Appendix C: Developing and Maintaining Numbers Needed to Treat (NNT) – Standard Operating Procedure (SOP)

Polypharmacy guidance: realistic prescribing
Scottish Government Effective Prescribing & Therapeutics Division
Polypharmacy icon of two pills

Scope

This SOP is intended to describe the roles of the Association of Scottish Medicines Information Practitioners (ASMIP) in the development and maintenance of the NNTs and to describe a systematic approach to their calculation.

Originally described by Laupacis et al (1988)31 and cited in Cook (1995)32, NNT was introduced as an approach to summarise the effect of treatment in terms of the number of patients a clinician needs to treat with a particular therapy to expect to prevent one adverse event over a specified time period.

Background

The Scottish Government Polypharmacy Guidance 2017 is intended as a practical tool to help prescribers decide when it is appropriate to initiate and continue long-term medicines, especially in the management of long term conditions. In some circumstances, and in consultation with the patient, it may be appropriate to discontinue treatments.  Presentation of numbers needed to treat (NNT) for a range of medicines is one tool that prescribers may use to aid discussions with patients about the likely benefit.

The NNT is defined as the expected number of people who need to receive the experimental rather than the comparator intervention for one additional person to either incur or avoid an event in a given time frame. An NNT of 10 can be interpreted that one additional (or less) person will incur an event for every 10 participants receiving the experimental intervention rather than control over a given time frame.

1. Defining NNTs

1.1Defining the medicine, intervention and the clinical outcome of relevance

The medicines used in previous editions of the Scottish Government Polypharmacy Guidance 2012and 2015should be included. These will be reviewed to ensure that they are both specific and measurable. Consideration also needs to be given to their relevance to clinical practice, e.g. is the medicine likely to be used in this clinical context and is the comparator described the most relevant to clinical practice?

1.2 Identifying relevant medical literature

The following principles should be applied:

  • Cochrane reviews where available should be used
  • Systematic reviews should generally be used in preference to individual randomised controlled clinical trials (RCT), unless the RCT includes a greater number of patients
  • Where systematic reviews are not available individual randomised controlled trials may be used

The MI pharmacist should carry out a standard Medline® or Embase® search using relevant Medical Subject Heading (MeSH) terms and Boolean operators.  In particular the following should be identified:

  • Cochrane systematic reviews
  • Other high quality systematic reviews
  • Pivotal trials for the medicine in the relevant indication

Ideally  studies should be identified from the previous five years, but in exceptional circumstances, e.g. where only a single pivotal trial has been published, or no newer systematic reviews have been published, older clinical trials or systematic reviews may be used.

1.3 Dealing with multiple trials and meta-analyses

Where more than one review or trial is identified for the relevant indication and intervention the following criteria should be assessed:

  • Relevance to the defined medicine and intervention
  • Size of the study or review
  • Similarity of review and study cohort to the Scottish population

A judgement can then be made, using the criteria above to identify the most relevant trial or review from which the NNT can be calculated. Where the studies are very similar, the NNT should be calculated for each individual study and the mean taken for inclusion in the table.

2. Calculating NNTs

The NNT can be calculated from the absolute risk reduction (ARR) taken from a clinical trial or systematic review.  ARR = p1- p2 , where p1 is the baseline or placebo rate and p2 is response rate in the intervention group in a clinical trial. 

The NNT can be calculated as 1/ (p1-p2).33 Where the benefit is accrued over a number of years, the annual NNT can be calculated by multiplying the NNT by the number of years over which the study was conducted.

3. Recording research

The MiDatabank® project management function should be used to record all research.  The following information should be recorded:

  • The literature search
  • Trials/ reviews identified
  • Absolute risk reduction figures taken from the study(ies)
  • The calculation used to define the NNT

4. Presenting the NNT data

All NNT data should be tabulated to include the following:

  • Intervention - the medicine or other intervention of interest
  • The comparator
  • Outcome - the desired outcome from the proposed treatment
  • NNT - calculated using standard methodology
  • Duration of study/ intervention
  • Demographics of population - age, sex (where relevant), co-morbidities
  • Reference - main reference used to calculate the NNT

5. Referencing

Vancouver style should be used to reference all trials/ reviews used in the calculation of NNTs. Where data has been taken from websites, the web address and the date accessed should be recorded.

