Effects of intermittent transdermal nitroglycerin on occurrence of ischemia after patch removal: results of the second transdermal intermittent dosing evaluation study (TIDES-II).

OBJECTIVES: We sought to evaluate the effects of intermittent transdermal nitroglycerin (TD-NTG) on the occurrence of ischemia during patch-off hours in patients with stable angina pectoris receiving a beta-adrenergic blocking agent or calcium antagonist, or both. BACKGROUND: The current recommendations for the use of intermittent TD-NTG may be associated with the occurrence of rebound ischemia. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, crossover trial with three study periods. Tolerability to TD-NTG was assessed in Period I. Seventy-two patients were assigned to receive either double-blind transdermal placebo or maximally tolerated TD-NTG for 2 weeks (Period II) and were then crossed over to the alternative treatment for another 2 weeks (Period III). The patients were instructed to apply medication daily at 8 AM, to remove it at 10 PM and to note symptoms and sublingual nitroglycerin (SL-NTG) use in a diary. The occurrence of ischemia was assessed from patient-perceived angina, symptom-limited exercise treadmill test (ETT) and 48-h ambulatory electrocardiographic (AECG) monitoring. RESULTS: Transdermal NTG (0.2 to 0.4 mg/h) significantly reduced the magnitude of ST segment depression at angina onset during ETT compared with placebo. Total angina frequency was not significantly different between TD-NTG (mean [+/-SD] 3.2 +/- 4.2) and placebo (3.3 +/- 5.2). During patch-off hours, angina frequency increased with TD-NTG (1.1 +/- 2.1) compared with placebo (0.7 +/- 1.6) (p = 0.03). Similar trends for an increase in ischemia after TD-NTG were also observed from AECG analyses. Specifically, ischemia frequency tended to be lower during patch-off hours for placebo than with TD-NTG (0.05 +/- 0.09 vs. 0.08 +/- 0.20 episodes/h, respectively, p = 0.08), even though frequency of ischemia tended to be higher during patch-on hours for placebo than with TD-NTG (0.12 +/- 0.19 vs. 0.07 +/- 0.15 episodes/h, respectively, p = 0.11). During placebo, ischemia frequency decreased 58% (patch-on to patch-off, p = 0.01) compared with a 14% increase with TD-NTG. These changes attenuate the usual circadian variation in ischemia. CONCLUSIONS: An increase in ischemia frequency during patch-off hours after use of intermittent TD-NTG was perceived by patients, and this subjective finding was supported by a corresponding trend for AECG ischemia to increase during these same hours.

Rationale and design of the International Verapamil SR/Trandolapril Study (INVEST): an Internet-based randomized trial in coronary artery disease patients with hypertension.

OBJECTIVES: The primary objective of the International Verapamil SR/Trandolapril Study (INVEST) is to compare the risk for adverse outcomes (all-cause mortality, nonfatal myocardial infarction [MI] or nonfatal stroke) in hypertensive patients with coronary artery disease (CAD) treated with either a calcium antagonist-based or a noncalcium antagonist-based strategy. BACKGROUND: Treatment recommendations for hypertension include initial therapy with a diuretic or beta-adrenergic blocking agent, for which reductions in morbidity and mortality are documented from randomized trials but are less than expected from epidemiologic data. For this reason, recent attention has focused on calcium antagonists or angiotensin-converting enzyme inhibitors. While these agents reduce blood pressure, outcome data from large randomized trials are lacking, but some case-control data, dominated by short-acting dihydropyridines, suggest an increased risk of cardiovascular events. These studies had methodologic limitations and did not differentiate among calcium antagonist types and formulations. Several studies differentiating among calcium antagonist types and an overview of published randomized trials show no increased risk with verapamil and suggestion for benefit in CAD patients. METHODS: A total of 27,000 CAD patients with hypertension will be randomized at 1,500 primary care sites to receive either a calcium antagonist-based (verapamil) or beta-blocker/diuretic-based (atenolol/hydrochlorothiazide) antihypertensive care strategy. The study uses a novel, electronic "paper-less" system for direct on-screen data entry, randomization and drug distribution from a mail pharmacy linked to the coordination center via the Internet. RESULTS: Contract negotiations with the United States and international sites are ongoing. Patients being enrolled are predominantly elderly (72% aged 60 years or older) men (54%), with either an abnormal coronary angiogram or prior MI (71%). In addition to hypertension, CAD and elderly age, most patients (89%) have one or more associated conditions (diabetes, dyslipidemia, smoking, cerebral or peripheral vascular disease, etc.) contributing to increased risk for adverse outcome. While 26% have diabetes, most of these are noninsulin dependent. Using the protocol strategies, target blood pressures (according to JNC VI) have been reached in 58% at the fourth visit, and as expected most (89%) are requiring multiple antihypertensive drugs. CONCLUSION: The design and baseline characteristics of the initial patients recruited for a prospective, randomized, international, multicenter study comparing two therapeutic strategies to control hypertension in CAD patients are described.

