ABSTRACT
Conclusion:
Donepezil and rivastigmine treatments significantly prolong QTc interval compared to controls in patients with AD. The donepezil treatment also prolongs PR and QT intervals. The donepezil and rivastigmine therapy had comparable effects on the cardiac conduction system.
Results:
A total of 24 patients were enrolled in the donepezil treatment group, 14 patients in the rivastigmine treatment group, and 37 patients in the control group. Donepezil treatment resulted in significant prolongation in PR interval, QT interval and QTc interval (p=0.027, p=0.001, p=0.023, respectively). Rivastigmine treatment resulted in significant prolongation only in QTc interval (p=0.018). There was no significant difference between the donepezil and rivastigmine treatment groups for all ECG parameters.
Materials and Methods:
We retrospectively enrolled 38 consecutive patients with AD, who were prescribed ChEIs for at least 3 months, and age, sex, and comorbidity-matched treatment-naive 37 control subjects. The electrocardiographic (ECG) parameters including heart rate, PR interval, QRS duration, QT interval, and QTc interval were recorded for each patient and control subject.
Aim:
Cholinesterase inhibitors (ChEIs), such as donepezil and rivastigmine, are used safely in the treatment of Alzheimer’s disease (AD). However, the effects of these drugs on the cardiac conduction system are not clear. In this study, we aimed to investigate the effect of donepezil and rivastigmine treatment on the cardiac conduction system in comparison with the controls, especially on the QTc interval.
INTRODUCTION
Cardiovascular diseases and cognitive impairment often coexist in elderly patient populations. Alzheimer’s disease (AD) is the most frequent cause of dementia in these elderly patients1. AD causes progressive deterioration in cognitive functions. The primary therapeutic target for the treatment is the cholinesterase enzyme2. Cholinesterase enzyme inhibitors (ChEIs), including donepezil and rivastigmine, are the first-line treatment options that have a positive effect on promoting the cognitive functions of AD patients3.
The effects of ChEIs are not limited to the central nervous system. ChEIs also affect intrinsic cardiac neurons in mammalian hearts which modulate the chronotropic and dromotrophic functions of the heart4. The donepezil treatment significantly reduces heart rate5 and it has also been demonstrated that there is a strong link between donepezil treatment and QTc prolongation and risk of Torsades de pointes (TdP) but data on rivastigmine are scarce so it is challenging to clarify the effect of rivastigmine on QTc prolongation6. On the other hand, recent studies have shown the cardioprotective effects of ChEIs. A retrospective database study has demonstrated that therapy with ChEIs has significantly decreased the risk of cardiac pacemaker implantation7.
The potential electrocardiographic (ECG) effects of each ChEIs were evaluated in the literature6,8. However, the comparison between donepezil and rivastigmine therapy on ECG parameters with respect to controls was not extensively studied. Thus, we aimed to investigate the effects of donepezil and rivastigmine treatment on ECG parameters including heart rate, PR interval, QRS duration, QT, and QTc interval in comparison with control subjects and between each treatment group.
GİRİŞ
Yaşlı hasta popülasyonlarında kardiyovasküler hastalıklar ve kognitif bozukluk çoğunlukla bir arada bulunmaktadır. Alzheimer hastalığı (AH), bu yaşlı hastalarda demansın en sık nedenidir1. AH, bilişsel işlevlerde ilerleyici bozulmaya neden olmaktadır. Tedavi için birincil terapötik hedef kolinesteraz enzimidir2. Donepezil ve rivastigmin gibi kolinesteraz enzim inhibitörleri (ChEI), AH’de bilişsel işlevleri iyileştirmede olumlu etkisi olan birinci basamak tedavi seçenekleridir3.
ChEI’lerin etkileri merkezi sinir sistemi ile sınırlı değildir. ChEI’ler ayrıca, memeli kalplerinde kalbin kronotropik ve dromotropik fonksiyonlarını modüle eden kardiyak nöronları da etkilerler4. Donepezil tedavisi kalp atım hızını önemli ölçüde azaltır5 ve donepezil tedavisi ile QTc uzaması ve Torsades de pointes (TdP) riski arasında güçlü bir ilişki olduğu gösterilmiştir, ancak rivastigmin tedavisine ilişkin veriler yeterli olmadığından bu ilacın QTc uzaması üzerindeki etkisini değerlendirmek zordur6. Öte yandan yapılan son çalışmalar ChEI’lerin kardiyoprotektif etkilerinin de olduğunu göstermiştir. Yapılan retrospektif bir veri tabanı çalışmasında, ChEI tedavisinin kalp pili implantasyonu riskini önemli ölçüde azalttığı gösterilmiştir7.
