Brian Harte, MD

The pendulum of expert opinion is swinging away from routinely recommending beta-blockers to prevent cardiac events in non-cardiac surgery patients. We won’t be abandoning the perioperative use of beta-blockers altogether, but we will probably be using them more selectively than in the past.

The latest factor driving the trend is the online publication in May 2008 of the results of the Perioperative Ischemic Evaluation (POISE) trial,¹ the largest placebo-controlled trial of perioperative beta-blocker use to date. In brief, in a cohort of patients with atherosclerotic disease or at risk for it who were undergoing noncardiac surgery, fewer patients who received extended-release metoprolol succinate had a myocardial infarction, but more of them died or had a stroke compared with those receiving placebo. (Extended-release metoprolol succinate is available in the United States as Toprol-XL and generically.)

Not so long ago, the pendulum was going the other way. After two small trials in the 1990s concluded that beta-blockers reduced the risk of perioperative cardiac events in selected patients with known or suspected coronary disease,^2,3 their perioperative use was subsequently endorsed by the Leapfrog Group and the Agency for Healthcare Research and Quality. The National Quality Forum included perioperative beta-blockade in its “Safe Practices for Better Healthcare 2006 update,”^4,5 and the Physician Consortium for Performance Improvement and the Surgical Care Improvement Project both listed it as a quality measure.

Since then, this practice has been closely studied, especially as concomitant research has failed to demonstrate that pre-operative coronary revascularization improves outcomes, even in the presence of ischemic disease. But evidence has been accumulating that routine use of beta-blockers may not benefit as many patients as was hoped, and may actually cause harm. The 2007 joint American College of Cardiology (ACC) and American Heart Association (AHA) guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery gives its strongest recommendation (class I: benefit clearly outweighs risk) for perioperative beta-blocker use only for patients at high risk: those with known ischemic heart disease undergoing vascular surgery and those who are already on these drugs before surgery.⁶

However, there are still gaps in our knowledge. Perhaps, with proper implementation, we may be able to use beta-blockers to improve outcomes in patients at intermediate risk as well. In this paper, we review the rationale and the evidence for and against perioperative use of beta-blockers and provide practical guidance for internists and hospitalists.

WHY CARDIAC EVENTS OCCUR AFTER SURGERY

Adverse cardiovascular events such as myocardial infarction and unstable angina are the leading causes of death after surgery.⁷ Such events occur in approximately 1% of patients older than 50 years undergoing elective inpatient surgery, but this number may be higher (approximately 5%) in those with known or suspected coronary disease.^8,9 Perioperative cardiac events can also be harbingers of further complications, dramatically increasing hospital length of stay.¹⁰

Some ischemic events are caused by physiologic derangements involving the balance between inflammatory mediators, sympathetic tone, and oxygen supply and demand that occur under the stress of surgery. Others are more “traditional” in etiology, involving acute plaque rupture, thrombosis, and occlusion. Studies have consistently found a correlation between perioperative ischemia and cardiac events (both in-hospital and long-term) and death.^11–17 Other studies suggest that most perioperative cardiac infarcts are non-Q-wave events,¹⁸ and most events occur within the first few days after surgery, particularly the first 48 hours, when the effects of anesthetics, pain, fluid shifts, and physiologic derangements are greatest.

Factors that may trigger acute occlusion in the perioperative period include abrupt changes in sympathetic tone, increased levels of cortisol and catecholamines, and tissue hypoxia. Other potential triggers activated or increased by the stress of surgery include coagulation factors such as alterations in platelet function; inflammatory factors such as tumor necrosis factor alpha, interleukin 1, interleukin 6, and C-reactive protein; and metabolism of free fatty acids (which contribute to increased oxygen demand as well as endothelial dysfunction).^9,19,20

A 1996 autopsy study found that 38 (90%) of 42 patients who died of a perioperative infarct had evidence of acute plaque rupture or plaque hemorrhage on coronary sectioning, findings corroborated in another, similar study.^21,22 These studies suggest that multiple causes contribute to perioperative myocardial infarction, and a single strategy may not suffice for prevention.

IF BETA-BLOCKERS PROTECT, HOW DO THEY DO IT?

Beta-blockers have several effects that should, in theory, protect against cardiac events during and after surgery.²³ They reduce cardiac oxygen demand by reducing the force of contraction and the heart rate, and they increase the duration of diastole, when the heart muscle is perfused. They are also antiarrhythmic, and they may limit free radical production, metalloproteinase activity, and myocardial plaque inflammation.²⁴

Some researchers have speculated that using beta-blockers long-term may alter intra-cellular signaling processes, for example decreasing the expression of receptors that receive signals for cell death, which in turn may affect the response to reperfusion cell injury and death. If this is true, there may be an advantage to starting beta-blockers well in advance of surgery.²⁵

EARLY CLINICAL EVIDENCE IN FAVOR OF PERIOPERATIVE BETA-BLOCKER USE

Evidence in patients at high risk

Mangano et al,² in a study published in 1996, randomized 200 patients with known coronary disease or established risk factors for it who were undergoing noncardiac surgery to receive the beta-blocker atenolol orally and intravenously or placebo in the immediate perioperative period. Fewer patients in the atenolol group died in the first 6 months after hospital discharge (0 vs 8%, P < .001), the first year (3% vs 14%, P = .005), and the first 2 years (10% vs 21%, P = .019). However, there was no difference in short-term outcomes, and the study excluded patients who died in the immediate postoperative period. If these patients had been included in the analysis, the difference in the death rate at 2 years would not have been statistically significant.²⁶ Other critical findings: more patients in the atenolol group were using angiotensin-converting enzyme inhibitors and beta-blockers when they were discharged, and the placebo group had slightly more patients with prior myocardial infarction or diabetes.²⁷ (Atenolol is available in the United Sates as Tenormin and generically.)

Poldermans et al,³ in a study published in 1999, randomized 112 vascular surgery patients to receive either oral bisoprolol or placebo. These patients were selected from a larger cohort of 1,351 patients on the basis of high-risk clinical features and abnormal results on dobutamine echocardiography. Bisoprolol was started at least 1 week before surgery (range 7–89 days, mean 37 days), and patients were reevaluated before surgery so that the dose could be titrated to a goal heart rate of less than 60 beats per minute. After surgery, the drug was continued for another 30 days. The study was stopped early because the bisoprolol group had a 90% lower rate of non-fatal myocardial infarction and cardiac death at 30 days. Despite the study’s limitation (eg, enrolling selected patients and using an unblinded protocol), these compelling findings made a strong case for the use of beta-blockers perioperatively in patients at high risk, ie, those with ischemic heart disease who are undergoing major vascular surgery. (Bisoprolol is available in the United States as Zebeta and generically)

Evidence in patients at intermediate risk

Boersma et al²⁸ performed a follow-up to the study by Poldermans et al, published in 2001, in which they analyzed characteristics of all 1,351 patients who had been originally considered for enrollment. Using regression analysis, they identified seven clinical risk factors that predicted adverse cardiac events: angina, prior myocardial infarction, congestive heart failure, prior stroke, diabetes, renal failure, and age 70 years or older. Furthermore, for the entire cohort, patients receiving beta-blockers had a lower risk of cardiac complications (0.8%) than those not receiving beta-blockers (2.3%). In particular, the patients at intermediate risk (defined as having one or two risk factors) had a very low event rate regardless of stress test results, provided they were on beta-blockers: their risk of death or myocardial infarction was 0.9%, compared with 3.0% for those not on beta-blockers.

The authors concluded that dobutamine stress testing may not be necessary in patients at intermediate risk if beta-blockers are appropriately prescribed. However, others took issue with their data and conclusions, arguing that there have been so few trials that the data are still inconclusive and inadequate to ascertain the benefit of perioperative beta-blockade, particularly in patients not at high risk.^26,29

The Revised Cardiac Risk Index. Although the Boersma risk-factor index is not used in general practice, numerous experts^27,20–32 recommend a similar one, the Revised Cardiac Risk Index, devised by Lee et al.⁸ This index consists of six risk factors, each of which is worth one point:

• Congestive heart failure, based on history or examination
• Myocardial infarction, symptomatic ischemic heart disease, or a positive stress test
• Renal insufficiency (ie, serum creatinine level > 2 mg/dL)
• History of stroke or transient ischemic attack
• Diabetes requiring insulin
• High-risk surgery (defined as intrathoracic, intra-abdominal, or suprainguinal vascular surgery).

Patients with three or more points are considered to be at high risk, and those with one or two points are considered to be at intermediate risk. The ACC/AHA 2007 guidelines⁶ use a modified version of this index that considers the issue of surgical risk separately from the other five clinical conditions.

Devereaux et al³³ performed a meta-analysis, published in 2005, of 22 studies of perioperative beta-blockade. They concluded that beta-blockers had no discernable benefit in any outcome measured, including deaths from any cause, deaths from cardiovascular causes, other cardiac events, hypotension, bradycardia, and bronchospasm. However, they based this conclusion on the use of a 99% confidence interval for each relative risk, which they believed was justified because the trials were small and the numbers of events were only moderate. When the outcomes are assessed using the more common 95% confidence interval, benefit was detected in the combined end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal cardiac arrest.

Yang et al,³⁴ Brady et al,³⁵ and Juul et al³⁶ performed three subsequent randomized trials that added to the controversy. Most of the patients in these trials were at intermediate or low risk, and none of the trials found a significant benefit with perioperative beta-blocker use. However, the protocols in these studies were different from the one in the study by Poldermans et al,³ which had found perioperative beta-blockade to be beneficial. Whereas patients in that earlier study started taking a beta-blocker at least 1 week before surgery (and on average much earlier), had their dose aggressively titrated to a target heart rate, and continued taking it for 30 days afterward, the protocols in the later trials called for the drug to be started within 24 hours before surgery and continued for only a short time afterward.

Lindenauer et al,³⁷ in a retrospective study published in 2005, found that fewer surgical patients who received beta-blockers in the hospital died in the hospital. The researchers used an administrative database of more than 780,000 patients who underwent noncardiac surgery, and they used propensity-score matching to compare the postoperative mortality rates of patients who received beta-blockers and a matched group in the same large cohort who did not. Beta-blockers were associated with a lower morality rate in patients in whom the Revised Cardiac Risk Index score was 3 or greater. However, although there was a trend toward a lower rate with beta-blocker use in patients whose score was 2 (ie, at intermediate risk), the difference was not statistically significant, and patients with a score of 0 or 1 saw no benefit and were possibly harmed.

The authors admitted that their study had a number of limitations, including a retrospective design and the use of an administrative database for information regarding risk index conditions and comorbidities. In addition, because they assumed that any patient who received a beta-blocker on the first 2 hospital days was receiving appropriate perioperative treatment, they may have incorrectly estimated the number of patients who actually received these drugs as a risk-reduction strategy. For instance, some patients at low risk could have received beta-blockers for treatment of a specific event, which would be reflected as an increase in event rates for this group. They also had no data on what medications the patients received before they were hospitalized or whether the dose was titrated effectively. The study excluded all patients with congestive heart failure and chronic obstructive pulmonary disease, who may be candidates for beta-blockers in actual practice. In fact, a recent observational study in patients with severe left ventricular dysfunction suggested that these drugs substantially reduced the incidence of death in the short term and the long term.³⁸ Finally, half the surgeries were nonelective, which makes extrapolation of their risk profile by the Revised Cardiac Risk Index difficult, since Lee et al excluded patients undergoing emergency surgery from the cohorts from which they derived and validated their index criteria.

