Medicolegal Issues

In the Literature


CARP Trial Suggests No Benefit to Revascularization Before Vascular Surgery

McFalls, EO, Ward HB, Mortiz TE, et al. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med. 2004;351:2795-2804.

Recent studies have presented evidence that treatment with beta-blockers for patients with CAD could reduce the risk of perioperative cardiac complications. Beta-blockers have since become a critical part of the management plan for the perioperative patient. Evidence-based practice guidelines for cardiac risk assessment have been published by both the American College of Physicians and the American College of Cardiology/American Heart Association. However, practice patterns continue to vary between physicians and cardiologists, particularly for patients clinically stratified into the intermediate-risk category. Some physicians feel comfortable with a conservative approach of medical optimization even in the setting of established CAD, while others favor more aggressive treatment, even though the prospective data supporting cardiac revascularization before major surgery has been lacking. The study investigators sought to clarify this uncertainty.

The prospective trial enrolled 510 patients at 18 VA centers. Patients scheduled for major vascular operations were eligible, and were preoperatively assessed via clinical criteria, stress imaging, and angiography when appropriate. Eligible patients had significant (at least 70%) stenosis of at least one coronary artery. High-risk patients (i.e., those with left main disease, severe aortic stenosis, and LVEF <20%) were excluded. Patients were then randomized to one

of two groups. The first group underwent revascularization with PTCA or CABG plus medical optimization; the second group received only medical optimization. Most patients in both groups received beta-blockers, and more than half in each received statins. The patient populations were appropriately randomized, although overwhelmingly male (98%). Most patients had one- or two-vessel CAD. The primary endpoint was long-term mortality. Secondary endpoints included MI, stroke, renal failure requiring dialysis, and limb loss. Follow-up rates were similar in both groups (86% and 85%).

The major finding of the study was the lack of difference in mortality between the two groups at an average follow-up of 2.7 years (22% vs. 23%, RR= 0.98, 95% CI 0.70 to 1.37, p = 0.92). Analyzing by “treatment-received” instead of “intention-to-treat” did not significantly change this result. Of note, ten patients in the revascularization arm died between the revascularization procedure and the vascular surgery. Not surprisingly, revascularization also delayed the time to surgery for patients in that arm of the study. In the authors’ analysis, the patients were also divided into subgroups based on high-risk variables (prior CABG, category of Revised Cardiac Risk Index, etc.), but the study was not powered to detect mortality differences between the two arms within these subgroups. The authors concluded that there was no benefit to revascularization in patients with stable coronary syndromes prior to elective vascular surgeries.

The results of this study validate the conservative practice recommended by the existing guidelines— that is, to perform revascularization procedures in the preoperative setting only when indicated by clinical criteria such as unstable ischemic symptoms, and if likely to improve long-term survival. Beta-blockers, and based on recent studies probably “statins,” should continue to be the mainstay of perioperative risk optimization for patients with stable coronary disease.

There were, however, several important considerations: first, the study group was exclusively male, although there is little reason to believe that women would have better outcomes from revascularization. And second, the highest-risk patients were excluded, and therefore the results should not be extrapolated to that population. Prospective identification of the group of patients who may benefit from aggressive intervention should remain a target of risk assessment and further research. (BH)

Blood Transfusion May Increase Mortality in Acute Coronary Syndrome

Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA. 2004;292:1555-62.

The increased use of invasive procedures and anticoagulant and fibrinolytic drugs in patients with ischemic heart disease in recent years predictably increases the potential for bleeding and perceived need for transfusion. Studies evaluating the association between transfusion and mortality have produced mixed results. A more pertinent clinical question is whether transfusion is beneficial or harmful in patients with acute coronary syndromes who acutely develop anemia during their hospitalization.

The authors used clinical data from three large international trials of patients with acute coronary syndromes (GUSTO IIb, PURSUIT, and PARAGON B) to determine the association between blood transfusion and outcomes among patients who developed moderate to severe bleeding, anemia, or both during their hospitalization.

