Significant study today from the NEJM that lends support to ALXN:
The New England Journal of Medicine -- February 8, 2001 -- Vol. 344, No. 6
Longitudinal Assessment of Neurocognitive Function after Coronary-Artery Bypass Surgery
Mark F. Newman, Jerry L. Kirchner, Barbara Phillips-Bute, Vincent Gaver, Hilary Grocott, Robert H. Jones, Daniel B. Mark, Joseph G. Reves, James A. Blumenthal, for the Neurological Outcome Research Group and the Cardiothoracic Anesthesiology Research Endeavors Investigators
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Abstract
Background. Cognitive decline complicates early recovery after coronary-artery bypass grafting (CABG) and may be evident in as many as three quarters of patients at the time of discharge from the hospital and a third of patients after six months. We sought to determine the course of cognitive change during the five years after CABG and the effect of perioperative decline on long-term cognitive function.
Methods. In 261 patients who underwent CABG, neurocognitive tests were performed preoperatively (at base line), before discharge, and six weeks, six months, and five years after CABG surgery. Decline in postoperative function was defined as a drop of 1 SD or more in the scores on tests of any one of four domains of cognitive function. (A reduction of 1 SD represents a decline in function of approximately 20 percent.) Overall neurocognitive status was assessed with a composite cognitive index score representing the sum of the scores for the individual domains. Factors predicting long-term cognitive decline were determined by multivariable logistic and linear regression.
Results. Among the patients studied, the incidence of cognitive decline was 53 percent at discharge, 36 percent at six weeks, 24 percent at six months, and 42 percent at five years. We investigated predictors of cognitive decline at five years and found that cognitive function at discharge was a significant predictor of long-term function (P<0.001).
Conclusions. These results confirm the relatively high prevalence and persistence of cognitive decline after CABG and suggest a pattern of early improvement followed by a later decline that is predicted by the presence of early postoperative cognitive decline. Interventions to prevent or reduce short- and long-term cognitive decline after cardiac surgery are warranted. (N Engl J Med 2001;344:395-402.)
And this editorial:
The New England Journal of Medicine -- February 8, 2001 -- Vol. 344, No. 6
Coronary-Artery Bypass Surgery and the Brain
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Coronary-artery bypass grafting (CABG) is a very effective procedure for reducing angina and stabilizing ventricular function. It is not surprising, therefore, that more than 500,000 bypass procedures are performed in the United States each year. As techniques for anesthesia and surgery have advanced, the population considered eligible for this procedure has changed; candidates for CABG may now be not only older than in the past but also more likely to have such health problems as hypertension and diabetes. In addition, an increasing number of patients have previously undergone angioplasty, thereby delaying their initial CABG surgery to a more advanced age.
There is increasing recognition, however, that although CABG may be successful in revascularizing the heart, the surgical procedure may have adverse effects on the brain. (1) Four neurologic and cognitive complications have been observed after CABG: stroke, postoperative delirium, short-term cognitive changes, and possible long-term cognitive changes. Stroke is the most serious, with an incidence of 1.5 to 5.2 percent in prospective studies. Methods of identifying patients at risk for stroke have been developed that rely primarily on the analysis of cardiovascular risk factors, including older age and the presence of hypertension, diabetes, and evidence of vascular disease. (2) Postoperative delirium occurs after CABG in about 10 to 30 percent of patients and may be related in part to anesthesia. A recent study suggests that patients who have delirium after CABG are more likely to have a history of stroke. (3)
Short-term cognitive changes after CABG, primarily involving memory, have long been recognized. The reported incidence of short-term cognitive decline varies widely (from 33 to 83 percent), depending, at least to some extent, on the tests used to assess cognition and the methods used to evaluate test results, as well as on differences in the populations of patients undergoing CABG. (4) For example, European patients undergoing CABG are likely to be younger and to have fewer associated health problems than patients in the United States.
Long-term cognitive changes after CABG have received less attention, despite common reports by patients that they are "just not the same" after surgery. The cognitive changes are often subtle, involving problems with following directions, mental arithmetic, and planning complex actions. Family members or colleagues may also notice that a patient is more short-tempered, is less able to withstand frustration, and has wider mood swings.
In this issue of the Journal, Newman and coworkers from Duke Medical Center have raised another concern -- the possibility of a late decline in cognitive function as long as five years after bypass surgery. (5) The investigators evaluated a group of patients before surgery and performed follow-up testing at the time of discharge and six weeks, six months, and five years after surgery. Cognitive decline was defined as a reduction of 1 SD from the patient's base-line score on tests of function in one or more of four domains. At the time of discharge, they found a high incidence of decline (53 percent) from presurgical base-line performance, which decreased to 36 percent at six weeks and 24 percent at six months. Surprisingly, at five years of follow-up, 42 percent of patients were performing below their base-line levels.
