Systematic Review Scenario

In your out-patient clinic you see a 27 year old postgraduate student who describes long-standing depression, tiredness and lack of enjoyment. You diagnose dysthymia, but do not consider that there is a current superimposed depressive illness. You wonder about prescribing antidepressants. However, you are unsure which type of antidepressants are most effective in dysthymia or, indeed, whether there is evidence supporting their use in dysthymia at all. You formulate the clinical question ‘in adults with dysthymia (problem), do antidepressants (intervention) improve mood (outcome) more than placebo (comparison intervention)?’

Fortunately, you have The Cochrane Library on your laptop in clinic. You enter the search term ‘dysthymia’. In a second or two, it reveals that there are three completed systematic reviews of possible relevance, including one entitled ‘drugs versus placebo for dysthymia’. Clicking on this title reveals the full text of the review, including a structured abstract.

• Is the evidence from this systematic review valid?
• Is this valid evidence from this systematic review important?
• Can you apply this valid and important evidence from this systematic review in caring for your patient?

Completed Harm Worksheet for Evidence-Based Mental Health

Citation

Kulin, NA. Pastuszak, A; Sage, AR et al Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study.
JAMA 279 (8):609-610, 1998.

Completed Systematic Reviews Worksheet for Evidence-Based Mental Health

Citation

Lima M, Moncrieff J. Drugs versus placebo for dysthymia (Cochrane Review). In: The Cochrane Library, Issue 1, 1999. Oxford: Update Software.

Are the results of this systematic review of therapy valid?

Is it a systematic review of randomised trials of the treatment you’re interested in?
Yes
Does it include a methods section that describes finding and including all the relevant trials?
Yes. The authors searched several electronic databases, and attempted to locate unpublished trials.
Does it include a methods section that describes assessing their individual validity?
Yes. The authors used two methods to assess this.
Were the results consistent from study to study?
Yes. Consistent results were obtained for studies making each comparison (such as tricyclics and placebo, or MAOIs and placebo).

Are the valid results of this systematic review important?

It is necessary to be able to understand the size of the effect of treatments. A study may show a statistically significant advantage of one treatment over another. However, the magnitude of this effect may not be clinically significant. Odds ratios (ORs) and numbers needed to treat (NNTs) help us to understand the size of this effect.

The systematic review presents the results in terms of odds ratios. These may be translated into NNTs, by using the following table. The numbers in the body of the table are the NNTs for the corresponding odds ratios at that particular control event rate (or patient’s expected event rate, PEER).

When OR < 1
Odds Ratios
0.9 0.85 0.8 0.75 0.7 0.65 0.6 0.55 0.5 0.4 0.3 0.2
Patient’s Expected Event Rate (PEER) 0.05 2091 139 104 83 69 59 52 46 412 34 29 26
0.10 110 73 54 43 36 31 27 24 21 18 15 13
0.20 61 40 30 24 20 17 14 13 11 10 8 7
0.30 46 30 22 18 14 12 10 9 8 7 5 5
0.40 40 26 19 15 12 10 9 8 7 6 4 4
0.503 38 25 18 14 11 9 8 7 6 5 4 3
0.70 44 28 20 16 13 10 9 7 6 5 4 3
0.90 1014 64 46 34 27 22 18 15 125 9 4 3
1. The relative risk reduction (RRR) here is 10%
2. The RRR here is 49%
3. For any OR, NNT is lowest when PEER = .50
4. The RRR here is 1%
5. The RRR here is 9%
When OR > 1
Odds Ratios
1.1 1.25 1.5 1.75 2 2.25 2.5 2.75 3 3.5 4 5
Patient’s Expected Event Rate (PEER) 0.05 212 86 44 30 23 18 16 14 12 10 9 7
.10 113 46 24 16 13 10 9 8 7 6 5 4
.20 64 27 14 10 8 7 6 5 5 4 4 3
.30 50 21 11 8 7 6 5 5 4 4 3 3
.40 44 19 10 8 6 5 5 5 4 4 3 3
.501 42 18 10 8 6 6 5 5 4 4 4 3
.70 51 23 13 10 9 8 7 7 6 6 5 5
.90 121 55 33 25 22 19 18 17 16 15 14 13
1. For any OR, NNT is lowest when PEER = .50

Can you apply this valid, important evidence from a systematic review in caring for your patient?