Assessment of clinically significant bleeding complications was based on the GUSTO definition of severe (intracranial hemorrhage or hemodynamic compromise and requiring intervention) or moderate (hemodynamically stable but requiring blood transfusion) bleeding. The GUSTO IIb and PURSUIT trials used the above definition; PARAGON B categorized bleeding as “major or life threatening” (intracranial hemorrhage or bleeding leading to hemodynamic compromise requiring intervention) or “intermediate” (requiring transfusion or a decrease in hemoglobin of 5 g/dL or more, or a decrease in hematocrit ( 15%). Major or life-threatening bleeding episodes and intermediate bleeding episodes in PARAGON B were deemed equivalent to severe and moderate bleeding episodes in GUSTO.

Data were collected on the date, time, severity, and location of each bleeding event, and on the date and number of units of packed red blood cells and whole blood transfused. The primary end-point was 30-day all-cause mortality. Secondary end-points were occurrence of the composite of 30-day death or MI.

The unadjusted rates of 30-day death, MI, and composite death/MI were significantly higher among patients who received a transfusion (30-day death, 8.00% vs. 3.08%; p<.001; 30-day MI, 25.16% vs. 8.16%; p<.001; 30-day composite death/MI, 29.24% vs. 10.02%; p<.001).

After adjustment for baseline characteristics, bleeding and transfusion propensity, and nadir hematocrit, blood transfusion was associated with a hazard ratio for death of 3.94 (95% confidence interval, 3.26–4.75).

No significant association was found between transfusion and 30-day mortality at a nadir hematocrit of 25% or less (adjusted OR 1.13; 95% CI 0.70-1.82). However, at a nadir hematocrit higher than 25%, transfusion was associated with significantly higher odds of 30-day death, even after excluding patients who underwent CABG or those who died within the first 5 days of follow-up.

These findings differ from the findings of Wu et al. (1) who noted that blood transfusion was associated with lower 30-day mortality among elderly patients with MI if the admission hematocrit was 30% or lower. The current authors propose that their data is more robust due to meticulous collection through clinical trial records, and that their analysis accounts for timing of transfusion and indications for transfusion.

Many clinicians logically believe that augmentation of oxygen carrying capacity via transfusion would be beneficial to patients with active ischemia. However, the authors note that red blood cells in stored blood may be depleted of both 2,3-diphosphoglyceric acid and nitric oxide, both of which are critical components to oxygen delivery and exchange. These cells then function as nitric oxide “sinks,” promoting vasoconstriction, platelet aggregation, and impaired oxygen delivery to tissues. In addition, inflammatory mediators associated with exacerbation of myocardial ischemia may remain in transfused blood, potentially contributing to adverse outcomes.

As this is a nonrandomized, post hoc observational study, further prescriptive conclusions regarding transfusion cannot be made. However, the authors, along with an accompanying editorial, call for prospective randomized trials of transfusion in anemic patients with acute coronary syndromes to better define the role of this commonly used therapy. (CW)

  1. Wu WC, Rathore SS, Wang Y, Radford MJ, Krumholz HM. Blood transfusion in elderly patients with acute myocardial infarction. N Engl J Med. 2001;345:1230-6.

Cost-effectiveness of Rhythm Versus Rate Control in Atrial Fibrillation

Marshall DA, Levy AR, Vidaillet H, et al. Cost-effectiveness of rhythm versus rate control in atrial fibrillation. Ann Intern Med. 2004;141:653-61.

Atrial fibrillation is the most common arrhythmia treated by physicians. It afflicts nearly 10% of patients age 80 years or older. There are two primary modalities of managing patients with atrial fibrillation; rate control versus cardioversion into sinus rhythm.

AFFIRM was a multicenter randomized controlled trial involving 213 centers in USA and Canada that compared rate versus rhythm control in 4060 patients. These patients had a mean age of 70 years. Sixty-one percent of the enrolled patients were men, and 66% had recurrent atrial fibrillation. Seventy-one percent of patients had hypertension, 39% had coronary artery disease, and 9% had congestive heart failure. Patients were block randomized by center to either rate control or rhythm control and followed for an average of 3.5 years. AFFIRM results showed no significant mortality difference between the two groups (hazard ratio for rate versus rhythm control, 0.87 with 95% CI, 0.75 to 1.01).