Characteristics of a contemporary population with angina pectoris. TIDES Investigators.

To characterize a contemporary, nonhospitalized population with angina pectoris, data were obtained from a geographically diverse cohort of 5,125 outpatients with chronic stable angina cared for by 1,266 primary care physicians between September and November of 1990. Diagnosis was based on history supported by evidence for coronary artery disease (coronary angiography, old myocardial infarction, or an abnormal stress test, either alone or in combination). The mean age of the patients was 69 years and 53% were women. Seventy percent had > 1 associated illness and 64% took > 1 cardiovascular drug. Median angina frequency was approximately 2 episodes/week and increased angina frequency (p < 0.0001) was associated with decreased overall feeling of well-being. Although effort angina was present in 90% of patients, 47% also had rest angina and 35% had mental stress-evoked angina. Female gender (relative risk [RR] 1.09; 95% confidence interval [CI] 1.02 to 1.16), concomitant illness (RR 1.17; CI 1.09 to 1.25), and pharmacotherapy (RR 1.14; CI 1.07 to 1.22) were associated with excess risk for rest angina. Younger age (RR 1.30; CI 1.20 to 1.41), female gender (RR 1.16; CI 1.07 to 1.26), concomitant illness (RR 1.13; CI 1.03 to 1.24), and pharmacotherapy (RR 1.28; CI 1.15 to 1.93) were associated with excess risk for mental stress angina. These data suggest that contemporary outpatients with angina are frequently women and elderly patients with high rates of associated illness, rest, and mental stress-related angina.

A longitudinal evaluation of drug use in an ambulatory elderly population.

Participants in a geriatric health screening program were studied longitudinally to determine the patterns of drug use over a 10 year period. There were 314 (34.0%) men and 610 (66.0%) women who completed 10 yearly health screening evaluations. The mean number of prescribed and non-prescribed drugs used per participant increased from 2.90 in 1978-79 to 4.08 in 1987-88 (p less than 0.0001). There was no significant difference between men and women in the rate of increased drug use. There was no significant increase in the mean number of drug ingredients per participant used over the 10 year period. The most frequently reported therapeutic categories for 1978-79 were antihypertensives, analgesic-antipyretics, antirheumatics, multiple vitamins, cathartics and vitamin E, which represented 10.2, 7.2, 6.5, 4.9, 4.8 and 3.8% of all categories used. There was a decline in all of these categories between interval 1 and 10. Increased use of drugs, particularly prescribed medications, by the elderly population may present problems of adverse drug reactions, drug interactions and medication compliance in the future. Changing patterns of drug use may have resulted, in part, from introduction of new therapeutic classes and from new treatment concepts over the 10 year study period.

A longitudinal evaluation of dipyridamole drug use in an ambulatory elderly population.

