In the Literature
The authors of this analysis concluded that early treatment for six weeks with zofenopril was effective in reducing death and severe CHF in non-thrombolysed anterior wall NSTEMI patients. The results were independent of SBP reduction, suggesting that zofenopril may have cardioprotective effects, preventing infarct expansion, left ventricular remodeling, and neurohormonal activation, which is involved in coronary vasoconstriction and endothelial dysfunction. Further, the relative risk reduction in composite endpoints of mortality and severe CHF exceeded that observed in the overall population in the SMILE trial (which included STEMI), drawing attention to a particular advantage of the early use of ACEI in NSTEMI patients.
Despite relevant findings, these results were derived from a post hoc analysis of the SMILE study, only including about one third of the original population. It is also a retrospective analysis, albeit recognizing the sparse availability of research in this area, thought to be related to the exclusion of such patients from most clinical trials. This analysis strongly highlights the beneficial effects of early administration ACE inhibition and should prompt prospective evaluation of these agents as first-line therapy in anterior wall NSTEMI. TH
Prior to this landmark study, internists and cardiologists had few (if any) proven methods of reducing perioperative cardiac morbidity and mortality. Although risk stratification models such as the Goldman index had been developed to permit clinicians to predict outcomes based on clinical criteria, the utility of interventions, including revascularization, was (and in some cases, remains) unknown. Work by Mangano and others in the years preceding this study, however, established that patients with coronary disease, or cardiac risk factors, experienced ischemia during noncardiac surgery while under general anesthesia and that such ischemia was a marker for increased long-term mortality. The hypothesis was that perioperative beta blockers would reduce this ischemia and improve long-term surgical outcomes.
This randomized, double-blind study included 200 Veterans Affairs patients in San Francisco, all of whom had known coronary artery disease or multiple risk factors. All underwent elective noncardiac surgery: general vascular, orthopedic, or intra-abdominal procedures. The intervention consisted of up to 10 milligrams of intravenous atenolol or placebo administered in the hour prior to surgery and immediately following, according to heart rate and blood pressure parameters. The study drug was continued from postoperative day one until discharge, up to a maximum of seven days. Patients were evaluated at six months, at one year, and again two years after discharge. The primary outcome was two-year all-cause mortality; the secondary outcome consisted of combination of major cardiac events and death.
The results were striking. Of the 194 patients who survived to discharge, two-year follow-up data was available for 192. The two-year mortality rate in the treatment group was 55% lower (P=0.019), and the cardiac mortality rate was 65% lower (P=0.033). Ten patients in the control group died in the first six to eight months post-discharge, versus only one in the treatment group. Results in the secondary outcome were equally impressive, with a two-year decrease of 48% in the treatment group (P=0.008). Treated patients had a lower heart rate during treatment, and no patients required therapy for hemodynamic instability due to the drug.
The authors estimated that if this intervention were administered to all appropriate patients each year, approximately 60,000 Americans would then receive an extra two years of life. This was a dramatic conclusion at the time, but a subsequent study by Poldermans and colleagues, who studied high-risk patients undergoing vascular surgeries, found equally dramatic short-term benefit from perioperative beta blockade.
Unfortunately, the study was open to a number of criticisms. Patients who were already on beta blockers at the time of enrollment were taken off them immediately prior to the study; randomization did not distribute all variables equally; and the authors excluded from their analysis six patients who died in the immediate postoperative setting. Further, recent studies of perioperative beta blockade on patients with clinical risk factors have not yielded similar benefits, although they also have not followed the same rigorous dosing regimen. Nevertheless this study, which coincidentally was published just four months after the Wachter and Goldman “Sounding Board” piece in the New England Journal of Medicine ushered in the era of hospitalist medicine, opened the door for the systematic approach to medical perioperative risk attenuation that hospitalists today, ten years later, continue to champion.
