Abstract
Objective:
Rivastigmine is commonly used for the treatment of Alzheimer’s disease (AD). All cholinesterase inhibitors, including rivastigmine, may cause cardiac side effects. The aim of this study is to compare the electrocardiographic (ECG) and hypotensive effects of formulations of rivastigmine.
Methods:
Eighty-five newly diagnosed patients with AD who were treated with rivastigmine were retrospectively evaluated. The ECG records were reviewed at baseline and at administration of either 12 mg of oral rivastigmine or 10 cm2 transdermal rivastigmine.
Results:
When compared with the baseline, there were no changes in any of the ECG parameters in all of the patients (P > .05). Moreover, when compared with the mean change from baseline for each treatment group, there were no changes, except heart rate (P = .035).
Conclusion:
It was demonstrated that rivastigmine formulations were not associated with increased arrhythmogenic or hypotensive effects in elderly patients with AD and was not superior to each other.
Keywords: rivastigmine patch, oral rivastigmine, Alzheimer’s disease, arrhythmia, hypotension, elderly
Introduction
Rivastigmine is a centrally acting cholinesterase inhibitor (ChEI), which is commonly used for the treatment of Alzheimer’s disease (AD) and is the only ChEI available in a transdermal drug delivery formulation. 1 Although the target organ for all ChEIs including rivastigmine is the brain, their inhibition may adversely affect cardiac function since the heart is also rich in cholinesterases. These potential cardiac adverse effects, including bradycardia, heart block, and QT prolongation with or without a history of cardiac disease, can emerge as vagotonic effects due to ChEIs. 2 -6 On the other hand, it was reported that rivastigmine transdermal system was not associated with increased negative chronotropic, arrhythmogenic, and hypotensive effects in elderly patients with AD. 7 Furthermore, it was also reported that oral rivastigmine did not have cardiac adverse effects on electrocardiogram (ECG). 8
The transdermal rivastigmine provides continuous delivery of the drug into the bloodstream over 24 hours and is as efficacious as the highest oral doses with approximately 3 times less reports of gastrointestinal adverse events, such as nausea and vomiting. It was also demonstrated that rivastigmine patch is more tolerable and more compliant than the oral formulation 1,9 -11 and represents an advance of therapeutic effectiveness in AD. 12 Till now, arrhythmogenic and hypotensive effects of both rivastigmine formulations have not been compared in elderly patients with AD. Since cardiac disease prevalence in the elderly patients is increased, the choice of better formulation of rivastigmine without any cardiac adverse events is important. Therefore, this study was aimed to compare the ECG and hypotensive effects of transdermal and oral formulations of rivastigmine in the elderly patients with AD.
Methods
A total of 212 elderly patient medical records were retrospectively reviewed and 85 newly diagnosed patients with AD (23 of whom were treated with oral rivastigmine and 62 with transdermal rivastigmine), who were examined with a comprehensive geriatric assessment and had 12-lead surface ECG measurements during the rivastigmine therapy as defined in our previous study, 7 were enrolled in this study. Before the data collection, legally authorized representatives according to the local guidelines. The investigation confirms to the Declaration of Helsinki.
Patients were diagnosed with Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) criteria for primary degenerative dementia of the Alzheimer’s type and the National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association criteria 13 for probable AD. Those patients who had been treated with cardio-stimulatory drugs and pacemakers, as detailed in our previous study, 7 were excluded.
Blood Pressure and ECG
Exogenous variables that can influence blood pressure including food intake, exercise, smoking, and the ingestion of caffeine were avoided in the 60 minutes before evaluation, and both blood pressure measurement and ECG were recorded at the same time. After patients rested quietly for 5 minutes in a quiet and warm setting, their blood pressure measurements were taken in the sitting position by Mercury sphygmomanometers with a proper-sized cuff. 14 The 12-lead surface ECG measurement was recorded using 25 mm/s paper speed and standardized at 0.1 mV/mm after the patients had rested for at least 10 minutes in a supine position. 7
Patients with AD were treated with a flexible 4 weekly rivastigmine (Exelon oral solution and patch, Novartis, Istanbul, Turkey) dosage titration regimen up to 12 mg/d and 10 cm2/d, respectively. The ECG parameters and blood pressure measurements were recorded at baseline and at 4 weeks after the administration of drugs in dose mentioned earlier.
