CABG

Effects of perioperative vitamin E and zinc co-supplementation on systemic inflammation and length of stay following coronary artery bypass graft surgery: a randomized controlled trial

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Abstract

Objectives

Coronary artery bypass graft (CABG) surgery has been reported to be associated with lower postoperative plasma antioxidant and zinc levels. We hypothesized that perioperative supplementation of vitamin E and zinc might improve short-term postoperative outcomes.

Methods

In this placebo-controlled double-blind, randomized study, patients undergoing CABG performed with cardiopulmonary bypass were recruited. The intervention group received zinc and vitamin E supplementation (1200 IU vitamin E and 120 mg elemental zinc) the day before surgery, followed by postoperative daily supplementation of 30 mg zinc and 200 IU vitamin E from the 2nd day after surgery to 3 weeks. The control group received placebos. Length of stay (LOS) in the intensive care unit and hospital, sequential organ failure assessment score on 3rd day after surgery, and plasma inflammatory markers on days 3 and 21 post-surgery were evaluated.

Results

Seventy-eight patients completed the study (40 in the intervention group and 38 in the placebo group). The hospital LOS was significantly shorter (p < 0.05) in the intervention group. Postoperative changes in plasma albumin levels were not different between the two groups. The plasma zinc level was higher (p < 0.0001), but plasma C-reactive protein (p = 0.01), pentraxin 3 (p < 0.0001), interferon γ (p < 0.05), malondialdehyde (p < 0.05), and aspartate aminotransferase (p < 0.01) were lower in the intervention group compared to the placebo group.

Conclusions

Perioperative vitamin E and zinc supplementation significantly reduced hospital LOS and the inflammatory response in CABG surgery patients. In these patients, the optimal combination and dose of micronutrients need further study but could include zinc and vitamin E.

Discussion

Our study is among the few studies reporting the effects of perioperative micronutrient supplementation among patients undergoing CABG surgery. Preoperative vitamin E (1200 IU) and zinc ( 120 mg) supplementation in adult patients undergoing CABG surgery, followed by 200 IU vitamin E and 30 mg zinc per day postoperatively, seems to be effective in shortening hospital LOS. These dietary supplements had no significant effect on SIRS and SOFA score on postoperative day 3, but decreased postoperative plasma concentrations of PTX3, CRP, IFN-γ, MDA, and AST, without significant impacts on the postoperative plasma IL-4, cTnI levels.

The motivation for using the combination of vitamin E and zinc supplements in the present study was their antioxidant as well as their immunomodulatory effects. Furthermore, it has previously been shown that plasma zinc [12] and vitamin E [9] are reduced following CABG surgery. This reduction may be a redistribution that occurs as a result of inflammatory responses [19]. In the present study, we did not measure plasma vitamin E levels. Still, the dose of tested vitamin E in the present study is comparable to the amount used in the study by Lassnigg et al., who showed that four doses (270 mg each) of vitamin E between 16 h before and 48 h after CABG surgery normalizes plasma vitamin E levels in the postoperative period [9]. On the other hand, the tested dose of zinc was comparable to the amount used in a previous study, in which patients received 50 mg for the first two days after admission to ICU, followed by 25 mg/day [20]. Although the doses of vitamin E and zinc in the present study were higher than the Dietary Reference Intake values, they were not higher than the Tolerable Upper Intake Levels. Besides, the recommended dietary amounts are recommended for healthy people and the amount required during acute illness may be different. In the case of zinc, studies have shown that the medical doses used are relatively safe, and regardless of dietary intake, the use of medical doses of zinc may be beneficial for a wide variety of clinical situations [21].

Perfusion time was different between the two groups. Since cardiac surgery with CPB induces activation of a systemic inflammatory response [1] and perfusion time has been shown to correlate with postoperative inflammatory mediators levels [22], it was included as one of the confounding factors in statistical analysis.

The ICU and hospital length of stay as the primary outcomes were shorter in the intervention than in the placebo group. This is in contrast to the findings of a previous study in which the administration of several micronutrients with antioxidant activity, including vitamin E and zinc, in patients admitted to the ICU after complex cardiac surgery did not shorten the length of stay in the ICU [20]. This discrepancy could be related to the study population which was complicated heart surgery patients or to the lack of preoperative administration of loading doses of micronutrients. However, our finding is somehow consistent with the result of a previous study in which prophylactic treatment with vitamin E and allopurinol in patients with pre-existing chronic kidney disease reduced the length of stay in the ICU after CABG surgery [23]. Furthermore, the early administration of vitamins E and C reduced ICU length of stay in critically ill surgical patients [24].

