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Ann Thorac Surg 2006;82:1430-1435
© 2006 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Piracetam Prevents Cognitive Decline in Coronary Artery Bypass: A Randomized Trial Versus Placebo

Ildikó Szalma, MDa, Ágnes Kiss, MDa, László Kardos, MD, PhDb, Géza Horváth, MDb, Erika Nyitrai, PhDd, Zita Tordai, PhDc, László Csiba, MD, PhDd,*

a Department of Neurology, University of Targu-Mures, Targu Mures, Romania
b Department of Cardiac Surgery, University of Debrecen, Debrecen, Hungary
c Department of Neurology, University of Debrecen, Debrecen, Hungary
d Institute of Psychology, University of Debrecen, Debrecen, Hungary

Accepted for publication May 3, 2006.

* Address correspondence to Prof Csiba, Department of Neurology, University of Debrecen, Nagyerdei krt. 98, H-4012 Debrecen, Hungary (Email: csiba{at}jaguar.unideb.hu).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Coronary artery bypass grafting (CABG) can be associated with postoperative cognitive impairment and ischemic stroke. No effective treatment is currently available. The aim of this study was to evaluate the effectiveness of piracetam to treat the cognitive impairment after CABG in an investigator-initiated, double-blind, placebo-controlled, randomized clinical trial.

METHODS: Patients undergoing CABG (n = 98) were randomized to placebo (n= 48) or piracetam (n= 50). Study drugs were administered intravenously (150 mg/kg daily; 300 mg/kg on the day of surgery) from the day before surgery to 6 days after surgery, then orally (12 g/day) up to 6 weeks after surgery. Cognitive function was assessed before surgery (baseline) and 6 weeks after surgery (outcome) by using a battery of 12 neuropsychologic tests. The Spielberger Anxiety Inventory and the Beck Depression Inventory were also administered. The combined score derived from the standardized neuropsychologic assessments was analyzed by using an analysis of covariance with baseline and education as covariates.

RESULTS: Six weeks after surgery, the combined score indicated a statistically significant treatment effect in the per protocol population (1.848, p = 0.041) and a tendency towards statistical significance in the intent-to-treat population (1.624, p = 0.064) in the group treated with piracetam, but no statistically significant treatment effect was seen in the placebo. The state of anxiety measured by the Spielberger Anxiety Inventory was decreased in both groups (–9.27 and –6.37 in the placebo and piracetam groups, respectively).

CONCLUSIONS: Six weeks after CABG, cognition was significantly improved in patients treated with piracetam. Additional trials are required to confirm these effects.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Coronary artery bypass grafting (CABG) surgery is a common cardiac intervention recognized to be highly effective in stabilizing ventricular dysfunction [1]. The morbidity after CABG has decreased considerably during the past two decades because of improved surgical and patient management techniques. Nevertheless, a significant proportion of patients undergoing CABG are reported to develop postoperative cognitive impairments [1–4], ranging from slight to more pronounced disturbances and lasting some weeks, months, or years [1,2,5,6]. These cognitive impairments result in increased in-hospital mortality, longer duration of hospitalization, and increased use of resources [7].

The pathophysiologic mechanisms for postoperative cognitive decline associated with CABG are unknown but are probably multifactorial [1,2,6]. Microemboli [8,9], ischemic hypoperfusive brain lesions[10], low body temperature during surgery [11], individual susceptibility to cerebrovascular disease [12], and possession of the gene for apolipoprotein E {epsilon}4 isoform [13] are reported to be involved in this cognitive decline. A long-term cognitive decline has been reported 5 years after CABG surgery in 42% of patients [14], and similar neuropsychologic deficits have also been reported in patients 1 and 3 years after CABG and in comparable nonsurgical controls [3,4,15].