6. Checking/ Peer Review

A peer check should be undertaken by another MI or clinical pharmacist prior to publication.  The check should include:

  • Clarity and completeness
  • Any obvious gaps in the information concerning the patient demographics
  • A calculation check for the NNT

Drug Efficacy Chart

Medicine / intervention

Comparator

Study population

Outcome

Duration of trial

Number needed to treat (NNT)

Annualised

NNT

Comments

Ref

Hypertension

Blood Pressure control (<140/90mmHg)

 No treatment

Patients with hypertension and age > 80 years

Total mortality

2 years

333

666

High risk is defined as patients with a previous history of stroke.

Cardiovascular  mortality and morbidity includes fatal and non-fatal MI, sudden cardiac death, aneurysms, congestive heart failure, fatal and non-fatal stroke and transient ischaemic attacks

Total mortality is death from all causes

NB the evidence base to support the NNT for impact on mortality in the over 80 years is very limited

34

Cardiovascular mortality and morbidity

2 years

35

70

Blood Pressure control (<140/90mmHg)

No treatment

Patients with hypertension and high risk* and age > 80 years

Total mortality

2 years

333

666

Cardiovascular mortality and morbidity

2 years

16

32

Blood Pressure control (<140/90mmHg)

 No treatment

Patients with hypertension and age > 60 years

Total mortality

4.5 years

83

374

Cardiovascular mortality and morbidity

4.5 years

23

104

Blood Pressure control (<140/90mmHg)

 No treatment

Patients with hypertension and high risk*  and age > 60 years

Total mortality

4.5 years

33

149

Cardiovascular mortality and morbidity

4.5 years

9

41

Heart Failure

Spironolactone 25 mg daily

Placebo

Patients with heart failure

Patients has NYHA class IV heart failure in the 6 months prior to enrolment, but were NYHA class III or IV at the time of enrolment

Prevent one death (all causes)

24 months (mean duration of follow-up)

9

18

Mean age of patients was 65 years.

Spironolactone also reduced the frequency of hospitalisation for heart failure and produced a significant improvement in the symptoms of heart failure.

Patients in the trial were on an ACE inhibitor (if tolerated) and a diuretic.  10% of patients were also on a beta-blocker.

35

Beta-blocker (bisoprolol titrated to target dose of 10 mg/day )

Placebo

Patients with moderate to severe heart failure

NYHA class III or IV and LVEF </=0.35

Prevent one death (all causes)

1.3 years (mean duration of follow-up)

18

24

Mean age of patients was 61 years, 83% of whom were NYHA class III.

Current treatment had to include a diuretic and an ACE inhibitor although other vasodilators were allowed if patients were intolerant of ACE inhibitors.

96% of patients were on ACE inhibitors.

36

Beta-blocker

(carvedilol titrated to target dose of 25 mg twice daily)

Placebo

Patients with severe heart failure

NYHA class  IV and LVEF < 0.25

Prevent one death (any cause)

10.4 months (mean duration of follow-up)

18

16

Mean age of patients was 63 years.

Conventional therapy included diuretics and an ACEI or ARB. 

97% of patients were on ACE inhibitor or ARB.

37

Beta-blocker (Metoprolol modified-release titrated to a target dose of 200 mg/day)

Placebo

Patients with mild to severe heart failure

NYHA class II to IV and LVEF </=0.40

Prevent one death (all causes)

12 months (mean duration of follow-up)

28

28

Mean age of patients was 64 years.

Optimum standard therapy was defined as any combination of ACE inhibitors, Angiotensin receptor blockers and diuretics.

97% of patients were on an ACE inhibitor or Angiotensin receptor blocker.

38

Beta-blocker

(nebivolol titrated to a target dose of 10 mg/day)

Placebo

Patients >70 years old with mild-severe heart failure

NYHA class I to IV irrespective of LVEF

Prevent one death (all causes)

21 months (mean duration of follow-up)

44

78

Median age of patients  was 75 years.

64% of patients had a LVEF of </=0.35. >95% of enrolled patients were NYHA class II or III. 

87% of patients were on an ACE inhibitor or Angiotensin receptor blocker.

