elderly Program (SHEP) also reported a 36% reduction in the incidence of stroke and decreases in cardiovascular events, including myocardial infarctions, when hypertension was treated. Additional EWPHE data suggest that the optimal level of systolic blood pressure control is between 146 and 158mm Hg, while patients in the SHEP trial with isolated systolic hypertension derived benefits at an average treated systolic blood pressure of 143mm Hg.Elderly study populations comply well with antihypertensive treatment, and blood pressure can be safely lowered with simple drug regimens. Nonpharmacological treatment is recommended for initial treatment of mild diastolic hypertension and isolated systolic hypertension, and as adjuvant treatment with medication. Since all antihypertensive agents can lower blood pressure in the elderly, therapy should be chosen based on its potential for side effects, drug interactions and effects on concomitant disease states.

Acute effects of increasing doses of urapidil in patients with hypertension

In a randomized, double‐blind, dose‐ranging trial, the acute antihypertensive effects of 7.5, 15, 30, 45, 60, 90, and 120 mg single daily doses of urapidil were compared with those of placebo in 10 patients with essential hypertension. Patients were randomized to either urapidil or placebo, such that each active drug day was followed by a placebo washout day. Blood pressure and heart rate responses were measured in the supine position, immediately upon standing, and after 3 to 5 minutes of standing for each dose. A variable but significant reduction in systolic and diastolic blood pressures that lasted from 4.5 to 8 hours was observed primarily at the 60, 90, and 120 mg doses (P < 0.05). The maximum reduction in diastolic blood pressure occurred in the standing position at 3 to 5 hours after dosing. When urapidil was compared with placebo, a change from the supine to the standing positions produced a significantly larger reduction in systolic and diastolic blood pressures (P < 0.05) but no significant change in heart rate. This suggests an acute blood pressure lowering effect of urapidil that occurs predominately in the standing position and that does not significantly increase heart rate.