Author + information
- Received September 30, 1996
- Revision received June 19, 1997
- Accepted July 1, 1997
- Published online October 1, 1997.
- Carl J. Pepine, MD, FACCA,* (, )
- Larry M. Lopez, PharmD, FCCPB,
- Dawn M. Bell, PharmDD,
- Eileen M. Handberg-Thurmond, ARNP, MSNB,
- Ronald G. Marks, PhDC,
- Susan McGorray, PhDC,
- for the TIDES-II Investigators1
- ↵*Dr. Carl J. Pepine, Department of Medicine, Division of Cardiovascular Medicine, University of Florida College of Medicine, Box 100277, Gainesville, Florida 32610-0277.
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 pmand 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.
Transdermal nitroglycerin (TD-NTG) patches were originally introduced as a sustained-action NTG delivery system when pharmacokinetic studies showed that this formulation produced steady-state blood concentrations when affixed to skin . Notably, investigations of safety and efficacy were not conducted before approval. Since then, results of a number of trials revealed that TD-NTG patch use is associated with development of partial or complete tolerance when applied continuously over 24 h . As a consequence, labeling of TD-NTG patches was changed to read “… in order to avoid tolerance to NTG drug-free intervals of 10–12 hours are known to be sufficient; shorter intervals have not been well studied” .
If a TD-NTG patch is used in this manner, it is possible that patients who have been relatively free of ischemia while wearing the TD-NTG patch (patch-on) may develop more ischemia during the 10- to 12-h nitrate-free interval (patch-off). This possible “rebound ischemia phenomenon” has not been well studied. Accordingly, this study was designed to evaluate the effects of intermittent TD-NTG on the frequency of perceived (i.e., angina) as well as objectively documented myocardial ischemia (i.e., ST segment depression) and to determine whether ischemia increases during the patch-off period in patients with stable angina taking other medications to suppress angina.
1.1 Study design
This was a multicenter (see Appendix A), double-blind, placebo-controlled, crossover study that included three experimental periods. The first period was the qualifying and dose tolerability phase, which lasted 3 weeks. The second and third periods each lasted 2 weeks and comprised the double-blind evaluation phase.
In Period I, if a patient was using any nitrate preparation, it was discontinued gradually, except for sublingual-NTG (SL-NTG), which was permitted for relief of angina at any time throughout the study. All other medications were continued for the study duration at a constant dose if such therapy had been used in the same dose for at least 4 weeks before enrollment. After determining qualification and dose tolerability, patients were randomized by a centrally generated code to receive either active TD-NTG or placebo. In Period II, after 2 weeks of therapy and after assessments for ischemia, patients were crossed over to alternate treatment. After another 2 weeks in period III, assessments for ischemia were repeated. The study was approved by the Institutional Review Boards of all participating centers, and each patient gave written, informed consent before participation.
1.2 Study patients
The patients were recruited from 12 centers and qualified for entry if they had 1) one or more typical angina episodes during the month before study entry; 2) evidence of coronary artery disease (CAD) by at least one of the following criteria: a) previously documented myocardial infarction; b) concordant abnormalities consistent with CAD on two different types of stress tests (e.g., electrocardiography and thallium perfusion); or c) angiographic evidence of ≥70% diameter narrowing of one or more major coronary arteries; 3) evidence of myocardial ischemia during an exercise treadmill test (ETT); and 4) transient ischemia on ambulatory electrocardiographic (AECG) monitoring within 3 weeks before randomization. Ischemia was considered present when horizontal or downsloping ST segment depression ≥1 mm from the level recorded before the episode persisted for either three consecutive beats during ETT or for ≥1 min during AECG monitoring. All AECG readings were evaluated at a core laboratory by investigators who had no knowledge of the other findings, and ischemic-type ST segment depression lasting ≥5 min/48 h or two or more episodes/48 h was required for qualification.