Nevertheless, the authors concluded that patients at intermediate risk derive no benefit from perioperative beta-blocker use, and that the odds ratio for death was actually higher in patients with no risk factors who received a beta-blocker.

DOES PERIOPERATIVE BETA-BLOCKER USE CAUSE HARM?

The published data on whether perioperative beta-blocker use harms patients are conflicting and up to now have been limited.

Stone et al³⁹ reported a substantial incidence of bradycardia requiring atropine in patients treated with a single dose of a beta-blocker preoperatively, but the complications were not clearly characterized.

The Perioperative Beta-Blockade trial.³⁵ Significantly more patients given short-acting metoprolol had intraoperative falls in blood pressure and heart rate, and more required inotropic support during surgery, although the treating anesthesiologists refused to be blinded in that study. (Short-acting metoprolol is available in the United States as Lopressor and generically.)

Devereaux et al,³³ in their meta-analysis, found a higher risk of bradycardia requiring treatment (but not a higher risk of hypotension) in beta-blocker users in nine studies, including the study by Stone et al and the Perioperative Beta-Blockade trial (relative risk 2.27, 95% confidence interval 1.36–3.80).

Conversely, at least three other studies found no difference in rates of intraoperative events.^36,40,41 There are few data on the incidence of other complications such as perioperative pulmonary edema and bronchospasm.

POISE: THE FIRST LARGE RANDOMIZED TRIAL

In May 2008, results were published from POISE, the first large randomized controlled trial of perioperative beta-blockade.¹ An impressive 8,351 patients—most of them at intermediate risk—were randomized to receive extended-release metoprolol succinate or placebo starting just before surgery and continuing for 30 days afterward.

Although the incidence of the primary composite end point (cardiovascular death, nonfatal myocardial infarction, and nonfatal cardiac arrest) was lower at 30 days in the metoprolol group than in the placebo group (5.8% vs 6.9%, hazard ratio 0.83, P = .04), other findings were worrisome: more metoprolol recipients died of any cause (3.1% vs 2.3%, P = .03) or had a stroke (1.0% vs 0.5%, P = .005). The major contributor to the higher mortality rate in this group appears to have been sepsis.

How beta-blockers might promote death by sepsis is unclear. The authors offered two possible explanations: perhaps beta-blocker-induced hypotension predisposes patients to infection and sepsis, or perhaps the slower heart rate and lower force of contraction induced by beta-blockers could mask normal responses to systemic infection, which in turn could delay recognition and treatment or impede the normal immune response. These mechanisms, like others, are speculative.

The risks of other adverse outcomes such as bradycardia and hypotension were substantially higher in the metoprolol group. The authors also pointed out that most of the patients who suffered nonfatal strokes were subsequently disabled or incapacitated, while most of those who suffered nonfatal cardiac events did not progress to further cardiac problems.

This new study has not yet been rigorously debated, but it will likely come under scrutiny for its dosing regimen (extended-release metoprolol succinate 100 mg or placebo 2–4 hours before surgery; another 100 mg or placebo 6 hours after surgery or sooner if the heart rate was 80 beats per minute or more and the systolic blood pressure 100 mm Hg or higher; and then 200 mg or placebo 12 hours after the second dose and every 24 hours thereafter for 30 days). This was fairly aggressive, especially for patients who have never received a beta-blocker before. In contrast, the protocol for the Perioperative Beta-Blockade trial called for only 25 to 50 mg of short-acting metoprolol twice a day. Another criticism is that the medication was started only a few hours before surgery, although there is no current standard practice for either the dose or when the treatment should be started. The population had a fairly high rate of cerebrovascular disease (perhaps predisposing to stroke whenever blood pressure dropped), and 10% of patients were undergoing urgent or emergency surgery, which carries a higher risk of morbidity.

ANY ROLE FOR BETA-BLOCKERS IN THOSE AT INTERMEDIATE RISK?

Thus, in the past decade, the appropriate perioperative use of beta-blockers, which, after the findings by Mangano et al and Poldermans et al, were seen as potentially beneficial for any patient at risk of coronary disease, with little suggestion of harm, has become more clearly defined, and the risks are more evident. The most compelling evidence in favor of using them comes from patients with ischemic heart disease undergoing vascular surgery; the 2007 ACC/AHA guidelines recommend that this group be offered beta-blockers in the absence of a contraindication (class I recommendation: benefit clearly outweighs risk).⁶ The guidelines also point out that these drugs should be continued in patients already taking them for cardiac indications before surgery, because ischemia may be precipitated if a beta-blocker is abruptly discontinued.^42,43

Additionally, the guidelines recommend considering beta-blockers for vascular surgery patients at high cardiac risk (with a Revised Cardiac Risk Index score of 3 or more), even if they are not known to have ischemic heart disease. This is a class IIa recommendation (the benefit outweighs the risk, but more studies are required).

The guidelines also recommend that beta-blockers be considered for patients who have a score of 0 if they are undergoing vascular surgery (class IIb recommendation) or a score of 1 if they are undergoing vascular surgery (class IIa recommendation) or intermediate-risk surgery (class IIb recommendation). However, in view of the POISE results, these recommendations need to be carefully scrutinized.

These data notwithstanding, beta-blockers still might be beneficial in perioperative patients at intermediate risk.

Start beta-blockers sooner?

To help patients at intermediate risk (such as those with diabetes without known heart disease), we may need to do what Poldermans et al did³: instead of seeing patients only once a day or two before surgery, we may need to do the preoperative assessment as much as a month before and, if necessary, start a beta-blocker at a low dose, titrate it to a goal heart rate, and follow the patient closely up until surgery and afterward.

The importance of heart-rate control was illustrated in a recent cohort study of perioperative beta-blockers in vascular surgery patients,⁴⁴ in which higher beta-blocker doses, carefully monitored, were associated with less ischemia and cardiac enzyme release. In addition, long-term mortality rates were lower in patients with lower heart rates. And Poldermans et al⁴⁵ recently performed a study in more than 700 intermediate-risk patients who were divided into two groups, one that underwent preoperative stress testing and one that did not. Beta-blockers were given to both groups, and doses were titrated to a goal heart rate of less than 65. The patients with optimally controlled heart rates had the lowest event rates.

However, the logistics of such a program would be challenging. For the most part, internists and hospitalists involved in perioperative assessment do not control the timing of referral or surgery, and adjustments cannot be made for patients whose preoperative clinic visit falls only a few days before surgery. Instituting a second or third visit to assess the efficacy of beta-blockade burdens the patient and may not be practical.

Are all beta-blockers equivalent?

An additional factor is the choice of agent. While the most significant studies of perioperative beta-blockade have used beta-1 receptor-selective agents (ie, metoprolol, atenolol, and bisoprolol), there is no prospective evidence that any particular agent is superior. However, a recent retrospective analysis of elderly surgical patients did suggest that longer-acting beta-blockers may be preferable: patients who had been on atenolol in the year before surgery had a 20% lower risk of postoperative myocardial infarction or death than those who had been on short-acting metoprolol, with no difference in noncardiac outcomes.⁴⁶

The pendulum of expert opinion is swinging away from routinely recommending beta-blockers to prevent cardiac events in non-cardiac surgery patients. We won’t be abandoning the perioperative use of beta-blockers altogether, but we will probably be using them more selectively than in the past.

The latest factor driving the trend is the online publication in May 2008 of the results of the Perioperative Ischemic Evaluation (POISE) trial,¹ the largest placebo-controlled trial of perioperative beta-blocker use to date. In brief, in a cohort of patients with atherosclerotic disease or at risk for it who were undergoing noncardiac surgery, fewer patients who received extended-release metoprolol succinate had a myocardial infarction, but more of them died or had a stroke compared with those receiving placebo. (Extended-release metoprolol succinate is available in the United States as Toprol-XL and generically.)

Not so long ago, the pendulum was going the other way. After two small trials in the 1990s concluded that beta-blockers reduced the risk of perioperative cardiac events in selected patients with known or suspected coronary disease,^2,3 their perioperative use was subsequently endorsed by the Leapfrog Group and the Agency for Healthcare Research and Quality. The National Quality Forum included perioperative beta-blockade in its “Safe Practices for Better Healthcare 2006 update,”^4,5 and the Physician Consortium for Performance Improvement and the Surgical Care Improvement Project both listed it as a quality measure.

Since then, this practice has been closely studied, especially as concomitant research has failed to demonstrate that pre-operative coronary revascularization improves outcomes, even in the presence of ischemic disease. But evidence has been accumulating that routine use of beta-blockers may not benefit as many patients as was hoped, and may actually cause harm. The 2007 joint American College of Cardiology (ACC) and American Heart Association (AHA) guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery gives its strongest recommendation (class I: benefit clearly outweighs risk) for perioperative beta-blocker use only for patients at high risk: those with known ischemic heart disease undergoing vascular surgery and those who are already on these drugs before surgery.⁶

However, there are still gaps in our knowledge. Perhaps, with proper implementation, we may be able to use beta-blockers to improve outcomes in patients at intermediate risk as well. In this paper, we review the rationale and the evidence for and against perioperative use of beta-blockers and provide practical guidance for internists and hospitalists.

WHY CARDIAC EVENTS OCCUR AFTER SURGERY

Adverse cardiovascular events such as myocardial infarction and unstable angina are the leading causes of death after surgery.⁷ Such events occur in approximately 1% of patients older than 50 years undergoing elective inpatient surgery, but this number may be higher (approximately 5%) in those with known or suspected coronary disease.^8,9 Perioperative cardiac events can also be harbingers of further complications, dramatically increasing hospital length of stay.¹⁰

Some ischemic events are caused by physiologic derangements involving the balance between inflammatory mediators, sympathetic tone, and oxygen supply and demand that occur under the stress of surgery. Others are more “traditional” in etiology, involving acute plaque rupture, thrombosis, and occlusion. Studies have consistently found a correlation between perioperative ischemia and cardiac events (both in-hospital and long-term) and death.^11–17 Other studies suggest that most perioperative cardiac infarcts are non-Q-wave events,¹⁸ and most events occur within the first few days after surgery, particularly the first 48 hours, when the effects of anesthetics, pain, fluid shifts, and physiologic derangements are greatest.

Factors that may trigger acute occlusion in the perioperative period include abrupt changes in sympathetic tone, increased levels of cortisol and catecholamines, and tissue hypoxia. Other potential triggers activated or increased by the stress of surgery include coagulation factors such as alterations in platelet function; inflammatory factors such as tumor necrosis factor alpha, interleukin 1, interleukin 6, and C-reactive protein; and metabolism of free fatty acids (which contribute to increased oxygen demand as well as endothelial dysfunction).^9,19,20

A 1996 autopsy study found that 38 (90%) of 42 patients who died of a perioperative infarct had evidence of acute plaque rupture or plaque hemorrhage on coronary sectioning, findings corroborated in another, similar study.^21,22 These studies suggest that multiple causes contribute to perioperative myocardial infarction, and a single strategy may not suffice for prevention.

IF BETA-BLOCKERS PROTECT, HOW DO THEY DO IT?

