Gastroenterology and Hepatology

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Evidence-based Gastroenterology and Hepatology

AUTHOR

William Rosenberg MA MBBS DPhil MRCPUniversity Department of MedicineMailpoint 811 Level D South BlockSouthampton General HospitalTremona RoadSouthamptonSO16 6YD

Tel: 01703 796883Fax: 01703-796968e-mail: [email protected]

mailto:[email protected]

á CD Contents ã Contents å â


Table of Contents

Ø Introduction to Evidence-Based Gastroenterology and Hepatology

Ø Other resources for Evidence-Based Gastroenterology and Hepatology

Ø Sample scenarios, searches, completed worksheets and CATs for Gastroenterology andHepatology



Introduction to Evidence Based Gastroenterology and Hepatology

In this essay I will present a working definition of evidence-based medicine, discuss the ways in which itdiffers from traditional approaches to clinical practice: suggest some benefits for gastroenterologists andhepatologists and highlight some of the particular challenges that it presents to us.

Evidence-based medicine is the explicit and judicious use of current best evidence and clinical expertisein making decisions about the care of patients. As such it requires the integration of individual clinicalexpertise and acumen with the best available external evidence and with our patients’ values andpreferences. By individual clinical expertise we mean the increasing proficiency acquired through clinicalexperience, reflected in more effective and efficient clinical decision making, and the ability to accommodatepatients’ rights needs and preferences when making decisions about their care. When using the term “bestavailable external evidence” we refer to clinically relevant research that often comes from the basicsciences such as immunology, physiology and molecular biology, but especially from patient-centred clinical



research into the accuracy and precision of diagnostic tests, the predictive power of prognostic markers,and the efficacy and safety of therapies. Throughout we aim to recall that the research method should bedetermined by the question so that while an RCT is the appropriate methodology to investigate the efficacyof a therapy, a prospective cohort study (and not an RCT) will provide the best evidence about prognosis.

When considering evidence we must bear in mind that today’s certainties are tomorrows bad practice!External clinical evidence has a short doubling-time. It both invalidates previously accepted tests andtreatments and replaces them with new ones that are more powerful, more accurate, more efficacious, andsafer, for the moment! So we must attempt to keep up to date. In advocating the integration of clinicalexpertise and external evidence we argue that neither alone is enough. Without the former, practice risksbecoming evidence-tyrannised, for even excellent external evidence may be inapplicable or inappropriatefor an individual patient. Without the latter, practice risks becoming rapidly out of date, to the detriment ofpatients and patient-care.

When applying this process in the care of patients it is of prime importance that we acknowledge the rights,needs and preferences of patients. This requires that we not only maintain an awareness of the evidence,but that we understand it sufficiently well to be able to explain it to our patients in a variety of different ways.Acquiring the skills to communicate effectively with a broad range of patients thus becomes one of the corecompetencies of EBM. This is likely to involve mastery of verbal, numerical and visual methods ofcommunicating risks, benefits and consequences and may be augmented by many of the novel



biostatistical techniques developed by practitioners of EBM such as Numbers Needed to Treat or Harm,Likelihood Ratios and Odds ratios.

Many thoughtful and experienced traditional physicians have asked what is the difference between theseprecepts that we have labeled “EBM” and traditional best practice? At first glance this is a valid question. Inanswer we identify five areas in which EBM differs from prior models.1. First, in many of the conceptual ways in which EBM addresses clinical practice, such as explicit question

formulation, EBM differs from traditional approaches. We have found that many of the difficulties thatstudents and qualified clinicians experience when trying to find evidence relate to problems with defininga clear, searchable, answerable and relevant question. Emphasising the process of explicitly formulatingsuch a question represents a conceptual advance of EBM.

2. Secondly, EBM has introduced a number of strategies into the practice of medicine that have improvedaccess to evidence, and the evaluation, integration into clinical care and dissemination of this evidence.These include the development of optimal strategies for searching electronic databases, “users’ guides”to critical appraisal, biostatistical methods of expressing the impact of evidence (such as NNT) anddissemination of evidence through sources of secondary publication such as ACP Journal Club andEvidence-Based Medicine.



3. Thirdly, EBM encompasses interpreting and appraising advances in research methodologies such asthe use of systematic reviews and meta-analyses.

4. Fourth, are the new ways of presenting the results of research in numerical form such as NNT,LR, ORand NNH that have developed from biostatistics. These ways of presenting data provide new ways ofviewing results and some can be used to enhance communication with patients and colleagues.

5. Finally, EBM provides an integrated system for promoting patient problem based, self-directed learningwhich can be fully integrated into service delivery, meeting the competing demands of training andpatient care.

Thus EBM is an approach to clinical problem solving, a means of determining rational practice, a method ofintegrating service with training and education, a way of generating research ideas and, in summary, Bestpractice made EXPLICIT and ACCESSIBLE. In contrast it is specifically not just what we’ve always beendoing, or cook-book medicine and it is not only about RCTs and meta-analyses. Although these researchmethods have their place, they are inappropriate ways of studying some questions. EBM does not lead torationing or cost-cutting except where costly practices are ineffective. Indeed evidence-based practices maybe costly as in the case of adding ribavirin to interferon in the treatment of chronic hepatitis C. Finallybecause EBM requires the integration of individual expertise with the best available external evidence, EBMis not disrespectful of experience, rather it values experience.