39

ACE inhibitor (ramipril 10 mg/day)

Placebo

Patients at high-risk of cardiovascular disease without LVSD or heart failure

High-risk of cardiovascular disease defined as: history of coronary heart disease, stroke, peripheral vascular disease or diabetes plus one other cardiovascular risk factor (see comments)

Prevent one death (any cause)

60 months

54

270

Mean age of enrolled patients was 66 years. >50% of patients had a history of MI.

Cardiovascular risk factors: hypertension, elevated total cholesterol, low HDL, smoker, microalbuminuria.

Ramipril reduced the risk of myocardial infarction, stroke, coronary revascularisation and heart failure.

There are no data to support ARBs for this indication.

40

Angiotensin II receptor antagonist (telmisartan 80 mg/day)

Placebo

Patients intolerant of ACE Inhibitors with

established cardiovascular disease:

coronary artery, peripheral vascular or cerebrovascular disease, or diabetes with end organ damage

Patients with heart failure were excluded

Prevent one of a composite of cardiovascular death, MI or stroke

56 months (median duration of follow-up)

55

258

Mean age of patients was approximately 67 years.

Death rate (of any cause) was higher in treatment group than placebo group. When hospitalisations for cardiac failure were added to the composite endpoint as a primary outcome, the results were non-significant. Study concluded that telmisartan did not significantly reduce cardiovascular death.

41

ACE inhibitor (enalapril 2.5 to– 40 mg/day (up-titrated as tolerated))

Placebo

Patients with severe heart failure

NYHA class IV

Co-morbidities included coronary heart disease, previous MI ,  hypertension and diabetes

Prevent one death (any cause)

188 days (mean follow-up)

7

3

Mean age of patients was 70 years.

Symptomatic improvement  was observed i.e. a significant improvement in NYHA classification.

NB Patient numbers in the study were low (n=253).

42

ACE inhibitor (enalapril 2.5 to 20 mg/day (up-titrated as tolerated))

Placebo

Patients with heart failure

NYHA class I – IV and LVEF ≤0.35

Prevent one death (any cause)

41.4 months (mean follow-up)

22

76

Mean age of patients was 61 years, approximately 80% were male. Less than 2% were NYHA Class IV.

Treatment also reduced hospital admissions for heart failure.

Mortality benefit appears to be most marked in the first 24 months.

43

ACE inhibitor (enalapril 2.5 to 20 mg/day (up-titrated as tolerated))

Placebo

Patients with heart failure and chronic kidney disease

NYHA class I - IV and LVEF  ≤0.35 and eGFR <60 mL /min /1.73m2

Prevent one death (any cause)

41.4 months (mean follow-up)

29

101

Mean age of patients was 64 years. Approximately 75% were male.

44

ACE inhibitor (enalapril 2.5 to 20 mg/day (up-titrated as tolerated))

Placebo

Patients with asymptomatic heart failure

NYHA class I and LVEF ≤0.35

Prevent one death (any cause)

34 months (mean follow-up)

88

251

Mean age of enrolled patients was 60 years.

Treatment reduced the incidence of congestive heart failure and related hospital admissions.

45

Angiotensin receptor blocker (candesartan 4 to 32 mg/day)

Placebo

Patients with intolerance to ACE inhibitors with symptomatic heart failure

NYHA Class II-IV and  ejection fraction ≤0.4

Prevent one death (cardiovascular  cause) or hospital admission for chronic heart failure

33.7 months

14

40

Mean age of enrolled patients was approximately 66 years.

Patients were already taking other drugs as part of therapy for heart failure.  Approximately 70% had

heart failure of ischaemic cause.

46

Prevent one death

34

94

ACE inhibitor and indapamide (perindopril 4 mg/day and idapamide 2.5 mg/day)

Placebo

Patients who had a history of stroke or TIA in the last 5 years

Prevent one stroke (any cause)

3.9 years (mean duration of follow-up)

17

68

Mean age of patients was 64 years.

70% of patients in the trial had  ischaemic stroke.

There were similar reductions in the risk of stroke in hypertensive v. non-hypertensive patients.

