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                               Coursebook Chapter 9 Problems
                        Quantifying the Benefits and Harms of Therapy

1.      Otitis Media with Effusion (OME) is very common in infants and young children. The
basic problem is that the eustachian tube doesn't work well, and the kids get fluid and negative
pressure in the middle ear, which can cause mild to moderate conductive hearing loss and an
increased risk of acute (purulent) otitis media. If it goes on for a long time, sometimes people
implant tubes to ventilate the middle ear.

       A very controversial clinical trial (Mandel et al., NEJM 1987;316:432-7) found that, in
children with three months of OME, resolution rates at 4 weeks were about 30% with amoxicillin
(with or without an antihistamine/decongestant) and about 14% with placebo.

a.     What are the RRR, the RR, the absolute difference in risk, and the NNT?

b.      The reason why the study was so controversial is that one of the investigators (Erdem
Cantekin) so disagreed with the other investigators that he (after a huge battle) published an
alternative report on the same study (JAMA 1991;266:3309-17). (For details on the battle, see a
very thoughtful editorial by Drummond Rennie in the same issue; "The Cantekin Affair" JAMA
1991;266:3333-7, and a separate article by Catekin ("Biomedical information, peer review, and
conflict of interest as they influence public health" JAMA 1990;263:1427-30)) One of
Cantekin's main points was that no benefit was apparent when the outcome was assessed
objectively (by tympanometry). After excluding 43 children (13.3% of the placebo group and
7.4% of amoxicillin group; P = .122)) who had developed acute otitis media during the follow-up
period, he came up with the following numbers (simplified from his Table 3).

 Outcome Measure                     Amoxicillin (%)       Placebo (%)     Difference (%)      P
 Normal by otoscopy                         35.2               19.2                16.0     .004
 Normal by algorithm (defined               25.6               13.9                11.7     .027
 in protocol)
 Normal by tympanometry                     17.8               10.0                7.8      .121
 Normal by hearing test                     21.9               18.0                3.9      .611
 Hearing improved > 10 dB                   31.5               32.5                -1.0     .311

                i.      Do you agree with Cantekin's exclusion of children who developed acute
otitis during the follow-up period? What effect might this have had on the results tabulated

               ii.      Do you agree with his conclusion that amoxicillin was not effective, based
on the negative result for the most objective outcome measurement?

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2. (2pt)        A randomized, double-blinded trial finds that oral corticosteroids are superior to
placebo in hastening the resolution of symptoms of pneumocystis pneumonia in patients with
AIDS (P<.05). Which of the following are possible reasons why this study might have given a
falsely positive result? Briefly (1 sentence or so) explain each answer.

       a.     It may be difficult accurately to determine the extent of resolution of symptoms,
       leading to errors in determining the outcome of the study.

       b.      The apparent effect might be a result of chance.

       c.      Lax inclusion criteria may have led to inclusion of some subjects in the study who
       did not really have pneumocystis pneumonia or HIV.

       d.      The sample size may have been too small.

3.     (2 pt) Consider the following abstract:

         Odio CM; Faingezicht I; Paris M; Nassar M; Baltodano A; Rogers J;
         Saez-Llorens X; Olsen KD; McCracken GH Jr. The beneficial effects of early
         dexamethasone administration in infants and children with bacterial meningitis
         [see comments]. New England Journal of Medicine, 1991 May 30,

         Abstract: ... METHODS. We conducted a ... double-blind trial of dexamethasone therapy in 101
         infants and children...who had... bacterial meningitis... RESULTS...At follow-up examination, 7
         of the surviving 51 dexamethasone-treated children (14 percent) and 18 of 48 surviving controls
         (38 percent) had one or more neurologic or audiologic sequelae (P = 0.007); the relative risk of
         sequelae for a child receiving placebo as compared with a child receiving dexamethasone was
         3.8 (95 percent confidence interval, 1.3 to 11.5)...

       a. Forget about the children that did not survive. One of the numbers in this abstract is
       clearly wrong. Which is it? (Try before going on to the next part.)

       b. Can you explain what the authors did wrong (i.e., how they got the wrong number?)

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4. (2pt) Review the abstract below. What did they leave out that you need to know in order to
interpret the results?