Practising EBM in isolation tends to be lonely and is likely to be inefficient. Forming a team with colleaguesis, in our experience rewarding and pleasurable. Expertise can be shared and tasks distributed. Participantsat different stages of training may work together to mutual benefit and the shared practice of EBM can makepowerful contributions to team building. Multidisciplinary groups can practise EBM together with greatsuccess. In our experience, differences in experience, background and perspective can require skill infacilitation but the benefit of recognising different perspectives on common shared problems can beenormous. Most groups will encompass members who bring specific expertise but any skills not sharedwithin the group can be sought outside and learnt. We have enjoyed and benefited greatly from training insearching and library skills by librarians. By contrast we have rarely had to request help from statisticians,finding that esoteric statistical tests are a reliable surrogate marker for low impact research findings.

Much of the pioneering work in EBM has centred on questions and research in cardiology. EBM posesslightly different challenges to gastroenterologists and hepatologists and consideration of these differencesis instructive. By contrast with cardiologists we use a wider range of diagnostic tests and we tend to workwith colleagues from many different disciplines such as histopathology, biochemistry, radiology and surgery.We have had to rely on the results of many small trials of therapy, partly because of the lower prevalence ofmany gastroenterological and hepatological diseases and partly because we have been slower to embrace“megatrial” methodology. In contrast with the acute interventional cardiologist, we tend to spend more timemanaging patients with chronic relapsing conditions such as inflammatory bowel disease and viral hepatitis.



Although there are similarities in our use of interventional or procedural techniques, many of those used ingastroenterology are more operator dependent than those used by cardiologists. These contrasts bothexplain some of the differences in quality and quantity of EBM resources between gastroenterology andcardiology but also highlight some of the challenges that face us, all of which may be easily addressed. Asgastroenterologists and hepatologists there is much we can take from EBM and there are many ways inwhich we can use it to our benefit. When confronted by clinical problems the strategy of questionformulation can be used to reduce complex clinical scenarios into an array of addressable questions thatcan then be prioritised in a hierarchy of importance. We advocate placing common questions asked bypatients and physicians at the top, followed by common problems asked by us, less common problems ofinterest to patients and ourselves and finally rare questions of interest to us alone.

We try to make optimal use of information technology, learning the most successful searching strategies forthe best databases and taking note of useful websites such as ScHARR and HEPNET.http://www.hepnet.com/liver/index.html

In a discipline so reliant on interdisciplinary working, we have found that mastering the skills of criticalappraisal has greatly enhanced our ability to contribute to debates about practice outside our individualareas of expertise but within the specialty. Thus a meeting between physicians, surgeons and radiologistsabout the management of hepatic tumours involved each group using a common strategy for criticallyappraising the evidence in order to reach consensus.

http://www.hepnet.com/liver/index.html

Alison Leese



It would be very wrong to ignore the considerable achievements that have already been attained inevidence-based gastroenterology and hepatology. Important systematic reviews have changedperspectives and practice in the areas of therapy for primary biliary cirrhosis1, inflammatory bowel diseases2

and hepatitis C3.

1 Simko-V; Michael-S; Prego-V. Ursodeoxycholic therapy in chronic liver diisease: a meta-analysis in primary biliarycirrhosis and in chronic hepatitis. Am-J-Gastroenterol. 1994 Mar; 89(3): 392-8.

2 Pearson DC, May GR, Fick G, Sutherland LR. Azathioprine for maintaining remission of Crohn's disease (CochraneReview). In: The Cochrane Library, Issue 1, 1999. Oxford: Update Software.

3 Poynard, T., Leroy, V., Cohard, M., Thevenot, T., Mathurin, P., Opolon, P., and Zarski, J.P. Meta-analysis of interferonrandomized trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 24(4):778-789, 1996.



There are many examples of new initiatives in which gastroenterologists are working together to answer bigquestions with large multicenter trials addressing the use of new therapies in IBD, colorectal cancerdiagnosis and the use of serological markers of liver fibrosis. The success of various Cochrane groupingswithin the field provides further evidence of the growing recognition within the speciality of the power ofEBM approaches to clinical research.

In the sphere of clinical excellence recent years have witnessed the proliferation of valid practice guidelinesand studies designed to generate the evidence that underpins them such as the BSG gastrointestinalbleeding. The challenges that lie ahead are the application of good quality clinical research into theeffectiveness of the treatments and diagnostic tests that we use; promotion of EBM in the primary sourcesof publication and the development of EB secondary sources of publication. EB workshops within thespecialty would be exciting. New publications are in preparation and there is undoubtedly the need anddemand for an evidence-based gastroenterology and hepatology journal.

