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(Stroke. 1996;27:593-598.)
© 1996 American Heart Association, Inc.

Articles

Nimodipine Neuroprotection in Cardiac Valve Replacement

Report of an Early Terminated Trial

Claudine Legault, PhD; Curt D. Furberg, MD, PhD; Lynne E. Wagenknecht, DrPH; Anne T. Rogers, MBChB; David A. Stump, PhD; Laura Coker, MSN; B. Todd Troost, MD John W. Hammon, MD

From the Department of Public Health Sciences (C.L., C.D.F., L.E.W.), Department of Anesthesia (A.T.R., D.A.S.), Department of Neurology (L.C., B.T.T.), and Division of Surgical Sciences (J.W.H.), Bowman Gray School of Medicine, Winston-Salem, NC.

Correspondence to Dr C. Legault, Department of Public Health Sciences, Bowman Gray School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1063. E-mail Legault@phs.bgsm.wfu.edu.

	Abstract

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Background We conducted a double-blind, randomized clinical trial in patients undergoing cardiac valve replacement to determine whether nimodipine, a dihydropyridine calcium antagonist, reduced the risk of new neurological, neuro-ophthalmologic, or neuropsychological deficits—common complications associated with cardiac surgery—1 week after surgery.

Methods and Results Enrollment for a total of 400 patients started in May 1992 and was stopped in September 1994, with 150 patients randomized to the study. Nimodipine was given to the patients during the perioperative period. Patients underwent examinations before surgery and at approximately 1 week, 1 month, and 6 months after surgery. Major adverse events, including deaths and strokes, were monitored monthly. The trial was terminated early because of both an unexpected disparity in death rates between groups and a lack of evidence of a beneficial effect of nimodipine. New deficits were observed in 72% of the placebo group versus 77% of the nimodipine group (P=.55). In the 6-month follow-up period, 8 deaths (10.7%) occurred in the nimodipine group (n=75) compared with 1 death (1.3%) in the placebo group (n=74) (P=.02). Major bleeding occurred in 10 patients in the nimodipine group versus 3 in the placebo group (13.3% versus 4.1%; P=.04). Six (46.2%) of the 13 patients with major bleeding died compared with 3 deaths (2.2%) among the 136 patients without major bleeding.

Conclusions Our findings add to the growing evidence that calcium antagonists have a prohemorrhagic effect in some patients and suggest that nimodipine use should be restricted perioperatively in patients scheduled for cardiac valve replacement.

Key Words: hemorrhage • nimodipine • complications • calcium channel blockers

	Introduction

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Patients undergoing CVR surgery have an increased risk of developing cerebrovascular complications.^{1 2} The incidence of overt stroke after cardiac surgery ranges from <1.0% to 5%.^{3 4} Neuropsychological deficits were reported in 73% of 66 patients 8 days after coronary artery bypass surgery and persisted in 37% 12 months after surgery.⁵ The most frequently reported deficits are in concentration, memory and learning, and speed of response.⁶ It has been assumed that these complications are due to arterial microemboli that occur while the patient is attached to the heart-lung machine. Indeed, in one study,⁷ 100% of patients had evidence of retinal emboli at the time of surgery; none showed emboli preoperatively.

Focal dilatations or very small aneurysms in terminal arterioles and capillaries have been observed in humans and animals soon after CPB.⁸ It has been hypothesized that interventions which might reduce the development of emboli, increase cerebral blood flow, or protect against anoxic brain-cell damage may decrease the incidence and severity of neurological deficits after cardiac surgery. Nimodipine, a potent vasodilator with a possible neuroprotective effect mediated through a direct neuronal action, met two of these criteria.⁹ Thus, we designed a clinical trial to determine whether nimodipine, a dihydropyridine calcium antagonist, reduced the combined incidence of new neurological, neuro-ophthalmologic, or neuropsychological deficits 1 week after CVR surgery.

This report describes the design of the trial and the baseline characteristics of the study population and reviews the early termination of the trial because of both an unexpected disparity in death rates between the placebo- and nimodipine-treated patients and a lack of evidence of a beneficial effect of nimodipine. The rationale for the termination of the trial and plausible harmful, underlying drug actions are discussed.

