Editorials

Who Should Operate in Carotid Disease?

JAMES R. PERRY, M.D., FRCP(C)
Sunnybrook and Women's College Health Science Centre,
Toronto, Ontario

See article in this issue.

With the publication of randomized controlled trials on carotid endarterectomy, the appropriate indications for this surgery ("when to operate") are becoming better defined. From a public health perspective, however, the benefits of carotid surgery are convincing only when surgical morbidity and mortality rates are very low. Thus, an equally important question needs to be considered: "Who should operate in carotid disease?"

In this issue of American Family Physician, Biller and Thies¹ review evidence showing that carotid endarterectomy can be highly effective in preventing stroke. Patients with high-grade internal carotid artery stenosis (greater than 70 percent) that is ipsilateral to the side of previous symptoms or nondisabling stroke benefit dramatically from the combined use of surgery and medical therapy compared with the use of medical therapy alone. In patients with severe carotid artery stenosis, fewer than eight carotid endarterectomies are required to prevent one stroke. The benefits of carotid endarterectomy are not as dramatic in symptomatic patients with lesser degrees of stenosis (50 to 69 percent), and surgery may not be beneficial in patients with less than 50 percent stenosis.

The benefits of surgery in asymptomatic patients have been controversial. In these patients, carotid endarterectomy may prevent only nondisabling strokes rather than disabling ones, and the clinical significance of a small risk reduction for such an outcome is questionable.² A recent meta-analysis³ of all randomized controlled trials conducted in asymptomatic patients indicated that the number of surgeries needed to prevent one stroke over three years is close to 50.¹

Although some authorities speculate that certain subgroups of asymptomatic patients might benefit from surgery, we have no idea who these patients are. Many experts believe that surgery is not indicated for patients without symptoms, regardless of the severity of carotid stenosis.² Treatment must always be individualized, but risk-factor reduction and education about the warning signs of ischemic stroke, rather than surgery, are appropriate measures in most asymptomatic patients.

When carotid surgery is an appropriate recommendation, who should be performing the operation? In all categories of carotid disease, low perioperative complication rates are crucial for the benefits of surgery to be realized. The surgeons who participated in the carotid surgery trials were high-volume experienced technicians with low mortality rates for the procedures they performed. For example, the 30-day mortality rate was 0.6 percent in the North American Symptomatic Carotid Endarterectomy Trial (NASCET)⁴ and 0.1 percent in the Asymptomatic Carotid Atherosclerosis Study (ACAS).⁵ In fact, the risk of surgery in ACAS was lower than the risk of angiography.

Several population-based studies have demonstrated that the low complication rates cited for the NASCET and the ACAS are almost impossible to achieve outside of centers of excellence such as those in which these trials were performed.^6-9 Mortality rates in American and Canadian hospitals are substantially higher than those reported in the surgical trials, and no evidence indicates that selective referral to surgeons with a proven track record of excellence in carotid surgery is taking place.⁹ Physicians and, indeed, patients have a right to know the performance data on carotid surgery for local surgeons and hospitals. However, a recent national survey found that only 19 percent of referring physicians had this information.¹⁰

Performance rates for carotid endarterectomy rose with publication of the NASCET and ACAS results in the 1990s.⁹ Referring physicians and surgeons are now better aware of the appropriate indications for carotid surgery. Yet, endarterectomies continue to be performed for inappropriate reasons. Even when patient selection is appropriate, selection of the surgeon can influence outcome. For example, investigators in one study found that low surgeon volume (fewer than six cases per year) was associated with higher complication rates and suggested that a minimum volume threshold for this procedure should be established.⁷

One study¹¹ found that the use of a city-wide audit, combined with an education campaign and ongoing audit, improved the appropriateness and safety of carotid endarterectomies. Public health pressures will probably continue to affect our access to performance data such as these. For now, it is wise for referring physicians to seek out surgeons and hospitals with a proven track record in performing successful, safe carotid surgery. Selective referral to regionalized centers of excellence may be one model for this approach.

