Susan L. Pereira, MD

ILLUSTRATIVE CASE

A mother brings in her 14-year-old daughter for a routine check-up. The girl has no chronic medical problems and an unremarkable physical exam. When you’re alone with your patient, you inquire about substance abuse and sexual activity. She denies both. What questions would you ask to screen for depression?

Estimates of the prevalence of adolescent depression range from 3% to 9%,^2-4 and nearly 20% of teens will experience a depressive disorder before the age of 20.² But less than half of depressed adolescents are diagnosed or treated.²

Depressed teens face multiple risks
Teens with depressive disorders are at elevated risk, not only for poor family and social relationships and difficulties at school, but also for early pregnancy, substance abuse, hospitalization, recurrent episodes of depression, and suicide.^2,4 Thirteen percent of adolescents have seriously contemplated suicide, and 6.3% have made a suicide attempt in the previous 12 months.⁵

The US Preventive Services Task Force (USPSTF) recommends screening all adolescents for depression—provided that effective treatments and counseling are available for those who need it.⁶ Nearly all primary care clinicians agree that it is important to screen for adolescent depression, yet many feel hindered by both a lack of training and time constraints.² The study by Richardson et al¹ shows that targeted screening can be effective, even when time is tight.

STUDY SUMMARY: 2-question screen is fairly accurate

The Patient Health Questionnaire (PHQ)-9 is a simple and reasonably accurate test for depression in adults.⁷ A much shorter version, using only the first 2 of the PHQ-9’s questions, is an effective screening tool for adults.⁸ Richardson et al evaluated this brief screen—the PHQ-2—for adolescent depression.¹

The researchers invited 4000 teens (ages 13-17) who had seen a clinician within the previous 12 months to participate in a mailed survey, with parental or guardian approval. The survey included questions about age, gender, height, weight, sedentary and functional behaviors, and overall health, as well as depressive symptoms identified with the PHQ-2. This simple screen asks patients to rate how often in the past 2 weeks they have had:

1) a depressed mood, and/or

2) a lack of pleasure in usual activities.

Each question is scored from 0 to 3, with 0=not at all, and 3=nearly every day.

Next, the authors randomly selected 271 respondents with scores of ≥3 and 228 respondents with scores <3, matched for age and gender. Of those, 89% (n=444) participated in a longer telephone interview, which included the PHQ-9 and the Diagnostic Interview Schedule for Children (DISC-IV). Participants were predominantly female (60%), Caucasian (71%), and from urban areas (83%), with a mean household income of $57,442.

Compared with the DISC-IV—which the researchers considered the gold standard—the PHQ-2 had a sensitivity of 74% and a specificity of 75% at a cut point score ≥3; the sensitivity and specificity were 96% and 82%, respectively, for detecting young people who met the criteria for major depression on the PHQ-9. The area under the receiver operating curve was 0.84 (95% confidence interval, 0.75-0.92), meaning that the PHQ-2 correctly classified 84% of the participants as depressed or not depressed.

PHQ-2 helps identify related symptoms
Most of those with false-positive screens had other mental health problems. These included depressive symptoms that did not meet the criteria for major depression, an episode of major depression within the past year (but not in the last month), significant psychosocial impairment, and clinically significant anxiety symptoms.

WHAT’S NEW: Screening can be quick

Prior to this study, most validated tools for depression screening of adolescents were relatively time-consuming, and not likely to be performed during routine visits. The PHQ-2 is a reasonably accurate screen that requires minimal time (and minimal training).

CAVEATS: Study assessed a homogenous group

This study included mostly white girls from urban areas, relatively few of whom had public insurance. Whether the results are applicable to teens from different backgrounds is unclear. While the accuracy of the PHQ-2 was not perfect, almost 95% of those with a positive screen had some psychological problems.

CHALLENGES TO IMPLEMENTATION: Physicians may lack psych resources

Routinely using a 2-question screen for adolescent depression is unlikely to interfere with workflow in most practices. However, the USPSTF recommends screening teens only when there are systems in place to ensure accurate diagnosis, psychotherapy, and follow-up. Unfortunately, not all clinicians are adequately trained to diagnose or treat depressed teens, and some may lack access to appropriate psychotherapy referrals or consultation.

Despite the benefit of medications such as selective serotonin reuptake inhibitors (SSRIs) for teens with major depression, the antidepressants carry some risk. The black box warning for suicidality among adolescents treated with SSRIs⁹ necessitates accurate diagnosis, informed consent, and appropriate follow-up with clinicians who are comfortable treating adolescents.

Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A mother brings in her 14-year-old daughter for a routine check-up. The girl has no chronic medical problems and an unremarkable physical exam. When you’re alone with your patient, you inquire about substance abuse and sexual activity. She denies both. What questions would you ask to screen for depression?

Estimates of the prevalence of adolescent depression range from 3% to 9%,^2-4 and nearly 20% of teens will experience a depressive disorder before the age of 20.² But less than half of depressed adolescents are diagnosed or treated.²

Depressed teens face multiple risks
Teens with depressive disorders are at elevated risk, not only for poor family and social relationships and difficulties at school, but also for early pregnancy, substance abuse, hospitalization, recurrent episodes of depression, and suicide.^2,4 Thirteen percent of adolescents have seriously contemplated suicide, and 6.3% have made a suicide attempt in the previous 12 months.⁵

The US Preventive Services Task Force (USPSTF) recommends screening all adolescents for depression—provided that effective treatments and counseling are available for those who need it.⁶ Nearly all primary care clinicians agree that it is important to screen for adolescent depression, yet many feel hindered by both a lack of training and time constraints.² The study by Richardson et al¹ shows that targeted screening can be effective, even when time is tight.

STUDY SUMMARY: 2-question screen is fairly accurate

The Patient Health Questionnaire (PHQ)-9 is a simple and reasonably accurate test for depression in adults.⁷ A much shorter version, using only the first 2 of the PHQ-9’s questions, is an effective screening tool for adults.⁸ Richardson et al evaluated this brief screen—the PHQ-2—for adolescent depression.¹

The researchers invited 4000 teens (ages 13-17) who had seen a clinician within the previous 12 months to participate in a mailed survey, with parental or guardian approval. The survey included questions about age, gender, height, weight, sedentary and functional behaviors, and overall health, as well as depressive symptoms identified with the PHQ-2. This simple screen asks patients to rate how often in the past 2 weeks they have had:

1) a depressed mood, and/or

2) a lack of pleasure in usual activities.

Each question is scored from 0 to 3, with 0=not at all, and 3=nearly every day.

Next, the authors randomly selected 271 respondents with scores of ≥3 and 228 respondents with scores <3, matched for age and gender. Of those, 89% (n=444) participated in a longer telephone interview, which included the PHQ-9 and the Diagnostic Interview Schedule for Children (DISC-IV). Participants were predominantly female (60%), Caucasian (71%), and from urban areas (83%), with a mean household income of $57,442.

Compared with the DISC-IV—which the researchers considered the gold standard—the PHQ-2 had a sensitivity of 74% and a specificity of 75% at a cut point score ≥3; the sensitivity and specificity were 96% and 82%, respectively, for detecting young people who met the criteria for major depression on the PHQ-9. The area under the receiver operating curve was 0.84 (95% confidence interval, 0.75-0.92), meaning that the PHQ-2 correctly classified 84% of the participants as depressed or not depressed.

PHQ-2 helps identify related symptoms
Most of those with false-positive screens had other mental health problems. These included depressive symptoms that did not meet the criteria for major depression, an episode of major depression within the past year (but not in the last month), significant psychosocial impairment, and clinically significant anxiety symptoms.

WHAT’S NEW: Screening can be quick

Prior to this study, most validated tools for depression screening of adolescents were relatively time-consuming, and not likely to be performed during routine visits. The PHQ-2 is a reasonably accurate screen that requires minimal time (and minimal training).

CAVEATS: Study assessed a homogenous group

This study included mostly white girls from urban areas, relatively few of whom had public insurance. Whether the results are applicable to teens from different backgrounds is unclear. While the accuracy of the PHQ-2 was not perfect, almost 95% of those with a positive screen had some psychological problems.

CHALLENGES TO IMPLEMENTATION: Physicians may lack psych resources

Routinely using a 2-question screen for adolescent depression is unlikely to interfere with workflow in most practices. However, the USPSTF recommends screening teens only when there are systems in place to ensure accurate diagnosis, psychotherapy, and follow-up. Unfortunately, not all clinicians are adequately trained to diagnose or treat depressed teens, and some may lack access to appropriate psychotherapy referrals or consultation.

Despite the benefit of medications such as selective serotonin reuptake inhibitors (SSRIs) for teens with major depression, the antidepressants carry some risk. The black box warning for suicidality among adolescents treated with SSRIs⁹ necessitates accurate diagnosis, informed consent, and appropriate follow-up with clinicians who are comfortable treating adolescents.

Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A mother brings in her 14-year-old daughter for a routine check-up. The girl has no chronic medical problems and an unremarkable physical exam. When you’re alone with your patient, you inquire about substance abuse and sexual activity. She denies both. What questions would you ask to screen for depression?

Estimates of the prevalence of adolescent depression range from 3% to 9%,^2-4 and nearly 20% of teens will experience a depressive disorder before the age of 20.² But less than half of depressed adolescents are diagnosed or treated.²

Depressed teens face multiple risks
Teens with depressive disorders are at elevated risk, not only for poor family and social relationships and difficulties at school, but also for early pregnancy, substance abuse, hospitalization, recurrent episodes of depression, and suicide.^2,4 Thirteen percent of adolescents have seriously contemplated suicide, and 6.3% have made a suicide attempt in the previous 12 months.⁵

The US Preventive Services Task Force (USPSTF) recommends screening all adolescents for depression—provided that effective treatments and counseling are available for those who need it.⁶ Nearly all primary care clinicians agree that it is important to screen for adolescent depression, yet many feel hindered by both a lack of training and time constraints.² The study by Richardson et al¹ shows that targeted screening can be effective, even when time is tight.

STUDY SUMMARY: 2-question screen is fairly accurate

The Patient Health Questionnaire (PHQ)-9 is a simple and reasonably accurate test for depression in adults.⁷ A much shorter version, using only the first 2 of the PHQ-9’s questions, is an effective screening tool for adults.⁸ Richardson et al evaluated this brief screen—the PHQ-2—for adolescent depression.¹

The researchers invited 4000 teens (ages 13-17) who had seen a clinician within the previous 12 months to participate in a mailed survey, with parental or guardian approval. The survey included questions about age, gender, height, weight, sedentary and functional behaviors, and overall health, as well as depressive symptoms identified with the PHQ-2. This simple screen asks patients to rate how often in the past 2 weeks they have had:

1) a depressed mood, and/or

2) a lack of pleasure in usual activities.

Each question is scored from 0 to 3, with 0=not at all, and 3=nearly every day.

Next, the authors randomly selected 271 respondents with scores of ≥3 and 228 respondents with scores <3, matched for age and gender. Of those, 89% (n=444) participated in a longer telephone interview, which included the PHQ-9 and the Diagnostic Interview Schedule for Children (DISC-IV). Participants were predominantly female (60%), Caucasian (71%), and from urban areas (83%), with a mean household income of $57,442.

Compared with the DISC-IV—which the researchers considered the gold standard—the PHQ-2 had a sensitivity of 74% and a specificity of 75% at a cut point score ≥3; the sensitivity and specificity were 96% and 82%, respectively, for detecting young people who met the criteria for major depression on the PHQ-9. The area under the receiver operating curve was 0.84 (95% confidence interval, 0.75-0.92), meaning that the PHQ-2 correctly classified 84% of the participants as depressed or not depressed.

PHQ-2 helps identify related symptoms
Most of those with false-positive screens had other mental health problems. These included depressive symptoms that did not meet the criteria for major depression, an episode of major depression within the past year (but not in the last month), significant psychosocial impairment, and clinically significant anxiety symptoms.

WHAT’S NEW: Screening can be quick

Prior to this study, most validated tools for depression screening of adolescents were relatively time-consuming, and not likely to be performed during routine visits. The PHQ-2 is a reasonably accurate screen that requires minimal time (and minimal training).

CAVEATS: Study assessed a homogenous group

This study included mostly white girls from urban areas, relatively few of whom had public insurance. Whether the results are applicable to teens from different backgrounds is unclear. While the accuracy of the PHQ-2 was not perfect, almost 95% of those with a positive screen had some psychological problems.

CHALLENGES TO IMPLEMENTATION: Physicians may lack psych resources

Routinely using a 2-question screen for adolescent depression is unlikely to interfere with workflow in most practices. However, the USPSTF recommends screening teens only when there are systems in place to ensure accurate diagnosis, psychotherapy, and follow-up. Unfortunately, not all clinicians are adequately trained to diagnose or treat depressed teens, and some may lack access to appropriate psychotherapy referrals or consultation.

Despite the benefit of medications such as selective serotonin reuptake inhibitors (SSRIs) for teens with major depression, the antidepressants carry some risk. The black box warning for suicidality among adolescents treated with SSRIs⁹ necessitates accurate diagnosis, informed consent, and appropriate follow-up with clinicians who are comfortable treating adolescents.

Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 67-year-old man with recurrent transient ischemic attacks comes in for a preoperative evaluation for carotid endarterectomy. The patient’s total cholesterol is 207 mg/dL and his low-density lipoprotein cholesterol (LDL-C) is 109 mg/dL. He takes metoprolol and lisinopril for hypertension.