 Mortality rates after 10.5 years for participants in the Multiple Risk Factor Intervention
 Trial. Findings related to a priori hypotheses of the trial. The Multiple Risk Factor
 Intervention Trial Research Group. JAMA, 1990 Apr 4, 263(13):1795-801.

 Abstract: The Multiple Risk Factor Intervention Trial was a primary prevention trial to test the
 effect of multifactor intervention on coronary heart disease mortality in high-risk men who
 were randomly assigned to special intervention (n = 6428) or to their usual sources of health
 care (n = 6438). As previously reported, after 6 to 8 years of intervention, mortality from
 coronary heart disease and from all causes did not differ... This report describes the mortality
 findings after 10.5 years... Mortality rates were lower for men who received special
 intervention than for men who received their usual care by 10.6% for coronary heart disease
 and by 7.7% for all causes... These data suggest that multiple risk factor intervention confers
 a mortality benefit in middle-aged men over a period of about 10 years.

5. (3pt) Read the following abstract. Does it provide evidence of improved clinical outcome
       from treatment with Interferon Alpha in this group of patients?

Niederau et al: "Long-Term Follow-Up of HBeAg-Positive Patients Treated with Interferon Alfa
for Chronic Hepatitis B" (NEJM 1996; 334:1422-1427).

Background In patients with chronic hepatitis B, treatment with interferon alfa and the
consequent loss of hepatitis B e antigen (HBeAg) from the blood leads to a reduction in
inflammatory activity, but the clinical benefits of this treatment have not been established. We
evaluated whether HBeAg seroconversion induced by interferon alfa improves clinical
outcome. [Emphasis added]

Methods We studied prospectively a cohort of 103 patients treated with interferon alfa for
chronic hepatitis B; the mean (±SD) follow-up was 50.0±19.8 months. Fifty-three untreated
patients served as controls.

Results After treatment with interferon alfa, 53 of 103 patients no longer had detectable HBeAg
or hepatitis B virus DNA, although only 10 patients became seronegative for hepatitis B surface
antigen (HBsAg) (Kaplan–Meier estimates of cumulative clearance rates at five years, 56.0
percent for HBeAg and 11.6 percent for HBsAg). Of the 53 untreated patients, only 7
spontaneously eliminated HBeAg (28.1 percent at five years), and all remained positive for
HBsAg (P<0.001 for the comparison with the treated patients, by the proportional-hazards
model). During follow-up, 6 of the 103 treated patients died of liver failure, and 2 needed liver
transplantation; all 8 were persistently positive for HBeAg. In another eight treated patients,
complications of cirrhosis developed; all but one of these patients remained positive for HBeAg.
Overall survival and survival without clinical complications were significantly longer in patients
who were seronegative for HBeAg after therapy with interferon alfa than in those who remained
seropositive (P = 0.004 and P = 0.018, respectively). In a regression analysis, clearance of
HBeAg was the strongest predictor of survival. Of the 53 untreated patients, 13 had severe

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complications (including 4 deaths and 1 need for liver transplantation); all 13 continued to be

Conclusions In patients with chronic hepatitis B infection, the clearance of HBeAg after
treatment with interferon alfa is associated with improved clinical outcomes.

A. The treatment group had 103 patients and the control group had 53 patients. How were
patients assigned to these groups?

B. Create a 2x2 table comparing the composite outcome of liver transplant or death from liver
failure in the treated and untreated patients. Lay out the 2x2 table and calculate RR, RRR, ARR,
and NNT according to the conventions suggested in the chapter.

C. Is the conclusion of the abstract correct? Discuss?

D. Bonus Point: If you know how, calculate the confidence interval for one of the numbers (RR,
RRR, ARR, or NNT) reported in part B of this question. Hint: the Stata command is “csi”

6. (5pt) Please read the following abstract on an RCT of adding Ribavirin to Interferon in the
treatment of Chronic Hepatitis C:

Interferon Alfa-2b Alone or in Combination with Ribavirin as Initial Treatment for Chronic
Hepatitis C. John G. McHutchison, M.D., et al for The Hepatitis Interventional Therapy Group.
NEJM 339:1485-1492, November 19, 1998

Background Only 15 to 20 percent of patients with chronic hepatitis C have a sustained
virologic response to interferon therapy. We compared the efficacy and safety of recombinant
interferon alfa-2b alone with those of a combination of interferon alfa-2b and ribavirin for the
initial treatment of patients with chronic hepatitis C.