What does the future hold? Yet another trial, the Asymptomatic Carotid Surgery Trial, is ongoing. This trial may help to answer questions about the suitability of surgery in patients without symptoms. In addition, noninvasive forms of imaging the carotid arteries, such as magnetic resonance angiography, may replace conventional angiography and lower the overall risk of intervention. Nonsurgical alternatives, such as carotid angioplasty and stenting, may play a role in selected patients. At present, however, carotid angioplasty and stenting should be performed only in research studies. Finally, the results of the Aspirin in Carotid Endarterectomy (ACE) trial¹² indicated that 30-day perioperative morbidity and mortality following carotid endarterectomy were significantly reduced by the use of low doses of aspirin (80 or 325 mg) compared with high doses (650 or 1,300 mg). High-dose aspirin is likely better than no aspirin at all; however, patients scheduled for carotid artery surgery should be placed on low-dose aspirin prior to surgery and remain on such a dose indefinitely.

Risk-factor reduction, aspirin in an appropriate dosage and selective referral to surgeons with proven track records of excellence are measures presently available to family physicians. In particular, it is up to referring physicians to wisely select "who should operate."

Dr. Perry is assistant professor and a member of the stroke research unit in the neurology division at Sunnybrook and Women's College Health Science Centre, Toronto, Ontario.

Address correspondence to James R. Perry, M.D., Sunnybrook and Women's College Health Science Centre, Division of Neurology, Room A-442, 2075 Bayview Ave., Toronto, Ontario, Canada M4N 3M5.

REFERENCES

1. Biller J, Thies WH. When to operate in carotid artery disease. Am Fam Physician 2000;61:400-6.
2. Perry JR, Szalai JP, Norris JW. Consensus against both endarterectomy and routine screening for asymptomatic carotid artery stenosis. Canadian Stroke Consortium. Arch Neurol 1997;54:25-8.
3. Benavente O, Moher D, Pham B. Carotid endarterectomy for asymptomatic carotid stenosis: a meta-analysis. BMJ 1998;317:1477-80.
4. North American Symptomatic Carotid Endarterectomy Trial (NASCET) Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445-53.
5. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995;273:1421-8.
6. Hannan EL, Popp AJ, Tranmer B, Fuestel P, Waldman J, Shah D. Relationship between provider volume and mortality for carotid endarterectomies in New York state. Stroke 1998;29:2292-7.
7. Kucey DS, Bowyer B, Iron K, Austin P, Anderson G, Tu JV. Determinants of outcome after carotid endarterectomy. J Vacs Surg 1998;28:1051-8.
8. Pearce WH, Parker MA, Feinglass J, Ujiki M, Manheim LM. The importance of surgeon volume and training in outcomes for vascular surgical procedures. J Vasc Surg 1999;29:768-76.
9. Tu JV, Hannan EL, Anderson GM, Iron K, Wu K, Vranizan K, et al. The fall and rise of carotid endarterectomy in the United States and Canada. N Engl J Med 1998;339:1441-7.
10. Goldstein LB, Bonito AJ, Matchar DB, Duncan PW, DeFriese GH, Oddone EZ, et al. US national survey of physician practices for the secondary and tertiary prevention of ischemic stroke. Design, service availability, and common practices. Stroke 1995;26:1607-15.
11. Wong JH, Lubkey TB, Suarez-Almazor ME, Findlay JM. Improving the appropriateness of carotid endarterectomy: results of a prospective city-wide study. Stroke 1999;30:12-5.
12. Taylor EW, Barnett HJ, Haynes RB, Ferguson GG, Sackett DL, Thorpe KE, et al. Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial. ASA and Carotid Endarterectomy (ACE) Trial Collaborators. Lancet 1999;353:2179-84.

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Controversy in Otitis Media Management: Should We Follow the CDC Recommendations?