The shorter ICU and hospital length of stays might be partly caused by the reduction of inflammation intensity in the zinc and vitamin E groups. Systemic inflammation can predict poor outcomes in patients under elective CABG [25]. Both CRP and PTX3, which are acute-phase proteins, are released significantly during and after CABG surgery. In a study in which serum level of PTX3 was prospectively monitored in ICU patients, higher PTX3 level was associated with sepsis development, and a higher 90-day mortality rate [26]. Furthermore, in patients undergoing cardiac surgery with the use of CBP, the dynamics of serum CRP levels were comparable in patients with SIRS and those with no SIRS, with a peak on the postoperative day 3, whereas serum PTX3 was significantly higher in patients with SIRS than those with uneventful postoperative period [27]. However, perioperative administration of antioxidant vitamins (300 mg/day vitamin E and 500 mg/day vitamin C) in patients who underwent CPB, reduced CRP levels on the first day after surgery compared to the control but, the difference disappeared on the second postoperative day [28]. In addition to antioxidant vitamins, zinc may also be inversely related to oxidative stress and inflammatory factors in critically ill patients, particularly in those with sepsis [29].

In the present study, the lower IFN-γ plasma level on the 3rd and 21st days after surgery in the vitamin E and zinc supplementation group could also be related to the lower intensity of inflammation. Aberrant expression of IFN-γ may be associated with some inflammatory and autoimmune diseases [30] and the decrease in IFN-γ synthesis might prevent excessive stimulation of the non-specific immune system. In a previous study on patients who underwent CABG with CPB, serum IFN-γ levels did not change significantly on the 3rd day after surgery. However, its production by cultured mixed mono-nuclear leukocytes was temporarily decreased on postoperative day 1 but recovered on postoperative day 3 [31]. In another study, mixed mono-nuclear leukocytes of patients who underwent CABG surgery were obtained pre-operatively and on the first and third postoperative days and cultured along with adding exogenous IFN-γ. The addition of IFN-γ significantly increased pro-inflammatory cytokine tumor necrosis factor-α but did not affect the synthesis of anti-inflammatory cytokines interleukin-10, and IL-4 levels [32].

Enhanced lipid peroxidation can lead to the production of end products such as MDA, which, by attaching to biomolecules, can generate self-MDA epitopes capable of inducing the immune system to neutralize, causing inflammatory responses [33]. In the present study, the vitamin E and zinc supplementation reduced the MDA of the plasma that was incubated with oxidant. A significant decrease in MDA was observed only for the plasma samples of the third postoperative day, without a significant effect on the samples of the 21st postoperative day. It seems that the postoperative acute phase responses and the production of free radicals are higher on the third than on the 21st day after the operation. Therefore, one reason for the observed findings could be related to the higher intensity of oxidative stress in the early days after surgery, which vitamin E and zinc were able to reduce it. However, since the spectrophotometric method to detect MDA is less sensitive than fluorometric methods, it may not have revealed the difference on the 21st day.

The plasma cTnI concentration in the intervention group was not significantly different from the placebo group. However, the beneficial effects of antioxidant supplements on cardiac markers have been reported in some studies. In this regard, the administration of vitamin E into the coronary arteries during surgery attenuated the post-surgery increase in cTn-I levels [34]. In the current study, vitamin E and zinc supplementation decreased AST levels on the 21st day after surgery compared to the placebo group. AST is released when cells are damaged. It used to be a regular cardiac marker before more specific markers became common. Elevated postoperative AST level has been suggested as an independent predictor of early and late mortality after CABG [35]. Furthermore, increased pre- and post-operative AST to ALT ratios seem to be associated with an increased incidence of acute kidney injury after elective CABG surgery [36]. The vitamin E supplement consumed was probably effective in reducing AST levels. Vitamin E supplementation has been reported to improve AST levels in patients with liver disease [37].

The present study had some limitations. Due to the diversity of eligibility criteria, the generalizability of the results is limited to relatively low-risk patients undergoing CABG surgery. The single-center nature of this trial can be considered both a limitation and an advantage due to the reduction of variation in care. Furthermore, we did not collect SIRS and SOFA scores on different days after surgery, which might have provided valuable information. Moreover, the concentration of vitamin E in the plasma of the patients was not measured. Finally, despite the inclusion of 78 patients, the study could still be underpowered for some study variables. Despite this, many parameters were oriented towards a clinical benefit in favor of nutrient supplementation. However, a larger trial is needed.