In summary the benefits of EBM to us as gastroenterologists and heptologists are to ourselves, our patientsand the health care systems in which we work. For ourselves, EBM provides a means for keeping up todate and maintaining our clinical independence. Our patients should benefit as a result of us being as wellinformed and contemporary as possible and the process of EBM should ensure that we take account oftheir needs and wishes when integrating external evidence with their individual cases. We may become



better at finding more comprehensible ways of sharing evidence with our patients by adopting some of theEBM methods of expressing the results of research. Healthcare systems such as the NHS benefit fromEBM by providing a structure in which we can easily and efficiently integrate education with service delivery.Health economic issues can be resolved using EBM to justify the elimination of ineffective and costlypractises to release resources better used in effective practices. EBM should also meet some of the needsof quality assurance by promoting the more uniform delivery of “best practice.”

Other resources for Evidence-Based Gastroenterology and Hepatology

• http://www.hepnet.com/liver/index.html

http://www.hepnet.com/liver/index.html



Sample scenarios, searches, completed worksheets and CATs for Gastroenterologyand Hepatology:

DIAGNOSIS

Clinical Scenario

You admit a well 75 year old woman with community-acquired pneumonia. She responds nicely toappropriate antibiotics but her haemoglobin remains at 100 g/l with a mean cell volume of 80. Herperipheral blood smear shows hypochromia, she is otherwise well, and is on no incriminating medications.You contact her GP and find out that her haemoglobin was 105 g/l 6 months ago. She has never beeninvestigated for anaemia. You discuss this patient with your registrar and debate the use of ferritin in thediagnosis of iron deficiency anaemia. You admit to yourself that you are unsure how to interpret a ferritinresult and how precise and accurate a serum ferritin is for diagnosing iron deficiency anaemia.



You therefore form the question, “In an elderly woman with hypochromic, microcytic anaemia, can a lowferritin diagnose iron deficiency anaemia?” You order a ferritin and head for the library (10 days later itcomes back at 40 µg/l).

Searching Best Evidence on Disk with the single word “ferritin” yielded a very encouraging meta-analysis of55 studies and a nice individual study, but your library didn’t carry either journal. You perform a MEDLINEsearch using the MeSH terms “ferritin” and “sensitivity and specificity” and find an article on diagnosing irondeficiency anaemia in the elderly published in a journal that your library does take (Am J Med 1990;88:205-9).

Read this article and decide,1. Are the results of this diagnostic article valid?2. Are the valid results of this diagnostic study important?3. Can you apply this valid, important evidence about a diagnostic test in caring for your patient?



DIAGNOSIS WORKSHEET: page 1 of 2

Citation: Guyatt GH, Patterson C, Ali M, Singer J, Levine M, Turpie I, Meyer R: Diagnosis of iron-deficiencyanemia in the elderly. Am J Med 1990; 88: 205-9

Are the results of this diagnostic study valid?1. Was there an independent, blind

comparison with a reference(“gold”) standard of diagnosis?

Yes, they underwent bone-marrowaspirations.

2. Was the diagnostic test evaluatedin an appropriate spectrum ofpatients (like those in whom itwould be used in practice)?

Yes

3. Was the reference standardapplied regardless of thediagnostic test result?

Yes



Are the valid results of this diagnostic study important?

FERRITIN IRONDEFICIENCY

NO IRONDEFICIENCY

Likelihood Ratio

� <45 70/85 15/150 8.2>45 <100 7/85 27/150 0.44

>100 8/85 108/150 0.13TOTALS 85 150

• For pre-test probabilities in the 30-70% range, a ferritin <45 would be very helpful, yielding post-testprobabilities of 78-95% (in the latter case, a SpPin4).

• In that same pre-test probability range, a ferritin >100 would yield post-test probabilities of 5-23% (in theformer case, a SnNout5).

• So it can give quite important results. 4 When a diagnostic test has a very high Specificity, a Positive result Rules-In the diagnosis5 When a diagnostic test has a very high Sensitivity, a Negative result Rules-Out the diagnosis.



DIAGNOSIS WORKSHEET: page 2 of 2

Can you apply this valid, important evidence about a diagnostic test in caring for your patient?

Is the diagnostic test available,affordable, accurate, and precise inyour setting?

Needs to be assessed in eachsetting.

Can you generate a clinically sensibleestimate of your patient’s pre-testprobability (from practice data, frompersonal experience, from the reportitself, or from clinical speculation).

Approximately 30%.

Will the resulting post-testprobabilities affect your managementand help your patient? (Could it moveyou across a test-treatmentthreshold?; Would your patient be awilling partner in carrying it out?)

Her result of 40 brings her post-test probability to 78%, certainlyhigh enough for you to want toinvestigate her for causes ofanaemia (GI loss, etc.).

Would the consequences of the testhelp your patient?

Yes, if it led to a reversible cause.But this would have to be weighedagainst early detection of anuntreatable cause (e.g., cancer)that would simply take away“healthy” time. The options wouldneed to be discussed with yourpatient.

Additional Notes:

An excellent overview of 55 studies of lab tests for Fe-deficient anaemia: Guyatt et al: J Gen Intern Med1992;7:145-53 (with a correction on page 423).



ANAEMIA: DIAGNOSIS OF IRON DEFICIENCY ANEMIA IN THE ELDERLY

Clinical Bottom LineIn community dwelling elderly medical patients in whom iron deficiencyanaemia is suspected, serum ferritin is a valid, precise diagnostic test.