Beta-blockers have several effects that should, in theory, protect against cardiac events during and after surgery.²³ They reduce cardiac oxygen demand by reducing the force of contraction and the heart rate, and they increase the duration of diastole, when the heart muscle is perfused. They are also antiarrhythmic, and they may limit free radical production, metalloproteinase activity, and myocardial plaque inflammation.²⁴

Some researchers have speculated that using beta-blockers long-term may alter intra-cellular signaling processes, for example decreasing the expression of receptors that receive signals for cell death, which in turn may affect the response to reperfusion cell injury and death. If this is true, there may be an advantage to starting beta-blockers well in advance of surgery.²⁵

EARLY CLINICAL EVIDENCE IN FAVOR OF PERIOPERATIVE BETA-BLOCKER USE

Evidence in patients at high risk

Mangano et al,² in a study published in 1996, randomized 200 patients with known coronary disease or established risk factors for it who were undergoing noncardiac surgery to receive the beta-blocker atenolol orally and intravenously or placebo in the immediate perioperative period. Fewer patients in the atenolol group died in the first 6 months after hospital discharge (0 vs 8%, P < .001), the first year (3% vs 14%, P = .005), and the first 2 years (10% vs 21%, P = .019). However, there was no difference in short-term outcomes, and the study excluded patients who died in the immediate postoperative period. If these patients had been included in the analysis, the difference in the death rate at 2 years would not have been statistically significant.²⁶ Other critical findings: more patients in the atenolol group were using angiotensin-converting enzyme inhibitors and beta-blockers when they were discharged, and the placebo group had slightly more patients with prior myocardial infarction or diabetes.²⁷ (Atenolol is available in the United Sates as Tenormin and generically.)

Poldermans et al,³ in a study published in 1999, randomized 112 vascular surgery patients to receive either oral bisoprolol or placebo. These patients were selected from a larger cohort of 1,351 patients on the basis of high-risk clinical features and abnormal results on dobutamine echocardiography. Bisoprolol was started at least 1 week before surgery (range 7–89 days, mean 37 days), and patients were reevaluated before surgery so that the dose could be titrated to a goal heart rate of less than 60 beats per minute. After surgery, the drug was continued for another 30 days. The study was stopped early because the bisoprolol group had a 90% lower rate of non-fatal myocardial infarction and cardiac death at 30 days. Despite the study’s limitation (eg, enrolling selected patients and using an unblinded protocol), these compelling findings made a strong case for the use of beta-blockers perioperatively in patients at high risk, ie, those with ischemic heart disease who are undergoing major vascular surgery. (Bisoprolol is available in the United States as Zebeta and generically)

Evidence in patients at intermediate risk

Boersma et al²⁸ performed a follow-up to the study by Poldermans et al, published in 2001, in which they analyzed characteristics of all 1,351 patients who had been originally considered for enrollment. Using regression analysis, they identified seven clinical risk factors that predicted adverse cardiac events: angina, prior myocardial infarction, congestive heart failure, prior stroke, diabetes, renal failure, and age 70 years or older. Furthermore, for the entire cohort, patients receiving beta-blockers had a lower risk of cardiac complications (0.8%) than those not receiving beta-blockers (2.3%). In particular, the patients at intermediate risk (defined as having one or two risk factors) had a very low event rate regardless of stress test results, provided they were on beta-blockers: their risk of death or myocardial infarction was 0.9%, compared with 3.0% for those not on beta-blockers.

The authors concluded that dobutamine stress testing may not be necessary in patients at intermediate risk if beta-blockers are appropriately prescribed. However, others took issue with their data and conclusions, arguing that there have been so few trials that the data are still inconclusive and inadequate to ascertain the benefit of perioperative beta-blockade, particularly in patients not at high risk.^26,29

The Revised Cardiac Risk Index. Although the Boersma risk-factor index is not used in general practice, numerous experts^27,20–32 recommend a similar one, the Revised Cardiac Risk Index, devised by Lee et al.⁸ This index consists of six risk factors, each of which is worth one point:

• Congestive heart failure, based on history or examination
• Myocardial infarction, symptomatic ischemic heart disease, or a positive stress test
• Renal insufficiency (ie, serum creatinine level > 2 mg/dL)
• History of stroke or transient ischemic attack
• Diabetes requiring insulin
• High-risk surgery (defined as intrathoracic, intra-abdominal, or suprainguinal vascular surgery).

Patients with three or more points are considered to be at high risk, and those with one or two points are considered to be at intermediate risk. The ACC/AHA 2007 guidelines⁶ use a modified version of this index that considers the issue of surgical risk separately from the other five clinical conditions.

Devereaux et al³³ performed a meta-analysis, published in 2005, of 22 studies of perioperative beta-blockade. They concluded that beta-blockers had no discernable benefit in any outcome measured, including deaths from any cause, deaths from cardiovascular causes, other cardiac events, hypotension, bradycardia, and bronchospasm. However, they based this conclusion on the use of a 99% confidence interval for each relative risk, which they believed was justified because the trials were small and the numbers of events were only moderate. When the outcomes are assessed using the more common 95% confidence interval, benefit was detected in the combined end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal cardiac arrest.

Yang et al,³⁴ Brady et al,³⁵ and Juul et al³⁶ performed three subsequent randomized trials that added to the controversy. Most of the patients in these trials were at intermediate or low risk, and none of the trials found a significant benefit with perioperative beta-blocker use. However, the protocols in these studies were different from the one in the study by Poldermans et al,³ which had found perioperative beta-blockade to be beneficial. Whereas patients in that earlier study started taking a beta-blocker at least 1 week before surgery (and on average much earlier), had their dose aggressively titrated to a target heart rate, and continued taking it for 30 days afterward, the protocols in the later trials called for the drug to be started within 24 hours before surgery and continued for only a short time afterward.

Lindenauer et al,³⁷ in a retrospective study published in 2005, found that fewer surgical patients who received beta-blockers in the hospital died in the hospital. The researchers used an administrative database of more than 780,000 patients who underwent noncardiac surgery, and they used propensity-score matching to compare the postoperative mortality rates of patients who received beta-blockers and a matched group in the same large cohort who did not. Beta-blockers were associated with a lower morality rate in patients in whom the Revised Cardiac Risk Index score was 3 or greater. However, although there was a trend toward a lower rate with beta-blocker use in patients whose score was 2 (ie, at intermediate risk), the difference was not statistically significant, and patients with a score of 0 or 1 saw no benefit and were possibly harmed.

The authors admitted that their study had a number of limitations, including a retrospective design and the use of an administrative database for information regarding risk index conditions and comorbidities. In addition, because they assumed that any patient who received a beta-blocker on the first 2 hospital days was receiving appropriate perioperative treatment, they may have incorrectly estimated the number of patients who actually received these drugs as a risk-reduction strategy. For instance, some patients at low risk could have received beta-blockers for treatment of a specific event, which would be reflected as an increase in event rates for this group. They also had no data on what medications the patients received before they were hospitalized or whether the dose was titrated effectively. The study excluded all patients with congestive heart failure and chronic obstructive pulmonary disease, who may be candidates for beta-blockers in actual practice. In fact, a recent observational study in patients with severe left ventricular dysfunction suggested that these drugs substantially reduced the incidence of death in the short term and the long term.³⁸ Finally, half the surgeries were nonelective, which makes extrapolation of their risk profile by the Revised Cardiac Risk Index difficult, since Lee et al excluded patients undergoing emergency surgery from the cohorts from which they derived and validated their index criteria.

Nevertheless, the authors concluded that patients at intermediate risk derive no benefit from perioperative beta-blocker use, and that the odds ratio for death was actually higher in patients with no risk factors who received a beta-blocker.

DOES PERIOPERATIVE BETA-BLOCKER USE CAUSE HARM?

The published data on whether perioperative beta-blocker use harms patients are conflicting and up to now have been limited.

Stone et al³⁹ reported a substantial incidence of bradycardia requiring atropine in patients treated with a single dose of a beta-blocker preoperatively, but the complications were not clearly characterized.

The Perioperative Beta-Blockade trial.³⁵ Significantly more patients given short-acting metoprolol had intraoperative falls in blood pressure and heart rate, and more required inotropic support during surgery, although the treating anesthesiologists refused to be blinded in that study. (Short-acting metoprolol is available in the United States as Lopressor and generically.)

Devereaux et al,³³ in their meta-analysis, found a higher risk of bradycardia requiring treatment (but not a higher risk of hypotension) in beta-blocker users in nine studies, including the study by Stone et al and the Perioperative Beta-Blockade trial (relative risk 2.27, 95% confidence interval 1.36–3.80).

Conversely, at least three other studies found no difference in rates of intraoperative events.^36,40,41 There are few data on the incidence of other complications such as perioperative pulmonary edema and bronchospasm.

POISE: THE FIRST LARGE RANDOMIZED TRIAL

In May 2008, results were published from POISE, the first large randomized controlled trial of perioperative beta-blockade.¹ An impressive 8,351 patients—most of them at intermediate risk—were randomized to receive extended-release metoprolol succinate or placebo starting just before surgery and continuing for 30 days afterward.

Although the incidence of the primary composite end point (cardiovascular death, nonfatal myocardial infarction, and nonfatal cardiac arrest) was lower at 30 days in the metoprolol group than in the placebo group (5.8% vs 6.9%, hazard ratio 0.83, P = .04), other findings were worrisome: more metoprolol recipients died of any cause (3.1% vs 2.3%, P = .03) or had a stroke (1.0% vs 0.5%, P = .005). The major contributor to the higher mortality rate in this group appears to have been sepsis.

How beta-blockers might promote death by sepsis is unclear. The authors offered two possible explanations: perhaps beta-blocker-induced hypotension predisposes patients to infection and sepsis, or perhaps the slower heart rate and lower force of contraction induced by beta-blockers could mask normal responses to systemic infection, which in turn could delay recognition and treatment or impede the normal immune response. These mechanisms, like others, are speculative.

The risks of other adverse outcomes such as bradycardia and hypotension were substantially higher in the metoprolol group. The authors also pointed out that most of the patients who suffered nonfatal strokes were subsequently disabled or incapacitated, while most of those who suffered nonfatal cardiac events did not progress to further cardiac problems.

This new study has not yet been rigorously debated, but it will likely come under scrutiny for its dosing regimen (extended-release metoprolol succinate 100 mg or placebo 2–4 hours before surgery; another 100 mg or placebo 6 hours after surgery or sooner if the heart rate was 80 beats per minute or more and the systolic blood pressure 100 mm Hg or higher; and then 200 mg or placebo 12 hours after the second dose and every 24 hours thereafter for 30 days). This was fairly aggressive, especially for patients who have never received a beta-blocker before. In contrast, the protocol for the Perioperative Beta-Blockade trial called for only 25 to 50 mg of short-acting metoprolol twice a day. Another criticism is that the medication was started only a few hours before surgery, although there is no current standard practice for either the dose or when the treatment should be started. The population had a fairly high rate of cerebrovascular disease (perhaps predisposing to stroke whenever blood pressure dropped), and 10% of patients were undergoing urgent or emergency surgery, which carries a higher risk of morbidity.

ANY ROLE FOR BETA-BLOCKERS IN THOSE AT INTERMEDIATE RISK?

Thus, in the past decade, the appropriate perioperative use of beta-blockers, which, after the findings by Mangano et al and Poldermans et al, were seen as potentially beneficial for any patient at risk of coronary disease, with little suggestion of harm, has become more clearly defined, and the risks are more evident. The most compelling evidence in favor of using them comes from patients with ischemic heart disease undergoing vascular surgery; the 2007 ACC/AHA guidelines recommend that this group be offered beta-blockers in the absence of a contraindication (class I recommendation: benefit clearly outweighs risk).⁶ The guidelines also point out that these drugs should be continued in patients already taking them for cardiac indications before surgery, because ischemia may be precipitated if a beta-blocker is abruptly discontinued.^42,43

Additionally, the guidelines recommend considering beta-blockers for vascular surgery patients at high cardiac risk (with a Revised Cardiac Risk Index score of 3 or more), even if they are not known to have ischemic heart disease. This is a class IIa recommendation (the benefit outweighs the risk, but more studies are required).