STUDY OBJECTIVE: To determine the pattern of dipyridamole use over the past 14 years. DESIGN: A longitudinal health screening program of ambulatory elderly participants was used to study changes in dipyridamole drug use. Participants included all subjects screened in the Florida Geriatric Research Program since 1978. The main outcome measure in this study was self-reported dipyridamole use at every visit to the program since August 1, 1978. RESULTS: A total of 3.6% of men (mean age, 82.6 years) and 3.4% of women (mean age, 80.8 years) reported the use of dipyridamole in the 1991-1992 period. The prevalence of dipyridamole use ranged from a low of 1.6% in 1978-1979 to a high of 7.3% in 1986-1987. There was a significant increase in the use of this drug from 1978-1979 to 1991-1992 (p < 0.038). Over the 14-year period of study, the percent of subjects using dipyridamole concurrently with coumarin anticoagulants ranged from a low of 5.8% to a high of 17.9%. CONCLUSIONS: The level of dipyridamole use in this elderly population has increased since 1978-1979. The only FDA indication for this drug is in combination with coumarin anticoagulants to prevent postoperative thromboembolic complications of cardiac valve replacement. Less than 20% of patients in this study used the drug in combination with coumarin anticoagulants. Educational programs are needed to improve the prescribing of dipyridamole.

Central nervous system symptoms of elderly subjects using antihypertensive drugs.

The effects of antihypertensive agents on the frequencies of reported fainting, dizziness, losses of consciousness, and bone fractures were studied in a large, ambulatory elderly population. The frequencies of these symptoms were compared for subjects who used one or more of nine different antihypertensive agents and for subjects who were not using these medications and who served as a control group. Over 40 per cent of the total population were using at least one of the nine drug groups. Women who used antihypertensive medications reported significantly more fainting (P less than 0.001), dizziness (P less than 0.005) and "blacking-out spells" (P less than 0.002) but significantly fewer bone fractures (P less than 0.02) compared with women who were not using such medication in the control group. For men, the use of only one drug group, propranolol, was associated with a significant increase in fainting and dizziness but not blacking-out spells compared with men in the control. These results suggest that elderly persons may be subject to a variety of central nervous system side effects induced by antihypertensive drugs.

Drug use in a geriatric population.

Drug usage was studied in a geriatric hypertension-screening program. A questionnaire was used to collect the required information from patients visiting the clinic during three successive years. The study included 1,711 patients, of whom 76.6 percent were regularly using a drug preparation. A consistent increase was noted in the average number of drug categories used with increasing age, from 1.6 in patients under 70 to 2.6 in patients over 84 years old. The most common drug categories involved were antihypertensive agents, cardiovascular drugs, vitamins, and internal analgesics.

The Dunedin program, a Florida geriatric screening process: design and initial data.

The Dunedin program was started in 1975 for the purpose of screening participants over the age of 65, for medical disorders. Data are collected on family history, past medical history, drug history, current symptoms and disorders, and numerous biochemical and physiologic factors. In the past four years, 4,363 participants have been evaluated and a large data base has been derived concerning the 65+ age group. It is hoped that data from this program will facilitate the future assessment, treatment and care of the elderly.

Screening for hypertension in an elderly population: report from the Dunedin Program.

Hypertension detection and follow-up programs have recently received increased attention. The authors studied the effect of screening for hypertension in a geriatric screening program for a large ambulatory elderly population in Dunedin, Florida, over a three-year period. Of the 4,247 participants initially screened, 39 percent had some form of hypertension, and 15.6 percent of these had not received any form of treatment. At the time of the first year follow-up, the proportion of participants with treated, controlled hypertension had increased from 14.7 to 21 percent. These data lend support to the value of hypertension screening among persons over 65 years of age.

Nocturia: a risk factor for falls in the elderly.

OBJECTIVE: To determine if nocturia is a risk factor for reported falls and bone fractures in older persons. DESIGN: Cross-sectional study comparing falls in men and women with and without nocturia. SETTING: Longitudinal health screening program of ambulatory elderly participants. PARTICIPANTS: Participants included 988 (65.5%) women and 520 (34.5%) men who had completed their tenth annual visit to the program. MAIN OUTCOME MEASURES: Reported falls in the past year and reported bone fractures in the past 5 years. RESULTS: Participants who reported nocturia at least twice during the night were at significantly greater risk to report falls (Odds Ratio = 1.84; 95% CI = 1.05-3.22), and the risk increased in subjects reporting more than three nocturia events (Odds Ratio = 2.15; 95% CI = 1.04-4.44). The significant increase in falls reported by nocturia participants did not result in an increase in reported bone fractures in the past 5 years (P < 0.4360). CONCLUSIONS: Nocturia is an important risk factor for falls in ambulatory elderly persons. Preventive measures should be taken to decrease nocturia events and to decrease the risk of falling during these nocturia events.