Should you start him on a statin before surgery?

Nearly 25% of patients with peripheral vascular disease suffer from a cardiac event within 72 hours of elective, noncardiac vascular surgery.³ While most of these “complications” have minimal clinical impact and are detected by biochemical markers alone, some patients experience serious cardiac complications—including fatal myocardial infarction (MI).

That’s not surprising, given that most patients who require noncardiac vascular surgery suffer from severe coronary vascular disease.⁴ What is surprising is that most candidates for noncardiac vascular surgery are not put on statins prior to undergoing surgery.^1,2,5

Statins were thought to increase—not prevent—complications
Until recently, taking statins during the perioperative period was believed to increase complications, including statin-associated myopathy. Indeed, guidelines from the American Heart Association (AHA), American College of Cardiology (ACC), and National Heart, Lung and Blood Institute (NHLBI) suggest that it is prudent to withhold statins during hospitalization for major surgery.⁶

1 small study hinted at value of perioperative statins
A small Brazilian trial conducted in 2004 called the AHA/ACC/NHLBI guidelines into question. the researchers studied 100 patients slated for noncardiac vascular surgery who were randomized to receive either 20 mg atorvastatin (Lipitor) or placebo preoperatively —and monitored them for cardiac events 6 months postoperatively. They found that the incidence of cardiac events (cardiac death, nonfatal MI, stroke, or unstable angina) was more than 3 times higher in the placebo group compared with patients receiving atorvastatin (26% vs 8%, number needed to treat [NNT]=5.6; P=.031).²

The results of this small single study, although suggestive, were not sufficiently convincing to change recommendations about the preoperative use of statins, however. A more comprehensive study was needed to alter standard practice, and the Schouten study that we report on below fits the bill.¹

STUDY SUMMARY: Preoperative statin use cuts risk in half

Schouten et al followed 500 patients, who were randomized to receive either 80 mg extended-release fluvastatin (Lescol XL) or placebo for a median of 37 days prior to surgery.¹ All enrollees were older than 40 years of age and were scheduled for noncardiac vascular surgery. the reasons for the surgery were abdominal aortic aneurysm repair (47.5%), lower limb arterial reconstruction (38.6%), or carotid artery endarterectomy (13.9%). Patients who were taking long-term beta-blocker therapy were continued on it; otherwise, bisoprolol 2.5 mg was initiated at the screening visit. Patients who were already taking statins (<50% of potential subjects) were excluded. Other exclusions were a contraindication to statin therapy; emergent surgery; and a repeat procedure within the last 29 days. Patients with unstable coronary artery disease or extensive stress-induced ischemia consistent with left main artery disease (or its equivalent) were also excluded.

The primary study outcome was myocardial ischemia, determined by continuous electrocardiogram (EKG) monitoring in the first 48 hours postsurgery and by 12-lead EKG recordings on days 3, 7, and 30. Troponin T levels were measured on postoperative days 1, 3, 7, and 30, as well. the principal secondary end point was either death from cardiovascular causes or nonfatal MI. MI was diagnosed by characteristic ischemic symptoms, with EKG evidence of ischemia or positive troponin T with characteristic rising and falling values.

To gauge fluvastatin’s effect on biomarkers, lipids, high-sensitivity C-reactive protein, and interleukin-6 were measured upon initiation of the medication and on the day of admission for surgery. Serum creatine kinase, alanine aminotransferase (ALT) levels, clinical myopathy, and rhabdomyolysis were monitored as safety measures, with levels measured prior to randomization, on the day of admission, and on postoperative days 1, 3, 7, and 30.

Both groups were similar in age (mean of 66 years), total serum cholesterol levels, risk factors for cardiac events, and medication use. About 75% of the enrollees were men. At baseline, 51% of the participants had a total cholesterol <213 mg/dL, and 39% had an LDL-C <116 mg/dL. Within 30 days after surgery, 27 (10.8%) of those in the fluvastatin group and 47 (19%) of patients in the placebo group had evidence of myocardial ischemia (hazard ratio=0.55; 95% confidence interval [CI], 0.34-0.88; P=.01). the NNT to prevent 1 patient from experiencing myocardial ischemia was 12.

Statin users had fewer MIs. A total of 6 patients receiving fluvastatin died, with 4 deaths attributed to cardiovascular causes. In the placebo group, 12 patients died, 8 of which were ascribed to cardiovascular causes. Eight patients in the fluvastatin group experienced nonfatal MIs, compared with 17 patients in the placebo group (NNT=19 to prevent 1 nonfatal MI or cardiac death (hazard ratio= 0.47; 95% CI, 0.24-0.94; P=.03).