The guidelines also recommend that beta-blockers be considered for patients who have a score of 0 if they are undergoing vascular surgery (class IIb recommendation) or a score of 1 if they are undergoing vascular surgery (class IIa recommendation) or intermediate-risk surgery (class IIb recommendation). However, in view of the POISE results, these recommendations need to be carefully scrutinized.

These data notwithstanding, beta-blockers still might be beneficial in perioperative patients at intermediate risk.

Start beta-blockers sooner?

To help patients at intermediate risk (such as those with diabetes without known heart disease), we may need to do what Poldermans et al did³: instead of seeing patients only once a day or two before surgery, we may need to do the preoperative assessment as much as a month before and, if necessary, start a beta-blocker at a low dose, titrate it to a goal heart rate, and follow the patient closely up until surgery and afterward.

The importance of heart-rate control was illustrated in a recent cohort study of perioperative beta-blockers in vascular surgery patients,⁴⁴ in which higher beta-blocker doses, carefully monitored, were associated with less ischemia and cardiac enzyme release. In addition, long-term mortality rates were lower in patients with lower heart rates. And Poldermans et al⁴⁵ recently performed a study in more than 700 intermediate-risk patients who were divided into two groups, one that underwent preoperative stress testing and one that did not. Beta-blockers were given to both groups, and doses were titrated to a goal heart rate of less than 65. The patients with optimally controlled heart rates had the lowest event rates.

However, the logistics of such a program would be challenging. For the most part, internists and hospitalists involved in perioperative assessment do not control the timing of referral or surgery, and adjustments cannot be made for patients whose preoperative clinic visit falls only a few days before surgery. Instituting a second or third visit to assess the efficacy of beta-blockade burdens the patient and may not be practical.

Are all beta-blockers equivalent?

An additional factor is the choice of agent. While the most significant studies of perioperative beta-blockade have used beta-1 receptor-selective agents (ie, metoprolol, atenolol, and bisoprolol), there is no prospective evidence that any particular agent is superior. However, a recent retrospective analysis of elderly surgical patients did suggest that longer-acting beta-blockers may be preferable: patients who had been on atenolol in the year before surgery had a 20% lower risk of postoperative myocardial infarction or death than those who had been on short-acting metoprolol, with no difference in noncardiac outcomes.⁴⁶

The pendulum of expert opinion is swinging away from routinely recommending beta-blockers to prevent cardiac events in non-cardiac surgery patients. We won’t be abandoning the perioperative use of beta-blockers altogether, but we will probably be using them more selectively than in the past.

The latest factor driving the trend is the online publication in May 2008 of the results of the Perioperative Ischemic Evaluation (POISE) trial,¹ the largest placebo-controlled trial of perioperative beta-blocker use to date. In brief, in a cohort of patients with atherosclerotic disease or at risk for it who were undergoing noncardiac surgery, fewer patients who received extended-release metoprolol succinate had a myocardial infarction, but more of them died or had a stroke compared with those receiving placebo. (Extended-release metoprolol succinate is available in the United States as Toprol-XL and generically.)

Not so long ago, the pendulum was going the other way. After two small trials in the 1990s concluded that beta-blockers reduced the risk of perioperative cardiac events in selected patients with known or suspected coronary disease,^2,3 their perioperative use was subsequently endorsed by the Leapfrog Group and the Agency for Healthcare Research and Quality. The National Quality Forum included perioperative beta-blockade in its “Safe Practices for Better Healthcare 2006 update,”^4,5 and the Physician Consortium for Performance Improvement and the Surgical Care Improvement Project both listed it as a quality measure.

Since then, this practice has been closely studied, especially as concomitant research has failed to demonstrate that pre-operative coronary revascularization improves outcomes, even in the presence of ischemic disease. But evidence has been accumulating that routine use of beta-blockers may not benefit as many patients as was hoped, and may actually cause harm. The 2007 joint American College of Cardiology (ACC) and American Heart Association (AHA) guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery gives its strongest recommendation (class I: benefit clearly outweighs risk) for perioperative beta-blocker use only for patients at high risk: those with known ischemic heart disease undergoing vascular surgery and those who are already on these drugs before surgery.⁶

However, there are still gaps in our knowledge. Perhaps, with proper implementation, we may be able to use beta-blockers to improve outcomes in patients at intermediate risk as well. In this paper, we review the rationale and the evidence for and against perioperative use of beta-blockers and provide practical guidance for internists and hospitalists.

WHY CARDIAC EVENTS OCCUR AFTER SURGERY

Adverse cardiovascular events such as myocardial infarction and unstable angina are the leading causes of death after surgery.⁷ Such events occur in approximately 1% of patients older than 50 years undergoing elective inpatient surgery, but this number may be higher (approximately 5%) in those with known or suspected coronary disease.^8,9 Perioperative cardiac events can also be harbingers of further complications, dramatically increasing hospital length of stay.¹⁰

Some ischemic events are caused by physiologic derangements involving the balance between inflammatory mediators, sympathetic tone, and oxygen supply and demand that occur under the stress of surgery. Others are more “traditional” in etiology, involving acute plaque rupture, thrombosis, and occlusion. Studies have consistently found a correlation between perioperative ischemia and cardiac events (both in-hospital and long-term) and death.^11–17 Other studies suggest that most perioperative cardiac infarcts are non-Q-wave events,¹⁸ and most events occur within the first few days after surgery, particularly the first 48 hours, when the effects of anesthetics, pain, fluid shifts, and physiologic derangements are greatest.

Factors that may trigger acute occlusion in the perioperative period include abrupt changes in sympathetic tone, increased levels of cortisol and catecholamines, and tissue hypoxia. Other potential triggers activated or increased by the stress of surgery include coagulation factors such as alterations in platelet function; inflammatory factors such as tumor necrosis factor alpha, interleukin 1, interleukin 6, and C-reactive protein; and metabolism of free fatty acids (which contribute to increased oxygen demand as well as endothelial dysfunction).^9,19,20

A 1996 autopsy study found that 38 (90%) of 42 patients who died of a perioperative infarct had evidence of acute plaque rupture or plaque hemorrhage on coronary sectioning, findings corroborated in another, similar study.^21,22 These studies suggest that multiple causes contribute to perioperative myocardial infarction, and a single strategy may not suffice for prevention.

IF BETA-BLOCKERS PROTECT, HOW DO THEY DO IT?

Beta-blockers have several effects that should, in theory, protect against cardiac events during and after surgery.²³ They reduce cardiac oxygen demand by reducing the force of contraction and the heart rate, and they increase the duration of diastole, when the heart muscle is perfused. They are also antiarrhythmic, and they may limit free radical production, metalloproteinase activity, and myocardial plaque inflammation.²⁴

Some researchers have speculated that using beta-blockers long-term may alter intra-cellular signaling processes, for example decreasing the expression of receptors that receive signals for cell death, which in turn may affect the response to reperfusion cell injury and death. If this is true, there may be an advantage to starting beta-blockers well in advance of surgery.²⁵

EARLY CLINICAL EVIDENCE IN FAVOR OF PERIOPERATIVE BETA-BLOCKER USE

Evidence in patients at high risk

Mangano et al,² in a study published in 1996, randomized 200 patients with known coronary disease or established risk factors for it who were undergoing noncardiac surgery to receive the beta-blocker atenolol orally and intravenously or placebo in the immediate perioperative period. Fewer patients in the atenolol group died in the first 6 months after hospital discharge (0 vs 8%, P < .001), the first year (3% vs 14%, P = .005), and the first 2 years (10% vs 21%, P = .019). However, there was no difference in short-term outcomes, and the study excluded patients who died in the immediate postoperative period. If these patients had been included in the analysis, the difference in the death rate at 2 years would not have been statistically significant.²⁶ Other critical findings: more patients in the atenolol group were using angiotensin-converting enzyme inhibitors and beta-blockers when they were discharged, and the placebo group had slightly more patients with prior myocardial infarction or diabetes.²⁷ (Atenolol is available in the United Sates as Tenormin and generically.)

Poldermans et al,³ in a study published in 1999, randomized 112 vascular surgery patients to receive either oral bisoprolol or placebo. These patients were selected from a larger cohort of 1,351 patients on the basis of high-risk clinical features and abnormal results on dobutamine echocardiography. Bisoprolol was started at least 1 week before surgery (range 7–89 days, mean 37 days), and patients were reevaluated before surgery so that the dose could be titrated to a goal heart rate of less than 60 beats per minute. After surgery, the drug was continued for another 30 days. The study was stopped early because the bisoprolol group had a 90% lower rate of non-fatal myocardial infarction and cardiac death at 30 days. Despite the study’s limitation (eg, enrolling selected patients and using an unblinded protocol), these compelling findings made a strong case for the use of beta-blockers perioperatively in patients at high risk, ie, those with ischemic heart disease who are undergoing major vascular surgery. (Bisoprolol is available in the United States as Zebeta and generically)

Evidence in patients at intermediate risk

Boersma et al²⁸ performed a follow-up to the study by Poldermans et al, published in 2001, in which they analyzed characteristics of all 1,351 patients who had been originally considered for enrollment. Using regression analysis, they identified seven clinical risk factors that predicted adverse cardiac events: angina, prior myocardial infarction, congestive heart failure, prior stroke, diabetes, renal failure, and age 70 years or older. Furthermore, for the entire cohort, patients receiving beta-blockers had a lower risk of cardiac complications (0.8%) than those not receiving beta-blockers (2.3%). In particular, the patients at intermediate risk (defined as having one or two risk factors) had a very low event rate regardless of stress test results, provided they were on beta-blockers: their risk of death or myocardial infarction was 0.9%, compared with 3.0% for those not on beta-blockers.

The authors concluded that dobutamine stress testing may not be necessary in patients at intermediate risk if beta-blockers are appropriately prescribed. However, others took issue with their data and conclusions, arguing that there have been so few trials that the data are still inconclusive and inadequate to ascertain the benefit of perioperative beta-blockade, particularly in patients not at high risk.^26,29

The Revised Cardiac Risk Index. Although the Boersma risk-factor index is not used in general practice, numerous experts^27,20–32 recommend a similar one, the Revised Cardiac Risk Index, devised by Lee et al.⁸ This index consists of six risk factors, each of which is worth one point:

• Congestive heart failure, based on history or examination
• Myocardial infarction, symptomatic ischemic heart disease, or a positive stress test
• Renal insufficiency (ie, serum creatinine level > 2 mg/dL)
• History of stroke or transient ischemic attack
• Diabetes requiring insulin
• High-risk surgery (defined as intrathoracic, intra-abdominal, or suprainguinal vascular surgery).

Patients with three or more points are considered to be at high risk, and those with one or two points are considered to be at intermediate risk. The ACC/AHA 2007 guidelines⁶ use a modified version of this index that considers the issue of surgical risk separately from the other five clinical conditions.

Devereaux et al³³ performed a meta-analysis, published in 2005, of 22 studies of perioperative beta-blockade. They concluded that beta-blockers had no discernable benefit in any outcome measured, including deaths from any cause, deaths from cardiovascular causes, other cardiac events, hypotension, bradycardia, and bronchospasm. However, they based this conclusion on the use of a 99% confidence interval for each relative risk, which they believed was justified because the trials were small and the numbers of events were only moderate. When the outcomes are assessed using the more common 95% confidence interval, benefit was detected in the combined end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal cardiac arrest.