Conclusion

Perioperative supplementation of vitamin E and zinc in CABG surgery patients was associated with postoperative shortened ICU and hospital length of stay and lower postoperative plasma concentrations of inflammatory biomarkers. Although the reduction in ICU length of stay observed following supplementation was not long, it could be considered an achievement with such easy access and cheap intervention. Following cardiac surgery, the plasma concentration of several micronutrients undergoes significant changes, and it appears that this field requires more investigation to reveal their association with some complications after surgery. The optimal combination and dose of micronutrients remain to be determined but could include zinc and vitamin E.

Bypass Surgery for Multivessel CAD Reaffirmed in Newer Data

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Surgeons fire back at downgrading of CABG in recent guidelines

The recently weakened endorsement of coronary artery bypass grafting (CABG) for multivessel disease is not supported by contemporary real-world data, heart surgeons argued.

Based on over 100,000 Medicare beneficiaries presenting with acute coronary syndrome (ACS) who underwent revascularization, risk-adjusted rates of death, myocardial infarction (MI), heart failure, acute kidney injury, and readmissions at 30 days after discharge all favored CABG over multivessel percutaneous coronary intervention (PCI).

Moreover, CABG was associated with improved 3-year survival (HR 0.448, 95% CI 0.437-0.458) and the composite endpoint of reintervention, MI, and death (HR 0.476, 95% CI 0.46-0.493). Longitudinal outcomes favored CABG in key subgroups of patients older than 75 years and those with baseline diabetes, heart failure, or non-ST-segment elevation MI (NSTEMI).

Only stroke readmission rates did not significantly favor CABG over PCI after risk adjustment of longitudinal outcomes, reported J. Hunter Mehaffey, MD, MSc, a cardiac surgeon at West Virginia University in Morgantown, during this year’s meeting of the Society of Thoracic Surgeons (STS)opens in a new tab or window.

“These longitudinal data support the superiority of CABG compared to PCI and may have current and future policy and practice implications,” Mehaffey said, adding that he wished to “take back the narrative about bypass surgery to make sure patients are getting optimal treatment.”

Fellow surgeon Joseph Sabik, III, MD, of University Hospitals Cleveland Medical Center, called this an important study with “impressive” findings that should prompt reevaluation of the recent controversial guideline change that had not been endorsed by surgeon societies — namely the STS and the American Association for Thoracic Surgery.

The controversy erupted in 2021 when American guidelines downgraded CABG from class I to class IIbopens in a new tab or window, on par with PCI, in multivessel disease and normal left ventricular ejection fraction in stable ischemic heart disease. This change was attributed to the guideline writers considering only the most recent studies from the prior 5 years — meaning the downgrade of CABG was based largely on the ISCHEMIA trial that had found an initial invasive approach to be no better than medical therapy aloneopens in a new tab or window in stable coronary artery disease.

Yet ISCHEMIA was not representative of patients undergoing CABG and failed to capture those with multivessel disease in particular, Mehaffey argued.

Sabik, speaking as the STS session discussant, pointed out that the controversy is in stable ischemic disease, whereas the study by Mehaffey’s group covers an ACS population. Nevertheless, the results at least raise the question of whether CABG should be the preferred therapy for all patients with ACS, Sabik said.

Mehaffey acknowledged the disparate patient populations being discussed but warned of guideline creep as “many clinical providers do not read the fine print,” only reviewing the executive summary or a lay media report. He reminded the audience that his results persisted in NSTEMI.

Sabik also cautioned that the improved clinical outcomes after CABG surgery came at the cost of greater in-hospital morbidity: In-hospital outcome of death favored CABG, whereas PCI was associated with less bleeding, stroke, acute kidney injury, and acute renal failure.

Moreover, CABG was associated with significantly higher hospital cost compared with PCI ($57,189 vs $36,342, P< 0.001) and longer total hospital stays (11.9 days vs 5.8 days, P<0.001), the study authors found.

Aiming to give guideline committees the contemporary data that they want, Mehaffey and colleagues had limited their analysis to Medicare beneficiaries presenting from January 2018 to December 2020.

The observational study relied on a database of Centers for Medicare & Medicaid Services inpatient claims. Participants were people who underwent CABG (n=51,389) or multivessel PCI (n=52,738), excluding those with a history of concomitant valvular procedures, prior CABG, and heart transplantation.