Effects of statins were evident preoperatively. At the time of surgery, patients in the fluvastatin group had, on average, a 20% reduction in their total cholesterol and a 24% reduction in LDL-C; in the placebo group, total cholesterol had fallen by 4% and LDL-C, by 3%.

Patients receiving fluvastatin had an average 21% decrease in C-reactive protein, compared with a 3% increase for the placebo group. Interleukin-6 levels also were reduced far more in the fluvastatin group (33% vs a 4% reduction in the placebo group [P<.001]).

The medication was well tolerated. Overall, 6.8% of participants discontinued the study because of side effects, including 16 (6.4%) patients in the fluvastatin group and 18 (7.3%) in the placebo group. (After surgery, 115 [23.1%] of patients in the statin group temporarily discontinued the drug because of an inability to take oral medications for a median of 2 days.)

Rates of increase in creatine kinase of >10× the upper limit of normal (ULN) were similar between the fluvastatin and placebo groups (4% vs 3.2%, respectively). Increases in ALT to >3× ULN were more frequent in the placebo group compared with the fluvastatin group (5.3%, placebo; 3.2%, fluvastatin). No cases of myopathy or rhabdomyolysis were observed in either group.

WHAT’S NEW: Preop statins can be a lifesaver

The initiation of fluvastatin prior to vascular surgery reduced the incidence of cardiovascular events by 50%—a remarkable result. While patients at the highest risk were excluded from the study, those with lower cardiac risk nonetheless benefi ted from statin therapy. Experts have not typically recommended statins in the perioperative period for this patient population. the results of this study make it clear that they should.

CAVEATS: Extended-release formulation may have affected outcome

The statin used in this study was a longacting formulation, which may have protected patients who were unable to take oral medicines postoperatively. While we don’t know if the extended-release formulation made a difference in this study, we do know that atorvastatin was effective in the Brazilian study discussed earlier.

CHALLENGES TO IMPLEMENTATION: Preop statins may be overlooked

Not all patients see a primary care physician prior to undergoing vascular surgery. This means that it will sometimes be left to surgeons or other specialists to initiate statin therapy prior to surgery, and they may or may not do so.

Optimal timing is unknown. It is not clear how little time a patient scheduled for vascular surgery could spend on a statin and still reap these benefits. Nor do we know if the benefits would extend to patients undergoing other types of surgery; in a large study of patients undergoing all kinds of major noncardiac surgery, no benefits of perioperative statins were found.⁷

Adherence to the medication regimen presents another challenge, at least for some patients. In this case, however, we think the prospect of preventing major cardiac events postoperatively simply by taking statins for a month should be compelling enough to convince patients to take their medicine.

Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources; the grant is a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the ofcial views of either the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 67-year-old man with recurrent transient ischemic attacks comes in for a preoperative evaluation for carotid endarterectomy. The patient’s total cholesterol is 207 mg/dL and his low-density lipoprotein cholesterol (LDL-C) is 109 mg/dL. He takes metoprolol and lisinopril for hypertension.

Should you start him on a statin before surgery?

Nearly 25% of patients with peripheral vascular disease suffer from a cardiac event within 72 hours of elective, noncardiac vascular surgery.³ While most of these “complications” have minimal clinical impact and are detected by biochemical markers alone, some patients experience serious cardiac complications—including fatal myocardial infarction (MI).

That’s not surprising, given that most patients who require noncardiac vascular surgery suffer from severe coronary vascular disease.⁴ What is surprising is that most candidates for noncardiac vascular surgery are not put on statins prior to undergoing surgery.^1,2,5

Statins were thought to increase—not prevent—complications
Until recently, taking statins during the perioperative period was believed to increase complications, including statin-associated myopathy. Indeed, guidelines from the American Heart Association (AHA), American College of Cardiology (ACC), and National Heart, Lung and Blood Institute (NHLBI) suggest that it is prudent to withhold statins during hospitalization for major surgery.⁶

1 small study hinted at value of perioperative statins
A small Brazilian trial conducted in 2004 called the AHA/ACC/NHLBI guidelines into question. the researchers studied 100 patients slated for noncardiac vascular surgery who were randomized to receive either 20 mg atorvastatin (Lipitor) or placebo preoperatively —and monitored them for cardiac events 6 months postoperatively. They found that the incidence of cardiac events (cardiac death, nonfatal MI, stroke, or unstable angina) was more than 3 times higher in the placebo group compared with patients receiving atorvastatin (26% vs 8%, number needed to treat [NNT]=5.6; P=.031).²