Epidemiology of hyperuricemia in an ambulatory elderly population.

The relationship of serum uric acid concentration to age and sex was assessed in 1,701 participants in a geriatric multiphasic screening clinic. Included were 1,067 women and 634 men. The mean uric acid level for men was 6.35 mg/100 ml compared to 5.44 mg/100 ml for women. No statistically significant increases in serum uric acid between age groups were apparent, except for women over 84 years of age. The mean serum urate concentrations found in this geriatric study are higher than those reported for other population groups, suggesting a higher normal value for the elderly.

Selected physiologic and drug effects on serum uric acid levels in an elderly population.

A total of 2,923 elderly subjects were studied to determine the relationship between obesity, hypertension, thyroid disease, renal function, alcohol consumption, selected drugs, and the serum uric acid level. Comparison of the serum uric acid levels with indices of obesity demonstrated a strong correlation in normotensive (p less than .0001) and hypertensive (p less than .001) subjects. The serum creatinine level, when used alone, was not a reliable indicator of renal function. Of the drugs evaluated, diuretics had the most pronounced effect upon the serum uric acid level.

Use of nutritional supplements in an ambulatory elderly population.

The use of nutritional supplements by 3,192 ambulatory elderly participants in a health screening program is described. The 2,009 women used vitamin (45.5 per cent) and mineral (22.4 per cent) products with significantly greater frequencies than did the 1,183 men (34.0 per cent and 15.0 per cent, respectively); chi-square, P less than 0.01. The most commonly used vitamin products were multiple vitamins, multiple vitamins with minerals, vitamin E, and vitamin C; for minerals, the ranking was potassium chloride, calcium salts, and ferrous sulfate. Eighty-two participants (2.5 per cent) reported the use of four or more supplements. Many older Americans are spending a great deal of money for nutritional supplements, whereas it would seem that the money could be better spent to improve the quality of their diet.

Symptom prevalence in the elderly. An evaluation of age, sex, disease, and medication use.

Prevalence of reported symptoms was studied in 1927 women and 1140 men over 65 years of age in an ambulatory health screening program. Reports of 28 common symptoms were obtained from a standardized questionnaire completed by participants at the time of their fourth annual visit to the program. A comparison was made of the prevalence of specific symptoms by sex, age, disease states, and drug use patterns. The most common symptoms reported by women were nocturia (80.4%), swollen feet or ankles (30.5%), cold feet and/or legs (28.6%), and irregular heartbeat (23.2%), whereas men complained most often of nocturia (79.8%), irregular heartbeat (24.8%), cold feet and/or legs (23.6%), and tinnitus (23.1%). Women reported a mean of 3.99 symptoms compared with 3.22 reported by men (P less than .0001). In women their was a statistically significant association for most symptoms in subjects reporting the use of medication compared with a group who did not use medication. In men the use of medication was less highly correlated with reports of symptoms. Nearly 100% of participants reported having at least one disease state. The number of symptoms reported was strongly related to the number of disease states, and after adjusting for diseases, women reported more symptoms than men. The best predictor of symptom prevalence was the number of disease states followed by the number of drugs used and then age.

Incidence of hypertension in an ambulatory elderly population.

Investigations of the natural history of blood pressure have generally evaluated mean systolic and diastolic pressure changes. While information, this information is not directly applicable to clinical practice settings, in which patients are usually classified as normotensive or hypertensive. We measured the actual incidence of hypertension, using two different definitions, in an ambulatory elderly population of 2,584 individuals over an 8-year period. Using the less stringent blood pressure definition (systolic blood pressure greater than 140 mmHg and diastolic blood pressure greater than or equal to 90 mmHg), 884 (34.2%) participants were normotensive and 1,700 (65.8%) were hypertensive at an initial screening. The average annual incidence of hypertension over the subsequent eight years was 13.2%, and life tables demonstrated a gradual risk of developing hypertension. The development of hypertension was not associated with gender or age; while older age groups had a greater chance of developing hypertension than younger, the difference did not reach statistical significance.

