Early aspirin after CABG should be the norm, experts say

October 23, 2002

San Francisco, CA - Early use of aspirin following coronary bypass surgery is safe and is associated with a remarkable 68% reduction in overall mortality, a new global registry study in more than 5000 patients shows[1]. The results indicate that early aspirin use after bypass surgery "should become standard practice," says an accompanying editorial by Dr Eric Topol (Cleveland Clinic, OH).

Dr Dennis T Mangano (Ischemia Research and Education Foundation, San Francisco) and colleagues for the Multicenter Study of Perioperative Ischemia Research Group report their findings in the New England Journal of Medicine this week. They explain that clinicians have been reluctant to recommend early antiplatelet therapy for patients undergoing coronary bypass surgery because of 2 widely held beliefsthat it would be of limited benefit and might be unsafe due to excessive bleeding.

Dr Bruce Reitz (Stanford University) told heartwire : "I was pretty impressed with the magnitude of changes and the consistency of changes which Mangano and colleagues found with a fairly simple therapy. I'm sure that this will change the way we do things."

In his accompanying editorial, Topol (Cleveland Clinic Foundation, OH) says the findings of Mangano et al are "quite striking."

 
I'm sure that this will change the way we do things.
 

Mangano et al included 70 centers in 17 countries in their registry and prospectively studied 5065 coronary bypass patients, of whom 3001 received aspirin ranging from a total of 80 mg to a total of 650 mg within 48 hours of surgery. There were 43 deaths within 48 hours of surgery, and these patients were excluded from the analysis to mitigate confounding by indication.

Similarly substantial reduction in all other complications

Aspirin use begun during the first 48 hours after surgery was associated with a 68% reduction in overall mortality and "similarly substantial" reductions in the rates of ischemic complications affecting the heart (44% reduction in fatal and nonfatal MI or CHF), the brain (62% reduction in fatal and nonfatal stroke or encephalopathy), the kidneys (60% reduction in renal dysfunction or failure), and the intestines (70% reduction in ischemia or infarction).

Fatal and nonfatal ischemic outcomes among patients who received aspirin within the first 48 hours and those who did not

Outcome

Aspirin (n=2999), n (%)

No aspirin (n=2023), n (%)

p

Death from any cause 40 (1.3) 81 (4) <0.001
MI 80 (2.8) 105 (5.4) <0.001
Congestive heart failure 175 (5.8) 222 (11) <0.001
Death from cardiac causes 32 (1.1) 62 (3.1) <0.001
Stroke 40 (1.3) 52 (2.6) 0.01
Encephalopathy 13 (0.4) 47 (2.4) <0.001
Death from cerebral causes 6 (0.2) 16 (0.8) 0.02
Renal dysfunction 55 (1.8) 97 (4.9) <0.001
Renal failure 26 (0.9) 68 (3.4) <0.001
Death from renal causes 18 (0.6) 46 (2.3) <0.001
Gastrointestinal ischemia or infarction 8 (0.3) 17 (0.8) 0.01
Death from gastrointestinal
causes
4 (0.1) 10 (0.5) 0.02
Composite outcome 302 (10.6) 349 (18.6) <0.001

According to multivariate analysis, no other factor apart from aspirin, including any other medication, was associated with reduced rates of these outcomes after surgery, Mangano et al say. "Furthermoreand contrary to current beliefaspirin therapy was safe and was not associated with increased risk of bleeding, gastritis, infection, or impaired wound healing."

"Both the magnitude of the effect of aspirin and its benefits in multiple organ systems are noteworthy," the authors continue. "Given the fact that inexpensive generic formulations [of aspirin] are readily available, our findings support the institution of aspirin therapy during the first 48 hours after revascularization."

Concern about routine transfusion of platelets or clotting factors

In his editorial, Topol says that "numerous" studies have emphasized that aspirin administered before surgery leads to more mediastinal blood loss, transfusion, and repeated operations. "The consensus has been that aspirin should be avoided before surgery to minimize the risk of bleeding complications." But the use of aspirin in the early hours after CABG "has been controversial, and in many centers, it is considered taboo," he comments.

 

Aspirin therapy was safe and was not associated with increased risk of bleeding, gastritis, infection, or impaired wound healing.

 

Mangano and colleagues say that concern about bleeding "has been paramount" and has resulted in the preoperative discontinuation of aspirin therapy, abrupt reversal of antithrombotic therapy, "and even the active use of antifibrinolytic agents to promote clotting during the early reperfusion period." These new findings thus "raise concern about practices involving the routine transfusion of platelets or clotting factors and the widespread use of antifibrinolytic therapy during the critical period of reperfusion in these patients."

But Reitz says he does not believe that use of clotting factors etc is routine; rather it is "usually done in response to a clinical need." At Stanford, the protocol is to start aspirin around 24 hours after surgery, he explained, but there are instances where this may be delayed even longerfor example, if patients are on a ventilator, doctors will often wait until they are off it and can take aspirin orally. "But paradoxically, these might be the patients who most need aspirin," he said, adding that there are other options that could be considered for these patients, such as aspirin suppositories or delivering the drug via nasogastric tube.

Is this too good to be true? No, it's better than it seems

Topol adds that although the work of Mangano et alshowing better survival, fewer major multiorgan ischemic events, and less bleedingmay seem too good to be true, "there are reasons to believe that the report may actually underestimate the benefit of early aspirin use."

There are several reasons for thinking this, he says, including the fact that the deaths that occurred during the first 48 hours after CABG were not included in the analysis. There were only 2 such deaths in the aspirin group, with the remaining 41 in the group that did not receive aspirin: "This large imbalance favoring aspirin appears unlikely to be due to chance and would have amplified the point estimate of survival benefit," Topol writes.

He continues, "What is perhaps most intriguing about the report by Mangano et al is the magnitude and breadth of the benefit of early aspirin after CABG in terms of survival, nonfatal ischemic events, and bleeding complications, as well as the comprehensive sweep of benefits for the heart, brain, kidneys, and bowel." He believes, "the extent and scope of the influence of aspirin are most likely a reflection of its anti-inflammatory effect rather than its antithrombotic effect." Since these 2 processes are inextricably linked, it may be hard to sort out which is responsible, he says, adding that resolving this issue will require properly designed clinical trials.

What should we do now?

What is now "clearly needed" are trials of early aspirin use after CABG to determine the best time after surgery to give aspirin and the optimum dose, Topol says. "Although the best time for aspirin may be as early as 1 hour after CABG and the best dose may be 80 mg to 160 mg, it is not certain." However, he fears that such trials may never be conducted.

 

We felt we were starting aspirin therapy early, but clearly it is really important to be more aggressive.

 

In 2001, the sixth American College of Chest Physicians Consensus Conference offered a guideline, recommending 325 mg per day starting 6 hours after surgery, he notes. "The findings of the current study certainly lend strong support" to these recommendations, he adds.

Reitz told heartwire he was not aware of these guidelines and that he did not feel they had been widely disseminated among cardiothoracic surgeons. "We felt we were starting aspirin therapy early, but clearly it is really important to be more aggressive." He said that he felt a "baby" aspirin dose of 81 mg per day would be sufficient to provide the benefits seen in this study. He added that aspirin may ultimately prove to be beneficial in other forms of cardiothoracic surgery, such as after valve surgery, but that trials would need to be done in this indication.

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