Despite several recent attempts, as yet no gold standard treatment has been devised for the cognitive impairments associated with CABG. Positive effects of prostacyclin [16], GM1 gangliosides [17], remacemide [18], pexelizumab [19] and S(+)-ketamine [20] were either absent or questionable, although heparin [21], lidocaine [22], and piracetam [23] have been shown to be beneficial. The cognitive-enhancing properties of piracetam have been demonstrated in numerous studies [23,24]. Whereas in most other ischemic pathologies the drug is administered after the ischemia, the planning of CABG surgery allows administration of the drug before the ischemia. A more robust preventive effect should therefore be expected.

This was a double-blind, placebo-controlled clinical trial designed to assess the cognitive impairment after CABG and to evaluate the efficacy of piracetam in preventing this cognitive impairment. We hypothesized that a cognitive impairment would be obvious in placebo patients 6 weeks after surgery, and that piracetam would limit its extent.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
Study Design
This investigator-initiated, exploratory phase IV, double-blind, placebo-controlled trial was conducted in accordance with the ICH Guideline for Good Clinical Practice [25] and local laws and regulations. After approval was obtained from the Debrecen University Institutional Ethics Committee on October 30, 2000, patients (1) about to undergo CABG surgery, (2) considered as mentally capable of adhering to the protocol, (3) with a sufficient level of education, (4) a Mini Mental State Examination (MMSE) score exceeding 20; and (5) who gave their written informed consent were screened from January 31, 2001, to June 10, 2004.

Patients were excluded for any of the following reasons: (1) radiologic signs of cerebral territorial infarcts, (2) ischemic attack within the previous month, (3) primary central nervous system degenerative diseases, (4) major psychiatric disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria, (5) brain tumor, (6) history of infectious or inflammatory brain disease, (7) cranial trauma within the 12 previous months, (8) previous or current cardiac valvular disease, (9) uncontrolled hypertension, (10) active gastric or duodenal ulcer or severe hepatic or renal insufficiency, or any disorder that could result in cognitive deterioration, (11) diagnosed malignancies or autoimmune disease, or (12) current use of any psychotropic drug or any other drug that could significantly affect cognitive function.

Patient Management and Treatments
Before surgery, patients had carotid Doppler and cranial computed tomography (CT) scans, routine laboratory tests (hematology, biochemistry, and urinalysis), baseline cognitive assessment through a battery of 12 neuropsychologic tests, and review of the inclusion and exclusion criteria. Eligible patients were randomly assigned to receive either placebo or piracetam. Both treatments were identical in shape, size, and color.

The study was conducted in two successive phases. In the first study phase, patients were hospitalized from the day before surgery and received intravenous (IV) placebo or piracetam 150 mg/kg divided into three equivalent doses (maximum, 12 g). On the day of surgery, patients received IV placebo or piracetam at 75 mg/kg before and during surgery and 150 mg/kg divided in two equivalent doses after surgery (maximum, 24 g). During the first 6 days after surgery, patients received IV placebo or piracetam (150 mg/kg daily) divided into three equivalent daily doses (maximum, 12 g daily).

In the second study phase, patients were discharged from the hospital 7 days after surgery and took oral placebo or piracetam (12 g daily) divided into 3 equivalent daily doses for 6 ±1 weeks. At the end of this period, patients returned to the hospital and were evaluated with carotid Doppler and cranial CT scans, the same routine laboratory tests as before surgery, and an end point cognitive assessment.

Neuropsychologic Assessments
Neuropsychologic evaluations were administered before surgery (baseline) and 6 ± 1 weeks after surgery (end point). These consisted of The Word Fluency test adapted to the Hungarian language [26], the Digit Symbol, the Digit Span, and the Block Design subtests of the Wechsler Adult Intelligence Scale (WAIS) [27], the Trail Making test (Hungarian version of the "Nurnberger Alters-Inventar") [28], the Hungarian version of the Rey Auditory Verbal Learning test [29] (first recognition and delayed recall 30 minutes later), and the Pieron test [30]. The Simple Reaction Time, the Choice Reaction Time, and the Serial Reaction Time were used as described by Palombo and colleagues [31]. For the Word Fluency test, the Digit Symbol, Block Design, and Digit Span subtests of the WAIS, the Rey Auditory Verbal Learning test and the Pieron test, higher scores indicate better cognitive function. For the Trail Making test and for the three reaction time tasks, lower scores indicate better cognitive function.