Literatürde, her bir ChEI’nın potansiyel elektrokardiyografik (EKG) etkileri değerlendirilmiştir6,8. Bununla birlikte, donepezil ve rivastigmin tedavisinin, kontrol grubu ve birbirleri arasında EKG parametreleri üzerindeki etkisini karşılaştıran az sayıda veri bulunmaktadır. Bu nedenle bu çalışmada, donepezil ve rivastigmin tedavisinin kalp hızı, PR aralığı, QRS süresi, QT ve QTc aralığı gibi EKG parametreleri üzerindeki etkilerini kontrol grubuna göre ve her tedavi grubu arasında karşılaştırmalı olarak araştırmayı amaçladık.
MATERIALS AND METHODS
We retrospectively enrolled 38 consecutive patients who had been diagnosed with AD according to the National Institute on Aging-Alzheimer Association criteria between November 2021 and September 20229. Thirty-seven age, sex, and comorbidity-matched control subjects were also recruited for the study. We included patients aged 55-85 years, who had a 12-lead ECG as a part of any outpatient clinic visit while taking cholinesterase inhibitors for at least 3 months. All patients were compliant in taking their medication and reached steady state of donepezil 10 mg and rivastigmine 13.3 mg. The route of administration for donepezil included oral tablets and transdermal patches for rivastigmine. Patients with atrial fibrillation, heart failure, and pacemaker implantation, having a history of catheter ablation for any arrhythmia, thyroid abnormality, and chronic renal disease requiring dialysis were excluded from this study. Patients who were treated with antiarrhythmic medications (except beta blockers) and drugs that affected QT interval were also excluded. All data were collected from institutional electronic medical records.
Baseline patient characteristics and comorbidities were recorded. The current use of blood pressure-lowering medication was defined as hypertension and the current use of medication for diabetes was defined as diabetes mellitus. Hyperlipidemia was defined as the current use of cholesterol-lowering therapy. The presence of coronary artery disease was defined as prior history of myocardial infarction or coronary artery revascularization. Ischemic cerebrovascular disease was defined as having a history of minor stroke caused by a small or big blood vessel pathology. Among laboratory data, baseline hemoglobin, thyroid function tests, serum creatinine, estimated glomerular filtration rate, and serum electrolytes including sodium, potassium, and calcium levels were noted. A resting 12-lead ECG was recorded from all patients by using 25 mm/sec paper speed and standardized at 0.1 mV/mm. ECG parameters including heart rate, PR interval, QRS duration, QT interval, and QTc interval were calculated automatically by the ECG apparatus and reviewed by a cardiologist. QTc was corrected for heart rate using the Bazett’s formula (QTc=QT/ÖRR)10.
This study was approved by the Dokuz Eylül University Local Ethics Committee (approval no: 2021/27-01, date: 06.10.2021).
Statistical Analysis
A standard statistical software program [Statistical Package for the Social Sciences (SPSS) version 26; SPSS, Inc., Chicago, IL] was used. The Kolmogorov-Smirnov test was used to check continuous variables for normality. The categorical variables were represented as numbers and percentages and continuous variables were represented as the mean±standard deviation and median (interquartile range). If results were asymmetrically distributed, nonparametric tests were used. Comparisons between the three groups were performed using the Kruskal-Wallis test for non-normally distributed data, the one-way ANOVA test for normally distributed data, and the chi-square test for categorical variables. Multivariate analysis of variance test was used to examine ECG parameters including PR interval, QT duration, and QTc. A p-value <0.05 was considered to be statistically significant.
RESULTS
The study population was divided into three groups: The donepezil treatment group, the rivastigmine treatment group, and control group. A total of 24 patients were in the donepezil treatment group, 14 patients were in the rivastigmine treatment group, and 37 patients were in the control group. Table 1 represents the clinical and laboratory characteristic of the treatment and control groups. There were no significant differences in age, sex, comorbidities, baseline laboratory parameters, and beta-blocker usage among the three groups (Table 1).
Among ECG parameters, PR interval, QT interval and QTc interval were significantly different among three groups (p=0.03, p=0.001, p=0.005, respectively) whereas heart rate and QRS duration were not different between three groups (p=0.12, p=0.19, respectively) (Figure 1, Table 2).
