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In the Literature

From: The Hospitalist, January 2007

Atrial Flutter, Endarterectomy Versus Stenting, Care Transitions, Pleural Empyema, RRS Consensus, Treating VTE Patients, Classic Lit on Beta Blockers, and ACE Inhibitors

by Katherina Tillan-Martinez, MD; Preethi Patel, MD; Vesselin Dimov, MD; Vaishali Singh, MD, MBA, MPH; Brian Harte, MD

IN THE LITERATURE

Treat Atrial Flutter

Da Costa A, Thévenin J, Roche F, et al. Results from the Loire-Ardèche-Drôme-Isère-Puy-de-Dôme (LADIP) trial on atrial flutter, a multicentric prospective randomized study comparing amiodarone and radiofrequency ablation after the first episode of symptomatic atrial flutter. Circulation. 2006;114:1676-1681.

Radiofrequency ablation (RFA) has high success rates in atrial flutter, and American College of Cardiology/American Hospital Association guidelines classify a first episode of well-tolerated atrial flutter as a class IIa indication for RFA treatment. The LADIP trial compared RFA with the current practice of electroosmotic flow (EOF) cardioversion plus amiodarone after a first episode of symptomatic atrial flutter.

One hundred and four consecutive patients with a documented first episode of atrial flutter were enrolled over a period of 39 months. Excluded from the study were patients under the age of 70, those who had had previous antiarrythmic treatment for atrial flutter, those who had an amiodarone contraindication, patients with New York Heart Association class IV heart failure, and those who had a history of heart block. All 52 patients in group I received RFA by a standard method. Fifty-one of the 52 patients in group II underwent intracardiac stimulation, followed, if necessary, by external or internal cardioversion. All patients in group II received amiodarone as well as vitamin K antagonists.

The patients were followed up in the outpatient department at one, three, six, 12, and 18 months after randomization and at the end of the study. At each visit, arrhythmic or cardiovascular events were recorded, and a 12-lead ECG was obtained. Patients were fitted with a Holter monitor for seven days if they had recurring palpitations or symptoms. The primary outcome studied was recurrence of symptomatic atrial flutter and occurrence of atrial fibrillation.

After a mean follow-up of 13+/-6 months, atrial flutter recurred in two of the 52 (3.8%) patients in group I and 15 of 51 (29.5%) patients in group II (P<0.0001). In group I, one patient required a second, successful ablation. All the patients who recurred in group II were successfully treated using RFA. The occurrence of significant symptomatic atrial fibrillation was 8% in both groups at the end of the first year. By the end of the study, two patients in group I and one patient in group II were in chronic atrial fibrillation. When all the episodes of atrial fibrillation were counted (including those patients whose episodes lasted <10 minutes but were documented with an event monitor), the groups did not differ significantly.

No procedure-related complications occurred in group I. In the amiodarone group, however, two patients developed hypothyroidism, one developed hyperthyroidism, and two patients had symptomatic sick sinus syndrome. There were a total of 14 deaths during the course of the study (six patients in group I and eight patients in group II); none were related to the study protocol.

This study is the largest to date showing the superiority of RFA to cardioversion plus amiodarone after the first episode of symptomatic atrial flutter. The long-term risk of subsequent atrial fibrillation was found to be similar to that of the amiodarone-treatment group. Because the mean age of patients in this study was 78, however, these findings cannot necessarily be extrapolated to younger patient populations. Further, oral amiodarone was used initially in this study. It can be argued that IV amiodarone is far more efficacious than oral forms in the acute setting. Because RFA is an invasive procedure, it is user-dependent and may be unfeasible in different care settings. Also, RFA might not be as appropriate for many symptomatic patients with atrial flutter and hemodynamic instability. Nevertheless, this study presents hospital-based physicians with an additional consideration in the acute care setting for patients with a first episode of atrial flutter.

This study is the largest to date showing the superiority of RFA to cardioversion plus amiodarone after the first episode of symptomatic atrial flutter.

A Transitional Care Intervention Trial

Coleman EA, Parry C, Chalmers S, et al. The care transitions intervention: results of a randomized controlled trial. Arch Intern Med. 2006;166:1822-1828.