Methods We randomly assigned 912 patients with chronic hepatitis C to receive standard-dose
interferon alfa-2b alone or in combination with ribavirin (1000 or 1200 mg orally per day,
depending on body weight) for 24 or 48 weeks. Efficacy was assessed by measurements of
serum hepatitis C virus (HCV) RNA and serum aminotransferases and by liver biopsy.

Results The rate of sustained virologic response (defined as an undetectable serum HCV RNA
level 24 weeks after treatment was completed) was higher among patients who received
combination therapy for either 24 weeks (70 of 228 patients, 31 percent) or 48 weeks (87 of
228 patients, 38 percent) than among patients who received interferon alone for either 24
weeks (13 of 231 patients, 6 percent) or 48 weeks (29 of 225 patients, 13 percent) (P<0.001 for
the comparison of interferon alone with both 24 weeks and 48 weeks of combination
treatment)…Histologic improvement was more common in patients who were treated with
combination therapy for either 24 weeks (57 percent) or 48 weeks (61 percent) than in those

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who were treated with interferon alone for either 24 weeks (44 percent) or 48 weeks (41

Conclusions In patients with chronic hepatitis C, initial therapy with interferon and ribavirin was
more effective than treatment with interferon alone.

A.) The outcome measures in this study were HCV RNA Viral load, serum transaminases and
liver histology. Would you consider them surrogate outcomes?

B) Calculate the number needed to treat for 48 weeks (ignore the 24-week groups) to achieve
reduce the viral load to undetectable in one patient.

C) What is the approximate cost of combination treatment (interferon + ribavirin) for 48 weeks?
(You can look this up anywhere.) What is the approximate cost of interferon alone for 48
weeks? Indicate your source of information and how long it took you to find this.

D) What is the additional cost of combination treatment, compared with interferon alone, per
   additional outcome chosen in part (B)?

E) What more do you need to know to decide whether this is worth paying?

7. (3 pts) Review the abstract below:
   Maizels M; Scott B; Cohen W; Chen W. Intranasal lidocaine for treatment of migraine: a
   randomized, double-blind, controlled trial. JAMA, 1996 Jul 24-31, 276(4):319-21.

   OBJECTIVE: To evaluate the effectiveness of intranasal lidocaine for treatment of acute
   migraine headache.

   DESIGN: Prospective, randomized, double-blind, placebo-controlled trial.

   SETTING: Community urgent care department.

   PATIENTS: A total of 81 patients (67 women and 14 men; median age, 42 years; range,
   19-68 years) with a chief complaint of headache who fulfilled criteria of the International
   Headache Society for migraine participated…

   INTERVENTION: Patients were randomized in a 2:1 ratio to receive a 4% solution of
   intranasal lidocaine or saline placebo, respectively.

   MAIN OUTCOME MEASURES: The primary outcome measure was at least 50% reduction
   of headache within 15 minutes after treatment...

   RESULTS: Of 53 patients who received intranasal lidocaine 29 (55%) had at least a 50%
   reduction of headache compared with 6 (21%) of 28 controls (P=.004)

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     CONCLUSIONS: Intranasal lidocaine provides rapid relief of headache in approximately
     55% of ambulatory patients with migraine…

a.      What was the main outcome variable in this study? (1/2 pt)

b.      What are some potential problems with this outcome? (1 pt)

c.      For each of the problems listed in (b) above, what effect do you think it would have on
        the results? (1/2 pt)

d.      Do you agree with the conclusion that: “Intranasal lidocaine provides rapid relief of
        headache in approximately 55% of ambulatory patients with migraine?” Why or why
        not? (1pt)

8. ISIS-2. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among
17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International
Study of Infarct Survival) Collaborative Group. Lancet 1988;2(8607):349-60.