Citation

Guyatt GH, Patterson CH, Ali M. Diagnosis of iron-deficiency anemia in the elderly. Am J Med 1990;88:205-9.

Clinical Question: In a patient with anaemia can a low serum ferritin be used to diagnose iron deficiency?

Search terms: “ferritin” and “sensitivity and specificity” in MEDLINE



The Study

1. Gold Standard - bone marrow aspiration2. Study setting - consecutive pts over the age of 65 yr. who were admitted with anaemia to a university-

affiliated hospital in Canada.

The Evidence

FERRITIN IRONDEFICIENCY

NO IRONDEFICIENCY

LIKELIHOODRATIO

>45 70/85 15/150 8.2>45 >100 7/85 27/150 0.44

>100 8/85 108/150 0.13TOTALS 85 150

Comments

1. Excluded patients from institutions and patients who were “too ill” or had “severe dementia” althoughthese were not defined.



2. Weighted kappa for bone marrow interpretation by two haematologists was 0.84.3. Low values can SpPin, and high values can SnNout.4. Also see the meta-analysis in J Gen Intern Med 1992;7:145-53. (with a correction on page 423).

Appraised by S. Straus, 1996, Reviewed 1998, Expiry date: 2000

B. PROGNOSIS

Clinical scenario

You see a 29 year old woman in an outpatient clinical 3 months after she has been diagnosed as havingCrohn’s disease. She is married with two young children. Having adjusted to the initial shock of learningabout her diagnosis and recovering from a bout of ilieitis she has read about all the potential complicationsof Crohn’s disease and is very concerned that her life expectancy will be greatly reduced. She says “I’veread about all these bad problems, what are the chances of me dying young?”



Read the article and decide,1. Is this evidence about prognosis valid?2. Is this valid evidence about prognosis important?3. Can you apply this valid and important evidence about prognosis in caring for your patient?



COMPLETED PROGNOSIS WORKSHEET: page 1 of 2

Citation: Loftus EV, Silverstein MD, Sandborn WJ, et al. Crohn’s Disease in Olmstead County Minnesota,1940-1993: Incidence, Prevalence, and Survival. Gastroenterology 1998;114:1161-1168 .

Are the results of this prognosis study valid?1. Was a defined, representative

sample of patients assembled at acommon (usually early) point in thecourse of their disease?

Yes – 90% of the population areseen at the Mayo clinic in any 3year period and record linkageensures good coverage. Date ofonset of symptoms was identified.

2. Was patient follow-up sufficientlylong and complete?

Yes-minimum of 1 year but recordsfrom 1940 onwards were reviewed.Median follow-up=13.3 years (0.1-51.3).

3. Were objective outcome criteriaapplied in a “blind” fashion?

Death certificates were obtainedfor all patients who died. Causes ofdeath were recorded (table3).

4. If subgroups with differentprognoses are identified, was thereadjustment for important prognosticfactors?

No. No difference in survival wasobserved according to year ofdiagnosis or sex.

5. Was there validation in anindependent group (“test-set”) ofpatients?

No



PROGNOSIS WORKSHEET: page 2 of 2

Are the valid results of this prognosis study important?

1. How likely are the outcomes overtime?

43 patients died (19%). Survivalwas slightly less than expected:20 year survival 73%; expected86% ; 30 year survival 73%;expected 74%

Only survival for patientsdiagnosed between 1963 and 1974was less than expected.

2. How precise are the prognosticestimates?

Not stated.



If you want to calculate a Confidence Interval around the measure of Prognosis:

Clinical Measure Standard Error (SE) Typical calculation of CIProportion (as in the rate ofsome prognostic event,etc.) where:

The number of patients = n

the proportion of thesepatients who experiencethe event = p

√ {p x (1-p) / n}where p is proportion and nis number of patients

If p = 43/226 = 0.19(or19%) & n=226

SE=√{0.19 x (1-0.19) / 226}= 0.026 (or 2.6%)

95% CI is 19% +/- 1.96 x2.6% or 13.9% to 24.1%



Can you apply this valid, important evidence about prognosis in caringfor your patient?

1. Were the study patients similar toyour own?

Yes

2. Will this evidence make a clinicallyimportant impact on yourconclusions about what to offer ortell your patient?

Yes

Additional Notes:



CROHN’S DISEASE – OVERALL SURVIVAL MAY BE REDUCED

Clinical Bottom Line:Overall survival for Crohn’s disease patients is 92% of that expected but only for patients diagnosed before1974.

Citation: Loftus EV, Silverstein MD, Sandborn WJ, et al. Crohn’s Disease in Olmstead County Minnesota,1940-1993: Incidence, Prevalence, and Survival. Gastroenterology 1998;114:1161-1168 .

Clinical Question: In a patient with newly diagnosed Crohn’s disease what are the chances of dyingprematurely?

Search Terms: “crohn’s disease” and “survival” in Medline



The Study:

226 pts registered in a community-based Crohn’s registry and followed prospectively for median of 13.4years (range, 0.3-51.3) after diagnosis.