The ECG parameters, including heart rate, PR, QT and QTc interval, and QRS duration, were calculated automatically by the apparatus. The QT interval was corrected for the heart rate by using Bazett’s formula (QTc = QT/square root of RR) 15 and more than 450 ms was defined for QTc prolongation. 16
Statistical Analysis
Statistical analyses were performed using the SPSS software, version 15.0 ( SPSS Inc, Chicago, Illinois). Demographics and baseline characteristics were reported as the number (n) and percentage (%) for nominal variables and as the mean ± standard deviation for continuous variables. Differences in proportions were evaluated with Pearson’s chi-square test. All the comparisons were tested for statistical significance by using the Mann-Whitney U test, Mc-Nemar test, and κ coefficient, as appropriate. The other comparisons were tested. The differences were considered to be significant at P < .05.
Results
A total of 45 male and 40 female elderly patients with newly diagnosed AD were included. The demographics and baseline characteristics of the patients are given in Table 1. When compared with the baseline, there were no changes in any of the ECG parameters in all of the patients (P > .05). In addition, when compared with the mean change from baseline in each treatment group, there were no changes in any of the ECG parameters (P > .05) except heart rate (P = .035). The mean change in heart rate from baseline was significantly lower in the rivastigmine patch-treated patients. Only one patient’s heart rate was lower than 50 per minute and asymptomatic. The arterial blood pressure and pulse pressure of the patients remained unchanged according to the baseline in all of the patients (P > .05 for each comparison; Table 1).
Table 1.
Mean Demographics and Other Characteristics of Patients.a
| Rivastigmine Oral (n = 23) | Rivastigmine Patch (n = 62) | P 1 Value | P 2 Value | |||
|---|---|---|---|---|---|---|
| Age | 81.7 ± 6.6 | 76.7 ± 8.2 | .010 | |||
| Sex (♂/♀) | 11/12 | 29/33 | .931 | |||
| Education | 5.5 ± 2.2 | 5.3 ± 1.7 | .845 | |||
| Comorbidities, % | ||||||
| HT | 60.9 | 62.9 | .863 | |||
| CHF | 0 | 4.8 | .560 | |||
| AF | 17.4 | 8.1 | .245 | |||
| CAD | 26.1 | 19.4 | .555 | |||
| Assessment | ||||||
| Baseline | 12 mg/d | Baseline | 10 cm2/d | |||
| MMSE | 16.3 ± 5.4 | 15.5 ± 4.2 | .565 | |||
| IADL | 5.3 ± 4.2 | 5.5 ± 4.7 | .743 | |||
| BADL | 80.0 ± 20.2 | 83.3 ± 22.7 | .343 | |||
| MNA | 10.5 ± 2.2 | 10.2 ± 3.1 | .553 | |||
| Systolic BP, mm Hg | 139.5 ± 18.4 | 138.7 ± 24.2 | 137.0 ± 18.2 | 137.3 ± 19.6 | .693 | .777 |
| Diastolic BP, mm Hg | 80.2 ± 10.2 | 79.7 ± 12.9 | 80.0 ± 9.8 | 75.5 ± 8.9 | .962 | .245 |
| PP, mm Hg | 58.9 ± 11.6 | 58.9 ± 16.3 | 56.5 ± 13.9 | 61.9 ± 7.0 | .364 | .215 |
| ECG Parameters | ||||||
| Heart rate | 70.4 ± 13.0 | 72.7 ± 16.6 | 73.8 ± 16.3 | 69.4 ± 12.6 | .595 | .035 |
| PR, ms | 178.8 ± 29.0 | 174.1 ± 23.4 | 169.9 ± 30.3 | 171.0 ± 25.6 | .191 | .176 |
| QRS, ms | 92.2 ± 18.4 | 92.6 ± 18.0 | 92.3 ± 19.8 | 94.0 ± 18.9 | .976 | .287 |
| QT, ms | 396.5 ± 42.7 | 395.0 ± 45.6 | 390.8 ± 45.9 | 400.9 ± 39.8 | .498 | .111 |
| QTc, ms | 425.0 ± 27.4 | 428.0 ± 42.2 | 424.1 ± 32.5 | 423.6 ± 39.3 | .696 | .928 |
| QTc > 450 ms, n | 5 | 2 | 13 | 16 | .558 | .976 |
Abbreviations: AF, atrial fibrillation; BADL, Basic activity of daily living (0 [worst]-100 [best]); BP, blood pressure; CAD, coronary artery disease; CHF, congestive heart failure; ECG, electrocardiogram; HT, hypertension; IADL, Instrumental activity of daily living (0 [worst]-17 [best]); MMSE, Mini-Mental State Examination(0 [worst]-30 [best]); MNA, Mini Nutritional Assessment(0 [worst]-14 [best]; PP, Pulse Pressure.