Compared with the PCI arm, CABG recipients were younger (72.9 vs 75.2 years, P<0.001) but tended to have a higher Elixhauser Comorbidity Index (5.0 vs 4.2, P<0.001), and a higher likelihood of diabetes (48.5% vs 42.2%, P<0.001). The CABG cohort also had lower rates of ST elevation MI at presentation (14.4% vs 29.0%, P<0.001).

The groups were relatively well-balanced after matching by inverse probability of treatment weighting propensity scores.

Nevertheless, the observational analysis remained subject to potential confounding and biases inherent in its nonrandomized design.

“The findings of our study were very convincing,” Mehaffey maintained in a press releaseopens in a new tab or window. “The singular message to the public is that the optimal treatment for multivessel coronary artery disease — to improve not only long-term survival but also lower your risk of complications — is coronary artery bypass surgery.”

“These contemporary real-world data support prior existing trials highlighting the benefits of CABG in multivessel coronary artery disease, urging a re-evaluation of recent guidelines,” he said.

CABG best option of revascularization in diabetes

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https://speciality.medicaldialogues.in/cabg-best-option-of-revascularization-in-diabetes/

Repairing Moderate Mitral Regurgitation During CABG

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When the Cardiothoracic Surgical Trials Network randomized 301 patients with moderate mitral regurgitation to undergo coronary artery bypass grafting (CABG) alone or CABG plus mitral valve repair, the two groups had similar postsurgical ventricular dimensions, survival, and major adverse events at 1 year. However, the combined-procedure group had a significantly lower prevalence of moderate-to-severe mitral regurgitation — but longer postsurgical hospital stays and higher incidences of postoperative supraventricular arrhythmias and serious neurologic events (NEJM JW Cardiol Jan 2015 and N Engl J Med 2014; 371:2178). We now have the 2-year findings.

The postsurgical left-ventricular end-systolic volume index was again similar between the two groups. Two-year mortality was slightly, but not significantly, higher with CABG alone than with the combined procedure (10.6% vs. 10.0%) — but the CABG-alone group had a significantly higher incidence of moderate-to-severe mitral regurgitation (32% vs. 11%). The two groups had similar rates of hospital readmission and major adverse events, except that serious neurologic events and supraventricular arrhythmias were significantly more common with the combined procedure. Most quality-of-life scores were similar between the two groups.

Comment

This trial’s 2-year results — fairly consistent with those reported at 1 year in terms of major outcomes and adverse events — do not support widespread adoption of the combined procedure. The clinical implications of the greater incidence of postsurgical mitral regurgitation in the CABG-alone group are not clear. Notably, the data show that this population’s mortality rate is high; future efforts should explore whether it can be lowered.

 

Stroke Rounds: Clamping Methods Equal in CABG?

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Postop stroke risk similar in single-center observation, but the issue remains controversial.

The partial clamping method for on-pump coronary artery bypass grafting (CABG) was not associated with higher risk of stroke as a complication in an observational study, but experts said the data don’t settle the issue.

The 30-day observed postoperative stroke rates came out a similar 1.5% with single aortic clamping and 1.4% with combined partial aortic clamping (17 of 1,107 patients versus 10 of 712 patients, P>0.99), as predicted from the nearly identical preoperative stroke prediction scores in the single center cohort.

Mortality rates at 30 days were likewise “equally low” (1.9% versus 1.8%, respectively,P>0.99), Danny Chu, MD, of the University of Pittsburgh, and colleagues reported online in JAMA Surgery.

“In patients with significantly compromised myocardial function who are undergoing complex cardiac operations, partial aortic clamping may provide a safe alternative,” the group concluded.

The issue has been controversial, they noted, because a small single-institutionrandomized trial showed better cerebral protection with single aortic clamping, whereas “several high-volume, high-performing cardiac surgery centers continued to perform on-pump CABG using the partial aortic clamping technique with relatively low stroke rates.”

The reason for conflicting studies is “not the aortic clamping; it is the patient,” each with her or his unique atherosclerotic burden in the ascending aorta and arch, Michael D. Crittenden, MD, of the VA Health Care System in St. Louis, Mo., argued in an accompanying editorial.

“Aortic manipulation is one of many risk factors for embolic stroke,” he wrote. “Clearly, patients undergoing anaortic surgery are not spared this complication. The study by Chu and colleagues highlights the fact that there are factors beyond aortic manipulation that we have yet to control.”

Timothy Gardner, MD, medical director of Christiana Care Health System’s Center for Heart & Vascular Health in Newark, Del., and a past president of the American Heart Association, wasn’t so equivocal.