Exclusion criteria included myocardial infarction, surgical revascularization or angioplasty within 3 months. Also excluded were those patients for whom nitrates were contraindicated, those admitted to the hospital for unstable angina within the previous 4 weeks and those with other medical condition(s) that would interfere with evaluation or follow-up. Patients with rest electrocardiographic (ECG) abnormalities likely to interfere with interpretation of ECG changes of ischemia (e.g., bundle branch block, paced rhythm, ≥1.0 mm ST segment depression, left ventricular hypertrophy) were also excluded.
1.3 Patient evaluations
During the first visit in Period I, a medical history and physical examination were obtained. Each patient was instructed to record in a diary the number of perceived angina episodes, activity associated with its onset and SL-NTG consumption. Each patient completed a symptom-limited ETT using a modified Bruce protocol and wore an AECG monitor for 48 h. During ETT, blood pressure was recorded by a cuff sphygmomanometer and the ECG was recorded from 12 leads. The AECG monitor was a cassette type with two bipolar leads whose position had been optimized to those showing the greatest magnitude of ST segment depression during ETT.
1.4 Period I
During the last week of Period I, dose tolerability to the active, intermittent TD-NTG patch was assessed. Patients were instructed to wear the patch for 14 h/day (patch-on time) and to remove it at bedtime for the next 10 h (patch-off time). Patients with no history of nitrate sensitivity were first given a 0.4 mg/h dose of TD-NTG. If no adverse effects were reported after 3 days, the dose was increased to 0.6 mg/h for another 3 days. If mild or tolerable adverse effects occurred with the 0.4 mg/h dose, the higher dose was not evaluated. If intolerable adverse effects occurred with the 0.4 mg/h dose, it was decreased to 0.2 mg/h. Patients with a history of nitrate sensitivity were initially given 0.2 mg/h and titrated upward accordingly. Patients unable to tolerate 0.2 mg/h failed to qualify and did not continue in the study. All patients were asked not to use SL-NTG prophylactically.
1.5 Periods II and III
Each patient successfully completing qualifying procedures was then randomized to receive intermittent therapy with either a double-blinded placebo patch or an active TD-NTG patch individualized to the best tolerated dose identified in Period I. As before, patients were instructed to wear the patch for 14 h/day and to remove it at bedtime for the next 10 h. At the end of 2 weeks of double-blinded therapy (Period II), an ETT and 48-h AECG were completed. In Period III, each patient was crossed over to the alternative treatment and the same procedures were repeated. During biweekly clinic visits, patients were questioned about the occurrence of possible adverse effects and diaries were reviewed.
1.6 Data analysis and statistical considerations
Response variables of interest from the angina diaries and AECGs were frequency of perceived angina and frequency and duration of AECG-detected ischemia during both patch-on (8 amto 10 pm) and patch-off (10 pmto 8 am) hours. Because duration of patch-on and patch-off periods were different, ischemia was expressed as the number of episodes or minutes per hour. From the ETT the following were tabulated: time to onset of angina and/or 1-mm ST segment depression, total duration of ETT, maximal ST segment depression, rate–pressure product at onset of angina and extent of ST segment depression.
To investigate possible diurnal variation of AECG ischemia, frequency and duration of ischemia were determined for 2-h periods throughout the recording session. Data were then summarized by four time periods: midnight to 6 am, 6 amto noon, noon to 6 pmand 6 pmto midnight.
The limiting variable for sample size calculation was determined to be a change in total weekly number of AECG-detected ischemic episodes. Observations from a previous study using similar patient-entry criteria suggested that an average of 2 episodes of ischemia per 48 h of AECG monitoring (7/week [range 2 to 14]) could be expected. It was desirable to be able to detect a reduction of two episodes per week, on average, from the placebo condition to intermittent TD-NTG. The standard deviation of differences was estimated to be 5. To detect a mean difference of 2 with a two-tailed alpha of 0.05 at a power of 95%, the estimated sample size was 82 patients. The purpose of this overestimation was to be able to maintain adequate (e.g., 90%) statistical power if 5% to 10% of recruited patients were unable to complete the study.
Response variables were compared using methods appropriate for crossover trials, which included tests for order and period effects . Repeated measures analysis of variance was performed to evaluate treatment, carryover and period effects. Nonparametric Wilcoxon rank-sum tests were also used to evaluate treatment and period effects. The results are summarized as mean value ± SD and significance was defined at p ≤ 0.05.