The results of this small single study, although suggestive, were not sufficiently convincing to change recommendations about the preoperative use of statins, however. A more comprehensive study was needed to alter standard practice, and the Schouten study that we report on below fits the bill.¹

STUDY SUMMARY: Preoperative statin use cuts risk in half

Schouten et al followed 500 patients, who were randomized to receive either 80 mg extended-release fluvastatin (Lescol XL) or placebo for a median of 37 days prior to surgery.¹ All enrollees were older than 40 years of age and were scheduled for noncardiac vascular surgery. the reasons for the surgery were abdominal aortic aneurysm repair (47.5%), lower limb arterial reconstruction (38.6%), or carotid artery endarterectomy (13.9%). Patients who were taking long-term beta-blocker therapy were continued on it; otherwise, bisoprolol 2.5 mg was initiated at the screening visit. Patients who were already taking statins (<50% of potential subjects) were excluded. Other exclusions were a contraindication to statin therapy; emergent surgery; and a repeat procedure within the last 29 days. Patients with unstable coronary artery disease or extensive stress-induced ischemia consistent with left main artery disease (or its equivalent) were also excluded.

The primary study outcome was myocardial ischemia, determined by continuous electrocardiogram (EKG) monitoring in the first 48 hours postsurgery and by 12-lead EKG recordings on days 3, 7, and 30. Troponin T levels were measured on postoperative days 1, 3, 7, and 30, as well. the principal secondary end point was either death from cardiovascular causes or nonfatal MI. MI was diagnosed by characteristic ischemic symptoms, with EKG evidence of ischemia or positive troponin T with characteristic rising and falling values.

To gauge fluvastatin’s effect on biomarkers, lipids, high-sensitivity C-reactive protein, and interleukin-6 were measured upon initiation of the medication and on the day of admission for surgery. Serum creatine kinase, alanine aminotransferase (ALT) levels, clinical myopathy, and rhabdomyolysis were monitored as safety measures, with levels measured prior to randomization, on the day of admission, and on postoperative days 1, 3, 7, and 30.

Both groups were similar in age (mean of 66 years), total serum cholesterol levels, risk factors for cardiac events, and medication use. About 75% of the enrollees were men. At baseline, 51% of the participants had a total cholesterol <213 mg/dL, and 39% had an LDL-C <116 mg/dL. Within 30 days after surgery, 27 (10.8%) of those in the fluvastatin group and 47 (19%) of patients in the placebo group had evidence of myocardial ischemia (hazard ratio=0.55; 95% confidence interval [CI], 0.34-0.88; P=.01). the NNT to prevent 1 patient from experiencing myocardial ischemia was 12.

Statin users had fewer MIs. A total of 6 patients receiving fluvastatin died, with 4 deaths attributed to cardiovascular causes. In the placebo group, 12 patients died, 8 of which were ascribed to cardiovascular causes. Eight patients in the fluvastatin group experienced nonfatal MIs, compared with 17 patients in the placebo group (NNT=19 to prevent 1 nonfatal MI or cardiac death (hazard ratio= 0.47; 95% CI, 0.24-0.94; P=.03).

Effects of statins were evident preoperatively. At the time of surgery, patients in the fluvastatin group had, on average, a 20% reduction in their total cholesterol and a 24% reduction in LDL-C; in the placebo group, total cholesterol had fallen by 4% and LDL-C, by 3%.

Patients receiving fluvastatin had an average 21% decrease in C-reactive protein, compared with a 3% increase for the placebo group. Interleukin-6 levels also were reduced far more in the fluvastatin group (33% vs a 4% reduction in the placebo group [P<.001]).

The medication was well tolerated. Overall, 6.8% of participants discontinued the study because of side effects, including 16 (6.4%) patients in the fluvastatin group and 18 (7.3%) in the placebo group. (After surgery, 115 [23.1%] of patients in the statin group temporarily discontinued the drug because of an inability to take oral medications for a median of 2 days.)

Rates of increase in creatine kinase of >10× the upper limit of normal (ULN) were similar between the fluvastatin and placebo groups (4% vs 3.2%, respectively). Increases in ALT to >3× ULN were more frequent in the placebo group compared with the fluvastatin group (5.3%, placebo; 3.2%, fluvastatin). No cases of myopathy or rhabdomyolysis were observed in either group.