47

Cerebrovascular/ Cardiovascular Disease

Warfarin

(target INR 2 - 3)

Aspirin

75 mg daily

Age > 75 years with AF

1st occurrence of fatal or non-fatal disabling stroke  (ischaemic or haemorrhagic), other  intracranial haemorrhage or clinically significant arterial embolism

2.7 years

(mean duration of follow-up)

20

54

Mean age of patients prescribed warfarin was 81.5 years.

73% of patients had a CHADS2 score of 1-2.

67% of patients on warfarin remained on this treatment for the complete duration of the trial.

48

Direct Acting Oral Anticoagulants (DOACs)

There are no studies comparing DOACs against placebo. The NNT and NNH data in the table are based on comparative studies against warfarin, not against placebo. Great care is required in interpreting this data. It is of limited use to guide a decision on whether or not to continue with a DOAC.

In addition it should be noted that these studies were equivalence/non-inferiority studies against warfarin, so the validity of extrapolating the results could be questioned. However, these data are included as a useful representation of the potential relative risks and benefits between warfarin and the individual agents.

Apixaban

5 mg twice daily

Warfarin

(to maintain an INR of 2-3)

Patients with non valvular AF

Mean CHADS2 score 2.1

(CHADS2 score > 3 (30%))

Stroke or systemic embolism

1.8 years

167

301

Median age 70yrs (63-76).

Treating 167 patients with apixaban instead of warfarin for 1.8 years might prevent one stroke or systemic embolism Note: warfarin group were within therapeutic range only 66% of the time.

NNH of 67 with respect to major bleeding, so treating 67 patients with apixaban instead of warfarin for 1.8 years might prevent one major bleeding episode.

49

Apixaban

5 mg twice daily

Warfarin

(to maintain an INR of 2-3)

Patients with non valvular AF

Mean CHADS2 score 2.1

(CHADS2 score > 3 (30%))

Major bleeding

1.8 years

Dabigatran

110 mg or 150 mg twice daily

Warfarin

(to maintain an INR of 2-3)

Patients with non valvular AF

Mean CHADS2 score 2.1

(CHADS2 score 3-6 (33%))

Approx age 71 years

Stroke or systemic embolism

2 years

333

(for 110 mg twice daily dose)

91

(for 150 mg twice daily dose)

666

(for 110 mg twice daily dose)

182

(for 150 mg twice daily dose)

Approximate average age 71 yrs.

This means that treating 333 (110mg) or 91 (150mg) patients with dabigatran instead of warfarin for 2 years might prevent one stroke or systemic embolism (depending on the dose used). Note: warfarin group were within therapeutic range only 64% of the time.

NNH, with respect to major bleeding,

treating 83 (110mg) or 250 (150mg) patients with dabigatran instead of warfarin for 2 years might prevent one major bleeding episode (depending on the dose used).

50

Dabigatran

110 mg or 150 mg twice daily

Warfarin

(to maintain an INR of 2-3)

Patients with non valvular AF

Mean CHADS2 score 2.1

(CHADS2 score 3-6 (33%))

Major bleeding

2 years

Edoxaban

30 mg or 60 mg daily

Warfarin

(to maintain an INR of 2-3)

Patients with non valvular AF

Mean CHADS2 score 2.8

(CHADS2 score 4-6 (23%))

Stroke or systemic embolism

2.8 years

167

(for 60 mg daily dose)

468

(for 60 mg daily dose)

Median age 72 years (range 64-78)

This means that treating 167 patients with edoxaban instead of warfarin for 2.8 years might prevent one stroke or systemic embolism. Note, however, that the warfarin group were within therapeutic range only 68% of the time.

NNH, with respect to major bleeding, treating 67 patients with edoxaban instead of warfarin for 2.8 years might prevent one major bleeding episode.

51

Edoxaban

30 mg or 60 mg daily

Warfarin

(to maintain an INR of 2-3)

Patients with non valvular AF

Mean CHADS2 score 2.8

(CHADS2 score 4-6 (23%))

Major bleeding

2.8 years

Rivaroxaban

20 mg daily

Warfarin

(to maintain an INR of 2-3)

Patients with non valvular AF

Mean CHADS2 score 3.5

(CHADS2 score > 3 (10%))

Median age 73 years (range 65-78)

Stroke or systemic embolism

1.9 years

200

380

Median age 73 years (range 65-78)

This means that treating 200 patients with rivaroxaban instead of warfarin for 1.9 years might prevent one stroke or systemic embolism. Note, however, that the warfarin group were within therapeutic range only 55% of the time.