A growing body of evidence suggests that the quality of health management decreases when patients are transitioned across sites of care—particularly when they are not adequately prepared to self-manage their chronic disease, when they receive conflicting advice from various providers, or when they do not have access to their healthcare providers. Higher rates of medication errors and lack of appropriate follow up compromise patient safety during this vulnerable period. This is a particular problem for hospitalists, who introduce an additional discontinuity into the flow of patient care. Because patients and their caregivers are the only common thread moving across various sites of care, this study targeted them for an intervention designed to improve the quality of transitional care.

The study was done in collaboration with a not-for-profit capitated system in Colorado. To be eligible for the study, patients had to be over age 65 and admitted to one of the participating hospitals. Patients had to be community dwelling with no documented dementia and had to have one of eleven diagnoses selected to reflect a higher likelihood of long-term subacute care or anticoagulation, including stroke, congestive heart failure, COPD, diabetes, hip fracture, coronary artery disease, and pulmonary embolism. The intervention group comprised 379 patients, while the control group was made up of 371 patients.

The intervention model was built on four pillars derived from prior qualitative studies about care transitions:

  1. Assistance with medication self-management;
  2. A healthcare record owned and maintained by the patient;
  3. Timely physician follow-up; and
  4. A list of red flags indicative of clinical deterioration.

Intervention-group patients had access to a personal health record that included an active problem list, medications, allergies, and a list of red flags; in addition, these patients received a series of visits and telephone calls with a “transition coach,” an advanced care nurse who encouraged self-care by patients and their caregivers, facilitated communication between providers and patients, and assisted in medication review and reconciliation.

The primary outcome measure was the rate of nonelective rehospitalization at 30, 90, and 180 days after discharge from the index hospitalization. Ninety-five percent of the intervention patients and 94.9% of the control subjects were included in the analysis. Intervention patients had lower adjusted hospital readmission rates than controls at 30 (8.3% versus 11.9%) and 90 days (16.7% versus 22.5%), P=0.048 and 0.04 respectively. The result did not achieve significance at 180 days after discharge (P=0.28). Rehospitalization for the same diagnosis as the index diagnosis within 90 and 180 days of admission was 5.3% in the intervention group versus 9.8% in the control group (P=0.04) and 8.6% in the intervention group versus 13.9% (P=0.045) in the control group, respectively, but did not meet statistical significance within 30 days of readmission.

The concepts of a transition coach and a patient-maintained record are enticing, considering the amount of time hospitalists may invest in patient education and discharge planning processes. This study is different from prior studies in that it used transition coaches instead of healthcare professionals to assume the primary role in managing the post-hospitalization course, and it provided the caregiver and patient with tools that could be applied to future care transitions. The costs of intervention in this study were found to be about $74,310 for the transition coach and other related costs, compared with a semi-annual cost savings of $147,797.

The main drawbacks of the study were that the 180-day all-cause readmission rates did not achieve statistical significance, and even though the adjusted P values for all-cause 30- and 90-day readmission rates were reported to be significant, their 95% confidence interval for the odds ratio barely meets appropriate analytical criteria (OR 0.59 [0.35-1.00] and 0.64 [0.42-0.99]). Also disappointing was the fact that there was no difference in readmission rates at 30 days for the index diagnosis. Therefore, healthcare systems would likely hesitate to implement these interventions without more definitive data showing reductions in adverse outcomes and mortality rates.

Pleural Empyema in CAP Cases

Ahmed RA, Marrie TJ, Huang JQ. Thoracic empyema in patients with community-acquired pneumonia. Am J Med. 2006 Oct;119(10):877-883.

Pleural effusions complicate up to 44% of cases of community-acquired pneumonia (CAP). Of these cases, 10% develop complicated parapneumonic effusions. In the past, pleural empyema has been associated with poor outcomes and high mortality rate. Unfortunately, most of these studies were performed before the advent of newer antimicrobial agents and more modern diagnostic and therapeutic techniques.

This prospective, population-based study included all patients older than 17 who had been admitted with a diagnosis of CAP. Most of these patients were diagnosed and managed according to a “Pneumonia Critical Pathway.” Adherence to any aspect of the pathway by the admitting physician was completely voluntary.