Yang et al,³⁴ Brady et al,³⁵ and Juul et al³⁶ performed three subsequent randomized trials that added to the controversy. Most of the patients in these trials were at intermediate or low risk, and none of the trials found a significant benefit with perioperative beta-blocker use. However, the protocols in these studies were different from the one in the study by Poldermans et al,³ which had found perioperative beta-blockade to be beneficial. Whereas patients in that earlier study started taking a beta-blocker at least 1 week before surgery (and on average much earlier), had their dose aggressively titrated to a target heart rate, and continued taking it for 30 days afterward, the protocols in the later trials called for the drug to be started within 24 hours before surgery and continued for only a short time afterward.

Lindenauer et al,³⁷ in a retrospective study published in 2005, found that fewer surgical patients who received beta-blockers in the hospital died in the hospital. The researchers used an administrative database of more than 780,000 patients who underwent noncardiac surgery, and they used propensity-score matching to compare the postoperative mortality rates of patients who received beta-blockers and a matched group in the same large cohort who did not. Beta-blockers were associated with a lower morality rate in patients in whom the Revised Cardiac Risk Index score was 3 or greater. However, although there was a trend toward a lower rate with beta-blocker use in patients whose score was 2 (ie, at intermediate risk), the difference was not statistically significant, and patients with a score of 0 or 1 saw no benefit and were possibly harmed.

The authors admitted that their study had a number of limitations, including a retrospective design and the use of an administrative database for information regarding risk index conditions and comorbidities. In addition, because they assumed that any patient who received a beta-blocker on the first 2 hospital days was receiving appropriate perioperative treatment, they may have incorrectly estimated the number of patients who actually received these drugs as a risk-reduction strategy. For instance, some patients at low risk could have received beta-blockers for treatment of a specific event, which would be reflected as an increase in event rates for this group. They also had no data on what medications the patients received before they were hospitalized or whether the dose was titrated effectively. The study excluded all patients with congestive heart failure and chronic obstructive pulmonary disease, who may be candidates for beta-blockers in actual practice. In fact, a recent observational study in patients with severe left ventricular dysfunction suggested that these drugs substantially reduced the incidence of death in the short term and the long term.³⁸ Finally, half the surgeries were nonelective, which makes extrapolation of their risk profile by the Revised Cardiac Risk Index difficult, since Lee et al excluded patients undergoing emergency surgery from the cohorts from which they derived and validated their index criteria.

Nevertheless, the authors concluded that patients at intermediate risk derive no benefit from perioperative beta-blocker use, and that the odds ratio for death was actually higher in patients with no risk factors who received a beta-blocker.

DOES PERIOPERATIVE BETA-BLOCKER USE CAUSE HARM?

The published data on whether perioperative beta-blocker use harms patients are conflicting and up to now have been limited.

Stone et al³⁹ reported a substantial incidence of bradycardia requiring atropine in patients treated with a single dose of a beta-blocker preoperatively, but the complications were not clearly characterized.

The Perioperative Beta-Blockade trial.³⁵ Significantly more patients given short-acting metoprolol had intraoperative falls in blood pressure and heart rate, and more required inotropic support during surgery, although the treating anesthesiologists refused to be blinded in that study. (Short-acting metoprolol is available in the United States as Lopressor and generically.)

Devereaux et al,³³ in their meta-analysis, found a higher risk of bradycardia requiring treatment (but not a higher risk of hypotension) in beta-blocker users in nine studies, including the study by Stone et al and the Perioperative Beta-Blockade trial (relative risk 2.27, 95% confidence interval 1.36–3.80).

Conversely, at least three other studies found no difference in rates of intraoperative events.^36,40,41 There are few data on the incidence of other complications such as perioperative pulmonary edema and bronchospasm.

POISE: THE FIRST LARGE RANDOMIZED TRIAL

In May 2008, results were published from POISE, the first large randomized controlled trial of perioperative beta-blockade.¹ An impressive 8,351 patients—most of them at intermediate risk—were randomized to receive extended-release metoprolol succinate or placebo starting just before surgery and continuing for 30 days afterward.

Although the incidence of the primary composite end point (cardiovascular death, nonfatal myocardial infarction, and nonfatal cardiac arrest) was lower at 30 days in the metoprolol group than in the placebo group (5.8% vs 6.9%, hazard ratio 0.83, P = .04), other findings were worrisome: more metoprolol recipients died of any cause (3.1% vs 2.3%, P = .03) or had a stroke (1.0% vs 0.5%, P = .005). The major contributor to the higher mortality rate in this group appears to have been sepsis.

How beta-blockers might promote death by sepsis is unclear. The authors offered two possible explanations: perhaps beta-blocker-induced hypotension predisposes patients to infection and sepsis, or perhaps the slower heart rate and lower force of contraction induced by beta-blockers could mask normal responses to systemic infection, which in turn could delay recognition and treatment or impede the normal immune response. These mechanisms, like others, are speculative.

The risks of other adverse outcomes such as bradycardia and hypotension were substantially higher in the metoprolol group. The authors also pointed out that most of the patients who suffered nonfatal strokes were subsequently disabled or incapacitated, while most of those who suffered nonfatal cardiac events did not progress to further cardiac problems.

This new study has not yet been rigorously debated, but it will likely come under scrutiny for its dosing regimen (extended-release metoprolol succinate 100 mg or placebo 2–4 hours before surgery; another 100 mg or placebo 6 hours after surgery or sooner if the heart rate was 80 beats per minute or more and the systolic blood pressure 100 mm Hg or higher; and then 200 mg or placebo 12 hours after the second dose and every 24 hours thereafter for 30 days). This was fairly aggressive, especially for patients who have never received a beta-blocker before. In contrast, the protocol for the Perioperative Beta-Blockade trial called for only 25 to 50 mg of short-acting metoprolol twice a day. Another criticism is that the medication was started only a few hours before surgery, although there is no current standard practice for either the dose or when the treatment should be started. The population had a fairly high rate of cerebrovascular disease (perhaps predisposing to stroke whenever blood pressure dropped), and 10% of patients were undergoing urgent or emergency surgery, which carries a higher risk of morbidity.

ANY ROLE FOR BETA-BLOCKERS IN THOSE AT INTERMEDIATE RISK?

Thus, in the past decade, the appropriate perioperative use of beta-blockers, which, after the findings by Mangano et al and Poldermans et al, were seen as potentially beneficial for any patient at risk of coronary disease, with little suggestion of harm, has become more clearly defined, and the risks are more evident. The most compelling evidence in favor of using them comes from patients with ischemic heart disease undergoing vascular surgery; the 2007 ACC/AHA guidelines recommend that this group be offered beta-blockers in the absence of a contraindication (class I recommendation: benefit clearly outweighs risk).⁶ The guidelines also point out that these drugs should be continued in patients already taking them for cardiac indications before surgery, because ischemia may be precipitated if a beta-blocker is abruptly discontinued.^42,43

Additionally, the guidelines recommend considering beta-blockers for vascular surgery patients at high cardiac risk (with a Revised Cardiac Risk Index score of 3 or more), even if they are not known to have ischemic heart disease. This is a class IIa recommendation (the benefit outweighs the risk, but more studies are required).

The guidelines also recommend that beta-blockers be considered for patients who have a score of 0 if they are undergoing vascular surgery (class IIb recommendation) or a score of 1 if they are undergoing vascular surgery (class IIa recommendation) or intermediate-risk surgery (class IIb recommendation). However, in view of the POISE results, these recommendations need to be carefully scrutinized.

These data notwithstanding, beta-blockers still might be beneficial in perioperative patients at intermediate risk.

Start beta-blockers sooner?

To help patients at intermediate risk (such as those with diabetes without known heart disease), we may need to do what Poldermans et al did³: instead of seeing patients only once a day or two before surgery, we may need to do the preoperative assessment as much as a month before and, if necessary, start a beta-blocker at a low dose, titrate it to a goal heart rate, and follow the patient closely up until surgery and afterward.

The importance of heart-rate control was illustrated in a recent cohort study of perioperative beta-blockers in vascular surgery patients,⁴⁴ in which higher beta-blocker doses, carefully monitored, were associated with less ischemia and cardiac enzyme release. In addition, long-term mortality rates were lower in patients with lower heart rates. And Poldermans et al⁴⁵ recently performed a study in more than 700 intermediate-risk patients who were divided into two groups, one that underwent preoperative stress testing and one that did not. Beta-blockers were given to both groups, and doses were titrated to a goal heart rate of less than 65. The patients with optimally controlled heart rates had the lowest event rates.

However, the logistics of such a program would be challenging. For the most part, internists and hospitalists involved in perioperative assessment do not control the timing of referral or surgery, and adjustments cannot be made for patients whose preoperative clinic visit falls only a few days before surgery. Instituting a second or third visit to assess the efficacy of beta-blockade burdens the patient and may not be practical.

Are all beta-blockers equivalent?

An additional factor is the choice of agent. While the most significant studies of perioperative beta-blockade have used beta-1 receptor-selective agents (ie, metoprolol, atenolol, and bisoprolol), there is no prospective evidence that any particular agent is superior. However, a recent retrospective analysis of elderly surgical patients did suggest that longer-acting beta-blockers may be preferable: patients who had been on atenolol in the year before surgery had a 20% lower risk of postoperative myocardial infarction or death than those who had been on short-acting metoprolol, with no difference in noncardiac outcomes.⁴⁶

Hematocrit and Perioperative Mortality

Wu WC, Schifftner TL, Henderson WG, et al. Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery. JAMA. 2007 Jun 13;297(22):2481-2488.

Several studies have outlined the risk of preoperative anemia prior to noncardiac surgery in elderly patients. These studies have not linked anemia to risk of death unless cardiac disease is present.

Anemia management remains a challenge for many hospitals and is the most important predictor of the need for blood transfusion. Transfusion increases morbidity and mortality in the perioperative setting. At the same time, little is known about the risks of polycythemia in this setting.

This retrospective cohort study used the Veterans’ Affairs National Surgical Quality Improvement Program database of 310,311 veterans 65 or older from 132 VA hospitals. It explores the relationship between abnormal levels of hematocrit and adverse events among elderly surgical patients.

The data suggest an incremental relationship between positive and negative deviation of hematocrit levels with 30-day postoperative mortality in patients 65 and older. Specifically, the study found a 1.6% increase (95% confidence interval, 1.1%-2.2%) in 30-day mortality for every percentage point of increase or decrease in hematocrit from the normal range.

 Because this is an observational study of anemia and adverse events, no causal relationship can be established from this data. Hospitalists involved in perioperative care should be careful about drawing conclusions from this study alone and should not necessarily plan interventions to treat abnormal levels of hematocrit without carefully considering the risks and benefits of intervention.

Prognostic Utility of Pre-operative BNP

Feringa HH, Schouten O, Dunkelgrun M, et al. Plasma N-terminal pro-B-type natriuretic peptide as long term prognostic marker after major vascular surgery. Heart. 2007 Feb;93(2):226-231.

Traditional stratification of patients at high risk for cardiac complications and undergoing noncardiac surgery has included clinical risk index scoring and pre-operative stress testing. It is unclear if cardiac biomarkers can be used in conjunction with these measures to improve the identification of patients at risk.

Feringa and colleagues addressed this question by looking prospectively at 335 patients undergoing major vascular surgery over a two-year period. The mean age of patients was 62.2 years; 46% of patients underwent abdominal aortic aneurysm repair, and the remaining 54% received lower-extremity revascularization.