In the chapter, we learned that aspirin therapy (one month of 160 mg/day) in patients with acute
myocardial infarction (AMI) reduced 30-day cardiovascular mortality from 11.8% in the placebo
group to 9.4% in the aspirin group (p < 0.00001).

a) What is the absolute risk reduction (ARR)?

b) How many AMI patients need to be treated with aspirin to prevent one death?

c) At Rite Aid, a bottle (#120) of 81 mg aspirin tablets costs $5.00. Considering only the cost of
   the treatment drug, use this to calculate the cost effectiveness ratio ($/CV death prevented) for
   aspirin therapy of AMI. (Be careful, you only need 60 aspirin pills to treat one patient for 30

9. GUSTO. An international randomized trial comparing four thrombolytic strategies for acute
myocardial infarction. The GUSTO investigators. N Engl J Med 1993;329(10):673-82.

This was a famous study comparing tissue plasminogen activator (tPA) versus streptokinase (SK)
in reducing the 30-day mortality of patients with acute myocardial infarction (AMI). This study
showed a 14% relative risk reduction in the tPA-treated patients. Controversy exists because
other large studies showed no difference in 30-day mortality. Also, only the subgroup of US (not
European) patients showed a benefit, and it was not a blinded study. However, for this problem
assume that the 14% relative risk reduction is real. The 30-day mortality risk in the SK group
was 7.3%.

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   a) What was the mortality risk in the tPA group?

   b) What was the absolute risk reduction associated with tPA (vs. SK)?

   c) How many patients need to be treated with tPA instead of SK to prevent one death?

   d) At the time this study was published, the cost of tPA was $2300 per course of treatment,
      and the cost of SK was $300. What was the treatment drug cost per death prevented by
      using tPA instead of SK?

10. Acute Achilles tendon rupture is common in 40-something lawyers who play weekend
   basketball. Operative repair instead of conservative treatment (splinting) reduces re-rupture
   rate from about 21% to about 1%. The risk of wound infection is about 2%. If an orthopedic
   surgeon always treats Achilles tendon rupture with operative repair, how many re-ruptures
   does she prevent for each for each wound infection that she causes?

11. A meta-analysis of the effect of cholesterol lowering with statins on the risk of stroke,
      Hebert et al (JAMA 1997; 278:313-21) found statins reduce the risk of stroke by about

a. The three-year risk of stroke in the placebo-treated patients was about 2%. About what was
the risk of stroke in the statin-treated patients?

b. What is the risk ratio (RR)?

c. What is the number needed to treat (NNT) for three years to prevent one stroke?

d. Suppose you have a patient at exceptionally high risk of stroke, whose 3-year risk of stroke
without statins would be 10%. What would be the NNT for patients like this?

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12. Penciclovir cream was reported by Spruance et al (JAMA 1997;277:1374-9) to reduce the
   duration of herpes simplex labialis in a multicenter, double-blind trial of immunocompetent
   adults (P < 0.001). The authors report that the odds ratio (OR) for healing by day 7 was 1.7 (in
   favor of quicker healing in the penciclovir group). The proportions of patients healed by day
   7 were 78% in the penciclovir group and 68% in the placebo groups.

a. Explain in words what the odds ratio of 1.7 means.

b. What is the risk ratio (RR) for healing with penciclovir (put penciclovir on top)?

c. Make a 2x2 table and show how the proportions healed give the reported odds ratio of 1.7.

d. What is the risk ratio (RR) for NOT being healed by day 7 How does it compare with the RR
for being healed?

e. What is the odds ratio for NOT being healed by day 7? How does this relate to the odds ratio
for being healed?

f. How many patients need to be treated
 with penciclovir for each additional patient that is healed at 1 week?

13. What is missing from the abstract (reprinted in its entirety) below?

Kline RM, Kline JJ, Di Palma J, Barbero GJ. Enteric-coated, pH-dependent peppermint oil
capsules for the treatment of irritable bowel syndrome in children. J Pediatr 2001

In a randomized, double-blind controlled trial, 42 children with irritable bowel syndrome (IBS)
were given pH-dependent, enteric-coated peppermint oil capsules or placebo. After 2 weeks,
75% of those receiving peppermint oil had reduced severity of pain associated with IBS.
Peppermint oil may be used as a therapeutic agent during the symptomatic phase of IBS.

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