The Outcome: death

Well-defined sample at uniform (early) stage of illness?, yes; Follow-up long enough?, yes; Follow-upcomplete?, reasonably (20% drop out); Blind and objective outcome criteria?, yes; Adjustment for otherprognostic factors?, no; Validation in an independent "test-set" of patients?, no

The Evidence:

Overall survival for Crohn’s disease patients is 92% of that expected, but only for patients diagnosed before1974.

Prognostic Factor Outcome Time Measure ConfidenceInterval

Crohn’s disease Death 13.4 years 19% 13.9% to 24.1%



Comments:

1. Decreased survival only applies to patients diagnosed before 19742. 90% of Olmstead population included3. Rely on diagnosis of Crohn’s4. 20% lost in follow-up5. US study ? applicable worldwide?6. Small numbers in more recent decennial cohorts

Appraised by W. Rosenberg, 1999; Expiry date: 2000



C. THERAPY

Clinical Scenario

A 68 year old retired physician consults you about an episode of severe dyspepsia on a background of 20years of mild indigestion. She is overweight but otherwise in good health. She is taking omeprazole 20mgnocte, drinks 10 units of alcohol per week and takes naproxen for arthralgias two to three times per week.You perform an oesophago-gastro-duodenoscopy which reveals a small 5 cm hiatus hernia and mild antralgastritis but is otherwise normal. You take an antral biopsy and apply a CLO test for helicobacter pylori.This is strongly positive. Histological investigation confirms both gastritis and helicobacter infection.

You wonder if there is any new evidence about helicobacter eradication in patients with non-ulcer dyspepsiaand formulate the question, In a patient with nonulcer dyspepsia and helicobacter pylori infection, willhelicobacter eradication therapy result in a reduction in symptoms of dyspepsia?



You perform a MEDLINE search using the terms “nonulcer dyspepsia” and “helicobacter pylori” and“randomized controlled trial”

And retrieve two RCTs that appear to come to conflicting conclusions.

Read these two articles and decide for each,1. Is the evidence from this randomised trial valid?2. If valid, is this evidence important?3. If valid and important, can you apply this evidence in caring for your patient?

Then explain why the two trials come to different conclusions. What will you tell your patient?



COMPLETED THERAPY WORKSHEET: page 1 of 2

Citation: Symptomatic benefit from eradicating helicobacter pylori infection in patients with nonulcerdyspepsia. McColl K et al N Engl J Med 1998;339:1869-74.

Are the results of this single preventive or therapeutic trial valid?Was the assignment of patients totreatments randomised?-and was the randomisation listconcealed?

Yes

Were all patients who entered the trialaccounted for at its conclusion? -andwere they analysed in the groups towhich they were randomised?

Yes

Were patients and clinicians kept “blind”to which treatment was being received?

Yes. The study was placebocontrolled.

Aside from the experimental treatment,were the groups treated equally?

Yes

Were the groups similar at the start of thetrial?

Yes



Are the valid results of this randomised trial important?

SAMPLE CALCULATIONS

Occurrence of symptoms Relative RiskReduction

RRR

Absolute RiskReduction

ARR

Number Needed toTreatNNT

Omeprazolealone

Symptoms“control”

Event RateCER

HperadicationSymptoms

ExperimentalEvent Rate

EER

CER – EERCER

CER - EER 1/ARR

93% 79% 93% - 79% = 93%

15%

93% - 79% = 14% 1/15% = 7pts,



95% Confidence Interval (CI) on an NNT = 1 / (limits on the CI of its ARR) =

7.3%

YOUR CALCULATIONS:

Relative RiskReduction

RRR


ARR

NumberNeeded to

TreatNNT

CER EER CER - EERCER

CER – EER 1/ARR

0.93 0.79 0.93 - 0.79 = 15% 0.93

0.14 7




Can you apply this valid, important evidence about a treatment in caring for yourpatient?Do these results apply to your patient?

Is your patient so different fromthose in the trial that its resultscan’t help you?

Yes, she is similar to those patients includedin the trial

How great would the potentialbenefit of therapy actually be foryour individual patient?

Method I: f Risk of the outcome in your patient, relative topatients in the trial. expressed as a decimal: 1.0

NNT/F = 7/1 = 7(NNT for patients like yours)

Method II: 1 / (PEER x RRR) Your patient’s expected event rate if theyreceived the control treatment: PEER:______

1 / (PEER x RRR) = 1/________ = _______(NNT for patients like yours)

Are your patient’s values and preferences satisfied by the regimen and its consequences?

Do your patient and you have aclear assessment of their valuesand preferences?

Needs to be assessed in each patient

Are they met by this regimen andits consequences?

Needs to be assessed in each patient

Additional Notes:




Citation: Lack of effect of treating helicobacter pylori infection in patients with nonulcer dyspepsia. Blum A.L.et al N Engl J Med 1998;339:1875-81.


Yes


Yes


Yes. The study was placebocontrolled.

Aside from the experimental treatment,were the groups treated equally?

Yes


No. 66% of the eradication groupwere men compared to 76% ofomeprazole alone group.




