β-Agonists: all the facts please

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Perhaps the liquid-based cytol- ogy method used in most Ontario laboratories is another factor that facilitates quality assurance, as the specimen is placed in a centrifuge and separated from other extraneous material such as mucous and secre- tions. Also, cytotechnologists pre- pare the slide as a monolayer, which improves specimen adequacy for interpretation and quality.

The screening recommendations noted in Tsang and Osmun’s first paragraph differ slightly from the 2005 evidence-based Ontario recommendations for cervical cancer screening. After initiation of sexual activity, 3 annual Pap tests are recommended. If the first 3 Pap tests are normal, ongoing screening is recommended every 2 to 3 years.

A 3-year screening interval is recommended only if there is a recall system in place (either a provincial system or within a physician’s office).

There are ongoing efforts and recommendations for provincial recall systems to ensure regular screening for all eligible women.

Further, the authors’ suggestion to stop screening after meno- pause (with only 3 additional Pap tests) diverges substantially from Ontario’s (and other provincial) cervical screening guidelines, which recommend continuing regular Pap tests until age 70. Since there is no reference provided for their statement, this is likely their own per- sonal opinion, which does not coincide with existing provincial guidelines. Given that incidence and mortality rates for cervical cancer are the highest for women older than 50 years in Ontario² and other provinces, the suggestion to discon- tinue screening by age 60 is alarm- ing and should not be adopted as preferred practice.

—Stan Lofsky MD CCFP FCFP

—Robbi Howlett PhD North York, Ont by e-mail references

1. Tsang N, Osmun WE. Smear tactics. A more com- fortable Papanicolaou test. Can Fam Physician 2007;53:835.

2. Ontario Cervical Screening Program. Selected extracts from the OCSP Program Report 2001–2005.

Toronto, ON: Ontario Cervical Screening Program;

2005. Available from: www.cancercare.on.ca/

documents/OCSPProgramReport2001-2005.

pdf. Accessed 2007 October 9.

Competing interests

Dr Lofsky is a member of the Section on General and Family Practice of the Ontario Medical Association and repre- sents the Section at the Cervical Cancer Screening Collaborative Group of Cancer Care Ontario. He receives hon- oraria from the Section for attending meetings. In the past year he received honoraria for attending the Ontario Cervical Screening Collaborative Group biannual meeting and for attending the Ontario Colposcopy Standards Review Panel under the auspices of Cancer Care Ontario.

β-Agonists:

all the facts please

I

would like to share my comments about the recent debate titled

“Should we avoid β-agonists for moderate and severe chronic obstructive pulmonary disease?” (COPD) between Drs Salpeter and Aaron (Can Fam Physician 2007;53:1290-3 [Eng], 1294-7 [Fr]).

In support of the argument not to use β-agonists in the management of COPD, Salpeter leads the reader to believe that tolerance to β-agonists

Ontario cervical screening practice guidelines

english

www.cancercare.on.ca/

documents/CervicalScreening Guidelines.pdf

French

www.cancercare.on.ca/

documents/CervicalScreening Guidelines-French.pdf

Full report

www.cancercare.on.ca/pdf/

pebc_cervical_screen.pdf

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Correspondance Letters

might be the underlying mechanism associated with adverse events when these medications are used to treat obstructive lung disease. Salpeter develops this theme using references to both asthma and COPD studies.

Tolerance is a phenomenon observed with both short- and long-acting β- agonists¹ and, to date, its importance within a clinical framework appears to be minimal.

In a meta-analysis carried out by Salpeter et al² on the subject of tolerance to regular β–agonist use in patients with asthma there is no mention of the landmark Formoterol and Corticosteriod Establishing Therapy (FACET) trial³ where, despite the observation of tolerance to the bronchodilating effect of formoterol, the addition of formoterol to either low- or high-dose budesonide was associated with a reduction in severe exacerbations compared with budesonide use alone. Given her position on tolerance, it is important for Salpeter to reconcile these findings. I should note that current guidelines^1,4 on asthma management recommend the addition of a long-acting β-agonist when asthma remains sub- optimally controlled with inhaled corticosteroids for reasons outlined above.³ It is beyond the scope of this communication to address possible genetic factors that might influence β- receptor function and how this might be related to the phenomenon of tolerance. It is also important to note that safety concerns with respect to long-acting β-agonist use in asthma management centre on salmeterol use, as indicated in the reference list of the Salpeter debate.⁵