Patients had cardiac risk scores calculated based on the Revised Cardiac Risk Index (RCRI), and all patients had dobutamine stress echocardiogram (DSE) to assess for stress-induced ischemia. N-terminal pro­-B-type natriuretic peptide (BNP) was measured at a mean of 12 days before surgery. Patients were followed for all-cause mortality and post-op death for a mean follow-up time of 14 months.

The authors found that NT-pro BNP performed better than the RCRI and DSE for predicting six-month mortality and cardiac events. An NT-pro BNP cut-off level of 319 ng/l was identified as optimal for predicting six-month mortality and cardiac events with 69% sensitivity and 70% specificity for mortality. Patients with levels 319 mg/l had a lower survival during the follow up period (p<0.0001).

Based on this prospective study, it appears that a preoperative elevated NT-Pro BNP is associated with long-term mortality and morbidity and could be used as an additional risk-stratification tool along with clinical risk scoring and stress testing.

Utility of Combination Medications in COPD

Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease. Ann Intern Med. 2007 Feb 19;146:545-555

The appropriateness of multiple long-acting inhaled medications in treating chronic obstructive pulmonary disease (COPD) is poorly studied. This study evaluated whether combining tiotropium with fluticasone-salmeterol or with salmeterol alone improves clinical outcomes in adult patients with moderate to severe COPD, as compared with tiotropium plus placebo.

This randomized, double-blind, placebo-controlled trial was set in academic and community medical centers in Canada. Researchers monitored 449 patients in the three parallel treatment groups for COPD exacerbations for 52 weeks. Analysis was done on an intention-to-treat basis. The rate of COPD exacerbations within the follow-up period (the primary outcome) was not significantly different among the three treatment groups. However, secondary outcomes, such as rates for hospitalization for COPD exacerbations, all-cause hospitalizations, health-related quality of life and lung function were significantly improved in the group receiving tiotropium and fluticasone-salmeterol.

A notable limitation was that more subjects stopped taking the study medications in the tiotropium-placebo and the tiotropium-salmeterol group. Many crossed over to treatments with inhaled corticosteroids or beta-agonists.

The results are in contrast to current guidelines, which recommend adding inhaled steroids to reduce exacerbations in moderate to severe COPD. Whether these results are due to differing statistical analysis among studies remains unclear. The authors postulate that reduction in secondary outcomes may be related to fluticasone reducing the severity of exacerbations rather than the actual number.

COPD exacerbations are among the most common diagnoses encountered by hospitalists. Most patients are treated with multiple inhaled medications to optimize their pulmonary status. Polypharmacy and the added financial burdens on the patient (particularly the elderly) are important considerations when deciding discharge medications, and the evidence of efficacy for combination inhaled medications had not been assessed as a clinical outcome prior to this study.

Benefits of Rapid Response Teams

Winters BD, Pham JC, Hunt EA et al. Rapid response systems: a systematic review. Crit Care Med. 2007 May;35(5):1238-1243.

Although the Institute for Healthcare Improvement has endorsed rapid response teams, and many hospitalist groups are involved with such systems, quality research is lacking.

Following up on the 2006 “First Consensus Conference on Medical Emergency Teams,” this meta-analysis sought to evaluate current literature to identify the effect of rapid response systems (RRS) on rates of hospital mortality and cardiac arrest.

The authors included randomized trials and observational studies in their analysis. Only eight studies met their inclusion criteria (six observational studies, one multicenter randomized trial, and one single-center randomized trial).

The pooled results did not demonstrate a statistically significant benefit of rapid-response systems in rates of hospital mortality. When rates of in-hospital cardiac arrest were analyzed, there was a weak finding in support of RRS, with the relative risk of 0.70 (confidence interval 0.56-0.92) in favor of RRSs. But the confidence interval was wide, and there was substantial heterogeneity among the included studies.

The authors conclude that “it seems premature to declare RRS as the standard of care,” and that data are lacking to justify any particular implementation scheme or composition of RRS or to support the cost-effectiveness of RRS.

Finally, they recognized the need for larger, better-designed randomized trials. However, in an accompanying editorial, Michael DeVita, MD—a pioneer in the development of RRS—rejects the use of techniques of evidence-based medicine such as multicenter trials and meta-analysis in assessing the utility of RRS. Dr. DeVita essentially says that changing the systems and culture of care within the hospital to accommodate patients with unmet critical needs must be effective in improving outcomes.

This meta-analysis is hindered by the suboptimal quality and homogeneity of studies available for assessment. Hospitalists should be aware of the limitations of the data and literature, as well as the empirical arguments raised by Dr. DeVita, when considering involvement in or designing RRS. TH

CLASSIC LIT

Perioperative Statins

Kapoor AS, Kanji H, Buckingham J, et al. Strength of evidence for perioperative use of statins to reduce cardiovascular risk: systematic review of controlled studies. BMJ. 2006 Nov 6;333(7579):1149.

Recent literature and randomized trials have claimed statins decrease morbidity and mortality from cardiovascular events in patients with or at high risk of coronary artery disease. This meta-analysis sought to determine the strength of evidence leading to the recommendations that perioperative statins be used to reduce perioperative cardiovascular events.

The literature search and exclusion criteria identified 18 studies. Two were randomized controlled trials (n=177), 15 were cohort studies (n=799,632), and one was a case-control study (n=480). Of these, 12 studies enrolled patients undergoing noncardiac vascular surgery, four enrolled patients undergoing coronary bypass surgery, and two enrolled patients undergoing various surgical procedures. The 16 nonrandomized studies were rated good. The two randomized trials were rated five and two out of five using the Jadad quality scores.

The results showed that in the randomized trials the summary odds ratio (OR) for death or acute coronary syndrome during the perioperative period with statin use was 0.26 (95% confidence interval 0.07 to 0.99), but this was based on only 13 events in 177 patients and cannot be considered conclusive. In the cohort studies, the OR was 0.70 (95% confidence interval 0.57 to 0.87). Although the pooled cohort data provided a statistically significant result, these cannot be considered conclusive because the statins were not randomly allocated and the results from retrospective studies were more impressive (OR 0.65, 95% confidence interval 0.50 to 0.84) than those in the prospective cohorts (OR 0.91, 95% confidence interval 0.65 to 1.27) and dose, duration, and safety of statin use were not reported.

Limitations of this meta-analysis include that none of the studies reported patient compliance or doses of statins or cholesterol levels before and after surgery, and few reported the duration of therapy before surgery or the which statin was used. Thus, the authors were unable to demonstrate a dose-response association. They were also unable to ascertain if the benefits seen with statins in the observational studies were exaggerated owing to inclusion of patients in the nonstatin group who had their statins stopped prior to surgery, because acute statin withdrawal may be associated with cardiac events.

The authors concluded that although their meta-analysis—which included data from more than 800,000 patients—suggests considerable benefits from perioperative statin use, the evidence from the randomized trials is not definitive. They advocate only that statins be started preoperatively in eligible patients (e.g., patients with coronary artery disease, multiple cardiac risk factors, elevated LDL) who would warrant statin therapy for medical reasons independent of the proposed operation.

Electronic Alerts to Prevent Hospital-acquired VTE

Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med. 2005 Mar 10;352(10):969-977

Surveys conducted in North America and Europe have shown that prophylaxis against deep venous thrombosis (DVT) has been consistently underused in hospitalized patients despite consensus guidelines. Studies involving continuing medical education and computerized electronic alerts have shown that physician use of prophylaxis improves when such processes are in place, but have not demonstrated that they can reduce the rate of DVT.

A computer program was developed to identify consecutive hospitalized patients at increased risk for DVT. The program used eight common risk factors to determine each patient’s risk profile for DVT and each risk factor was assigned a score. A cumulative score of four or higher was used to determine patients at high risk for DVT. The computer alert program was screened daily to identify patients whose score increased to four or higher after admission into the hospital. If the cumulative risk score was at least four, the computer program reviewed the current electronic orders and active medications for the use of DVT prophylaxis.

In the study, 2,506 consecutive adult patients were identified as high risk for DVT. Further,1,255 were randomized to the intervention group—in which the responsible physician received one electronic alert about the risk of DVT—and 1,251 patients were randomized to the control group in which no alert was issued. The 120 physicians involved took care of patients in the intervention and control groups. Physicians responsible for the control group were not aware that patients were being followed for clinical events. When physicians received alerts, they had to acknowledge them and could either withhold prophylaxis or order it on the same computer screen.

Patients were followed for 90 days after the index hospitalization. The primary end point was clinically apparent DVT or pulmonary embolism (PE). Safety end points included mortality at 30 days, and the rate of hemorrhagic events at 90 days.

The results showed that prophylactic measures were ordered for 421 of the 1,255 patients in the intervention group (33.5%) and 182 of the 1,251 patients in the control group (14.5%, p <0.001). There were higher rates of both mechanical (10% versus 1.5%, p<0.001) and pharmacological (23.6% versus 13.0%, p<0.001) prophylaxis in the intervention group. The primary end point of DVT or PE at 90 days occurred in 61 patients in the intervention group (4.9%) as compared with 103 patients in the control group (8.2%).

The computer alert reduced the risk of events at 90 days by 41% (HR 0.59; 95% CI 0.43 to 0.81; P=0.001). Of the patients who received prophylaxis 5.1% had DVT or PE compared with 7.0% of those who did not. In the intervention group, DVT or PE occurred in 20 of 421 (4.8%) patients who received prophylaxis compared with 41 of 834 (4.9%) who did not receive any. In the control group, the same numbers were 11 of 182 (6.0%) and 91 of 1,069 (8.5%).

Some of this benefit might be attributed to the additional preventive measures such as physiotherapy and early ambulation in patients assigned to the intervention group. Diagnostic bias also could have played into the results. Not all patients were screened for VTE, and it is likely that symptomatic patients without prophylaxis were screened more frequently than symptomatic patients with prophylaxis. Because physicians took care of both the control and intervention group, alerts received by physicians in the control group could have influenced their decision in the control group as well.

The authors concluded that instituting computer alerts markedly reduced the rates of DVT or PE in hospitalized patients.

Hematocrit and Perioperative Mortality

Wu WC, Schifftner TL, Henderson WG, et al. Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery. JAMA. 2007 Jun 13;297(22):2481-2488.

Several studies have outlined the risk of preoperative anemia prior to noncardiac surgery in elderly patients. These studies have not linked anemia to risk of death unless cardiac disease is present.

Anemia management remains a challenge for many hospitals and is the most important predictor of the need for blood transfusion. Transfusion increases morbidity and mortality in the perioperative setting. At the same time, little is known about the risks of polycythemia in this setting.

This retrospective cohort study used the Veterans’ Affairs National Surgical Quality Improvement Program database of 310,311 veterans 65 or older from 132 VA hospitals. It explores the relationship between abnormal levels of hematocrit and adverse events among elderly surgical patients.

The data suggest an incremental relationship between positive and negative deviation of hematocrit levels with 30-day postoperative mortality in patients 65 and older. Specifically, the study found a 1.6% increase (95% confidence interval, 1.1%-2.2%) in 30-day mortality for every percentage point of increase or decrease in hematocrit from the normal range.

 Because this is an observational study of anemia and adverse events, no causal relationship can be established from this data. Hospitalists involved in perioperative care should be careful about drawing conclusions from this study alone and should not necessarily plan interventions to treat abnormal levels of hematocrit without carefully considering the risks and benefits of intervention.