Of 3,675 patients enrolled in the study, 47 (1.3%) were diagnosed with empyema by the attending physician—a number which correlates with previous studies. Of these, only 24 (0.7%) were ultimately classified as “definite empyema” by one or more of the following criteria:

  1. Presence of microorganisms on Gram stain or culture of the pleural fluid;
  2. Pleural fluid with a pH <7.2 plus radiographic evidence suggesting empyema; and
  3. Frank pus in the pleural space at time of thoracoscopy.

The remaining 23 (0.6%) patients were classified as suspected empyema.

The study then compared the patients without empyema with patients with definite empyema. Patients with definite empyema were younger, more likely to have received antibiotics before admission, and more likely to have been admitted to the ICU. Further, these patients had a higher incidence of illicit drug use and frequently presented with a history of systemic symptoms, including fevers, chills, and pleuritic chest pain. Laboratory studies—aside from elevated WBC—were not useful in distinguishing between the two groups. Also, there were no significant features on chest radiographs to separate the two groups, although in patients with complex fluid collections, 19 of 22 patients (86%) with definite empyema had computed tomography (CT) scans suggesting the diagnosis.

Streptococcus milleri was the most common pathogen, isolated in 50% of patients with definite empyema. Patients with definite empyema were more likely to have invasive diagnostic procedures and had longer hospital stays (23.5 +/- 17 days) compared with their CAP counterparts (12.4 +/- 20.2 days, P=0.007).

Clinical and laboratory features remain nonspecific and should be used with caution when differentiating between empyema and complicated pleural effusions. Diagnostic pleural effusion aspiration is essential if infection is suspected. This study also points out the greater need of ICU support in definite empyema cases that suggest a greater severity of illness.

Interestingly, definite empyema had an in-hospital mortality rate of 4.2%, compared with 10% for CAP (P<0.05). Possible reasons for this result included the fact that 50% of the empyema cases were suspected at admission and thereby received earlier antibiotic treatment and more aggressive management than CAP cases.

Rapid Response Systems: A Call for Research

Devita MA, Bellomo R, Hillman K, et al. Findings of the first consensus conference on medical emergency teams. Crit Care Med. 2006 Sep;34(9):2463-2478.

The Institute for Healthcare Improvement has endorsed the concept of Rapid Response Teams (RRTs), and the 2005-2006 SHM survey indicated that 35% of responding hospitalist groups were involved with such systems. The field of in-house medical emergency teams suffers from a lack of quality research, however. Most of the existing data come from single-institution studies, and analysis is limited by a lack of standard definitions or processes. This consensus document addresses these issues and offers a “state of the literature” in RRTs, or—as the authors redefine them—rapid response systems, and attempts to frame the research agenda going forward.

The authors define an in-hospital medical emergency as a “mismatch between patient needs and resources available” and then proceed to outline the various types of responses that have been described, including medical emergency teams (METs), RRTs, and critical care outreach teams (CCO). According to the authors, a MET generally brings ICU capabilities, including procedures and medications, to the bedside, whereas an RRT is a “ramp-up” response, sometimes led by a nurse, that can rapidly assess and triage patients to a higher level of care. To be part of a complete RRS, any of these response options needs to have an adequate detection/triggering arm (“afferent”), a response arm (“efferent”), and administrative and QI components.

After establishing their suggestions for standardized nomenclature and the necessary components of a rapid response system (RRS), the authors review the literature and make several recommendations regarding areas for future research. In particular, they note that there is no data to demonstrate that one set of triggering criteria is superior to another to identify patients who will benefit from an RRS intervention; nor is there adequate literature on the relative effectiveness of the different types of responses. Finally, the authors make a formal recommendation that hospitals implement both afferent and efferent systems, although, interestingly, they do so based on evidence from single-center, historical-control trials and in spite of the lack of benefit seen in the only published multicenter randomized controlled trial (MERIT).

The authors also describe RRS as potentially inexpensive, but offer no data to support this claim. In fact, the prospect of dedicated 24-hour response personnel is probably more daunting for most institutions than the authors acknowledge. In any case, this is excellent reading for hospitalists, who will continue to be key players in the evolution of these systems, and the report is also accompanied by an outstanding bibliography.