From Chu’s findings, “it would be incorrect to assume that partial aortic clamping is safe for all patients,” he told MedPage Today.

“Experienced cardiac surgeons understand the importance of reducing aortic manipulation in a patients with atherosclerotic involvement of the ascending aorta,” he said. “As has been demonstrated in many reports, such patients are best managed with a single aortic clamping for both distal and proximal grafting.

“In the report by Chu et al, the single clamp patients were older and had increased risk factors for stroke compared to the partial clamp patient group. There likely was some selection bias in the surgeons’ decision to use the single clamp technique versus partial clamping.”

The retrospective cohort study included 1,819 patients receiving conventional on-pump, arrested-heart CABG for the first time as an isolated, non-emergent procedure at a single U.S. major academic medical center.

Among those patients seen during the study period from January 1, 2005, to December 31, 2013, the procedure was done with a single aortic clamp for 1,107 and with side-biting partial aortic clamping for 712.

“To validate our findings, a prospective randomized trial designed to assess aortic clamping strategy for performing proximal coronary anastomosis as well as risk of postoperative stroke and distal embolic burden in CABG operations appears justified,” Chu’s group acknowledged.

“In the meantime, let’s hope that surgeons are not mislead by the authors’ unqualified conclusion statement that ‘no significant differences in post-op stroke were identified regardless of aortic clamping method used,'” Gardner cautioned

Does Preop Statin Help Survival in CABG?

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Study suggested simvastatin may help but other preop heart drugs weren’t useful

Going into coronary artery bypass surgery (CABG) on a statin might reduce mortality risk from the procedure, but other heart drugs might not make a difference, an observational study suggested.

The lipid-lowering drugs were associated with 65% to 74% relatively lower odds of perioperative death after adjusting for other factors, which was statistically significant across all five logistic regression models used in the study of 16,192 CABG patients ages 40 years and older in the U.K. Clinical Practice Research Datalink database.

Mortality risk out to 6 months also was significantly reduced among preoperative statin users, with a hazard ratio of 0.63 (95% CI 0.42 to 0.92),Robert Sanders, MD, of the University of Wisconsin in Madison, and colleagues reported at the European Society of Anaesthesiology’s Euroanaesthesia conference in Berlin.

The effect was only significant for the most commonly prescribed statin, simvastatin (adjusted OR 0.33, 95% CI 0.14-0.78), although it wasn’t clear whether this was the result of a statistical power issue or due to some real difference among statins because the study could not draw any causal conclusions.

“Further data are needed on whether all statins exert similar effects,” the researchers concluded.

They pointed to a prior meta-analysis of randomized, controlled trials and observational data that showed a 31% relative reduction in early death from any cause after cardiac surgery among people on a preoperative statin.

“In combination with previous studies, these data suggest that patients not taking statins should be considered for statin therapy based on their perioperative and chronic health risks,” Sanders’s group suggested in a press release.

Perhaps not surprisingly, statins were the most common of the heart medications the patients getting CABG were on in the study (85.1%).

The other medications considered ranged from 72.8% prevalence for beta-blockers to 60.5% for ACE inhibitors and 42.8% for calcium channel blockers all the way down to 1.2% for alpha-2 agonists.

None of them showed any consistent association between preoperative use and perioperative mortality across the propensity score-matched, Cox, and other regression analyses.

Mass. Sees Steep Drop in Revascularization

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Rates fell over the past decade for both PCI and CABG

Coronary revascularization has declined dramatically over the past decade, according to a population-based study in Massachusetts.

The age- and sex-adjusted rate fell 39% from 2003 through 2012, from 423 per 100,000 population to 258 (P<0.001), Robert W. Yeh, MD, MBA, of Massachusetts General Hospital in Boston, and colleagues reported online in a research letter in JAMA Internal Medicine.

The drop was significant for both percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG):
  • PCI: 318 to 200 per 100,000
  • CABG: 113 to 63 per 100,000

The exact reason for the trends wasn’t clear, but likely relates to dropping rates of myocardial infarction (MI) reported in multiple populations, “likely attributable to improved primary and secondary prevention.”

“These data have broad implications for regional health policy, training and provider accreditation, hospital resource allocation, and patient outcomes,” the researchers concluded.

The retrospective study included all 171,702 coronary revascularizations among Massachusetts residents seen at nonfederal hospitals from April 2003 through September 2012, whether inpatient or outpatient, and regardless of concomitant valve or aortic surgery. Only the first procedure per year per patient was counted.