	Materials and Methods

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Design
This study was a randomized, double-blind, single-center, placebo-controlled trial to assess the effect of nimodipine, a calcium antagonist of the dihydropyridine class, on the combined incidence of new neurological, neuro-ophthalmologic, and neuropsychological deficits 1 week after surgery in patients undergoing CVR surgery. Secondary aims included whether nimodipine, compared with a placebo, altered either the prevalence of deficits 1 and 6 months after surgery or the length of postoperative hospital stay.

If one assumes that at least 50% of the patients would experience one or more deficits 1 week after surgery, a total sample size of 400 patients would provide 90% power at the 5% two-sided level of significance to detect a 17% difference (from .5 to .33 or .5 to .67) in the proportion of patients with deficits. The assumed attrition rate was 4%. A blocked randomization system stratified by surgeon (eight strata) was used. A randomization table in a password-protected computer account was accessible only to the study programmer and biostatistician. A paper copy of the randomization code was kept by the pharmacy that distributed the study medications.

Population
Enrollment for a total of 400 patients started in May 1992 with a goal of 8 patients per month for the subsequent 4 years. By September 1994, when randomization was suspended, 150 patients had been enrolled. All patients were English-speaking men and women over the age of 21 years scheduled to undergo elective aortic and/or mitral valve replacement (with or without aortocoronary bypass grafting) at the North Carolina Baptist Hospitals. Patients with the following conditions were excluded: history of symptomatic Parkinson's disease, Alzheimer's disease, Huntington's chorea, or any neurodegenerative disease; major depressive disorder or psychosis in the past 5 years; class IV congestive heart failure; renal failure (serum creatinine >1.8 mg %); left ventricular ejection fraction <.35; or transmural myocardial infarction in the previous 30 days. Pregnant women and patients taking calcium channel blockers were also excluded. All patients gave informed consent, and the trial was approved by the institutional review board.

Surgery and Treatment
Standardized procedures were followed as much as possible for anesthesia and surgery. Anesthesia was induced with fentanyl (50 µg·kg^-1). Intraoperatively, anesthesia was maintained by constant infusion of fentanyl (6 mg·kg^-1·h^-1) and midazolam (60 mg·kg^-1·h^-1). No other anesthetic agents, either inhalant or intravenous, were administered. CPB was conducted by use of a membrane oxygenator and an arterial filter. All patients were administered bovine-lung heparin at a dose sufficient to maintain the activated clotting time above 400 seconds. During hypothermic CPB, patients were managed with the temperature-uncorrected method (-stat) of PaCO₂ management. CVR was performed in a standard fashion: all patients received ischemic arrest during replacement, with myocardial protection afforded by cold cardioplegia. The effect of heparin was reversed at the conclusion of CPB with equivalent doses of protamine. Blood products were administered by use of an institutional protocol based on hematocrit and clotting-factor assessment. At the decision of the surgeon or anesthesiologist, patients received a procoagulant aminocaproic acid (Amicar) either before CPB for platelet stabilization or after surgery for presumed hyperfibrinolysis.

An initial dose of 60 mg nimodipine (2 capsules) or a matching placebo was given 12 hours before surgery. One capsule (30 mg) was given 6 hours after the initial dose. The last preoperative dose (30 mg) was given in the holding room of the operating room just before surgery. Within an hour of the patient's arrival at the ICU, the oral administration of the drug (30 mg) was resumed and continued every 6 hours for the first 5 days after the day of surgery, for a total of 26 capsules per patient. Study medication and matching placebo were provided by Miles Inc, West Haven, Conn.