Given the established role of long- acting β-agonists as maintenance therapy in COPD, I was extremely surprised to see that Salpeter’s position was published without any mention of the Towards a Revolution in COPD Health (TORCH) study⁶—an issue addressed very appropriately by Dr Aaron. I cannot imagine that Dr Salpeter was not aware of the TORCH trial given its widespread international dissemination. The TORCH trial

(despite some limitations) represents perhaps the longest and most robust randomized, placebo-controlled COPD trial to date and clearly dem- onstrated that salmeterol did not increase mortality compared with placebo. In fact, in the TORCH study,⁶ salmeterol reduced severe exacerbations requiring hospitalization as compared with placebo. Dr Salpeter should discuss these findings in rela- tionship to her position.

Finally, many of the references included in Salpeter’s discussion include systemic reviews prepared by Salpeter. It is beyond the scope of this communication to outline important shortcomings of such studies, but it is relevant to note that unlike previous retrospective reports of reduced COPD mortality with inhaled corticosteroid use,^7,8 the TORCH trial did not show a mortality benefit among patients using fluticasone compared with placebo. This type of discrep- ancy between the results of randomized, placebo-controlled trials and historical analyses underscores how misleading the latter might be.

I am concerned that Salpeter’s argument is not supported by the best available evidence because the literature review is not comprehensive—

a limitation that introduces a serious bias. This might serve only to confuse family physicians who are far too busy looking after patients to carry out comprehensive literature searches of their own.

—Anthony D. D’Urzo MD MSc CCFP FCFP Toronto, Ont by e-mail references

1. Boulet LP, Becker AD, Beveredge R, Ernst P.

Canadian asthma consensus report, 1999: Canadian asthma consensus group. CMAJ 1999;61:51-61.

2. Salpeter SR, Ormiston TM, Salpeter EE. Meta- analysis: respiratory tolerance to regular β2-agonist use in patients with asthma.

Ann Intern Med 2004;140:802-13.

3. Pauwels RA, Lofdahl CG, Postma DS, Tattersfield AE, O’Byrne P, Barnes PJ, et al. Effect of inhaled formoterol on exacerbations of asthma.

Formoterol and Corticosteroid Establishing Therapy (FACET) International study group. N Engl J Med 1997;337:1405-11. Erratum in: N Engl J Med 1998;338:139.

4. Global Initiative for Asthma. Global strategy for asthma management and prevention. Revised 2006.

Hamilton, ON: Global Initiative for Asthma; 2006.

Available from: http://ginasthma.com. Accessed

2007 August 25. 2061

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5. Salpeter SR. Should we avoid β-agonists for moderate and severe chronic obstructive pulmonary disease? Yes [Debates]. Can Fam Physician 2007;53:1290-3 (Eng), 1294-7 (Fr).

6. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al.

Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775-89.

7. Sin DD, Wu L, Anderson JA, Anthonisen NR, Buist AS, Burge PS, et al.

Inhaled corticosteroid and mortality in chronic obstructive pulmonary disease. Thorax 2005;60:992-7.

8. Macie C, Wooldrage K, Manfreda J, Anthonisen NR. Inhaled corticosteroid and mortality in COPD. Chest 2006;130:640-6.

Response

I

appreciate the comments of Dr Anthony D’Urzo con- cerning the recent debate on the safety of β-agonist use in chronic obstructive lung disease (COPD).¹ I will respond to his comments here, but first I would like to point out that Dr D’Urzo has consultant arrangements with the pharmaceutical firms AstraZeneca and Novartis, has received grant support from AstraZeneca, and is on the speakers’ bureau for Schering-Plough.² It is possible that Dr D’Urzo’s comments are tempered by a serious bias toward promoting long-acting β-agonist use, espe- cially that of formoterol, the long-acting β-agonist made by these companies.