NNH, with respect to major bleeding, treating 260 (in favour of warfarin) patients with rivaroxaban instead of warfarin for 1.9 years might cause one major bleeding episode.

52

Rivaroxaban

20 mg daily

Warfarin

(to maintain an INR of 2-3)

Patients with non valvular AF

Mean CHADS2 score 3.5

(CHADS2 score > 3 (10%))

Major or clinically relevant non major bleeding

1.9 years

Aspirin

Placebo or no treatment

Primary prevention of CVD

Individuals without history of occlusive disease

Serious vascular event (MI, stroke or vascular death).

Mean 5.8 years

246

1428

Age range in trials was 19-94 years

Patients had hypertension or coronary risk factors without overt disease.

53

Aspirin or other antiplatelet*

Placebo or no treatment

Secondary prevention of CVD in patients with history of stroke or TIA

Serious vascular event (non-fatal MI, non-fatal stroke or vascular death).

29 -31 months

28-40

68 – 94

*Antiplatelets included aspirin (most widely studied), clopidogrel, dipyridamole, and other antiplatelets not commonly used in UK practice.

54, 55

Antiplatelet*

Placebo or no treatment

Secondary prevention in patients at high risk of cardiovascular events

(previous MI, acute MI, previous stroke/TIA, and other high risk (excluding acute stroke).

Serious vascular event (non-fatal MI, non-fatal stroke or vascular death).

26 months

15

32

*Antiplatelets include aspirin (most widely studied), clopidogrel, dipyridamole, and other antiplatelets not commonly used in UK practice.

54

Aspirin & dipyridamole

Placebo

Secondary prevention of CVD in patients with arterial vascular disease (coronary artery disease, MI, angina, retinopathy, nephropathy, PAD, stroke, TIA, amaurosis fugax)

Secondary prevention of CVD in patients with arterial vascular disease (coronary artery disease, MI, angina, retinopathy, nephropathy, PAD, stroke, TIA, amaurosis fugax)

Vascular event (non-fatal MI, non-fatal stroke or vascular death).

Vascular event (non-fatal MI, non-fatal stroke or vascular death).

30 months

29 months

25

50

163

121

Mean age of patients 54 years. 

Mean age of patients 55 years

56

Aspirin & dipyridamole

Aspirin

57

Clopidogrel or ticlopidine

Aspirin

Secondary prevention of CVD in patients with history of ischaemic stroke or TIA.

Stroke (all types)

22 months

100

184

Mean age of patients was 63 years

Ticlopidine is not available in the UK but has similar mode of action to clopidogrel

58

Stroke, MI or vascular death

28 months

100

223

Statin

(Simvastatin 40 mg daily, atorvastatin 80 mg daily, pravastatin 40 mg daily)

Placebo

Secondary prevention of CVD in patients with

history of ischaemic or haemorrhagic  stroke or TIA.

Ischaemic or haemorrhagic stroke

48 months

100

400-420

59

Serious vascular events (non-fatal stroke, non-fatal myocardial infarction, vascular death) and all-cause mortality including sudden deaths

41- 44 months

20

68-74

Diabetes

Intensive sulphonylurea with insulin to achieve fasting plasma glucose less than 6.0mmol/L

Conventional treatment with diet to aim for fasting blood glucose less than 15mmol/L

(Metformin and/or sulphonyl-urea could be added, or patients changed to insulin if target not achieved)

Any diabetes end point

10 years (median duration of follow-up)

20

200

Mean age of patients was 54 years (range 25-65).

Any diabetes-related endpoint: sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, digital amputation, vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction.

Diabetes related death was death due to: myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death.

Reduction in micro-vascular events were mostly retinal.

Median HbA1c over 10 years 7.0% in intensive group versus 7.9% in conventional group.

Intensive group had more hypo-glycaemic episodes per year and higher weight gain than conventional group.