Symptomatic Severe Carotid Stenosis: Endarterectomy Versus Stenting

Mas JL, Chatellier G, Beyssen B, et al. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med. 2006;355(16):1660-1671.

Two large, randomized, clinical trials have established endarterectomy as the standard treatment for severe symptomatic carotid artery stenosis. The new method of carotid stenting avoids the need for general anesthesia and may cost less than surgery, but it is unclear if stenting is as effective as or safer than endarterectomy.

The authors conducted a publicly funded, randomized controlled trial in 20 academic and 10 nonacademic centers in France to compare stenting with endarterectomy in patients with symptomatic carotid stenosis. Patients were eligible if they were 18 years of age or older, had had a hemispheric or retinal transient ischemic attack or a nondisabling stroke within 120 days of enrollment, and had a stenosis of 60% to 99% in the symptomatic carotid artery.

Patients were excluded if one of the following was present: a modified Rankin score of three or more (disabling stroke); nonatherosclerotic carotid disease; severe tandem lesions (stenosis of proximal common carotid artery or intracranial artery that was more severe than the cervical lesion); previous revascularization of the symptomatic stenosis; a history of bleeding disorder; uncontrolled hypertension or diabetes; unstable angina; contraindication to heparin, ticlopidine, or clopidogrel; life expectancy of less than two years; or percutaneous or surgical intervention within 30 days before or after the study procedure. The primary endpoint was the incidence of any stroke or death within 30 days after treatment.

The trial (EVA-3S) was stopped early, after the inclusion of 527 patients, for reasons of both safety and futility. The 30-day risk of any stroke or death was significantly higher after stenting (9.6%) than after endarterectomy (3.9%), resulting in a relative risk of 2.5 (95% CI, 1.2 to 5.1). The 30-day incidence of disabling stroke or death was 1.5% after endarterectomy (95% CI, 0.5 to 4.2) and 3.4% after stenting (95% CI, 1.7 to 6.7); the relative risk was 2.2 (95% CI, 0.7 to 7.2). At six months, the incidence of any stroke or death was 6.1% after endarterectomy and 11.7% after stenting (P=0.02). Cranial nerve injury was more common after endarterectomy than after stenting.

The practice of interventional physicians has expanded in the last few years to include placement of stents—not only in coronary arteries but also in carotid arteries and other vessels. As hospitalists, we must be aware of the latest research in this changing field to provide the best evidence-based advice to our patients.

Currently, the only use of carotid stenting that has been approved by the Food and Drug Administration (FDA) is in symptomatic patients with carotid artery stenosis of 70% or more who are at high surgical risk. This FDA approval is based on the results of the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) study, which included symptomatic patients with carotid artery stenosis exceeding 50% and asymptomatic patients, with stenosis exceeding 80%, who were at high surgical risk mainly due to severe coronary artery disease. The SAPPHIRE study showed that stenting was safer than endarterectomy mainly due to lower risk of myocardial infarction within 30 days after carotid stenting as compared with surgery. There was no significant difference in the rates of stroke or death between stenting and endarterectomy.

Why does the EVA-3S trial reported in NEJM show opposing results? The patients in the trial were different than the ones included in the SAPPHIRE study, and the periprocedural protocol was less strict. The patients in the EVA-3S trial were not at high surgical risk. Further, all patients in the EVA-3S trial had symptomatic carotid artery stenosis, whereas the majority of patients in the SAPPHIRE study were asymptomatic. Use of aspirin and clopidogrel or ticlopidine three days before carotid-artery stenting was only recommended in the EVA-3S trial but was required in the SAPPHIRE trial.

The ongoing Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), funded by the National Institutes of Health, is enrolling patients with an average surgical risk similar to those in the EVA-3S study. The CREST study, which is expected to enroll 2,500 patients, may be able to provide a more definitive answer regarding the best treatment for symptomatic patients with high-grade carotid stenosis with an average surgical risk.