The Spielberger State-Trait Inventory [32] provides a measure of both the state anxiety, and the trait or generalized anxiety. The Beck Depression Inventory [33] evaluates the depression. For both these inventories, higher scores indicate a greater anxiety or depression, respectively.

Coronary Artery Bypass Grafting Surgery
Before surgery, a premedication of morphine hydrochloride and atropine sulfate was administered. Anesthesia was managed with propofol (1 to 4 mL · kg–1 · min–1) and fentanyl bolus, together with relaxants (pipecuronium bromide and succinylcholine). Supportive medications were used on request. One team prepared the arteries or veins (mamillary or radial artery, or saphenous vein) used for grafting, while a second team opened the thorax and the pericardium, cannulated and cross-clamped the coronary and aortic arteries, and started the cardiopulmonary bypass (CPB), inducing a decrease of body temperature to 34°C. A perfusion of the coronary arteries with a cardioplegic solution stopped the heart, allowing the graft to be sutured to one end. The cross-clamp was then opened, and the heart started spontaneously to beat again or a defibrillator was used. The other end of the graft was then sutured to the aorta. During that time, the CPB was maintained, and the patient was slowly rewarmed to 36°C. The final step consisted of stopping the CPB, removing the cannulae, and restoring the normal circulation. Patients were transferred to the intensive care unit for 1 or 2 days, and then to the ward for up to 6 days after surgery.

Statistical Analysis
Test results were sign-corrected for greater values to mean better performance, standardized over subjects, and the standardized results were totalled in each subject to calculate aggregate test scores at baseline and at outcome. Subjects with more than two missing test results either at baseline or outcome were excluded from these calculations. Analysis of covariance models for the treatment effect on aggregate score at outcome were fitted with baseline aggregate score (continuous) and education (categoric) as covariates both in the intention-to-treat (ITT) and the per protocol (PP) subjects. Models were checked on residuals versus fitted values plots and by normality tests of residuals.

Power calculations were based on a single-outcome quantifier derived from the set of neuropsychologic tests known as the Cognitive Battery Composite Score (CBCS), described in the literature in sufficient details for sample size estimation [18]. To detect with a power of 80% a difference between the treatment groups of at least 1.10 CBCS units, assuming a standard deviation (SD) of 1.65 and using a two-tailed significance criterion of 5%, a sample size of 36 patients per group was needed.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
A total of 115 patients were screened, and 109 patients (90 men and 19 woman) were randomized and comprised the ITT population. Eleven patients (10.1%) discontinued the study, and 98 patients (83 men and 15 women) comprised the PP population. The demographic characteristics of the ITT population are presented in Table 1. Ages and body mass indexes were similar, and there were more men than women in both groups. Although a statistically significant difference (p = 0.032) was seen on the level of education between both groups, more than two thirds of the subjects had a secondary level of education.


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  		Table 1. Number of Patients and Demographic Characteristics Before Surgery
 
The summary statistics of the combined scores adjusted for the level of education and their comparison between treatment groups are presented in Table 2 for both the ITT and PP populations. In the ITT population, a trend towards a statistically significant difference in favor of piracetam was seen (1.624, p = 0.064). In the PP population, this tendency reached statistical significance (1.848, p = 0.041).