A total of 72 patients met all qualifying criteria and completed all study periods and the pertinent clinical characteristics of these patients are summarized in Table 1. Subjects were 64 ± 8 years old (range 40 to 77), and 93% were men. Approximately half of the patients had a previous revascularization procedure, 42% had hypertension, 46% had hypercholesterolemia and 51% were taking a calcium antagonist and 46% a beta-blocker, whereas 76% had used SL-NTG before. Randomization distributed these baseline characteristics so that there were no significant differences between those who received a double-blind TD-NTG patch first and those who received a double-blind placebo patch first. No significant order or period effects for any variable were observed and no interaction between TD-NTG and beta-blocker or calcium antagonist was observed.
2.1 Tolerability results
After completion of Period I, the optimal dose of TD-NTG was 0.2 mg/h, 0.4 mg/h and 0.6 mg/h in 28%, 29% and 43% of patients, respectively. During dose tolerability testing, 36% of patients reported no adverse effects at the maximal dose. The most frequently reported adverse effects were dizziness (14%) and headache (5%), but no serious adverse effects occurred. During subsequent double-blind periods, mild skin irritation and itching were reported by five patients, one of whom developed mild contact dermatitis. The frequency of these skin problems was similar with placebo (n = 3) and TD-NTG (n = 2). Headaches were reported by four patients using active TD-NTG and by one using placebo. While using placebo, another patient developed prolonged chest pain necessitating an emergency room visit.
2.2 Double-blind period results
Table 2summarizes the effects of TD-NTG and placebo on ETT variables in all patients with complete data. As expected, use of TD-NTG was associated with a significant decrease in ischemia at the onset of angina, as reflected by a reduction in the magnitude of ST segment depression as compared with placebo. Angina diaries (Table 3) revealed that there was no significant difference in the total number of perceived angina episodes reported during use of TD-NTG compared with placebo. There was, however, a trend for frequency of angina to decrease during patch-on hours with TD-NTG compared with placebo (2.0 ± 3.0 vs. 2.6 ± 4.2 episodes, respectively, p = 0.18). During patch-off hours, the frequency of angina was significantly greater when patients were using TD-NTG as compared with placebo (1.1 ± 2.1 vs. 0.7 ± 1.6 episodes, respectively, p = 0.03). This difference was related to consistent increases in the frequency of angina associated with activity, rest and sleep during these patch-off hours.
Analysis of AECG data for all hours (Table 4) revealed no overall difference between TD-NTG and placebo with respect to the frequency (0.08 ± 0.13 vs. 0.09 ± 0.12 episodes/h, respectively, p = 0.55) or duration (0.64 ± 1.52 vs. 0.63 ± 1.01 min/h, respectively, p = 0.94) of ischemia.
Evaluation of patch-on hours, however, revealed a trend for frequency and duration of ischemia to decline with TD-NTG as compared with placebo (0.07 ± 0.15 vs. 0.12 ± 0.19 episodes/h, respectively, p = 0.11; 0.62 ± 1.80 vs. 0.78 ± 1.19 min/h, respectively, p = 0.22). Notably, when the TD-NTG patch was removed (patch-off), the opposite trend was observed, with an increase in frequency and duration of ischemia as compared with placebo (0.08 ± 0.20 episodes/h vs. 0.05 ± 0.09 episodes/h, respectively, p = 0.08; 0.67 ± 2.43 vs. 0.43 ± 1.48 min/h). This change in frequency of ischemia from patch-on to patch-off periods differed significantly when using TD-NTG patches compared with placebo patches with the mean frequency increasing by 14% during TD-NTG and decreasing by 58% during placebo (p = 0.01) (Fig. 1). A similar pattern was observed for duration of ischemia from patch-on to patch-off hours, with an increase of 8% when using TD-NTG and a decrease of 45% during placebo (p = 0.22).