Pairwise comparisons revealed that the PR interval was significantly different between the donepezil treatment group and control group (p=0.027). There were no significant differences between the rivastigmine treatment group and control group and between the donepezil and rivastigmine treatment groups (p=0.43, p=0.64, respectively) (Table 3). For QT interval, the analysis revealed a significant difference between the donepezil treatment group and control group (p=0.001) whereas there was no significant difference between the rivastigmine treatment group and control group and between the donepezil and rivastigmine treatment groups (p=0.57, p=0.12, respectively) (Table 3). For QTc interval, significant differences emerged for the donepezil treatment group and control group and between the rivastigmine treatment group and control group (p=0.023, p=0.018, respectively). There was no significant difference between the donepezil and rivastigmine treatment groups for QTc (p=0.87) (Table 3).
DISCUSSION
Our study demonstrates that among ECG parameters, no significant difference was observed in heart rate and QRS duration among the three groups. The PR interval and QT interval were significantly prolonged only in the donepezil treatment group, whereas QTc interval was significantly longer in both donepezil and rivastigmine treatment groups. Regarding all ECG parameters, no significant difference was detected between the donepezil and rivastigmine treatment groups.
The previous reports suggest that ChEIs are associated with cardiovascular side effects, including bradycardia, complete atrioventricular block, and TdP11-14. As increased levels of acetylcholine in the heart enhance vagal tone, it is evident that ChEIs may decrease heart rate15. However, in concordance with our results, Isik et al.16 demonstrated that none of the ChEIs including donepezil, rivastigmine, and galantamine was associated with an increased risk of bradycardia. The discrepancies between these results may have been related to several factors. First, comorbidities of patients including ischemic heart disease differ among these studies. Second, serum electrolytes, especially potassium and calcium, may affect heart rate17 and not all studies report serum electrolyte levels that may affect their results. Finally, concomitant use of other medications may have been responsible for these discordant ChEIs-associated ECG changes.
The QT interval corresponds from the beginning of ventricular depolarization to the end of ventricular repolarization and QTc prolongation is associated with an increased risk of ventricular arrhythmias18, TdP, and sudden death19. When acetylcholinesterase receptors are inhibited in the heart, intracellular calcium concentrations increase. As a result, phase 2 of the cardiac action potential prolongs and increases the subsequent risk of ventricular arrhythmias20. Reports on the effects of ChEIs on QT interval prolongation and QTc are scarce. To date, most studies examining the effects of donepezil treatment on QT interval and QTc found that therapy with donepezil was associated with an increased risk of QT interval and QTc prolongation6,14,21, whereas some studies found no associations8,16. We demonstrated that therapy with both donepezil and rivastigmine significantly increased the QTc interval in comparison with control subjects. It has been shown that drug-associated QT prolongation and the risk of TdP are aggravated by the presence of at least one risk factor including female gender, presence of cardiac disease, electrolyte imbalances, overdosing, drug-drug interactions, and familial history of long QT syndrome22. For our present report and other clinical studies, it may be difficult to determine the alternative cause for this adverse effect as most cases and clinical studies included patients with at least one other risk factor for QT prolongation.
Besides, our study showed that donepezil and rivastigmine had similar effects on the cardiac conduction system. This result of the present study is in accordance with a previous study that demonstrated similar effects on ECG parameters of all three ChEIs including donepezil, rivastigmine, and galantamine16.
Study Limitations
Our study has several limitations. First, this is a retrospective study in a single center with a relatively small number of patients. Second, as this is a retrospective study, we could not examine the confounding factors that might prolong QTc interval including active infections, hypomagnesemia, metabolic problems, and other QTc-prolonging drugs. Finally, a 24-hour Holter monitoring would allow a more reliable evaluation of cardiac conduction abnormalities in patients taking QTc-prolonging agents.
TARTIŞMA
Bu çalışmada EKG parametrelerinden kalp hızı ve QRS süresinde donepezil, rivastigmin tedavi ve kontrol grupları arasında anlamlı bir fark olmadığı gösterilmiştir. PR aralığı ve QT aralığı sadece donepezil tedavi grubunda anlamlı olarak daha uzunken, QTc aralığı hem donepezil hem de rivastigmin tedavi gruplarında anlamlı olarak daha uzundu. Tüm EKG parametreleri birlikte değerlendirildiğinde donepezil ve rivastigmin tedavi grupları arasında anlamlı bir fark saptanmadı.