In the meantime, what should we recommend to our patients? For symptomatic patients with carotid artery stenosis of 70% or more, endarterectomy is superior to medical therapy alone. For asymptomatic patients with carotid artery stenosis exceeding 60%, endarterectomy is also superior to medical therapy alone, assuming a risk of perioperative stroke or death of less than 3%. Currently, the only accepted indication for stenting is in symptomatic patients with carotid artery stenosis exceeding 70% and a high surgical risk.

D-Dimer Testing to Risk Stratify VTE Patients

Palareti G, Cosmi B, Legnani C, et al. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med. 2006;355:1780-1789.

D-dimer levels have been used to assist in diagnosing initial episodes of venous thromboembolism (VTE). Although not specific, D-dimer testing is very sensitive for VTE, giving it a high negative predictive value. Further, duplex ultrasound often remains abnormal after VTE, making the distinction between recurrent disease and old disease problematic when symptoms recur.

A recent study by Rathbun and colleagues investigated the use of D-dimer measurement in excluding recurrent VTE, finding that of former VTE patients presenting with symptoms, only 0.75% with a negative D-dimer level had recurrent VTE on ultrasound, compared to 6.0% with a positive test who had recurrent VTE. This study, conducted by Palareti and colleagues, tries to go a step further and assess whether D-dimer testing can be used to risk stratify VTE patients who are asymptomatic following treatment for an initial episode of VTE, as well as whether or not it can be used to determine the need to continue anticoagulation.

The PROLONG study was a multicenter prospective study of patients between 18 and 85 who had had their first episode of unprovoked, symptomatic VTE (including pulmonary embolism). Patients were enrolled in this study after completing treatment with vitamin K antagonists (VKA) for at least three months with a target INR (international normalized ratio) in the range of 2-3. Exclusion criteria included severe liver insufficiency, renal insufficiency with serum creatinine >2, or clear indications/contraindications for anticoagulation.

Six hundred twenty-four patients treated for VTE were enrolled in the study. All underwent compressive ultrasound in both legs to establish a baseline at the start of the study and were then instructed to stop anticoagulation. Follow-up occurred in one month, with another ultrasound to assess recurrence of VTE. Five patients were found to have VTE and were excluded. The remaining 619 patients were tested for D-dimer levels and were given thrombophilia tests. A further 11 patients were excluded due to antiphospholipid antibodies or antithrombin deficiency. Patients with factor V Leidin and G20210A mutation on the prothrombin gene were allowed to participate in the study.

Three hundred and eighty-five patients had normal D-dimer levels and were not placed on anticoagulation. The 223 patients with abnormal D-dimer levels were randomized to receive VKA (103 patients) or no treatment (120 patients). All patients were followed for minimum of 18 months. Of the 120 patients with abnormal D-dimer levels who were randomized to no treatment, 18 patients (15.0%) had recurrent VTE. Of the 103 patients with abnormal D-dimer levels who resumed anticoagulation, one had a major bleeding episode and two had recurrent VTE, for a composite result of 2.9%—a statistically significant difference (P<0.005). The group with normal D-dimer levels after initial treatment had 24 episodes of recurrent VTE (6.2%).

The study suggested that the patients with abnormal D-dimer levels who stopped anticoagulation had a statistically significant higher rate of recurrent VTE than those who continued anticoagulation. There was also a statistically significant difference in the recurrent VTE rate in the two groups who did not resume anticoagulation. Interestingly, while the absolute difference between the normal D-dimer group and the abnormal D-dimer group who resumed anticoagulation was evident (6.2% versus 2.9%), this did not reach statistical significance.

This study is promising; however, there are some caveats to take into account when trying to apply these results to current clinical practice. First, the trial was not blinded and only evaluated patients with the first unprovoked episode of VTE. It is unknown if these results will apply to secondary VTE. Older people in this study had a higher incidence of elevated D-dimer at enrollment. The authors utilized a qualitative assay for D-dimer to obtain uniform results across the multiple testing centers. Applying these results to centers that use quantitative measurements of D-dimer then becomes more difficult due to the variability inherent in the interpretation of these quantitative results. Because this study excluded patients with either severe liver disease or renal insufficiency (Cr >2.0), it remains unknown if the results are applicable to these populations.