PCI accounted for 76.9% of the procedures overall; CABG, 23.1%.

The biggest declines were in elective PCI (down from 206 to 109 per 100,000) and in isolated CABG (down from 90 to 45 per 100,000). All other categories except combined CABG and aortic or mitral valve surgery also declined significantly from 2003-2012.

From the American Heart Association:

Can We Build a Better SYNTAX Score?

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Adding clinical factors to the anatomical SYNTAX model improved prediction of 4-year mortality with surgery versus stenting for complex coronary artery disease.

The SYNTAX score provides an anatomically based measure of coronary artery disease to help physicians and patients choose an appropriate revascularization strategy. However, other patient characteristics are often important factors in clinical decisions.

To improve the SYNTAX scoring system, investigators used SYNTAX trial data to identify six clinical factors — age, creatinine clearance, left ventricular ejection fraction [LVEF], peripheral vascular disease, female sex, and chronic obstructive pulmonary disease [COPD]) — that independently predicted 4-year mortality or showed an interaction effect between coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) for long-term mortality (notably, diabetes did not meet either of these criteria and was excluded from the model). These variables were combined with two anatomic measures: SYNTAX score and presence of left main disease.

Compared with the original SYNTAX model, the SYNTAX score II predicted similar 4-year mortality with CABG and PCI at lower scores with some clinical factors (female sex, lower LVEF) and at higher scores with others (older age, COPD, left main disease). The new model discriminated well between CABG and PCI, both in the SYNTAX population and in a validation cohort of 2900 participants in an international registry.

Comment: The inclusion of clinical variables improves the SYNTAX score by allowing clinicians to identify lower-risk patients in high categories of anatomic risk, and vice versa. Although externally validated, the new score requires further validation in randomized studies. In the meantime, clinicians should consider taking this common-sense approach to making revascularization decisions.

Source: Journal Watch Cardiology

CABG Again Outperforms PCI in Patients with Diabetes.

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In patients with diabetes and heart disease, coronary artery bypass grafting reduces cardiovascular events more effectively than PCI with drug-eluting stents, according to a study presented at the American Heart Association meeting and published in the New England Journal of Medicine.

Some 1900 diabetic patients with multivessel disease were randomized either to undergo PCI with drug-eluting stents or CABG.

During roughly 4 years’ follow-up, the primary composite outcome — death from any cause, nonfatal MI, and nonfatal stroke — occurred more often with PCI than with CABG (5-year event rate: 27% vs. 19%). In particular, death and MI were more common with PCI, while stroke was more common with CABG.

In Journal Watch Cardiology, Harlan M. Krumholz calls the observed superiority of CABG a “blockbuster result.” He adds: “The excess risk for stroke, however, may give some people pause. The issue is ripe for shared decision making; these findings will greatly benefit patients and their doctors working together to make well-informed choices.”

Source:NEJM

 

Acadesine Does Not Improve Outcomes of CABG.

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In a randomized trial, an adenosine-regulating agent had no apparent cardioprotective effect.

Despite advances in surgical technology, ischemia/reperfusion injury associated with coronary artery bypass grafting (CABG) remains an important cause of morbidity and mortality. To evaluate the protective effect of acadesine, an adenosine-regulating agent, investigators at 300 sites in 7 countries conducted a manufacturer-sponsored, randomized, double-blind, placebo-controlled trial involving intermediate- or high-risk patients undergoing nonemergent, on-pump CABG during 2009–2010. The primary composite endpoint was all-cause mortality, nonfatal stroke, or mechanical support for severe left ventricular dysfunction during CABG or 4 weeks of follow-up.

The trial was stopped for futility after enrollment of 30% of the projected study population. The final cohort included 2986 patients (median age, 66), most of whom were white men with hyperlipidemia, diabetes, and family history of cardiovascular disease. The primary-endpoint rate was 5.0% overall and did not differ significantly between the placebo and acadesine groups (5.0% and 5.1%, respectively), as demonstrated by a Kaplan-Meier curve. No between-group difference in the rate of any secondary endpoint reached or approached statistical significance, nor was any significant difference found among groups stratified by Society of Thoracic Surgeons risk quintile.

Comment: Although previous studies yielded promising findings, this well-designed trial failed to show any benefit of acadesine on outcomes in intermediate- or high-risk patients undergoing coronary artery bypass grafting. The rate of the primary endpoint, although lower than the 10% expected with placebo in this population, underscores the need for continued efforts to prevent ischemia/reperfusion injury during and after CABG.

Source: Journal Watch Cardiology