WHAT’S NEW: Preop statins can be a lifesaver

The initiation of fluvastatin prior to vascular surgery reduced the incidence of cardiovascular events by 50%—a remarkable result. While patients at the highest risk were excluded from the study, those with lower cardiac risk nonetheless benefi ted from statin therapy. Experts have not typically recommended statins in the perioperative period for this patient population. the results of this study make it clear that they should.

CAVEATS: Extended-release formulation may have affected outcome

The statin used in this study was a longacting formulation, which may have protected patients who were unable to take oral medicines postoperatively. While we don’t know if the extended-release formulation made a difference in this study, we do know that atorvastatin was effective in the Brazilian study discussed earlier.

CHALLENGES TO IMPLEMENTATION: Preop statins may be overlooked

Not all patients see a primary care physician prior to undergoing vascular surgery. This means that it will sometimes be left to surgeons or other specialists to initiate statin therapy prior to surgery, and they may or may not do so.

Optimal timing is unknown. It is not clear how little time a patient scheduled for vascular surgery could spend on a statin and still reap these benefits. Nor do we know if the benefits would extend to patients undergoing other types of surgery; in a large study of patients undergoing all kinds of major noncardiac surgery, no benefits of perioperative statins were found.⁷

Adherence to the medication regimen presents another challenge, at least for some patients. In this case, however, we think the prospect of preventing major cardiac events postoperatively simply by taking statins for a month should be compelling enough to convince patients to take their medicine.

Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources; the grant is a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the ofcial views of either the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 67-year-old man with recurrent transient ischemic attacks comes in for a preoperative evaluation for carotid endarterectomy. The patient’s total cholesterol is 207 mg/dL and his low-density lipoprotein cholesterol (LDL-C) is 109 mg/dL. He takes metoprolol and lisinopril for hypertension.

Should you start him on a statin before surgery?

Nearly 25% of patients with peripheral vascular disease suffer from a cardiac event within 72 hours of elective, noncardiac vascular surgery.³ While most of these “complications” have minimal clinical impact and are detected by biochemical markers alone, some patients experience serious cardiac complications—including fatal myocardial infarction (MI).

That’s not surprising, given that most patients who require noncardiac vascular surgery suffer from severe coronary vascular disease.⁴ What is surprising is that most candidates for noncardiac vascular surgery are not put on statins prior to undergoing surgery.^1,2,5

Statins were thought to increase—not prevent—complications
Until recently, taking statins during the perioperative period was believed to increase complications, including statin-associated myopathy. Indeed, guidelines from the American Heart Association (AHA), American College of Cardiology (ACC), and National Heart, Lung and Blood Institute (NHLBI) suggest that it is prudent to withhold statins during hospitalization for major surgery.⁶

1 small study hinted at value of perioperative statins
A small Brazilian trial conducted in 2004 called the AHA/ACC/NHLBI guidelines into question. the researchers studied 100 patients slated for noncardiac vascular surgery who were randomized to receive either 20 mg atorvastatin (Lipitor) or placebo preoperatively —and monitored them for cardiac events 6 months postoperatively. They found that the incidence of cardiac events (cardiac death, nonfatal MI, stroke, or unstable angina) was more than 3 times higher in the placebo group compared with patients receiving atorvastatin (26% vs 8%, number needed to treat [NNT]=5.6; P=.031).²

The results of this small single study, although suggestive, were not sufficiently convincing to change recommendations about the preoperative use of statins, however. A more comprehensive study was needed to alter standard practice, and the Schouten study that we report on below fits the bill.¹

STUDY SUMMARY: Preoperative statin use cuts risk in half

Schouten et al followed 500 patients, who were randomized to receive either 80 mg extended-release fluvastatin (Lescol XL) or placebo for a median of 37 days prior to surgery.¹ All enrollees were older than 40 years of age and were scheduled for noncardiac vascular surgery. the reasons for the surgery were abdominal aortic aneurysm repair (47.5%), lower limb arterial reconstruction (38.6%), or carotid artery endarterectomy (13.9%). Patients who were taking long-term beta-blocker therapy were continued on it; otherwise, bisoprolol 2.5 mg was initiated at the screening visit. Patients who were already taking statins (<50% of potential subjects) were excluded. Other exclusions were a contraindication to statin therapy; emergent surgery; and a repeat procedure within the last 29 days. Patients with unstable coronary artery disease or extensive stress-induced ischemia consistent with left main artery disease (or its equivalent) were also excluded.