Examinations
Patients underwent a standardized neurological, neuro-ophthalmologic, and neuropsychological examination before surgery and at approximately 1 week, 1 month, and 6 months after surgery. Neurological deficits were graded and recorded on the NIH stroke scale.¹⁰ The neuro-ophthalmologic examination emphasized the assessment of visual function (visual field defects, retinal emboli, optic-nerve infarction, etc) and oculomotor function. Eleven neuropsychological tests were administered, including visual reaction time, nonverbal memory and Rey auditory verbal memory,¹¹ trail-making tests A and B,¹² and the grooved-peg board,¹³ finger-tapping,¹⁴ digit-symbol,² and letter-cancellation tasks.¹⁵

As part of the trial protocol, a deficit was defined as (1) a new neurological deficit (based on the NIH stroke scale), including a new postoperative deficit, an exacerbation of a preexisting deficit, a stroke, or death associated with a neurological deficit; (2) a new neuro-ophthalmologic deficit or an exacerbation of a preexisting deficit; or (3) deterioration that exceeded 20% of preoperative performance in two or more neuropsychological tests. Major bleeding during the perioperative period was defined as (1) bleeding that required transfusion of more than 10 U of blood products during the operative period or (2) postoperative chest-tube drainage that exceeded 2400 mL in the first 24 hours. This definition, adapted from criteria reported by Woodman and Harker,¹⁶ was established after 13 major bleeding episodes were noted.

Data Analysis and Monitoring
Differences between groups were assessed with ², Fisher's exact, and Student's t tests. Log-transformed data were analyzed when normality assumptions were not met. Kaplan-Meier techniques, log-rank tests, and Cox proportional hazard models were used to compare survival curves. Binary outcomes were analyzed with logistic regression and likelihood ratio tests.

Major adverse events were monitored monthly in a nonblinded fashion by an epidemiologist in the Data Management Team. These events included deaths, strokes, cardiac arrests that required cardiopulmonary resuscitation, arrhythmias that required cardioversion, major adverse reactions to the study drug, rehospitalizations, and repeat cardiac surgery.

An independent EAC was appointed to monitor the progress of the trial and the safety of the patients during the trial. The EAC consisted of three clinicians, one biostatistician, and an ex officio member of the sponsor (NINDS). The EAC met 6, 18, and 30 months after the initiation of the study.

	Results

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Trial Termination
Enrollment was suspended at month 28 after 5 months of intensive monitoring by the Data Management Core and the EAC. During this period, analysis of the baseline data comparability was undertaken, medical records were abstracted and reviewed, and literature reviews were conducted. An independent external consultant (a clinician with experience in the classification of events) reviewed the medical records of all patients who died or were successfully resuscitated after cardiac arrest. This consultant established causes of death among the former group.

In November 1994, the EAC recommended termination of the trial. The rationale included an unexpected, statistically significant, greater mortality rate in patients randomized to the active treatment compared with patients in the placebo group and a lack of observed beneficial effect of nimodipine on the reduction of cerebrovascular complications. A brief report of the termination of the trial was published in March 1995.¹⁷

Population
Between May 1992 and September 1994, 356 patients were screened, 177 of whom were found to be ineligible. The main reasons for ineligibility included inability to comply with the study protocol (46%); use of a calcium channel blocker (29%); presence of congestive heart failure, cirrhosis, or renal failure (24%); and life-threatening intercurrent illness (15%). Subjects may have had more than one excluding condition. Twenty-nine eligible patients refused to participate in the study. One of the 150 randomized patients was excluded because he did not undergo valve replacement at the time of surgery. This report is based on 149 patients, 75 of whom were randomized to nimodipine treatment and 74 to placebo.

The randomization process resulted in a similar distribution of patient characteristics, with few statistically significant differences in demographic and clinical characteristics between the two groups (Table). On average, approximately half the patients were female, 95% were white, and 17% currently smoked, and the average age was 60 years. Approximately 25% were undergoing a repeat surgery and >60% had the aortic valve replaced as opposed to 40% for the mitral valve. At least three fourths of the patients were class II or III according to the New York Heart Association Classification. A higher proportion of patients assigned to the nimodipine group had a history of pulmonary disease (23% versus 9%; P=.03) and congestive heart failure (56% versus 38%; P=.03) compared with the placebo group.

