The topic for our 30th episode is stolen from the headlines. We look at the much publicized Jupiter trial of C-Reactive Protein (CRP) and the use of a statin. We review the details, strengths and weakness of the trial. From there we look at related questions of risk assessment with CRP, reducing CRP and the uncertainty in the lipid hypothesis. We end by concluding that although trust in mechanisms and theories can lead to poor decisions they are generally less confusing than our podcasts.

Show Notes

1) Jupiter – statins, lipids and CRP

NEJM 2008;359:2195-207

2) Knowing CRP doesn’t change estimation of cardiovascular risk

NEJM 2006;355:2631-9

Arch Intern Med 2006;166:1368-73

3) Web site calculator that uses CRP

Reynolds Risk Score

4) Ezetrol Study (reduces CRP but no other change)

N Engl J Med 2008;358:1431-43.

5) Mechanistic mistaken thinking Beta-blockers in CHF

Arch Intern Med 2002;162:641-8

Anti-oxidant studies

Lancet 2002;360:23-33

Lancet 2003;361:2017-23.

Atenolol for BP but not for outcomes

Lancet 2004;364:1684-9

In Episode 29, we review questions around informed decision-making, risk-benefits of statins across different populations (women, chronic kidney disease, etc), and comparisons of calculated risks and trial results. We also talk about prescribing of new antimicrobials, differentiating typical from atypical pneumonias and then attempt to clarify a few trials including HOPE. James desperately searches for pearls among Mike’s explanations of the uncertainty and gaps in the research.

Show Notes

1) The HOPE trial

NEJM 2000;342:145–53

2) HOPE was actually more like a blood pressure trial than originally thought – 24 hour blood pressure differences between the 2 groups were 10/4 mmHg

Hypertension 2001;38;e28-e32

4) Meta-analysis of statins in patients with chronic kidney disease

BMJ 2008;336:645-51

5) Meta-analysis CMAJ on high vs low dose statin in secondary prevention

CMAJ 2008;178:576-84

6) Mediterranean diet – no difference between the groups in weight, cholesterol or blood pressure at the end of the study but cardiovascular events were reduced

Lancet 1994;343:1454-9

7) ACCORD and ADVANCE trials

Podcast #9

8)UKPDS (recent results)

NEJM 2008;359:1577-89

9) BP trial for patients over age 80

NEJM 2008;358:1887-98

In Episode 28, we review questions around osteoporosis including: bone density testing and the limits of medical tests in general; the risks (including osteoporosis) and benefits of proton pump inhibitors for heartburn; and assessing calcium intake and the possible risks of calcium. We also briefly discuss topics of risk assessors of CVD, an approach to patients using complementary alternative therapies, and make a few random, but obviously brilliant suggestions.

Show Notes

1) Comparison of H2 Blocker vs PPI

CADTH report on the Evidence for PPI Use in GERD

2) Studies suggesting risk from PPI for osteoporosis/fracture and C. difficile CMAJ 2008;179:319-26 JAMA 2005;294:2989-95.

3) Calcium and vascular events BMJ 2008;336:262-6 Circulation 2007;115:846-54

4) STENO – multifactorial intervention for type 2 diabetes N Engl J Med 2008;358:580-91

5) The book The Bedford Murder: An Evidence-Based Clinical Mystery (Paperback) by Marshall Godwin & Geoffrey Hodgetts

In episode 27, we examine the management of COPD Exacerbation and adjunctive treatments. We review the relatively good evidence for antibiotics and steroids in Exacerbations including the options in choice, dosing, and mode of administration. We briefly examination some of the other treatment options in chronic COPD with combination puffers, immunizations, theophyline, and home oxygen. We close by discussing the general use of methylxanthines (like chocolate) for overall well-being.

Show Notes

1) Vaccinations

“An annual influenza vaccination reduces morbidity and mortality from the disease by as much as 50% in the elderly and reduces the incidence of hospitalization by as much as 39% in patients with chronic respiratory conditions. The benefit of pneumococcal vaccine in COPD is less well established”

Can Respir J 2007;Vol 14 Suppl 5b-32b

Influenza vaccine

“It appears, from the limited number of studies performed, that inactivated vaccine reduces exacerbations in COPD patients”

Cochrane Library 2008

Pneumococcal vaccine

“There is no evidence from randomised controlled trials that injectable pneumococcal vaccination in persons with COPD has a significant impact on morbidity or mortality

Cochrane Library 2008

2) Work-up for Exacerbation

Can Respir J 2003;10 Suppl A:11A-65A Ann Intern Med. 2001;134:600-620.