Visual, refractive, and keratometric results of radial keratotomy. A two-year follow-up.

We report two-year follow-up findings on 142 (91%) of the first 156 radial keratotomies performed. The results are contrasted with our earlier six-month and one-year results and with findings from other studies. Mean spherical equivalent before surgery was -5.0 diopters and two years after surgery was -0.10 D; 51% of the eyes were within 1 D of emmetropia. Uncorrected distance acuity was 20/200 or worse in 96% of the eyes before surgery. At two years, 39% had 20/20 acuity or better and 76% had 20/40 or better. At one year, 49% had 20/20 acuity and 76% had 20/40 acuity or better. Refractive results between one and two years showed an overall increase in mean spherical equivalent of 0.23 D. Our results indicate radial keratotomy to be relatively safe and effective two years after surgery.

Three-year results of radial keratotomy.

We complied three-year and longer follow-up data on 198 consecutive radial keratotomy surgeries performed by one of us (H.S.). Follow-up was obtained on 138 (70%) of these eyes. Results were compared with previously published two-year results. The mean spherical equivalent before surgery was -4.3 diopters, the average keratometry value was 44.11 D, and 75% of the eyes had an uncorrected distance acuity of 20/400 or more. The average change in the spherical equivalent was 3.74 D for eyes examined at three years, compared with 3.71 D for eyes examined at 18 months. Average keratometry value was 40.96 D after three years, compared with 41.16 D at 18 months. Uncorrected visual acuity was at least 20/40 in 73% of eyes examined after three years, as opposed to 72% at 18 months. For eyes examined at both 18 months and three years, the increase in spherical equivalent of 0.17 D was statistically significant, as was the decrease in average keratometry value of 0.20 D. Uncorrected visual acuity results were stable between 18 months and three years.

Visual, refractive, and keratometric results of radial keratotomy. Five-year follow-up.

This article presents five-year findings on the first 156 radial keratotomies in our series. Results are compared with findings on these same eyes at one and three years and with results from other studies. Follow-up at five years was on 123 eyes (79%). Before surgery, the mean spherical equivalent was -5.0 diopters (D). Five years after surgery, the mean change in the spherical equivalent was 5.17 D, and 53% of eyes were within 1 D of emmetropia. Uncorrected visual acuity was 20/200 or worse in 96% of eyes before surgery. At five years, 36% had 20/20 acuity or better, and 75% were 20/40 or better. Best corrected acuity was at least 20/20 in 90% of eyes before surgery. At five years, 85% retained at least 20/20 best corrected acuity. Although some patients still have shown refractive and visual acuity changes through five years after surgery, the overall group has been stable.

Two-year results of reoperations for radial keratotomy.

This study compared the two-year results of 320 radial keratotomy surgeries that did not result in reoperations with those of 67 cases that had reoperations. Follow-up was 76% for cases not reoperated and 79% for reoperated cases. Eyes that had reoperations averaged 2.2 diopters more initial myopia than eyes that did not have reoperations, and they averaged 43% myopia correction in the first surgery vs 84% for eyes that did not require reoperations; the reoperation corrected an additional 47% of residual myopia, for an overall 70% correction of myopia in the two surgeries. These results indicated that twice the desired effect of correction should be attempted in a reoperation to achieve the desired result.

Visual, refractive, and keratometric results of radial keratotomy. One-year follow-up.

Ongoing prospective evaluation of radial keratotomy was conducted on 156 eyes of the first 101 consecutive patients. We did a one-year follow-up and compared previously reported six-month findings. All eyes were examined both six months and one year after surgery. Findings obtained by an independent examiner both before and after surgery correlated highly with findings obtained in the surgeon's office. One year after surgery, mean change in spherical equivalent was +4.7 diopters; overall uncorrected distance acuity was 20/20 in 49% of cases and at least 20/40 in 76% of cases. Fifty-eight percent of eyes were within 1.0 D of emmetropia. Visual results showed slight general improvement between six and 12 months; refractive results were stable, except that excessive overcorrection was found to decrease. In this series, radial keratotomy seemed safe and effective one year after surgery.