Prognostic Utility of Pre-operative BNP

Feringa HH, Schouten O, Dunkelgrun M, et al. Plasma N-terminal pro-B-type natriuretic peptide as long term prognostic marker after major vascular surgery. Heart. 2007 Feb;93(2):226-231.

Traditional stratification of patients at high risk for cardiac complications and undergoing noncardiac surgery has included clinical risk index scoring and pre-operative stress testing. It is unclear if cardiac biomarkers can be used in conjunction with these measures to improve the identification of patients at risk.

Feringa and colleagues addressed this question by looking prospectively at 335 patients undergoing major vascular surgery over a two-year period. The mean age of patients was 62.2 years; 46% of patients underwent abdominal aortic aneurysm repair, and the remaining 54% received lower-extremity revascularization.

Patients had cardiac risk scores calculated based on the Revised Cardiac Risk Index (RCRI), and all patients had dobutamine stress echocardiogram (DSE) to assess for stress-induced ischemia. N-terminal pro­-B-type natriuretic peptide (BNP) was measured at a mean of 12 days before surgery. Patients were followed for all-cause mortality and post-op death for a mean follow-up time of 14 months.

The authors found that NT-pro BNP performed better than the RCRI and DSE for predicting six-month mortality and cardiac events. An NT-pro BNP cut-off level of 319 ng/l was identified as optimal for predicting six-month mortality and cardiac events with 69% sensitivity and 70% specificity for mortality. Patients with levels 319 mg/l had a lower survival during the follow up period (p<0.0001).

Based on this prospective study, it appears that a preoperative elevated NT-Pro BNP is associated with long-term mortality and morbidity and could be used as an additional risk-stratification tool along with clinical risk scoring and stress testing.

Utility of Combination Medications in COPD

Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease. Ann Intern Med. 2007 Feb 19;146:545-555

The appropriateness of multiple long-acting inhaled medications in treating chronic obstructive pulmonary disease (COPD) is poorly studied. This study evaluated whether combining tiotropium with fluticasone-salmeterol or with salmeterol alone improves clinical outcomes in adult patients with moderate to severe COPD, as compared with tiotropium plus placebo.

This randomized, double-blind, placebo-controlled trial was set in academic and community medical centers in Canada. Researchers monitored 449 patients in the three parallel treatment groups for COPD exacerbations for 52 weeks. Analysis was done on an intention-to-treat basis. The rate of COPD exacerbations within the follow-up period (the primary outcome) was not significantly different among the three treatment groups. However, secondary outcomes, such as rates for hospitalization for COPD exacerbations, all-cause hospitalizations, health-related quality of life and lung function were significantly improved in the group receiving tiotropium and fluticasone-salmeterol.

A notable limitation was that more subjects stopped taking the study medications in the tiotropium-placebo and the tiotropium-salmeterol group. Many crossed over to treatments with inhaled corticosteroids or beta-agonists.

The results are in contrast to current guidelines, which recommend adding inhaled steroids to reduce exacerbations in moderate to severe COPD. Whether these results are due to differing statistical analysis among studies remains unclear. The authors postulate that reduction in secondary outcomes may be related to fluticasone reducing the severity of exacerbations rather than the actual number.

COPD exacerbations are among the most common diagnoses encountered by hospitalists. Most patients are treated with multiple inhaled medications to optimize their pulmonary status. Polypharmacy and the added financial burdens on the patient (particularly the elderly) are important considerations when deciding discharge medications, and the evidence of efficacy for combination inhaled medications had not been assessed as a clinical outcome prior to this study.

Benefits of Rapid Response Teams

Winters BD, Pham JC, Hunt EA et al. Rapid response systems: a systematic review. Crit Care Med. 2007 May;35(5):1238-1243.

Although the Institute for Healthcare Improvement has endorsed rapid response teams, and many hospitalist groups are involved with such systems, quality research is lacking.

Following up on the 2006 “First Consensus Conference on Medical Emergency Teams,” this meta-analysis sought to evaluate current literature to identify the effect of rapid response systems (RRS) on rates of hospital mortality and cardiac arrest.

The authors included randomized trials and observational studies in their analysis. Only eight studies met their inclusion criteria (six observational studies, one multicenter randomized trial, and one single-center randomized trial).

The pooled results did not demonstrate a statistically significant benefit of rapid-response systems in rates of hospital mortality. When rates of in-hospital cardiac arrest were analyzed, there was a weak finding in support of RRS, with the relative risk of 0.70 (confidence interval 0.56-0.92) in favor of RRSs. But the confidence interval was wide, and there was substantial heterogeneity among the included studies.

The authors conclude that “it seems premature to declare RRS as the standard of care,” and that data are lacking to justify any particular implementation scheme or composition of RRS or to support the cost-effectiveness of RRS.

Finally, they recognized the need for larger, better-designed randomized trials. However, in an accompanying editorial, Michael DeVita, MD—a pioneer in the development of RRS—rejects the use of techniques of evidence-based medicine such as multicenter trials and meta-analysis in assessing the utility of RRS. Dr. DeVita essentially says that changing the systems and culture of care within the hospital to accommodate patients with unmet critical needs must be effective in improving outcomes.

This meta-analysis is hindered by the suboptimal quality and homogeneity of studies available for assessment. Hospitalists should be aware of the limitations of the data and literature, as well as the empirical arguments raised by Dr. DeVita, when considering involvement in or designing RRS. TH

CLASSIC LIT

Perioperative Statins

Kapoor AS, Kanji H, Buckingham J, et al. Strength of evidence for perioperative use of statins to reduce cardiovascular risk: systematic review of controlled studies. BMJ. 2006 Nov 6;333(7579):1149.

Recent literature and randomized trials have claimed statins decrease morbidity and mortality from cardiovascular events in patients with or at high risk of coronary artery disease. This meta-analysis sought to determine the strength of evidence leading to the recommendations that perioperative statins be used to reduce perioperative cardiovascular events.

The literature search and exclusion criteria identified 18 studies. Two were randomized controlled trials (n=177), 15 were cohort studies (n=799,632), and one was a case-control study (n=480). Of these, 12 studies enrolled patients undergoing noncardiac vascular surgery, four enrolled patients undergoing coronary bypass surgery, and two enrolled patients undergoing various surgical procedures. The 16 nonrandomized studies were rated good. The two randomized trials were rated five and two out of five using the Jadad quality scores.

The results showed that in the randomized trials the summary odds ratio (OR) for death or acute coronary syndrome during the perioperative period with statin use was 0.26 (95% confidence interval 0.07 to 0.99), but this was based on only 13 events in 177 patients and cannot be considered conclusive. In the cohort studies, the OR was 0.70 (95% confidence interval 0.57 to 0.87). Although the pooled cohort data provided a statistically significant result, these cannot be considered conclusive because the statins were not randomly allocated and the results from retrospective studies were more impressive (OR 0.65, 95% confidence interval 0.50 to 0.84) than those in the prospective cohorts (OR 0.91, 95% confidence interval 0.65 to 1.27) and dose, duration, and safety of statin use were not reported.

Limitations of this meta-analysis include that none of the studies reported patient compliance or doses of statins or cholesterol levels before and after surgery, and few reported the duration of therapy before surgery or the which statin was used. Thus, the authors were unable to demonstrate a dose-response association. They were also unable to ascertain if the benefits seen with statins in the observational studies were exaggerated owing to inclusion of patients in the nonstatin group who had their statins stopped prior to surgery, because acute statin withdrawal may be associated with cardiac events.

The authors concluded that although their meta-analysis—which included data from more than 800,000 patients—suggests considerable benefits from perioperative statin use, the evidence from the randomized trials is not definitive. They advocate only that statins be started preoperatively in eligible patients (e.g., patients with coronary artery disease, multiple cardiac risk factors, elevated LDL) who would warrant statin therapy for medical reasons independent of the proposed operation.

Electronic Alerts to Prevent Hospital-acquired VTE

Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med. 2005 Mar 10;352(10):969-977

Surveys conducted in North America and Europe have shown that prophylaxis against deep venous thrombosis (DVT) has been consistently underused in hospitalized patients despite consensus guidelines. Studies involving continuing medical education and computerized electronic alerts have shown that physician use of prophylaxis improves when such processes are in place, but have not demonstrated that they can reduce the rate of DVT.

A computer program was developed to identify consecutive hospitalized patients at increased risk for DVT. The program used eight common risk factors to determine each patient’s risk profile for DVT and each risk factor was assigned a score. A cumulative score of four or higher was used to determine patients at high risk for DVT. The computer alert program was screened daily to identify patients whose score increased to four or higher after admission into the hospital. If the cumulative risk score was at least four, the computer program reviewed the current electronic orders and active medications for the use of DVT prophylaxis.

In the study, 2,506 consecutive adult patients were identified as high risk for DVT. Further,1,255 were randomized to the intervention group—in which the responsible physician received one electronic alert about the risk of DVT—and 1,251 patients were randomized to the control group in which no alert was issued. The 120 physicians involved took care of patients in the intervention and control groups. Physicians responsible for the control group were not aware that patients were being followed for clinical events. When physicians received alerts, they had to acknowledge them and could either withhold prophylaxis or order it on the same computer screen.

Patients were followed for 90 days after the index hospitalization. The primary end point was clinically apparent DVT or pulmonary embolism (PE). Safety end points included mortality at 30 days, and the rate of hemorrhagic events at 90 days.

The results showed that prophylactic measures were ordered for 421 of the 1,255 patients in the intervention group (33.5%) and 182 of the 1,251 patients in the control group (14.5%, p <0.001). There were higher rates of both mechanical (10% versus 1.5%, p<0.001) and pharmacological (23.6% versus 13.0%, p<0.001) prophylaxis in the intervention group. The primary end point of DVT or PE at 90 days occurred in 61 patients in the intervention group (4.9%) as compared with 103 patients in the control group (8.2%).

The computer alert reduced the risk of events at 90 days by 41% (HR 0.59; 95% CI 0.43 to 0.81; P=0.001). Of the patients who received prophylaxis 5.1% had DVT or PE compared with 7.0% of those who did not. In the intervention group, DVT or PE occurred in 20 of 421 (4.8%) patients who received prophylaxis compared with 41 of 834 (4.9%) who did not receive any. In the control group, the same numbers were 11 of 182 (6.0%) and 91 of 1,069 (8.5%).

Some of this benefit might be attributed to the additional preventive measures such as physiotherapy and early ambulation in patients assigned to the intervention group. Diagnostic bias also could have played into the results. Not all patients were screened for VTE, and it is likely that symptomatic patients without prophylaxis were screened more frequently than symptomatic patients with prophylaxis. Because physicians took care of both the control and intervention group, alerts received by physicians in the control group could have influenced their decision in the control group as well.

The authors concluded that instituting computer alerts markedly reduced the rates of DVT or PE in hospitalized patients.

Hematocrit and Perioperative Mortality

Wu WC, Schifftner TL, Henderson WG, et al. Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery. JAMA. 2007 Jun 13;297(22):2481-2488.

Several studies have outlined the risk of preoperative anemia prior to noncardiac surgery in elderly patients. These studies have not linked anemia to risk of death unless cardiac disease is present.

Anemia management remains a challenge for many hospitals and is the most important predictor of the need for blood transfusion. Transfusion increases morbidity and mortality in the perioperative setting. At the same time, little is known about the risks of polycythemia in this setting.

This retrospective cohort study used the Veterans’ Affairs National Surgical Quality Improvement Program database of 310,311 veterans 65 or older from 132 VA hospitals. It explores the relationship between abnormal levels of hematocrit and adverse events among elderly surgical patients.