To further examine the effects of placebo and TD-NTG patch removal on diurnal frequency of AECG-detected ischemia, data were summarized at 2-h intervals (Fig. 2). The expected early morning increase in frequency of ischemia was observed when patients used placebo (top panel) but not when TD-NTG (bottom panel) was used. Using 6-h periods beginning at midnight, the frequency of ischemic episodes during TD-NTG therapy was not found to vary over time, most likely because TD-NTG suppressed the increase in ischemia that occurs with activation after awakening, as observed with placebo. With placebo, the difference in frequency of ischemia in the 6-h period after midnight compared with the 7 amto noon period or 1 pmto 6 pmperiod was highly significant (p = 0.0014). Although not shown here, duration of ischemia was similarly affected.
3.1 Rebound ischemia
An increase in ischemia, either symptomatic or asymptomatic, during patch-off hours could be important in the management of patients with ischemic heart disease. Because most ischemia is asymptomatic, it is therefore useful to consider both subjective and objective aspects of ischemia. In these clinically stable patients with CAD, we observed an increase in angina frequency during patch-off hours when patients used TD-NTG compared with placebo (Table 3). A similar trend was noted in daily life ischemia (Fig. 1). Our patients also received other antianginal agents (beta-blocker or calcium antagonist, or both) and had ischemia on the ETT as well as during daily activities, and these results were noted after 2 weeks of an optimal dose of TD-NTG.
These results are remarkably consistent with the observations of Freedman et al. , who studied a smaller group of patients. These investigators also found that rebound ischemia occurs during patch-off hours in stable patients with CAD taking TD-NTG and a beta-blocker or calcium antagonist, or both. Their patients were also not selected on the basis of stable ETT times, and only 60% had ischemia on the AECG. Similar to our observations, a trend toward increasing duration of ischemia during patch-off hours was found in patients receiving active TD-NTG compared with placebo (47 ± 18 vs. 23 ± 9 min/24 h, respectively, p = 0.07). In addition, the diurnal patterns of ischemia frequency observed in their TD-NTG group compared with their placebo group were very similar to those noted in our study. Specifically, during placebo, there was the usual diurnal variation in ischemia frequency, with little apparent attenuation by patch-on and patch-off (Fig. 2, top). During TD-NTG, however, there was a loss of the overnight nadir and mid-day zenith, with apparently the same ischemia frequency occurring from midnight to 6 amas during the other 6-hour periods (Fig. 2, bottom).
Our results and those of Freedman et al. differ from those of Parker et al. , who studied stable patients with CAD, most of whom were taking a beta-blocker without a calcium antagonist. Their patients received either placebo or one of three doses of TD-NTG (0.2 mg/h, 0.4 mg/h or 0.8 mg/h). After 30 days, no change in angina frequency occurred for either TD-NTG or placebo during patch-off or patch-on periods as compared with baseline. Their analyses differed from ours in that we directly compared patch-off and patch-on periods. In contrast to our patients, their patients were highly selected based on stable ETT times, and this selection bias probably relates to the infrequent angina observed while they were taking placebo (1.7 vs. 3.3 episodes/week in our patients). These observations suggest that CAD was functionally less severe in their patients compared with ours, and failure to detect a difference in angina frequency during patch-off hours may have been due to insufficient statistical power to detect these changes.
In our study, the magnitude of ischemia during ETT declined and a trend for angina to decrease during TD-NTG compared with placebo was observed. We also noted a trend suggesting an increase in ischemia when the TD-NTG patch was removed compared with placebo patch-off hours. One possibility to explain these observations is that TD-NTG partially suppresses increases in ischemia and when removed, rebound occurs. Based on our findings and those of Freedman et al. , it seems likely that some patients receiving intermittent TD-NTG are at risk for occurrence of an increase in ischemia during patch-off hours.
3.2 Comparison with placebo
In this study, the effectiveness of TD-NTG for angina was not apparent compared with placebo, but was found effective for an objective ischemia marker and ST segment depression during ETT. These less than expected effects may be attributed to a relatively low dose of TD-NTG (i.e., 0.2 and 0.4 mg/h) in the majority of cases. Angina was noted more frequently during patch-off hours when patients were using active TD-NTG compared with placebo. This overall increase in angina frequency was a result of increases associated with all types of reported activities.