SAMPLE CALCULATIONS

Occurrence of symptomsat end of treatment period


RRR


ARR

NumberNeeded to

TreatNNT

Omeprazolealone

Symptoms“control”

Event RateCER

HperadicationSymptoms

ExperimentalEventRateEER

CER – EERCER

CER - EER 1/ARR

79.3% 72.6% 79.3% - 72.6% 79.3%

=8.4%

79.3% - 72.6%= 6.7%

1/6.7% =15pts,



95% Confidence Interval (CI) on an NNT = 1 / (limits on the CI of its ARR)

9.2%

YOUR CALCULATIONS:


RRR


ARR

NumberNeeded to

TreatNNT


CER – EER 1/ARR

0.793 0.726 0.793 - 0.726 =8.4% 0.793

0.067 15




Can you apply this valid, important evidence about a treatment in caringfor your patient?Do these results apply to yourpatient?


Yes, she is similar to thosepatients included in the trial

How great would the potentialbenefit of therapy actually befor your individual patient?

Method I: f Risk of the outcome in your patient,relative to patients in the trial.expressed as a decimal: 1.0

NNT/F = 15/1 = 15(NNT for patients like yours)

Method II: 1 / (PEER x RRR) Your patient’s expected event rate ifthey received the control treatment:PEER:______

1 / (PEER x RRR) = 1/________ =_______(NNT for patients like yours)

Are your patient’s values and preferences satisfied by the regimen and its consequences?

Do your patient and you havea clear assessment of theirvalues and preferences?

Needs to be assessed in eachpatient

Are they met by this regimenand its consequences?




Additional Notes: The eradication group contained a higher proportion of women than the control group. Ifthere is a sex difference in response to treatment the study might have over or underestimated the effect. Imight question the validity of this study. Analysis of the data on a “per-protocol” basis provides a higherNNTof 23 due to the large number of exclusions in both randomisation limbs.

Comments on the 2 studies:

• The McColl study had greater validity in that the two groups of randomised patients were better matchedand there were no exclusions after randomisation.

• The power of the McColl study was greater due to the larger number of patients treated and analysed.• The McColl study is more widely applicable in that the definition of dyspepsia was broad and a broad

range of severity of symptoms was included.



NONULCER DYSPEPSIA - HELICOBACTER ERADICATION REDUCES THE PREVALENCE OFSYMPTOMS

Clinical Bottom Line:Helicobacter pylori eradication in patients with nonulcer dyspepsia using omeprazole and two antibiotics for2 weeks results in symptomatic improvement.

Citation: Symptomatic benefit from eradicating helicobacter pylori infection in patients with nonulcerdyspepsia. McColl K et al N Engl J Med 1998;339:1869-74.

Clinical Question: In a patient with nonulcer dyspepsia and helicobacter pylori infection, will helicobactereradication therapy result in a reduction in symptoms of dyspepsia?

Search Terms: "nonulcer dyspepsia" and "helicobacter pylori" and “randomised controlled trial” in MEDLINE



The Study:

Double-blinded concealed randomised placebo controlled trial with intention-to-treat analysis.

Patients: adults referred with dyspepsia for � >4 months, no previous or current peptic ulceration,oesophagitis or NSAID use.

Control group (N = 160: 160 analysed): placebos

Experimental group (N = 158; 158 analysed): 20mg omeprazole po; bd, amoxycillin 500mg po;tds, (ortetracycline 500mg po;tds for penicillin sensitivity), metronidazole 400mg po;tds all for 2 weeks VSomeprazole 20mg bd;po + placebo.

The Evidence:

Outcome Time toOutcome

CER EER RRR ARR NNT

Persistingsymptoms

1 year 0.93 0.79 15% 0.14 7

95%ConfidenceIntervals:

7.7% to22.3%

4 to 14



Comments:

1. Dyspepsia defined as intermittent or persistent pain or discomfort in upper abdomen or lower chest,heartburn, nausea, postprandial fullness or any other upper GI symptom.

2. Carbon-14 urea breath test used to preselect patients with evidence of Helicobacter pylori infection.3. Upper GI endoscopy confirmed diagnosis in all patients.4. Analysis of symptoms 1 year after treatment.

Appraised by William Rosenberg 1999; Expiry date: 2000

C. THERAPY (AN ALTERNATE SCENARIO)

A 35 year old former intravenous drug user who is now a successful investment banker has been found tobe HCV RNA positive. He last injected drugs 10 years ago after a 3 year period of needle sharing. He issent to see you for advice on treatment for his viral hepatitis. A liver biopsy reveals periportal inflammation,some piecemeal necrosis and early fibrosis. He drinks 30 units of alcohol per week. He wants to know if he



should have treatment and if so, does combination therapy of interferon with ribavirin really offer much morechance of viral clearance than interferon alone or just waiting to see what happens.

You formulate the question, “In 35 year old man who is HCV RNA positive does treatment with interferon +ribavirin, compared to interferon alone, or no treatment, offer a significant chance of viral clearance?”Fortunately, you have brought your notebook computer with you which has the latest version of BestEvidence on it. You search Best Evidence using the term “ hepatitis c” and “randomised controlled trial” findan abstract and commentary on an article by Poynard et al which looks promising. (Lancet 1998;352:1426-32). You tell the patient that you will obtain this article from your office and will return to her with theevidence.

Read this article and decide,1. Is the evidence from this randomised trial valid?2. If valid, is this evidence important?3. If valid and important, can you apply this evidence in caring for your patient?