The data suggest an incremental relationship between positive and negative deviation of hematocrit levels with 30-day postoperative mortality in patients 65 and older. Specifically, the study found a 1.6% increase (95% confidence interval, 1.1%-2.2%) in 30-day mortality for every percentage point of increase or decrease in hematocrit from the normal range.

 Because this is an observational study of anemia and adverse events, no causal relationship can be established from this data. Hospitalists involved in perioperative care should be careful about drawing conclusions from this study alone and should not necessarily plan interventions to treat abnormal levels of hematocrit without carefully considering the risks and benefits of intervention.

Prognostic Utility of Pre-operative BNP

Feringa HH, Schouten O, Dunkelgrun M, et al. Plasma N-terminal pro-B-type natriuretic peptide as long term prognostic marker after major vascular surgery. Heart. 2007 Feb;93(2):226-231.

Traditional stratification of patients at high risk for cardiac complications and undergoing noncardiac surgery has included clinical risk index scoring and pre-operative stress testing. It is unclear if cardiac biomarkers can be used in conjunction with these measures to improve the identification of patients at risk.

Feringa and colleagues addressed this question by looking prospectively at 335 patients undergoing major vascular surgery over a two-year period. The mean age of patients was 62.2 years; 46% of patients underwent abdominal aortic aneurysm repair, and the remaining 54% received lower-extremity revascularization.

Patients had cardiac risk scores calculated based on the Revised Cardiac Risk Index (RCRI), and all patients had dobutamine stress echocardiogram (DSE) to assess for stress-induced ischemia. N-terminal pro­-B-type natriuretic peptide (BNP) was measured at a mean of 12 days before surgery. Patients were followed for all-cause mortality and post-op death for a mean follow-up time of 14 months.

The authors found that NT-pro BNP performed better than the RCRI and DSE for predicting six-month mortality and cardiac events. An NT-pro BNP cut-off level of 319 ng/l was identified as optimal for predicting six-month mortality and cardiac events with 69% sensitivity and 70% specificity for mortality. Patients with levels 319 mg/l had a lower survival during the follow up period (p<0.0001).

Based on this prospective study, it appears that a preoperative elevated NT-Pro BNP is associated with long-term mortality and morbidity and could be used as an additional risk-stratification tool along with clinical risk scoring and stress testing.

Utility of Combination Medications in COPD

Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease. Ann Intern Med. 2007 Feb 19;146:545-555

The appropriateness of multiple long-acting inhaled medications in treating chronic obstructive pulmonary disease (COPD) is poorly studied. This study evaluated whether combining tiotropium with fluticasone-salmeterol or with salmeterol alone improves clinical outcomes in adult patients with moderate to severe COPD, as compared with tiotropium plus placebo.

This randomized, double-blind, placebo-controlled trial was set in academic and community medical centers in Canada. Researchers monitored 449 patients in the three parallel treatment groups for COPD exacerbations for 52 weeks. Analysis was done on an intention-to-treat basis. The rate of COPD exacerbations within the follow-up period (the primary outcome) was not significantly different among the three treatment groups. However, secondary outcomes, such as rates for hospitalization for COPD exacerbations, all-cause hospitalizations, health-related quality of life and lung function were significantly improved in the group receiving tiotropium and fluticasone-salmeterol.

A notable limitation was that more subjects stopped taking the study medications in the tiotropium-placebo and the tiotropium-salmeterol group. Many crossed over to treatments with inhaled corticosteroids or beta-agonists.

The results are in contrast to current guidelines, which recommend adding inhaled steroids to reduce exacerbations in moderate to severe COPD. Whether these results are due to differing statistical analysis among studies remains unclear. The authors postulate that reduction in secondary outcomes may be related to fluticasone reducing the severity of exacerbations rather than the actual number.

COPD exacerbations are among the most common diagnoses encountered by hospitalists. Most patients are treated with multiple inhaled medications to optimize their pulmonary status. Polypharmacy and the added financial burdens on the patient (particularly the elderly) are important considerations when deciding discharge medications, and the evidence of efficacy for combination inhaled medications had not been assessed as a clinical outcome prior to this study.

Benefits of Rapid Response Teams

Winters BD, Pham JC, Hunt EA et al. Rapid response systems: a systematic review. Crit Care Med. 2007 May;35(5):1238-1243.

Although the Institute for Healthcare Improvement has endorsed rapid response teams, and many hospitalist groups are involved with such systems, quality research is lacking.

Following up on the 2006 “First Consensus Conference on Medical Emergency Teams,” this meta-analysis sought to evaluate current literature to identify the effect of rapid response systems (RRS) on rates of hospital mortality and cardiac arrest.

The authors included randomized trials and observational studies in their analysis. Only eight studies met their inclusion criteria (six observational studies, one multicenter randomized trial, and one single-center randomized trial).

The pooled results did not demonstrate a statistically significant benefit of rapid-response systems in rates of hospital mortality. When rates of in-hospital cardiac arrest were analyzed, there was a weak finding in support of RRS, with the relative risk of 0.70 (confidence interval 0.56-0.92) in favor of RRSs. But the confidence interval was wide, and there was substantial heterogeneity among the included studies.

The authors conclude that “it seems premature to declare RRS as the standard of care,” and that data are lacking to justify any particular implementation scheme or composition of RRS or to support the cost-effectiveness of RRS.

Finally, they recognized the need for larger, better-designed randomized trials. However, in an accompanying editorial, Michael DeVita, MD—a pioneer in the development of RRS—rejects the use of techniques of evidence-based medicine such as multicenter trials and meta-analysis in assessing the utility of RRS. Dr. DeVita essentially says that changing the systems and culture of care within the hospital to accommodate patients with unmet critical needs must be effective in improving outcomes.

This meta-analysis is hindered by the suboptimal quality and homogeneity of studies available for assessment. Hospitalists should be aware of the limitations of the data and literature, as well as the empirical arguments raised by Dr. DeVita, when considering involvement in or designing RRS. TH

CLASSIC LIT

Perioperative Statins

Kapoor AS, Kanji H, Buckingham J, et al. Strength of evidence for perioperative use of statins to reduce cardiovascular risk: systematic review of controlled studies. BMJ. 2006 Nov 6;333(7579):1149.

Recent literature and randomized trials have claimed statins decrease morbidity and mortality from cardiovascular events in patients with or at high risk of coronary artery disease. This meta-analysis sought to determine the strength of evidence leading to the recommendations that perioperative statins be used to reduce perioperative cardiovascular events.

The literature search and exclusion criteria identified 18 studies. Two were randomized controlled trials (n=177), 15 were cohort studies (n=799,632), and one was a case-control study (n=480). Of these, 12 studies enrolled patients undergoing noncardiac vascular surgery, four enrolled patients undergoing coronary bypass surgery, and two enrolled patients undergoing various surgical procedures. The 16 nonrandomized studies were rated good. The two randomized trials were rated five and two out of five using the Jadad quality scores.

The results showed that in the randomized trials the summary odds ratio (OR) for death or acute coronary syndrome during the perioperative period with statin use was 0.26 (95% confidence interval 0.07 to 0.99), but this was based on only 13 events in 177 patients and cannot be considered conclusive. In the cohort studies, the OR was 0.70 (95% confidence interval 0.57 to 0.87). Although the pooled cohort data provided a statistically significant result, these cannot be considered conclusive because the statins were not randomly allocated and the results from retrospective studies were more impressive (OR 0.65, 95% confidence interval 0.50 to 0.84) than those in the prospective cohorts (OR 0.91, 95% confidence interval 0.65 to 1.27) and dose, duration, and safety of statin use were not reported.

Limitations of this meta-analysis include that none of the studies reported patient compliance or doses of statins or cholesterol levels before and after surgery, and few reported the duration of therapy before surgery or the which statin was used. Thus, the authors were unable to demonstrate a dose-response association. They were also unable to ascertain if the benefits seen with statins in the observational studies were exaggerated owing to inclusion of patients in the nonstatin group who had their statins stopped prior to surgery, because acute statin withdrawal may be associated with cardiac events.

The authors concluded that although their meta-analysis—which included data from more than 800,000 patients—suggests considerable benefits from perioperative statin use, the evidence from the randomized trials is not definitive. They advocate only that statins be started preoperatively in eligible patients (e.g., patients with coronary artery disease, multiple cardiac risk factors, elevated LDL) who would warrant statin therapy for medical reasons independent of the proposed operation.

Electronic Alerts to Prevent Hospital-acquired VTE

Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med. 2005 Mar 10;352(10):969-977

Surveys conducted in North America and Europe have shown that prophylaxis against deep venous thrombosis (DVT) has been consistently underused in hospitalized patients despite consensus guidelines. Studies involving continuing medical education and computerized electronic alerts have shown that physician use of prophylaxis improves when such processes are in place, but have not demonstrated that they can reduce the rate of DVT.

A computer program was developed to identify consecutive hospitalized patients at increased risk for DVT. The program used eight common risk factors to determine each patient’s risk profile for DVT and each risk factor was assigned a score. A cumulative score of four or higher was used to determine patients at high risk for DVT. The computer alert program was screened daily to identify patients whose score increased to four or higher after admission into the hospital. If the cumulative risk score was at least four, the computer program reviewed the current electronic orders and active medications for the use of DVT prophylaxis.

In the study, 2,506 consecutive adult patients were identified as high risk for DVT. Further,1,255 were randomized to the intervention group—in which the responsible physician received one electronic alert about the risk of DVT—and 1,251 patients were randomized to the control group in which no alert was issued. The 120 physicians involved took care of patients in the intervention and control groups. Physicians responsible for the control group were not aware that patients were being followed for clinical events. When physicians received alerts, they had to acknowledge them and could either withhold prophylaxis or order it on the same computer screen.

Patients were followed for 90 days after the index hospitalization. The primary end point was clinically apparent DVT or pulmonary embolism (PE). Safety end points included mortality at 30 days, and the rate of hemorrhagic events at 90 days.

The results showed that prophylactic measures were ordered for 421 of the 1,255 patients in the intervention group (33.5%) and 182 of the 1,251 patients in the control group (14.5%, p <0.001). There were higher rates of both mechanical (10% versus 1.5%, p<0.001) and pharmacological (23.6% versus 13.0%, p<0.001) prophylaxis in the intervention group. The primary end point of DVT or PE at 90 days occurred in 61 patients in the intervention group (4.9%) as compared with 103 patients in the control group (8.2%).

The computer alert reduced the risk of events at 90 days by 41% (HR 0.59; 95% CI 0.43 to 0.81; P=0.001). Of the patients who received prophylaxis 5.1% had DVT or PE compared with 7.0% of those who did not. In the intervention group, DVT or PE occurred in 20 of 421 (4.8%) patients who received prophylaxis compared with 41 of 834 (4.9%) who did not receive any. In the control group, the same numbers were 11 of 182 (6.0%) and 91 of 1,069 (8.5%).

Some of this benefit might be attributed to the additional preventive measures such as physiotherapy and early ambulation in patients assigned to the intervention group. Diagnostic bias also could have played into the results. Not all patients were screened for VTE, and it is likely that symptomatic patients without prophylaxis were screened more frequently than symptomatic patients with prophylaxis. Because physicians took care of both the control and intervention group, alerts received by physicians in the control group could have influenced their decision in the control group as well.

The authors concluded that instituting computer alerts markedly reduced the rates of DVT or PE in hospitalized patients.

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.

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.

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

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.

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.

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

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.

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.

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