Daha önce yapılan çalışmalarda ChEI’lerin bradikardi, atriyoventriküler tam blok ve TdP gibi kardiyovasküler yan etkilerle ilişkili olduğu gösterilmiştir11-14. Artmış asetilkolin seviyeleri vagal tonusu arttırdığından, ChEI’lerin kalp hızını azaltabileceği aşikardır15. Ancak bizim sonuçlarımızla uyumlu olarak Isik ve ark.’nın16 yaptıkları çalışmada donepezil, rivastigmin ve galantamin dahil olmak üzere hiçbir ChEI’nın artmış bradikardi riski ile ilişkili olmadığı gösterilmiştir. Bu farklı sonuç birkaç faktöre bağlı olabilir. Birincisi, yapılan çalışmalar arasında iskemik kalp hastalığı dahil olmak üzere hastaların komorbiditeleri farklılık göstermektedir. İkincisi, serum elektrolitleri, özellikle potasyum ve kalsiyum, kalp atış hızını etkileyebilir17 ve tüm çalışmalar, sonuçlarını etkileyebilecek bu serum elektrolit düzeylerini belirtmemiştir. Son olarak, diğer ilaçların eşzamanlı kullanımı bu uyumsuz ChEI’lerle ilişkili EKG değişikliklerini açıklayabilir.
QT aralığı, ventriküler depolarizasyonun başlangıcından ventriküler repolarizasyonun sonuna kadar geçen süre olarak tanımlanır ve QTc uzaması artmış ventriküler aritmi riski18, TdP ve ani ölüm19 ile ilişkilidir. Kalpte asetilkolinesteraz reseptörleri inhibe edildiğinde hücre içi kalsiyum konsantrasyonları artar. Sonuç olarak, kardiyak aksiyon potansiyelinin Faz 2’si uzar ve ventriküler aritmi riski artar20. ChEI’lerin QT aralığı uzaması ve QTc üzerindeki etkilerine ilişkin verilerde tutarsızlık mevcuttur. Donepezil tedavisinin QT aralığı ve QTc üzerindeki etkilerini değerlendiren bugüne kadar yapılmış çoğu çalışmada donepezil ile tedavinin artmış QT aralığı ve QTc uzaması riski ile ilişkili olduğu gösterilmişken6,14,21, bazı çalışmalarda hiçbir ilişki bulunmamıştır8,16. Bu çalışmada hem donepezil hem de rivastigmin ile tedavinin, kontrol grubuna kıyasla QTc aralığını önemli ölçüde uzattığı gösterilmiştir. İlaca bağlı QT uzaması ve TdP riskinin kadın cinsiyet, kalp hastalığı varlığı, elektrolit dengesizlikleri, aşırı doz, ilaç-ilaç etkileşimleri ve ailede uzun QT sendromu öyküsü gibi en az bir risk faktörünün varlığı ile agreve olduğu gösterilmiştir22. Mevcut çalışmamız ve diğer birçok klinik çalışma, QT uzaması için en az bir başka risk faktörüne sahip hastaları içerdiğinden, bu olumsuz etkinin alternatif nedenini belirlemek zor olabilir.
Çalışmamızda ayrıca donepezil ve rivastigmin tedavisinin kalp ileti sistemi üzerinde benzer etkileri olduğu gösterilmiştir. Bu sonuç donepezil, rivastigmin ve galantamin dahil olmak üzere üç ChEI’nin hepsinin EKG parametreleri üzerinde benzer etkileri olduğunu gösteren diğer bir çalışma ile uyumludur16.
Çalışmanın Kısıtlılıkları
Çalışmamızın çeşitli kısıtlılıkları vardır. İlk olarak bu çalışma, nispeten az sayıda hasta ile tek bir merkezde yapılan retrospektif bir çalışmadır. İkincisi, bu retrospektif bir çalışma olduğundan, aktif enfeksiyonlar, hipomagnezemi, metabolik problemler ve diğer QTc uzatan ilaçlar dahil QTc aralığını uzatabilecek diğer karıştırıcı faktörler değerlendirilememiştir. Son olarak, 24 saatlik Holter kaydı, QTc uzatıcı ajanlar alan hastalarda kardiyak iletim anormalliklerinin daha güvenilir bir şekilde değerlendirilmesini sağlayacaktır.
CONCLUSION
In conclusion, donepezil and rivastigmine treatment significantly prolongs QTc interval compared to controls in patients with AD. The donepezil treatment also prolongs PR and QT intervals. The donepezil and rivastigmine therapy had comparable effects on the cardiac conduction system. Elderly patients are more susceptible to drug-induced arrhythmias because of age-related prolongation of the QT interval and repolarization dispersion. The risk of arrhythmias could be minimized with a multidisciplinary approach both for the initiation of ChEI therapies and the follow-up of AD patients.