A placebo response affecting angina frequency is well documented and may confound analyses of intermittent TD-NTG effects on ischemia during patch-off hours. Early antianginal trials, which were not well designed, revealed up to a 90% reduction in angina frequency with inactive therapies . Placebo also improves other markers of ischemia such as ETT time to angina and time to 1-mm ST segment depression . In a randomized, double-blind study of atenolol versus placebo in stable patients with CAD and ischemia during ETT and on AECG, 39% had no recurrent ischemia on repeat AECG after 4 weeks of placebo , and this placebo response persisted for 1 year. More recently, a significant placebo effect was observed in other studies with TD-NTG. In a well designed trial in 18 patients with stable CAD, effects of TD-NTG therapy on ETT responses were evaluated . No differences were observed in ETT time to 1-mm ST segment depression with any nitrate regimens, and both placebo and nitrates increased ETT time to ischemia compared with baseline. Similar results were observed in 36 other patients with stable CAD in another well designed trial . No difference in either ETT time to ST segment depression or total ETT time was observed between placebo and continuous TD-NTG or intermittent TD-NTG. The only variable that was significantly different from placebo was ETT time to angina when patients removed the TD-NTG patch for 10 h.
Other possible explanations for a large placebo effect include positive interactions with clinicians, application of the topical patch (i.e., tactile stimulation) regardless of its contents, diminished mental stress or a conditioning effect. With the patch off, patients may be more aware of the absence of treatment than during patch-on periods. Actual wearing of a placebo patch may have a therapeutic effect. Unlike oral medication, as a consequence of tactile feedback, the patient is continually reminded of the presence of the patch even when it contains placebo. This reminder may lead to a reduction in anxiety and ischemia. To control for these possibilities, it may be appropriate to randomize patients to a no-therapy group in future trials.
The relative lack of significant effects of TD-NTG on efficacy may also relate to absence of documented nitrate responsiveness. Other studies reporting positive results with intermittent TD-NTG screened patients for nitrate responsiveness. For example, 14 patients with stable CAD receiving a beta-blocker and a calcium antagonist sequentially received continuous TD-NTG (0.4 mg/h), intermittent TD-NTG and placebo. Nitrate responsiveness was defined as a prolongation of ETT time by at least 1 min after SL-NTG administration. In this study no differences in frequency of angina were observed with either TD-NTG regimen compared with placebo, but intermittent TD-NTG increased total ETT time (440 vs. 360 s, p < 0.05). Other investigators who have observed beneficial effects from use of intermittent TD-NTG excluded patients who failed to respond to a variety of challenges with SL-NTG [12–17]. Although all patients in our study had a history of nitrate responsiveness, this responsiveness was not objectively evaluated, and this may have contributed to the equivocal effectiveness of intermittent TD-NTG.
Many studies evaluating intermittent TD-NTG in stable patients with CAD have failed to observe a decline in angina frequency or SL-NTG use [5, 13–19]. Effects of intermittent TD-NTG therapy on daily life ischemia detected by AECG has also been inconsistent [6, 16, 17, 20, 21].
Furthermore, most of the patients in this study were receiving a calcium antagonist or beta-blocker, or both. Other investigations of TD-NTG effectiveness have also failed to detect beneficial effects from TD-NTG when patients were taking other antianginal therapies [6, 11]. In one study, the comparative efficacy of intermittent TD-NTG and placebo was evaluated in 206 patients with stable CAD concurrently receiving a beta-blocker. In this study, no differences in angina frequency or SL-NTG use were observed between TD-NTG and placebo . In a similar trial of 40 patients with stable CAD receiving a beta-blocker and a calcium antagonist, use of intermittent TD-NTG failed to prolong ETT time to angina or 1-mm ST segment compared with placebo . An increase in ETT duration, however, was noted in patients receiving TD-NTG as compared with placebo. Perhaps patients requiring concurrent treatment with other antianginal agents have such severe disease that no additional benefit can be derived from addition of TD-NTG.