3) Acute Exacerbation “Treatment of an exacerbation of COPD with oral or parenteral corticosteroids significantly reduces treatment failure and the need for additional medical treatment”

Cochrane Library 2008

“This review shows that in COPD exacerbations with increased cough and sputum purulence antibiotics, regardless of choice, reduce the risk of short-term mortality by 77%, decrease the risk of treatment failure by 53% and the risk of sputum purulence by 44%; with a small increase in the risk of diarrhoea”

Cochrane Library2008

Can Respir J 2007;Vol 14 Suppl 5b-32b

4) Home Oxygen

Ann Intern Med. 2007;147:633-638 Ann Intern Med. 2007;147:639-653.

5) Theophylline

“This systematic review shows that orally administered theophylline improves lung function and levels of oxygen and carbon dioxide in the blood. However, there is limited data on its effect on symptoms, exercise capacity or quality of life. Despite being associated with increased side effects, particularly nausea, subjects preferred theophylline over placebo.”

Cochrane Library 2008

In episode 26, we examine the initial management of COPD. We first discuss the diagnosis of COPD and if screening is recommended. We encourage an initial focus on smoking cessation and then episodic, symptom control. We then review long acting puffers and the large body of confusing research with underwhelming and at times conflicting results. Unfortunately, the data available for long acting puffers serves as a good example of how more information can exacerbate confusion.

Show Notes

1) Diagnosis data

JAMA 2000;283:1853-7

Ann Intern Med. 2007;147:633-638.

2) Lung decline and smoking

JAMA 2003;290:2301-2312.

3) Evidence only for symptomatic and FEV<60%

Ann Intern Med 2007;147:639-653

4) Outcomes for puffers in COPD

Overall

Ann Intern Med 2007;147:639-653

Tiotropium

JGIM 2006;21:1011-9

LABA/Steroid

NEJM 2007;356:775-89 LABA/steroid

5) Latest tiotropium data

JAMA 2008;300:1439-50 NEJM 2008;359:1543-54

6) Inhaled steroid adverse events

Chest. 2005;127:89-97 NEJM 2000;343:1902-9

Cochrane 2007;4: CD 006829

NEJM 2007;356:775-89

In episode 25, we finish (for now) the discussion of in-office infectious disease management. We first review a case of sinusitis including the challenges of diagnosis and the benefit of antibiotics and/or nasal steroids. We then discuss a case of bronchitis with the concerns of diagnosis and the benefits of antibiotics. We wrap up our discussion of upper respiratory tract infections with a summary and tangent that will leave most listeners questioning our role as educators.

Show Notes

1) Antibiotics for sinusitis

Cochrane Review

2) Steroids for sinusitis

Cochrane Review

3) Macrolides created resistance within 4 days and it lasted for at least 3 months

Lancet 2007; 369:482-90

4) Antibiotics for Bronchitis – Cochrane Library

5) Suppositories – where do they fit in?

Journal of Clinical Nursing 2006;16:98–103

In episode 24, we continue the discussion of in-office infectious disease management. We discuss a case of AOM in an 8 year old child including the signs/symptoms important in making the diagnosis, pain control and the utility of antibiotics. We then discuss a case of sore throat in a 17 year old woman including a validated scoring system for diagnosis, pain control, and the utility of antibiotics. We don’t complete all upper respiratory infections but make a mess of those we do discuss.

Show Notes

1) Diagnosis of AOM – does this child have acute otitis media

JAMA. 2003;290:1633-1640

2) Ibuprofen vs acetaminophen for pain control and fever

In musculoskeletal pain in children for every 10 children treated with ibuprofen instead of acetaminophen

1 more will have “adequate” pain relief

Pediatrics 2007;119:460-7

In children with migraine, acetaminophen and ibuprofen produced similar pain relief at all endpoints (6 major endpoints) except ibuprofen treated subjects had a 20% absolute increase in the number of children who were completely pain free at 2 hours

Neurology 1997;48:103-7

Ibuprofen faster (by 26 minutes) for time to fever clearance and a greater time (39 minutes) without fever in the first 4 hours (39 minutes) compared to acetaminophen. No difference in symptoms of discomfort.

BMJ 2008;337;a1302

Meta-analysis of ibuprofen versus acetaminophen for pain or fever. In children, single doses of ibuprofen and acetaminophen have similar efficacy for relieving moderate to severe pain, and similar safety as analgesics or antipyretics. Ibuprofen was a more effective antipyretic than acetaminophen at 2, 4, and 6 hours post-treatment.

Arch Pediatr Adolesc Med 2004;158:521-6

3) Compared “love” of parent vs television

Arch Dis Child 2006;91:1015-7

4) Antibiotic treatment of AOM – Cochrane Library

5) Scoring system for Strep Throat.

CMAJ. 1998;158:75-83

CMAJ. 2000; 163:811-815

6) Antibiotic treatment of Strep throat – Cochrane Library

7) Meta-analysis of short course antibiotic treatment for Group A Streptococcal tonsillopharyngitis

Pediatr Infect Dis J 2005;24:909–17

In episode 23, we begin the discussion of antibiotic prescribing in common respiratory tract infections with a focus on pneumonia. We talk about the limited evidence for the clinical exam in diagnosing pneumonia. We review the variability in antibiotics suggested in guidelines and evidence for coverage of atypical pneumonia. We also discuss the research on dosing and duration of antibiotics. We find out what antibiotic James and Mike would take (and some infections they have had)!