JOHN R. MCCONAGHY, M.D., and
STEVEN R. SMITH, M.S., R.PH.
Toledo Hospital Family Practice Residency
Toledo, Ohio

In recent years, physicians have been moving toward using evidence-based, patient-oriented outcomes data to guide the management of a variety of medical conditions. Because of this evidence-based medicine approach, the treatment of acute otitis media has become controversial in the United States. Discussion in the medical literature has centered on inappropriate use of antibiotics in the treatment of acute otitis media and upper respiratory tract infections.^1,2 Current antibiotic usage patterns are thought to contribute to the increasing patterns of antimicrobial resistance in common pathogens of the middle ear.³ In response, the Centers for Disease Control and Prevention instituted a nationwide effort to address the problem of emerging infectious diseases and define patterns of antimicrobial resistance.⁴ More specifically, the Drug-Resistant Streptococcus pneumoniae (DRSP) Therapeutic Working Group has recommended doubling the dosage of amoxicillin to 80 to 90 mg per kg per day in the empiric treatment of acute otitis media, along with recommending earlier use of broader spectrum antibiotics for treatment "failures" after three days.⁵ These recommendations are of concern because they are not based on any patient-oriented outcomes evidence.

A brief review of the evidence in the approach to otitis media would be helpful. Three essential questions must be answered: Does acute otitis media need to be treated with antibiotics? If so, which antibiotic should be used? How long should treatment be continued? Four systematic reviews analyze the literature on these topics.^6-9 These reviews provided the following conclusions:

• More than 80 percent of cases of acute otitis media resolve spontaneously.^6-8
• The only short-term advantage of using antibiotics to treat otitis media is a modest decrease in the number of children with continued pain at two to seven days from diagnosis. Use of antibiotics has not affected the long-term outcomes.^6,7
• Narrow-spectrum antibiotics are still the recommended and effective treatment for acute otitis media⁸ and, in most children, a shortened course (five days) is adequate treatment with no negative impact on clinical outcomes.⁹

These conclusions are based on patient-oriented evidence, but the CDC guidelines are based on laboratory data (disease-oriented evidence) and consensus opinion. Guidelines developed using a nonsystematic approach can be misleading and, in this case, imply that all children with garden-variety otitis media require increased dosages of antibiotics. Whether intended or not, the implications of the CDC guidelines are already widely communicated by editorials, newsletters and the pharmaceutical industry. Despite the large amount of in vitro data cited, there is little correlation between the Petri dish and how a child responds to antibiotic treatment.

What are the costs of the recommended antibiotic regimens to the health care system and to patients and their families? Combinations of amoxicillin and amoxicillin-clavulanate will likely challenge patient adherence. Three daily doses of intramuscular ceftriaxone are expensive and are not likely to be an acceptable regimen for infants and children. The authors state that "...[in] the absence of any significant dose-related toxicity, it seems reasonable to use amoxicillin at 80 to 90 mg per kg per day...."⁵ However, antibiotic treatment of acute otitis media is associated with a doubling of the risk of rashes, vomiting and diarrhea.^6,7 Will doubling the antibiotic dose further increase the risk for drug reactions? If so, this will translate into more physician office visits, more time off from work for parents, and more missed days of school for children. Are these acceptable risks in a condition that resolves spontaneously 80 percent of the time without antibiotics?

The focus of the DRSP Therapeutic Working Group is to address increasing antibiotic resistance with increased doses of amoxicillin and the earlier use of broad-spectrum antibiotics. In the Netherlands and Iceland, however, the rate of antibiotic use for acute otitis media is one-third of that in the United States, and the rate of antibiotic resistance is much lower.^3,10 No clinical evidence shows that increasing the dosage of amoxicillin or using broad-spectrum antibiotics will overcome antibiotic resistance--and it may make it worse.

These recommendations by the CDC and the DRSP Therapeutic Working Group may be useful in some patient subpopulations, but we believe that they should not be generalized to primary care and family practice populations without solid, clinical, patient-oriented outcomes data to support them. Rather than throwing more antibiotics at ear infections, we should be focusing efforts on reducing their indiscriminate use and identifying subsets of children who truly need antibiotics.