Because D-dimer levels were only measured once at the time of the patients’ enrollment in the study, it is unknown if patients with normal levels of D-dimer might progress to abnormal D-dimer levels and, therefore, to a potentially higher risk of VTE. This question could be answered with serial testing of D-dimer levels. The study was not powered enough to detect relative risk of bleeding from anticoagulation alone. Thus, these results were taken as a composite with the VTE events.

This study argues that anticoagulation in VTE patients with abnormal D-dimer levels measured after a month of stopping a standard three-month course of anticoagulation should be continued. What is not clear is whether we should continue treating people with normal D-dimer levels. Although not statistically significant, the absolute rate of VTE of 6.2% in these patients was higher than the 2.9% rate in patients with high D-dimer levels who continued anticoagulation.

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.

Early Administration of ACE Inhibitors in MI Patients

Borghi C, Bacchelli S, Degli Esposti D, et al. Effects of early angiotensin-converting enzyme inhibition in patients with non-ST-elevation acute anterior myocardial infarction. Am Heart J. 2006 Sep;152(3):470-477.

Angiotensin-converting enzyme inhibitors (ACEIs) have demonstrated efficacy in improving long-term survival, particularly in patients with ST-elevation MI (STEMI) with left ventricular dysfunction (LVD) and/or congestive heart failure (CHF). There is less information available from clinical trial data, however, regarding the early use of ACEIs with non-ST-elevation MI (NSTEMI) patients, who are believed to be at an overall lower risk of in-hospital morbidity and mortality than STEMI patients.

Researchers focused on the question of ACEI efficacy in NSTEMI in a post hoc analysis of the patients enrolled in the Survival of Myocardial Infarction Long-term Evaluation (SMILE) study. The original study enrolled 1,556 patients with anterior acute MI (AMI) who were admitted to 154 coronary care units in Italy. Participants were patients who presented with chest pain within 24 hours, who demonstrated electrocardiographic signs of anterior wall AMI, and who were not eligible for thrombolytic therapy or reperfusion. These patients did receive beta blockers, nitrates, analgesic agents, inotropic drugs, diuretic agents, and anticoagulation agents as deemed appropriate.

Exclusion criteria included cardiogenic shock, systolic blood pressure below 100 mm Hg, serum creatinine above 2.5 mg per deciliter, a history of CHF, prior treatment with ACEI, and contraindication to the use of ACEI. Patients were randomized to either placebo or the short-acting ACEI zofenopril, with a starting dose of 7.5 mg every 12 hours. The dose was progressively doubled until the final target dose of 30 mg twice a day was reached. Upon completion of a six-week double-blind period, the study medications were stopped, but the patients continued taking their other medications for approximately 48 additional weeks, at which time vital status was blindly obtained by questionnaire or from registry offices. The primary endpoints were the occurrence of death or CHF during the treatment period.

In this post hoc analysis, only the 526 patients with anterior MI were studied. The baseline characteristics of the placebo and zofenopril group were closely matched but were predominantly male. The primary endpoint of this analysis was the combined occurrence of death or severe CHF during the six weeks of treatment with zofenopril or placebo, both given in addition to conventional treatment. Secondary endpoints were the six-week occurrence of severe CHF, nonfatal MI or angina, and cumulative one-year mortality.

The findings of this analysis indicate a relative risk reduction (RRR) of 65% (95% CI 20%­80%, 2P=0.003) of a major cardiovascular event using zofenopril in the first 6 weeks of treatment. Cumulative incidence of combined death and CHF was significantly (P=0.017) greater in the placebo group than in the group of patients given zofenopril. In addition, occurrence of severe CHF was lower in the zofenopril group (RRR 84%, 95% CI 33%­97%), as was one-year mortality (RRR 43%, 95% CI 14%-57%, 2P=0.36). During the six weeks, there was a slightly lower usage of beta blockers in the zofenopril group, as well as lower usage of calcium channel blockers and diuretics in this same group at one year. Systolic blood pressure (SBP) and heart rate did not differ between the two groups.

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

Classic Literature

Perioperative Use of Beta Blockers to Reduce Ischemia

Mangano DT, Layug EL, Wallace A, et al. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med. 1996 Dec 5;335(23):1713-1720.

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.


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