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  		Table 2. Summary Statistics for Baseline and Outcome Combined Scores in the ITT and PP Populations
 
Treatment effects for the 12 neuropsychologic assessments are presented in Table 3 for the ITT population. In the placebo group, the mean changes from baseline were all either slightly negative or slightly positive. In the piracetam group, all changes from baseline were positive. When not adjusted for education, treatment effects indicated a statistically significant improvement in patients treated with piracetam for the Trail Making (–7.452, p = 0.014) and the Simple Reaction Time for color (–0.0522, p = 0.021). These statistical significances disappeared when treatment effects were adjusted for education. Raw values at baseline, outcome, and changes from baseline for the 12 neuropsychologic assessments are presented in Table 4 for the ITT population.


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  		Table 3. Treatment Effects for the 12 Neuropsychologic Assessments in the ITT Population
 

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  		Table 4. Summary Statistics for Baseline, Outcome and Change from Baseline Raw Values of the 12 Neuropsychological Assessments in the ITT Population
 
The results of the Spielberger State-Trait Inventory and Beck Depression Inventory are presented in Table 5 for the ITT population. Changes from baseline indicated a consistent decrease of the state anxiety and to a lesser extent of the trait anxiety, together with nearly no change in depression.


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  		Table 5. Spielberger State Trait Anxiety Inventory and Beck Depression Inventory in the ITT Population
 
Piracetam was well tolerated, and no difference was seen in safety between the two treatment groups, including for blood loss and transfusion requirement. The cranial CT scan performed 6 weeks after surgery did not reveal any severe ischemic changes in the placebo or in the piracetam groups.


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
A total of 98 patients with comparable demographic characteristics in both treatment groups completed the study. Six weeks (± 1 week) after CABG, a statistically significant treatment effect in the combined score was observed in patients treated with piracetam in the PP population. This result demonstrates the medium-term positive effects of piracetam on cognitive function in patients undergoing CABG and confirms the short-term effects of piracetam previously reported 3 days after CABG surgery [23]. Our study demonstrated a statistically significant drug-induced protection of cognitive function in patients undergoing CABG.

The mechanisms of action of piracetam are not fully understood. According to Uebelhack and colleagues [23], a preoperative 12-g bolus of piracetam should protect patients against hypoxia. Numerous studies have shown piracetam-induced neuronal protection against brain insults through several neuronal and hemodynamic effects. Piracetam improves erythrocytes deformability and decreases blood viscosity and platelet hyperaggregation, resulting in a probable decreased incidence of microemboli. Further investigations are needed to understand the molecular mechanisms of restoration of cell membrane stability that is believed to be the explanation of these effects of piracetam.

Placebo patients did not show any deterioration of cognitive function after CABG surgery. Both the presence [1,2,5] and absence [3,4,15] of cognitive deterioration after CABG compared with nonsurgical controls have been demonstrated. There is no clear explanation for these discrepancies. The occurrence of stroke (or subclinical microembolization) is one of the major hypotheses to explain the deterioration of cognitive function [7,8]. Stygall and colleagues [34] found a significant correlation between the number of microemboli recorded during surgery and postoperative short-term and long-term changes. This hypothesis was not evaluated, because transcranial Doppler blood flow measurements were not performed during surgery.

The body temperature of patients during CABG varies with local conditions from approximately 32°C to 36°C, and the amnestic properties of hypothermia are well documented in animals[35] and humans [36]. Such differences in body temperature could account, at least in part, for the differences in cognitive outcome reported [12]. According to most authors [1,2,14], the cognitive performances of patients after CABG are multifactorial.

The decrease of state anxiety is not surprising, because anxiety is expected in patients who are about to undergo CABG, and less anxiety is therefore expected at the second assessment 6 weeks later. This anxiety might have impaired cognitive performance at baseline. Although this hypothesis could not be evaluated, it does not jeopardize the positive effects of piracetam on cognitive performances in patients 6 weeks after CABG. Additional trials are required to confirm this protection of cognitive function induced by piracetam.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
Piracetam was supplied by UCB S.A., Allée de la Recherche 60, B-1070 Brussels (Belgium). The grant of Ministry of Health 122/2003 was also used for the study. We thank Alain Platel for his help.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

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