John R. McConaghy, M.D., is associate director and medical director of the Toledo Hospital Family Practice Residency in Toledo, Ohio. Steven R. Smith, M.S., R.Ph., is a clinical pharmacist and a member of the faculty at the Toledo Hospital Family Practice Residency and an adjunct assistant professor of clinical pharmacy at the University of Toledo College of Pharmacy.

Address correspondence to John R. McConaghy, M.D., 2051 W. Central Ave., Toledo, Ohio 43606.

REFERENCES

1. 1. Dowell SF, Schwartz B, Phillips WR. Appropriate use of antibiotics for URI's in children: part 1. Otitis media and acute sinusitis. Am Fam Physician 1998;58:1113-8,1123.
2. 2. Culpepper L, Froom J. Routine antimicrobial treatment of acute otitis media: is it necessary? JAMA 1997;278:1643-5.
3. 3. Froom J. Culpepper L, Jacobs M, DeMelker RA, Green LA, van Buchem L, et al. Antimicrobials for acute otitis media? A review from the International Primary Care Network. BMJ 1997;315:98-102.
4. 4. Centers for Disease Control and Prevention. Preventing emerging infectious diseases: a strategy for the 21^st century. Atlanta, Ga.:1998.
5. 5. Dowell SF, Butler JC, Giebink GS, Jacobs MR, Jernigan D, Musher DM, et al. Acute otitis media: management and surveillance in an era of pneumococcal resistance--a report from the drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Ped Infect Dis J 1999;18:1-9.
6. 6. Glasziou PP, Hayem M, Del Mar CB. Antibiotic versus placebo for acute otitis media in children (Cochrane Review). In: The Cochrane Library, Issue 1, 1999. Oxford: Update Software.
7. 7. Del Mar C, Gasziou P, Hayem M. Are antibiotics indicated for children with acute otitis media? A meta-analysis. BMJ 1997;314:1526-9.
8. 8. Rosenfelf RM, Vertrees JE. Clinical efficacy of antimicrobial drugs for acute otitis media: Meta-analysis of 5400 children from thirty-three randomized trials. J Pediat 1994;124(3):355-67.
9. 9. Kozyrskyj AL, Hildres-Ripstein GE, Longstaffe SE, Wincott JL, Sitar DS, Klassen TP, Moffatt ME. Treatment of acute otitis media with a shortened course of antibiotics: a meta-analysis. JAMA June 3, 1998;279:1736-42.
10. 10. Stephenson J. Icelandic researchers are showing the way to bring down rates of antibiotic-resistant bacteria. JAMA 1996;275:175.

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Acute Otitis Media Caused by Resistant Pneumococci

SCOTT F. DOWELL, M.D., M.P.H.
Centers for Disease Control and Prevention
Atlanta, Georgia

McConaghy and Smith are to be congratulated for their carefully reasoned review of the importance of reducing inappropriate and broad-spectrum antimicrobial treatment of acute otitis media, which concludes that "we should be focusing efforts on reducing indiscriminate use and identifying subsets of children who truly need antibiotics." We agree wholeheartedly with these sentiments and have published principles of judicious use of antimicrobial agents for otitis media, as they cite.¹

The task of the Drug-Resistant Streptococcus pneumoniae (DRSP) Therapeutic Working Group, however, was different. This group was charged with providing advice for the management of acute otitis media, given an identified subset of children for whom antibiotics were truly needed. In 1999, resistant pneumococci were of primary concern in this subgroup of children, and few clinical, patient-oriented outcome studies were available to guide clinicians in making the best treatment decisions for their patients. In fact, none of the 18 drugs currently labeled for treatment of acute otitis media has gained U.S. Food and Drug Administration approval for use against resistant pneumococci, primarily because the clinical evidence for efficacy against these pathogens is so hard to come by.