Do these results apply to your patient?
Is your patient so different from those in the systematic review that its results can’t help you?
No. The patient appears similar.
How great would the potential benefit of therapy actually be for your individual patient?
Method 1:
In the table on page 1, find the intersection of the closest odds ratio from the overview and the CER that is closest to your patient’s expected event rate if they received the control treatment (PEER):
begin{align} quad &text{Odds ratio (no treatment response, TCA versus placebo)} \\
&= 0.36 \\
\\
&text{Risk to your patients similar to those in trial, therefore $PEER$ @ $CER$} \\
&= 208 / 305 \\
&= 0.7 \\
\\
&text{Closest intersection gives $NNT$ less than 6 (as intersection to the right of $OR$ = 0.5).} end{align}
Method 2:
To calculate the NNT for any OR and PEER:
begin{align} mathit{NNT} &= frac{1-[mathit{PEER} times (1-mathit{OR})]}{(1-mathit{PEER}) times mathit{PEER} times (1-mathit{OR})} \\
&mathit{NNT} = frac{1-[0.7times(1-0.36)]}{(1-0.7)times 0.7times (1-0.36)} \\
&= frac{0.552}{0.134} \\
&= 4.1 \\
\\
&text{rounded up to nearest whole number} \\
&= 5 \\
\\
&text{See below for a discussion of the relevance of confidence intervals around this $NNT$, $\\$and description of how it may be calculated.} end{align}
Method 3
To calculate the NNT from the original numbers in the studies. Calculate the ARR from the CER and EER. The NNT is the reciprocal of the ARR (i.e. 1/ARR).
If the risk of the outcome is different in your patient, divide the NNT by F, which is the risk of the outcome in your patient relative to the patients in the review (or trial), expressed as a decimal.

$$mathit{CER} = 208 / 305 = 0.6820 \\ mathit{EER} = 133 / 295 = 0.4508 \\ mathit{ARR} = 0.6820 – 0.4508 = 0.2312 \\ mathit{NNT} = 1 / mathit{ARR} = 1 / 0.23 = 4.3 \\ text{rounded up to nearest whole number = 5} \\ text{If risk higher, F = say 1.2} \\ mathit{NNT} = 4.3 / 1.2 = 3.6 text{ (rounded to 4)}$$

Are your patient’s values and preferences satisfied by the regimen and its consequences?
Do your patient and you have a clear assessment of their values and preferences?
Needs to be assessed in each patient
Are they met by this regimen and its consequences?
Needs to be assessed in each patient
Should you believe apparent qualitative differences in the efficacy of therapy in some subgroups of patients?

Only if you can say “yes” to all of the following:

• Do they really make biologic and clinical sense?
• Is the qualitative difference both clinically (beneficial for some but useless or harmful for others) and statistically significant?
• Was this difference hypothesised before the study began (rather than the product of dredging the data), and has it been confirmed in other, independent studies?
• Was this one of just a few subgroup analyses carried out in this study?

Confidence intervals around NNTs:

95% confidence interval (CI) of an NNT = 1 / limits of the CI of the absolute risk reduction (ARR)
The 95% CIs for the ARR will be 1.96 x standard error (SE) each side of the point estimate of the ARR.
begin{align} mathit{SE(ARR)} &= sqrt{frac{mathit{CER} times (1-mathit{CER})}{text{# of control pts}} + frac{mathit{EER}times(1-mathit{EER})}{text{# of exptal pts}}} \\
&= sqrt{frac{0.682 times 0.318}{305} + frac{0.451 times 0.549}{295}} \\
&= sqrt{0.0007 + 0.0008} \\
&= 0.039 \\
&text{1.96 x 0.039 = 0.076}
end{align}

Therefore 95% CIs for ARR are 0.231 +/- 0.076, i.e. 0.307 and 0.155.

The NNT is the reciprocal of the ARR. Therefore, the NNT is 4.3, with 95% CIs of 3.3 and 6.5. These figures are given in the abstract at the beginning of the review.

This means that it is 95% probable that the real treatment effect lies within an NNT of 3.3. and 6.5.

Note that during this calculation, as we are subtracting small numbers from small numbers, it is best to work to several decimal places, otherwise the result becomes inaccurate.

Dysthymia: Antidepressants are effective

Clinical Bottom Line

Antidepressants are effective in the treatment of dysthymia.

Citation

Lima M, Moncrieff J. Drugs versus placebo for dysthymia (Cochrane Review). In: The Cochrane Library, Issue 1, 1999. Oxford: Update Software.

Clinical Question

In an adult with dysthymia, are antidepressants effective in lifting mood?

Search Terms

‘dysthymia’ in The Cochrane Library

The Study

Systematic review of trials of any antidepressant versus placebo. Extensive search for literature. Rigorous appraisal of validity of individual studies.

The Evidence

• 15 RCTs, including trials of TCAs, SSRIs, MAOIs, and other drugs.
• Outcome: no treatment response
CER EER ARR (95% CIs) NNT (95% CIs)
TCAs 0.68 0.45 0.23 (0.31, 0.16) 4.3 (3.3, 6.5)
MAOIs 0.78 0.45 0.33 (0.22, 0.43) 3.1 (2.3, 4.5)
SSRIs 0.61 0.39 0.22 (0.15, 0.28) 4.7 (3.5, 6.9)

Price, 1999

2001