Primary data on survival and resource utilization were used to conduct the economic analysis from a third party payer perspective. Authors used intention to treat data for the economic analysis.

For resource utilization estimates, US healthcare cost figures for the year 2002 were used. All earlier costs were appropriately adjusted using Consumer Price Index, Medical Care component to estimate their nominal values in year 2002. Hospital costs were taken as the mean charges per day from Healthcare Cost and Utilization Project statistics for Diseases of the Circulatory System for patients older than 18 years age. Low and high end of these costs were assumed to be equivalent to 25th and 75th percentiles of the mean costs, respectively. Physician costs were assumed to be equivalent to be the average of all carriers’ payments for the relative value units of the services rendered based on a generic current procedural terminology code. Sensitivity analysis was conducted on these physician costs using minimum payment among these carriers as the low cost estimate and the standard charges for Marshfield Clinic for the high end. Costs of pacemaker and implantable cardioverter defibrillators were based on manufacturers’ list prices. For sensitivity analysis, hardware costs were excluded for low cost estimates and the maximum manufacturers’ list price for the high estimate was used.

At each follow-up visit during the AFFIRM trial, the number of cardioversion attempts since the prior visit was recorded. Costs of cardioversion were based on average payment to Marshfield Clinic for outpatient electrical cardioversion for the year 2002. Authors assigned no costs for low cost estimate and used billed charges for high costs for sensitivity analysis.

At each follow-up visit, the number of short stay and emergency department visits since the prior visit was recorded. Weighted average Medicare costs for level I and II facilities were used as the baseline estimate for these visits. Estimates for sensitivity analysis were the minimum and maximum Medicare payments for these visits. Physician fees were based on level III emergency department visit with low and high cost estimates assigned as described above.

Medication costs were based on the least average wholesale price (AWP) for a generic medication. Low and high cost estimates were taken from lowest quoted US Internet pharmacy price and highest AWP for the most expensive drug in the class respectively. Only medications used for atrial fibrillation and anticoagulation were considered for analysis.

The authors calculated the mean cost per patient In the Literature (continued) and the mean survival time between the two interventions. Future costs were discounted by 3%. For the base estimate, rhythm control was more expensive and less effective than rate control, i.e., dominated by the rate control. Rate control dominated rhythm control even for high and low estimates of the sensitivity analysis demonstrating stability of the results. Authors used 10,000 simulations to perform non-parametric bootstrapping analysis to find the 95% credible intervals around the base estimate. The bootstrap results showed that for 95% of the results rate control had higher survival time and was less costly than rhythm control. These simulation results clearly showed rate control is more cost-effective for patient population resembling that of AFFIRM trial.

The study has some limitations. These results are robust for patients similar to those in AFFIRM trial, i.e., older patients with cardiovascular defects that are at risk of cerebrovascular embolism. However these results may not be applicable to younger patients and those with “lone atrial fibrillation.” The study had a follow-up period of 3.5 years, and the cost-effectiveness analysis is confined to this period. It is difficult to determine mortality advantage of one treatment over another within the limited duration of the AFFIRM study. Most of the patients were on multiple pharmacologic agents for rhythm control and had a high incidence of cross-over from rhythm control to rate control reflecting modest benefits of the current agents. These results may not be applicable to patients whose atrial fibrillation is well controlled by a single agent or by non-pharmacological treatment. Patients on rhythm control agents had, as expected, more hospitalization days from the side effects and treatment protocols of the agents (especially pharmacologic) used to control the rhythm. With advances in both pharmacologic as well as nonpharmacologic methods for rhythm control generating safer and more efficacious technologies, the results of this analysis may become less valid in the future. The analysis was conducted from a third-party payer perspective, without accounting for the quality of life. Thus patients who have symptomatic atrial fibrillation and those with diastolic dysfunction may have improved quality of life from rhythm control over just rate control. The results may not be applicable to these patients. (SS)

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