Nevertheless, ample evidence shows that resistant pneumococci are of real clinical concern and that adequate treatment is important for good clinical outcomes. Of the major pathogens causing acute otitis media, pneumococci are not only the most common but are the least likely to resolve in the absence of appropriate therapy. For example, 50 percent of Haemophilus influenzae infections will resolve even if the patient is treated with a placebo, but only 20 percent of Streptococcus pneumoniae infections will resolve.² Clinical outcome is in fact well correlated with bacteriologic eradication of pathogens of the middle ear fluid,³ and pneumococcal resistance is directly correlated with clinical failure⁴ and bacteriologic persistence.⁵

What, then, is the family physician to do after careful examination of the child and determination that all criteria for acute otitis media requiring antimicrobial therapy have unequivocally been met? If resistant pneumococci are not a concern, any of the 18 approved drugs might appropriately be selected, but this is no longer the case for most areas of the United States. For pneumococci that are not susceptible to treatment with penicillin, drugs such as cefaclor, loracarbef, cefixime and ceftibuten are inactive and more likely to fail, clinically and bacteriologically.^5,6 Therefore, in the absence of controlled, patient-oriented outcome studies, the DRSP Therapeutic Working Group document was an attempt to provide some guidance for antimicrobial treatment in the era of resistant pneumococci.

Fortunately, amoxicillin remains an excellent first-line choice because it is effective, safe, inexpensive and convenient to administer. The higher dosage provides expanded coverage of resistant pneumococci. McConaghy and Smith ask if this will increase the risk of adverse drug reactions, and the answer is no, so far as we are aware. For those children with clinically documented treatment failures, the most likely pathogens are beta-lactamase­ producing H. influenzae and drug-resistant S. pneumoniae. The alternative agents identified are all effective against drug-resistant S. pneumoniae and are beta-lactamase stable. It is true that each has shortcomings for some patients (e.g., amoxicillin-clavulanate is expensive, cefuroxime axetil has a bitter taste and ceftriaxone must be injected). Most of the alternatives, however, are slightly yet measurably more likely to lead to treatment failure.

In summary, we are pleased to see that the DRSP Therapeutic Working Group document has generated such careful thought and criticism and heartily endorse the call for more patient-oriented outcomes studies and publications. We do not agree that "there is little correlation between the Petri dish and how a child responds to antibiotic treatment." Rather, we hope that the available bacteriologic and clinical efficacy data summarized in the document provide a rational interim approach for treating the subset of children with true acute otitis media.

Dr. Scott F. Dowell, M.D., M.P.H., is a medical epidemiologist at the Centers for Disease Control and Prevention and chair of the Drug-Resistant Streptococcus pneumoniae (DRSP) Therapeutic Working Group.

Address correspondence to Scott Dowell, M.D., M.P.H., Centers for Disease Control and Prevention, Respiratory Disease Branch, Division of Bacterial and Mycotic Diseases, Mailstop C23, 1600 Clifton Rd. E, Atlanta, GA 30333.

REFERENCES

1. Dowell SF, Schwartz B, Phillips WR. Appropriate use of antibiotics for URIs in children: part I. Otitis media and acute sinusitis. Am Fam Physician 1998;58:1113-8.
2. Klein JO. The "in vivo sensitivity test" for acute otitis media revisited. Pediatr Infect Dis J 1998;17: 774-5.
3. Dagan R, Leibovitz E, Greenberg D, Yagupsky P, Fliss DM, Leiberman A. Early eradication of pathogens from middle ear fluid during antibiotic treatment of acute otitis media is associated with improved clinical outcome. Pediatr Infect Dis J 1998;17:776-82.
4. Gehanno P, Lenoir G, Berche P. In vivo correlates for Streptococcus pneumoniae penicillin resistance in acute otitis media. Antimicrob Agents Chemother 1995;39:271-2.
5. Dagan R, Abramson O, Leibovitz E, Lang R, Goshen S, Greenberg D, et al. Impaired bacteriologic response to oral cephalosporins in acute otitis media caused by pneumococci with intermediate resistance to penicillin. Pediatr Infect Dis J 1996; 15:980-5.
6. Dowell SF, Butler JC, Giebink GS, Jacobs MR, Jernigan D, Musher DM, et al. Acute otitis media: management and surveillance in an era of pneumococcal resistance--a report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatr Infect Dis J 1999;18:1-9.

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