It is also possible that failure to detect significant differences between intermittent TD-NTG and placebo in our study was related to divergent results comparing patch-on and patch-off periods together with large variability. Although the number of patients completing the trial was less than planned, the actual power of this study to detect the expected difference in ischemic episodes was ≥0.90, as anticipated. The estimated sample size was calculated to detect a reduction of two episodes of ischemia per week between intermittent TD-NTG and placebo. The observed difference in frequency was 1.68 per week, but the variability was greater than expected. It is unlikely that enrollment of 10 more patients would have substantially altered these results. In future studies, the directionally different effects on ischemia observed in patch-off periods comparing active TD-NTG with placebo should be examined in detail.
The results of this study suggest that the anti-ischemic effects of intermittent TD-NTG in the low doses used were minimal and may be limited by a rebound increase in ischemia during patch-off hours. Furthermore, the results of this study support the suggestion that use of intermittent TD-NTG is associated with disruption in the normal diurnal pattern of ischemia. Definitive investigation of this issue would require evaluation of changes in ischemia using a variety of patch-on/patch-off times.
A.1 Second Transdermal Intermittent Dosing Evaluation Study Investigators
Peter F. Cohn, MD, Lynn Burger, RN, State University of New York at Stony Brook, New York; Stephen P. Glasser, MD, Nancy Ferzola, RN, University of South Florida, Tampa, Florida; Harold Karpman, MD, Joe D’Amico, Cardiovascular Medical Group of Southern California, Beverly Hills, California; Alan B. Miller, MD, Mary Hudson, RN, University Medical Center, Jacksonville, Florida; Carl J. Pepine, MD, Michele Mardis, Technician, University of Florida, Gainesville, Florida; Douglas Campbell Russell, MD, Tonda Thompson, RN, Debbie Woodson, RN, Veterans Administration Medical Center, Salem, Virginia; Udho Thadani, MD, Diane Stroud, RN, Oklahoma University, Oklahoma City, Oklahoma; John L. Walker, MD, Diane Martin, RN, Cardiology Research Associates, Ormond Beach, Florida; Alan Wasserman, MD, Anna Nys, RN, George Washington University Medical Center, Washington, D.C.; David Chinoy, MD, Cynthia Buda, RN, Jacksonville, Florida; Robert Gibson, MD, Sharon Sayre, RN, University of Virginia Medical Center, Charlottesville, Virginia.
- ambulatory electrocardiogram, electrocardiographic
- coronary artery disease
- electrocardiogram, electrocardiographic
- exercise treadmill test
- sublingual nitroglycerin
- transdermal nitroglycerin
- Received September 30, 1996.
- Revision received June 19, 1997.
- Accepted July 1, 1997.
- The American College of Cardiology
- Lopez LM,
- Lambert CR,
- Pepine CJ
- ↵Anonymous. Transdermal-Nitro (nitroglycerin): transdermal therapeutic system. In: Physician’s Desk Reference. 49th ed. Montvale, NJ: Medical Economics, 1995:2455–7.
- ↵Jones B, Kenward MG. The 2 × 2 cross-over trial with continuous data. In: Jones B, Kenward MG, editors. New York: Chapman and Hall, 1989:18–88.
- Freedman SB,
- Daxini BV,
- Noyce D,
- Kelly DT
- the Minitran Efficacy Study Group,
- Parker JD,
- Amies MH,
- Hawkinson RW
- Khurmi NS,
- Raftery EB
- for the ASSIST Study Group,
- Pepine CJ,
- Cohn PF,
- Deedwania PC,
- et al.
- Waters DD,
- Juneau M,
- Gossard D,
- Choquette G,
- Brien M
- on behalf of the Transderm-Nitro Study Group,
- DeMots H,
- Glasser SP
- Gumbrielle T,
- Freedman SB,
- Fogarty L,
- Ogasawara S,
- Sobb P,
- Kelly DT
- Fox KM,
- Dargie HJ,
- Deanfield J,
- Maseri A
- Luke R,
- Sharpe N,
- Coxon R
- Rosetti E,
- Luca C,
- Bonetti F,
- Chierchia S