The clinical implications of these high percentages are not entirely clear. The finding of cognitive decline in a surprisingly large proportion of patients at the time of discharge may be due to the fact that the patients underwent an ambitious assessment just days after undergoing a major surgical procedure. In addition, the precise incidence of neurocognitive decline at later points after surgery is dependent on the specific criteria used. (6) Although a decline of 1 SD would represent a substantial change in most instances, it cannot necessarily be equated with cognitive dysfunction or impairment.
Perhaps the most intriguing finding of this study is that there appears to be a biphasic course to cognitive change after surgery -- an immediate postoperative decline followed by improvement and then a subsequent late decline. Furthermore, the investigators suggest that patients with late decline tend to be older and to have less education and higher performance on cognitive tests at base line. It is noteworthy that the association between early postoperative decline and late decline remained significant, even after adjustment for demographic factors and other covariates. These observations raise the possibility that the late decline in cognitive performance is in some way causally linked to events that occur during the surgical procedure.
Before accepting this possibility, however, we must consider several alternative explanations. The observed late decline may simply reflect the effects of aging on the brain. The Duke study, like most other studies of cognitive outcomes after CABG, including our own, (7) did not include a control group. Although most published studies of "normal" controls similar in age to those undergoing CABG have not found a similar decline in cognitive performance over a five-year period, (8) it may be that all patients who undergo CABG are not cognitively normal. (9) Not only do they have symptomatic coronary artery disease, but they may also have cerebrovascular disease. A high rate of preexisting brain injury due to silent ischemia, as indicated by changes in subcortical white matter that are detectable on magnetic resonance imaging, has been reported in patients undergoing CABG. (10) The relation between these abnormalities of white matter, sometimes referred to as leukoaraiosis, and cognitive performance is not clear, but some studies suggest that patients with leukoaraiosis have cognitive impairment. (11)
In addition, short-term cognitive changes have been observed in elderly patients who have undergone noncardiac surgery, (12) but until recently, data on longer-term cognitive outcomes have not been available. Recent findings from a prospective, controlled study suggest that postoperative cognitive dysfunction, defined more conservatively as a decline of 2 SD from base-line values, may persist for up to two years in approximately 10 percent of patients, even after noncardiac surgery. (13)
If, indeed, the late decline in cognitive performance after CABG is related to the surgical procedure, what is the explanation for it? In some patients, as demonstrated by ultrasonographic studies of the carotid arteries, showers of embolic material can enter the cerebral vessels during surgery, resulting in occlusion of both small and large vessels. This embolic material probably comes from an aorta affected by atherosclerosis and is released during the manipulation of the aorta that is required by the CABG procedure. But how could this single insult result in delayed declines in cognitive performance several years later?
We have previously hypothesized that the mechanisms of cognitive changes that occur after CABG may be multifactorial (7) and that some of the short-term changes may be due to anesthesia or nonspecific effects of surgery. (12,14) These changes may well be reversible. But superimposed on these short-term changes, more slowly evolving or delayed effects may occur, perhaps as a result of an initial injury from a combination of hypoperfusion and microemboli. (15)
These various forms of neurologic and cognitive change after CABG have therapeutic implications. There is great interest in agents that may have neuroprotective effects against a variety of insults to the brain, such as stroke, head trauma, and anoxic injury. The population of patients undergoing CABG is an ideal group in which to evaluate such agents by introducing them in a controlled way either before or immediately after surgery. In addition, for patients at possible risk for late cognitive decline after CABG, vigorous attempts to slow the progress of vasculopathy by means of diet, medications, and changes in lifestyle are indicated.
There is still much to be learned about the mechanisms of late cognitive decline after cardiac bypass surgery. To determine the specificity of these changes and how they may relate to the bypass procedure itself, a longitudinal study is needed to compare patients undergoing CABG with those with similar cardiovascular risk factors and symptoms who have not had surgery. We are conducting such a longitudinal study, but it will not be completed for two to three years. Whatever the outcome of this and other studies, the report by Newman and colleagues deserves credit for bringing renewed scientific attention to the question of late cognitive changes after cardiac bypass surgery.
Ola A. Selnes, Ph.D.
Guy M. McKhann, M.D.
Johns Hopkins University
Baltimore, MD 21287
ALXN's C5 inhibitor in the earlier studies showed a significant impact on early cognitive decline after CPB. We don't yet have the results from ALXN's latest study, but if they hold up, then this NEJM study implies that they could have a significant long term impact.
At the open today I bought back part of the ALXN I sold a little while back.
Peter |