The primary study outcome was myocardial ischemia, determined by continuous electrocardiogram (EKG) monitoring in the first 48 hours postsurgery and by 12-lead EKG recordings on days 3, 7, and 30. Troponin T levels were measured on postoperative days 1, 3, 7, and 30, as well. the principal secondary end point was either death from cardiovascular causes or nonfatal MI. MI was diagnosed by characteristic ischemic symptoms, with EKG evidence of ischemia or positive troponin T with characteristic rising and falling values.

To gauge fluvastatin’s effect on biomarkers, lipids, high-sensitivity C-reactive protein, and interleukin-6 were measured upon initiation of the medication and on the day of admission for surgery. Serum creatine kinase, alanine aminotransferase (ALT) levels, clinical myopathy, and rhabdomyolysis were monitored as safety measures, with levels measured prior to randomization, on the day of admission, and on postoperative days 1, 3, 7, and 30.

Both groups were similar in age (mean of 66 years), total serum cholesterol levels, risk factors for cardiac events, and medication use. About 75% of the enrollees were men. At baseline, 51% of the participants had a total cholesterol <213 mg/dL, and 39% had an LDL-C <116 mg/dL. Within 30 days after surgery, 27 (10.8%) of those in the fluvastatin group and 47 (19%) of patients in the placebo group had evidence of myocardial ischemia (hazard ratio=0.55; 95% confidence interval [CI], 0.34-0.88; P=.01). the NNT to prevent 1 patient from experiencing myocardial ischemia was 12.

Statin users had fewer MIs. A total of 6 patients receiving fluvastatin died, with 4 deaths attributed to cardiovascular causes. In the placebo group, 12 patients died, 8 of which were ascribed to cardiovascular causes. Eight patients in the fluvastatin group experienced nonfatal MIs, compared with 17 patients in the placebo group (NNT=19 to prevent 1 nonfatal MI or cardiac death (hazard ratio= 0.47; 95% CI, 0.24-0.94; P=.03).

Effects of statins were evident preoperatively. At the time of surgery, patients in the fluvastatin group had, on average, a 20% reduction in their total cholesterol and a 24% reduction in LDL-C; in the placebo group, total cholesterol had fallen by 4% and LDL-C, by 3%.

Patients receiving fluvastatin had an average 21% decrease in C-reactive protein, compared with a 3% increase for the placebo group. Interleukin-6 levels also were reduced far more in the fluvastatin group (33% vs a 4% reduction in the placebo group [P<.001]).

The medication was well tolerated. Overall, 6.8% of participants discontinued the study because of side effects, including 16 (6.4%) patients in the fluvastatin group and 18 (7.3%) in the placebo group. (After surgery, 115 [23.1%] of patients in the statin group temporarily discontinued the drug because of an inability to take oral medications for a median of 2 days.)

Rates of increase in creatine kinase of >10× the upper limit of normal (ULN) were similar between the fluvastatin and placebo groups (4% vs 3.2%, respectively). Increases in ALT to >3× ULN were more frequent in the placebo group compared with the fluvastatin group (5.3%, placebo; 3.2%, fluvastatin). No cases of myopathy or rhabdomyolysis were observed in either group.

WHAT’S NEW: Preop statins can be a lifesaver

The initiation of fluvastatin prior to vascular surgery reduced the incidence of cardiovascular events by 50%—a remarkable result. While patients at the highest risk were excluded from the study, those with lower cardiac risk nonetheless benefi ted from statin therapy. Experts have not typically recommended statins in the perioperative period for this patient population. the results of this study make it clear that they should.

CAVEATS: Extended-release formulation may have affected outcome

The statin used in this study was a longacting formulation, which may have protected patients who were unable to take oral medicines postoperatively. While we don’t know if the extended-release formulation made a difference in this study, we do know that atorvastatin was effective in the Brazilian study discussed earlier.

CHALLENGES TO IMPLEMENTATION: Preop statins may be overlooked

Not all patients see a primary care physician prior to undergoing vascular surgery. This means that it will sometimes be left to surgeons or other specialists to initiate statin therapy prior to surgery, and they may or may not do so.

Optimal timing is unknown. It is not clear how little time a patient scheduled for vascular surgery could spend on a statin and still reap these benefits. Nor do we know if the benefits would extend to patients undergoing other types of surgery; in a large study of patients undergoing all kinds of major noncardiac surgery, no benefits of perioperative statins were found.⁷

Adherence to the medication regimen presents another challenge, at least for some patients. In this case, however, we think the prospect of preventing major cardiac events postoperatively simply by taking statins for a month should be compelling enough to convince patients to take their medicine.

Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources; the grant is a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the ofcial views of either the National Center for Research Resources or the National Institutes of Health.

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