Show Notes

1) Contributions of symptoms, signs, and other things to the diagnosis of pneumonia.

Br J Gen Pract 2003;53:358–64

2) Do you cover for atypical organisms or not when you are treating pneumonia?

Community acquired

BMJ 2005;330:456-9

Hospitalized patients

Cochrane Review

3) Amoxicillin for community acquired pneumonia – use 500 to 1000 mg TID

Thorax 2001;56(Suppl 4):iv1-iv64

4) Shorter duration and treating until “feeling better” for 72hours “

Until further data are available, it seems reasonable to treat bacterial infections such as those caused by S. pneumoniae until a patient is afebrile for 72 h”

Lancet 2003;362:1991–2001

Three days of antibiotics for hospitalized patients with community acquired pneumonia

BMJ 2006;332:1355

In our 22nd episode we continue our low dose discussion. We talk about the concept of n-of-1 trials and allowing patients to determine their dose. We review some of the benefits of low-dose prescribing, such as low side-effect risk and reduced costs, but emphasize the medical conditions in which low doses are inappropriate. We end by offering some practical suggestions to assist patients with very low doses (in which James forces Mike to acknowledge the superior power of pharmacists).

Show Notes

1) Placebo what it is and should you use it – go with low dose instead?

BMJ 2008;336;1020

BMJ 1995; 311:551-3

2) Cost has an effect on adherence

Med Care 2001 39: 296–301

J Manag Care Pharm 2006 12: 377–382

In our 21st episode we jump into our ongoing debate about low and very low dose of medication. We present the reason why initial doses of new drugs are often too high and the logic for trialing lower doses in patients. We also review over 10 examples of medications proven in randomized control trials to be equally effective (or more) at lower doses. Although promoting low dose, the size of the podcast is moderate dose (while the quality is high dose with minimal side-effects).

Show Notes

1) Examples of evidence for effective lower doses – these examples typically show lower doses were as effective as higher doses, but in some of the examples higher doses were somewhat more effective but lower doses nonetheless produced clinically important results

6.25 mg of hydrochlorothiazide is effective at lowering blood pressure, and comes in a number of combination products – initially 50 to 200 mg was the recommended starting dose

Arch Int Med 1994;154:1461-8

6.25 mg of captopril has been shown to be effective for blood pressure yet captopril 25 mg PO TID is still a commonly recommended initial starting dose for hypertension.

Circulation 1983;67:1340-6

25 mg of sildenafil (Viagra) has been shown to be an effective dose for erectile dysfunction

Bandolier

25 mg of sumatriptan (Imitrex) works almost as well as100 mg and in fact for most drugs in this class there is a flat dose-response curve seen at the doses studied.

Cephalalgia 2002;22:633-58.

5 mg daily of fluoxetine (Prozac) has been shown to have an effect similar to 20 mg daily.

N Engl J Med 1994;331:1354-61

0.25 mg (1/40th of the recommended initial starting dose of 10 mg) of ezetimibe (Ezetrol) provides 50% of the LDL lowering effect seen with 10 mg

Clin Ther 2001;23:1209-30

15 mg of elemental iron daily has been shown to be as effective for anemia as 50 mg and 150 mg, with a lower incidence of side effects.

Am J Med 2005;118:1142-7

150 mg daily of bupropion (Zyban) produces the same rate of smoking cessation at one year as 300 mg daily.

N Engl J Med 1997;337:1195-202

200 mg of ibuprofen (Motrin) is as effective as 400 mg for migraine headache.

Headache 2001;41:665-79

25 mg of ranitidine (Zantac) has been shown to be as effective as 125 mg for heartburn relief.

Aliment Pharmacol Ther 1999;13:475-81

Compared to standard-dose treatment, low-doses of depot antipsychotics improve psychosocial function and reduce the frequency of side effects.

Schizophrenia bulletin 1993;19:155-64

Tricyclic antidepressant doses of 75-100mg are as effective for depression as doses greater than100mg.

BMJ 2002;325:991-5

500 and 1000 µg of oral B12 was more effective than 2.5, 100 or 250 µg at improving the surrogate marker of B12 deficiency (methylmalonic acid).

Arch Intern Med. 2005;165:1167-1172

Meta-analysis showing higher doses of statins produced greater reductions in cardiovascular events – as an aside, a number of these trials compared different drugs in addition to different doses and the difference in outcome was approximately 1.5% in cardiovascular outcomes

CMAJ 2008;178:576-84

2) Doubling the dose of inhaled corticosteroids for asthma exacerbations is not effective

Lancet 2004;363:271-5

Thorax 2004;59:550–6