Citation: Poynard T, Marcellin P, Lee SS, et al. Interferon α 2b and ribavirin increased the loss of HCV RNAin chronic hepatitis C. Lancet 1998;352:1426-32.


Yes


Yes


Yes, the trial was placebocontrolled.

Aside from the experimental treatment,Were the groups treated equally?

Yes


Yes




SAMPLE CALCULATIONS

Virological presence at 6months post treatment


RRR


ARR

Number Neededto Treat

NNTInterferon

aloneControl

Event RateCER

Interferon +ribavirin

ExperimentalEvent Rate

EER

CER - EERCER

CER - EER 1/ARR

80.7% 57.4% 80.7%-57.4%=28.8% 80.7%

80.7%-57.4%=23.3%

1/23.3%= 4.3pts,



95% Confidence Interval (CI) on an NNT = 1 / (limits on the CI of its ARR)

7.4%

YOUR CALCULATIONS:


RRR


ARR

NumberNeeded to

TreatNNT


CER - EER 1/ARR

.81 .57 .29 .24 4



THERAPY WORKSHEET: page 2 of 2

Can you apply this valid, important evidence about a treatment in caringfor your patient?Do these results apply to yourpatient?


no, this patient is similar

How great would the potentialbenefit of therapy actually befor your individual patient?

Method I: f Risk of the outcome in your patient,relative to patients in the trial.Expressed as a decimal:1

NNT/f = 4/1 = 4(NNT for patients like yours)

Method II: 1 / (PEER x RRR) Your patient’s expected event rate ifthey received the control treatment:PEER:______

1 / (PEER x RRR) = 1/________ =_______(NNT for patients like yours)

Are your patient’s values and preferences satisfied by the regimen and itsconsequences?

Do your patient and you havea clear assessment of theirvalues and preferences?


Are they met by this regimenand its consequences?


Additional Notes:



CHRONIC HEPATITIS C - INTERFERON + RIBAVIRIN INCREASES VIROLOGICAL CLEARANCE OFHCV

Clinical Bottom Line:Interferon + Ribavirin “combination therapy” is significantly more effective than interferon alone or notreatment in clearing HCV.

Citation: Poynard T, Marcellin P, Lee SS, et al. Interferon a2b and ribavirin increased the loss of HCV RNAin chronic hepatitis C. Lancet 1998;352:1426-32.

Clinical Question: “In 35 year old man who is HCV RNA positive does treatment with interferon + ribavirin,compared to interferon alone, or no treatment, offer a significant chance of viral clearance?”

Search Terms: “HCV” and “RCT” in Best Evidence



The Study:

Double-blinded randomised controlled trial with intention-to-treat.

Patients >18 years, compensated CHC, naïve to IFN and Ribavirin, Hb>12 (F) 13(M). Exclusionsdecompensated liver disease or other serious illness.

Control group (N = 281; 281 analysed): interferon a2b plus placebo

Experimental group (N = 281; 281 analysed): virological status at 24 weeks after the end of treatment.

The Evidence:

Outcome CER EER RRR ARR NNTViralclearance

0.81 0.57 29 0.23 4

95%confidencelimits

0.16 to0.31

3 to 6



Comments:

1. Poynard’s trial results are very similar to those published by McHutchinson based on US data.2. The results should be compared with background rates of clearance of HCV in established CHC of ~1%.3. Drop out rate was low with 80% of patients completing the study.

Appraised by William Rosenberg 1999; Expiry date: 2000.

D. HARM

Clinical scenario

You are asked to see a 73 year old patient on ITU who is being treated for a head injury after a road trafficaccident. She has osteoarthritis and was taking a regular dose of a non-steroidal anti-inflammatory prior tohospitalization. She has had a small haematemesis and, on oesophago-gastro duodenoscopy you diagnose



NSAID erosions. She has a negative CLO test for helicobacter pylori. You suggest treatment with ranitidine.Your ITU colleague recommends sucralfate as an alternative and sites evidence of lower rates of infectionwith sucralfate. You appraise the literature together.

You formulate the question “In patients on ITU is rantidine or sucralfate associated with a lower rate ofinfections?” You track down the Annals of Surgery article that she has referred to. (Annals of Surgery1998;227:120-125).

Read this article and decide,1. Are the results of this harm study valid?2. Are the results of this harm study important?3. Should these valid, important results of this study about a potentially harmful treatment change the

treatment of your patient?



COMPLETED HARM/AETIOLOGY WORKSHEET: page 1 of 2

Citation: O’Keefe GE, Gentilello LM, and Maier RV. Incidence of infectious complications associated withthe use of Histamine-2-receptor antagonists in critically ill trauma patients. Annals of Surgery 1998;227:120-125.

Are the results of this harm study valid?1. Were there clearly defined groups of

patients, similar in all importantways other than exposure to thetreatment or other cause?

Subjects were participants in anRCT. Randomization shoulddistribute all other exposuresequally. The only significantdifference between groups wasduration of ITU stay (longer forranitidine patients). Aftercontrolling for other factors onlytreatment with ranitidine wasassociated with longer stay.