As Dr D’Urzo pointed out, my recent analysis of β-agonist use in COPD³ did not include the TORCH study,⁴ but this is because it had not been published at that time. As I discussed in the debate rebuttal, this trial also showed an increase in respiratory deaths for β-agonist use compared with placebo, although it was not statistically significant. It is true that the TORCH trial found an 18% reduction in hospitalizations due to COPD,⁴ while previous studies found no reduction in COPD hospitalizations with β-agonist use.³ This is consistent with the evidence that β-agonists improve COPD symptoms but might increase respiratory mortality compared with placebo. It is important to compare these results with those of anticholinergic agents, which have been shown to reduce hospitalizations by 33% and respiratory mortality by 73%, compared with placebo.³

Another published analysis evaluated long-acting β-agonists in asthma and found a similar increase in respiratory mortality compared with placebo.⁵ This adverse effect of β-agonists in obstructive lung disease is thought to be due, in part, to tolerance that develops to β-agonist use over time, although I agree with Dr D’Urzo that other factors might be involved.⁶ As Dr D’Urzo points out, the FACET trial⁷ was not included in my previous analysis, but that is because it was not a placebo-controlled trial. He also suggests that these safety concerns in asthma have centred on salmeterol and not formoterol, but pooled trial data have found a significant and equal increase in asthma hospitalizations for both formoterol and salmeterol, compared with placebo.⁵

Dr D’Urzo is worried that my arguments are not supported by the best available evidence because my literature review is not comprehensive and that this

might introduce a serious bias. He suggests that my review might “serve only to confuse family physicians who are far too busy looking after patients to carry out comprehensive literature searches of their own.” A full literature review was not possible in this short position statement, but I would like to assure the readers that my meta-analyses have included all of the randomized placebo-controlled trials that were available when the reviews were completed. The fact that Canadian Family Physician invited a debate on whether β-agonists should be avoided in COPD should alert readers that there might be some serious concerns about their safety. I myself am a practising general internist caring for patients with COPD, and I have no ties to the pharmaceutical indus- try. I personally use anticholinergic agents instead of β-agonists as the bronchodilator of choice in the treat- ment of these patients.

—Shelley R. Salpeter MD FACP San Jose, Calif by e-mail references

1. Salpeter SR. Should we avoid β-agonists for moderate and severe chronic obstructive pulmonary disease? Yes [Debates]. Can Fam Physician 2007;53:1290-3 (Eng), 1294-7 (Fr).

2. D’Urzo TD. Control of airway inflammation. J Allergy Clin Immunol 2007;119:252-4.

3. Salpeter SR, Buckley NS, Salpeter EE. Meta-analysis: anticholinergics, but not beta-agonists, reduce severe exacerbations and respiratory mortality in COPD. J Gen Intern Med 2006;21:1011-9.

4. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al.

Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775-89.

5. Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Long-acting beta-agonists increase severe asthma exacerbations and asthma-related deaths:

meta-analysis of randomized controlled trials. Ann Intern Med 2006;144:904-12.

6. Salpeter SR, Ormiston TM, Salpeter EE. Meta-analysis: respiratory tolerance to regular β2-agonist use in patients with asthma. Ann Intern Med 2004;140:802-13.

7. Pauwels RA, Lofdahl CG, Postma DS, Tattersfield AE, O’Byrne P, Barnes PJ, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma.

Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997;337:1405-11. Erratum in: N Engl J Med 1998;338:139.

Better generally?

I

support Dr Hennen in opposing the move to call general practice a specialty.¹ In fact, I was one of a dimin- ishing number of GPs present when Dr Irwin Bean of Saskatchewan argued against the change of name from general practice to family medicine in the early 60s—I tended to agree with him. However, I changed my let- terhead, enthusiastically supported the renamed orga- nization, became the first Certificant in Maple Ridge, BC, and was delighted to be honoured as a Fellow. But I think now that the term family physician is (sadly) too ambitious in the present context.

A primary care doctor has to be a generalist. She has to be ready to respond appropriately to any medical problem that presents to her on the street, in her office, or in the hospital. She is a generalist. She does not have the luxury of restricting her practice. The task is large and it is the first priority. Those physicians