View this table: [in this window] [in a new window]   Table 1. Distribution of Baseline Characteristics by Group

All patients received heparin intraoperatively. The average dose was 30 629±11 631 U in the nimodipine group compared with 29 662±9444 U in the placebo group (P=.58), and the dose did not vary significantly among surgeons (P=.40). Fifty-six percent of the patients in the nimodipine group received a procoagulant aminocaproic acid during surgery as opposed to 36% in the placebo group (P=.02). On average, there was no significant difference in dose (8.9±3.6 versus 8.8±4.4 g) between the nimodipine and placebo groups for those who received aminocaproic acid.

The follow-up rates 1 week, 1 month, and 6 months after surgery were 92%, 82%, and 69%, respectively, for the placebo group versus 87%, 80%, and 65% for the nimodipine group. Overall, 77% of the patients complied with the medication regimen (ie, at least 80% of the pills were consumed). No difference in compliance was observed between treatment groups.

Mortality and Morbidity
Eight deaths occurred in the treatment group and one in the placebo group (10.7% versus 1.3%), for an overall mortality rate of 6.0% (hazard ratio=8.0, P=.02). In the nimodipine group, seven of the eight patients died within 37 days of surgery. The one death in the placebo group occurred 2 days after surgery and was the result of surgical trauma to the heart during sternotomy. The age-adjusted hazard for the nimodipine group was 5.7 times the corresponding hazard for the placebo group (P=.05). After separate adjustment for history of congestive heart failure and history of pulmonary disease, the hazard ratios were 6.0 (P=.04) and 6.6 (P=.03), respectively.

In the nimodipine group, two patients experienced arrhythmia that required cardioversion and two others were resuscitated after cardiac arrest. Among patients who were discharged, 17 were rehospitalized during the 6 months after surgery, 10 of them in the nimodipine group.

Major bleeding was observed in several patients who died; therefore, a detailed review was undertaken. Seven patients in the nimodipine group and 2 in the placebo group received more than 10 U of blood products during surgery (Fig 1). Five patients in the nimodipine and 2 in the placebo group lost >2400 mL of blood during the first 24 hours in the ICU (Fig 2). Major bleeding, as defined previously, occurred in 10 patients in the nimodipine group (13.3%) compared with 3 patients (4.1%) in the placebo group (OR=3.6, P=.04). (Bleeding data for 1 patient who dropped out of the study early were not available at the time of a previous report.¹⁷ ) Adjustment for age did not affect the OR (OR=3.6, P=.04). None of the 6 patients who had both aortic and mitral valve replacements experienced major bleeding. There was no significant difference in the proportions of patients with major bleeding among surgeons (P=.07). ORs remained 3 after adjustment for pulmonary disease (OR=3.5, P=.05) and congestive heart failure (OR=3.0, P=.09), although the probability value for congestive heart failure was borderline.

View larger version (18K): [in this window] [in a new window]   Figure 1. Units of blood products used during surgery by treatment group.

View larger version (19K): [in this window] [in a new window]   Figure 2. Postoperative chest-tube drainage (in milliliters) during the first 24 hours by treatment group.

Of the 13 patients who experienced major bleeding, 6 died, 5 of whom were in the nimodipine group. As reported earlier,¹⁷ 3 of these 5 deaths were a direct result of blood loss and the other 2 were due to multiple organ failure associated with significant blood loss. Three other patients in the nimodipine group who did not experience major bleeding died of multiple organ failure, and bleeding was a possible contributing cause in 2 patients with postoperative chest-tube drainage >1600 mL during the first 24 hours in the ICU. Thus, 6 (46.2%) of 13 patients who met the definition of major bleeding died compared with 3 (2.2%) of 136 patients without major bleeding.

Overall, 72% of the patients in the placebo group had new deficits 1 week after surgery versus 77% in the nimodipine group (P=.55). One month after surgery, 46% of patients in the placebo group had deficits compared with their baseline status versus 50% in the nimodipine group (P=.71). At the end of the 6-month follow-up period, these percentages were 44% and 26%, respectively (P=.09). Of these deficits, only one patient had a stroke; all others had less severe deficits based on neurological and neuropsychological tests. A detailed report of these deficits is being prepared.