60

Diabetes related death

91

910

Micro-vascular

complications

36

360

Metformin to achieve fasting blood glucose <6.0mmol/l (maximum dose 2550mg)

Glibenclamide added if target not achieved and changed to insulin if required

Diet alone to achieve fasting blood glucose <15mmol/l. 

sulphonyl-urea or metformin or insulin could be added

Newly diagnosed type 2 diabetes patients  - between 25-65 years

Overweight defined as >120% ideal body weight

Any diabetes end point

10.7 years (median duration of follow-up)

7

80

Mean age of patients was 53 years; mean weight 87kg ; BMI 31.

Any diabetes-related endpoint: As above.

Median HbA1c during 10 years was 7.4% in metformin group and 8.0% in conventional group.

Hypoglycaemic episodes were higher in metformin group but lower than the sulfonylureas group.

Hypoglycaemia rates increased over time in insulin group as higher doses were required.

61

Diabetes related death

19

203

Microvascular disease

45

481

Intensive control of glucose by including Gliclazide mr to existing medication to achieve a HbA1c of 6.5% or less. 

Hypo-glycaemia agents chosen by the treating physician

Patients with type 2 diabetes mellitus at least 55 years old with a history of major macro-vascular or micro-vascular disease or at least one other risk factor for vascular disease

Major microvascular or macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke)

5 years (median)

53

263

Mean HbA1c in control group was 7.3% and intensive (gliclazide mr) arm was 6.5% after 5 years follow up.

Microvascular benefits were mostly due to reduction in nephropathy.

No significant effect on major macrovascular events alone.

Severe hypoglycaemia occurred in 2.7% of patients on intensive therapy compared with 1.5% of patients in the standard therapy group (NNH=80).

62

Major micro-vascular events (new or worsening nephropathy or retinopathy).

67

333

Osteoporosis

Alendronate

10 mg tablets

Placebo

Post-menopausal women

a) For primary prevention average T-score was within 2 standard deviations of the mean for bone density

b) For secondary prevention in women who had experienced  previous vertebral compression fractures

Rate of vertebral, non-vertebral or hip fractures (as below) over a 5 year period

60 months (5 years)

As per age range (left column) below

As per age range (left column) below

Age range 42-85 but >62 for secondary prevention

These NNTs apply to the first 5 years of treatment only.

63

Vertebral secondary prevention

65-74

16

65-69

80

70-74

13

70-74

65

75-79

9

75-79

45

80-84

12

80-84

60

85-89

11

85-89

55

90+

8

90+

40

Non-vertebral secondary prevention

65-69

52

65-69

260

70-74

39

70-74

195

75-79

36

75-79

180

80-84

27

80-84

135

85-89

24

85-89

120

90+

12

90+

60

Hip secondary prevention

65-69

21

65-69

105

70-74

86

70-74

430

75-79

36

75-79

180

80-84

21

80-84

105

85-89

9

85-89

45

90+

8

90+

40

Alendronate

Placebo

Postmenopausal women

a) For primary prevention average T-score was within 2 standard deviations of the mean for bone density

b) For secondary prevention women who had experienced  previous vertebral compression fractures

Rate of vertebral, non-vertebral or hip fractures (as below) over a 5 year period

60 months (5 years)

Age range 42-85 but >62 for secondary prevention.

These NNTs apply to the first 5 years of treatment only.

All patients received calcium and vitamin D.

63

Vertebral primary prevention

65-69

14

65-69

740

70-74

12

70-74

615

75-79

67

75-79

335

80-84

97

80-84

485

85-89

89

85-89

445

90+

47

90+

235

Non-vertebral

primary prevention

65-69

10

65-69

520

70-74

67

70-74

335

75-79

59

75-79

295

80-84

42

80-84

210

85-89

32

85-89

160

90+

12

90+

60

Hip primary prevention

65-69

23

65-69

118

70-74

11

70-74

590

75-79

50

75-79

250

80-84

27

80-84

135

85-89

11

85-89

55

90+

9

90+

45

References

31. Laupacis A, Sackett D, Roberts R. An Assessment of Clinically Useful Measures of the Consequences of Treatment. New England Journal of Medicine. 1988;318(26):1728-1733

32. Cook R, Sackett D. The number needed to treat: a clinically useful measure of treatment effect. BMJ. 1995;310(6977):452-454

 

33. Hutton J. Number needed to treat and number needed to harm are not the best way to report and assess the results of randomised clinical trials. British Journal of Haematology. 2009;146(1):27-30