a P 1 value for baseline and P 2 value for second comparisons.
Discussion
In this study, it was demonstrated that rivastigmine formulations were not associated with increased arrhythmogenic or hypotensive effects in elderly patients with AD and were not superior to each other.
It is known that a prolongation of the QT and QTc intervals is related to electrical instability and risk of ventricular arrhythmogenesis. 17 Due to age-associated degenerative changes in the conduction system, a large percentage of older people have complex arrhythmias. 18 Furthermore, rivastigmine is a butyrylcholinesterase inhibitor as well as an acetylcholinesterase inhibitor, unlike donepezil and galantamine, and the heart has a high density of butyrylcholinesterase. 2 -7 Although the target organ for rivastigmine like other ChEIs is the brain, the heart is also rich in cholinesterases and their inhibition may adversely affect cardiac function, especially in elderly patients. 2,3,7 Therefore, this potentially high risk in elderly patients should be kept in mind when they are treated with ChEIs including rivastigmine. 2 -7
Transdermal patches provide continuous drug delivery and maintain rivastigmine concentrations within the optimal therapeutic window avoiding the peaks and troughs associated with oral administration 10 ; thus, transdermal patches may have more cardiac adverse effects than oral rivastigmine. Although previous studies have reported that both oral and transdermal rivastigmine have no effect on the ECG parameters and arterial blood pressure compared with the baseline in the elderly patients with AD, 7,8 till now, the effects of rivastigmine formulations on cardiac and blood pressure were not compared with each other.
In the previous studies, it was reported that complete atrioventricular block and QT prolongation were seen in the patients taking rivastigmine. 4,5 Therefore, there has been significant anxiety among prescribers regarding the potential for cardiac adverse effects associated with ChEIs including rivastigmine in elderly patients with AD. 2,19 When the age-associated changes in the heart, increasing the risk of arrhythmia, 18,19 are considered, it is important not to have arrhythmogenic and hypotensive effects for elderly patients with AD. Furthermore, comorbidities and medications of patients may have also been responsible for these rivastigmine-induced ECG changes encountered in previous reports. 4,5 In the last case report, 6 it wasn’t completely demonstrated that third-degree atrioventricular block was associated with rivastigmine patch treatment because both the patients’ cardiac biomarkers were more than normal range and ischemic etiologies were not completely detailed. On the other hand, in the present study, it was demonstrated that only mean change from baseline of heart rate in patients treated with 12 cm2/d rivastigmine patch was significant compared to oral rivastigmine, but this wasn’t clinically important since only one patient’s heart rate was less than 50 pulse/min and asymptomatic.
The first limitation of this retrospective study was the small number of selected patients sampled. The duration may be second, as these results included only 2 months of treatment with both rivastigmine formulations. Other limitations of the study were difference in mean age of both groups and duration.
In conclusion, it was demonstrated that transdermal and oral formulations of rivastigmine were not associated with increased arrhythmogenic or hypotensive effects in elderly patients with AD and were not superior to each other. However, when physicians prescribe these drugs, they should be aware of the comorbidities, especially cardiac conduction disease and medications of the elderly patients.
Acknowledgments
The authors thank Hulya Ellidokuz for help in statistical evaluation and Rumeyza Kazancioglu for help in editing the manuscript.
Footnotes
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
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