Although there was no significant difference between the two groups in the median postoperative length of stay of the survivors (7 days for the placebo group versus 8 for the nimodipine group; P=.08), the overall distributions of postoperative length of stay were significantly different between the two groups (P=.0001 by log-rank test). Twelve patients in the nimodipine group were hospitalized for more than 13 days compared with two in the placebo group.

	Discussion

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Previous studies provided support for the hemorrhagic potential of calcium antagonists. Among nearly 4000 survivors of myocardial infarction who were given thrombolytic therapy, an increased incidence of intracerebral hemorrhage was observed in patients who had used a calcium channel blocker at study entry compared with nonusers (8 of 538 patients versus 15 of 3386) (P=.009).¹⁸ Rabbits exposed for 3 consecutive days to the calcium antagonist diltiazem had a fivefold increase in blood loss from standardized ear incisions (P=.003).¹⁹ This finding was apparent with or without recombinant tissue-type plasminogen activator administration. Thus, both animal and human studies show the hemorrhagic potential of calcium antagonists.

Excess bleeding may be the clinical result of the combination of vasodilation and the antiplatelet actions of calcium antagonists. These agents have been shown to inhibit platelet aggregation in vitro.^{20 21 22 23} Proposed mechanisms of action suggest that calcium antagonists reduce the release of thromboxane A₂,^{24 25 26} antagonize the calmodulin stimulation of phosphodiesterase,^{25 27} and inhibit both the serotonin uptake of endothelial cells²⁸ and the breakdown of cyclic AMP.²⁹ More recently, Akopov and Sarkisian³⁰ showed that nifedipine reduced platelet activity in subjects with essential hypertension in two ways: directly, via action on platelets; and indirectly, by increasing red-cell deformability. In dogs, nifedipine reduced thrombus formation in femoral artery grafts³¹ ; however, platelet function was unaffected in 12 young, healthy volunteers who took 30 mg nimodipine qid for 24 hours.³²

The surgical setting provides exposure to other factors that could interact with nimodipine to increase bleeding risk. Compounds such as anticoagulants, antifibrinolytic agents, and several platelet inhibitors in combination could have profound effects on the hemostatic mechanism, resulting in increased risk of hemorrhage.¹⁹ CPB affects both platelet count and function: platelet function decreases rapidly, bleeding time is significantly prolonged, and platelet aggregation is impaired. Platelet count, in particular, requires several days to return to preoperative levels.¹⁶

Several aspects of the study design provide strength to the validity of the findings reported herein. The trial was a randomized, blinded, clinical trial. Most variables assessed at baseline showed similar distributions in the nimodipine and placebo groups. Blood loss during the perioperative period was quantified as part of the trial protocol, and the definition of major bleeding was based on criteria previously reported. The excess episodes of major bleeding in the nimodipine group occurred despite the fact that significantly more patients treated with nimodipine received a procoagulant (Amicar) compared with control subjects. Finally, the association between major bleeding and treatment remained strong even after we controlled for predictors associated with bleeding.

In conclusion, our observation of major bleeding associated with the use of nimodipine in patients undergoing cardiac surgery has not been reported previously. It is unknown whether this finding applies to other dihydropyridines or to other types of calcium antagonists and whether all patients undergoing major surgery are at risk of major bleeding. Our findings add to the growing evidence that calcium antagonists in some patients have a prohemorrhagic effect and suggest that nimodipine use should be restricted perioperatively in patients scheduled for CVR.

	Selected Abbreviations and Acronyms

 

CPB = cardiopulmonary bypass CVR = cardiac valve replacement EAC = External Advisory Committee ICU = Intensive Care Unit NINDS = National Institute of Neurological Disorders and Stroke OR = odds ratio

	Acknowledgments

 
This study was supported by NINDS grant No. 5-P01-NS2500 and by the General Clinical Research Center of the Bowman Gray School of Medicine grant No. M01RR-07122. It could not have been performed without the support of the cardiac surgeons who participated in this study, including A.R. Cordell, MD, J.W. Hammon, MD, A.S. Hudspeth, MD, and N.D. Kon, MD.

Received January 16, 1996; accepted February 13, 1996.

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