2. Were treatment exposures andclinical outcomes measured thesame ways in both groups (e.g.,was the assessment of outcomeseither objective (e.g., death) orblinded to exposure)?

Yes.

3. Was the follow-up of study patientscomplete and long enough?

Yes. Up to discharge from hospital(same in both groups).

Do the results satisfy some “diagnostictests for causation”?

• Is it clear that the exposurepreceded the onset of theoutcome?

Not clear. Treatment wascommenced on admission to ITUbut some patients may haveentered ITU with infections.However randomisation shoulddistribute these cases equally inboth groups.

• Is there a dose-responsegradient?

No

• Is there positive evidencefrom a “dechallenge-rechallenge” study?

No

• Is the association consistentfrom study to study?

Not known

• Does the association makebiological sense?

Probably, given the widespreadeffects of H2 antagonists



HARM/AETIOLOGY WORKSHEET: page 2 of 2

Are the valid results from this harm study important?

Adverse Outcome TotalsPresent(Case)

Absent(Control)

Exposed tothe

Ranitidine(Cohort)

75.5%a b a+b

Treatment Sucralfate(Cohort)

c55.3%

d c+d

Totals a+c b+d a+b+c+d

In this study: Relative Risk = RR = 75.5%/55.3% = 1.36 p=0.04

NB: this differs from the RR presented in the text!!



Should these valid, potentially important results of a critical appraisal about a harmfultreatment change the treatment of your patient?1. Can the study results be extrapolated to your

patient?Yes

1. What are your patient’s risks of the adverseoutcome?

To calculate the NNH1 for any Odds Ratio (OR)and your Patient’s Expected Event Rate for thisadverse event if they were NOT exposed to thistreatment (PEER):

NNH = ___PEER (OR - 1) + 1________ PEER (OR - 1) x (1 - PEER)

If we assume our patient is like theaverage individual in this, then herAbsolute Risk Increase in infectiouscomplications whilst in hospital is75.5% - 55.3% = 20.2% = and 1/.202gives an NNH of 5.

2. What are your patient’s preferences, concernsand expectations from this treatment?

Need to be determined.

3. What alternative treatments are available?

Sucralfate is clearly one alternative.Proton pump inhibitors have notbeen investigated in this study.

Additional Notes:

The evidence favours the use of sucralfate rather than ranitidine in this situation leading us to chose to usea drug that we would not normally prescribe for NSAID induced gastric erosions.

1 The Number of Patients you Need to treat to Harm one of them.



CRITICALLY ILL TRAUMA PATIENTS - SUCRALFATE IS ASSOCIATED WITH LOWER INFECTIONRATE THAN RANITIDINE

Clinical Bottom Line(s):1. Sucralfate is associated with a lower incidence of infectious complications

than ranitidine in critically ill trauma patients2. The number of patients needed to be treated with sucralfate rather than

ranitidine to avoid one infectious complication is 5.

Citation: O’Keefe GE, Gentilello LM, and Maier RV. Incidence of infectious complications associated withthe use of Histamine-2-receptor antagonists in critically ill trauma patients. Annals of Surgery 1998;227:120-125.

Clinical Question: In critically ill trauma patients with gastric erosions are sucralfate or ranitidineassociated with fewer infectious complications?



Search terms: from our ITU colleagues desk top reprint or from MEDLINE using “sucralfate” and “infection*”

The Study: Data were extracted from a randomised controlled trial to compare sucralfate with ranitidine inthe control of stress gastritis in critically ill trauma patients. The data concerning pneumonia incidence werecollected prospectively, other infectious complications were obtained from the records retrospectively.

The Evidence

Infectious complications TotalsPresent Absent

Treated withranitidine

75.5%a b a+b

Treated withsucralfate

c55.3%

d c+d

Totals a+c b+d a+b+c+d

Relative Risk = RR = 75.5%/55.3% = 1.36 p=0.04



Comments:

1. Sucralfate is associated with fewer infectious complications than ranitidine in the treatment of critically illpatients with gastric erosions.

2. The mechanism leading to this finding is unknown but it is suggested that it may be due to the moregeneral effects on the immune system of H2 antagonism.

Appraised by W. Rosenberg 1999, Expiry date 2000.

E. SYSTEMATIC REVIEWS

Clinical scenario

You are referred a 75 year old man with longstanding ulcerative colitis who has been treated with manyrecurrent courses of oral steroids. He complains of back and hip pain. Plain X-rays show evidence ofmarked osteoporosis. He asks if there is anything he can do to help his bone problems,



You formulate the question, in a man with steroid-induced osteoporosis, does treatment withbisphosphonates reduce bone pain, fracture rate and improve bone mineral density? You search theCochrane Library using the terms “steroid” and “osteoporosis” and find the following systematic review:Bisphosphonates for steroid induced osteoporosis (CDSR 1999;issue 1)

Read the systematic review and decide,1. Is the evidence from this systematic review valid?2. Is this valid evidence from this systematic review important?3. Can you apply this valid and important evidence from this systematic review in caring for your patient?



COMPLETED SYSTEMATIC REVIEW (OF THERAPY) WORKSHEET: page 1 of 2

Citation: Homik J, Cranney A, Shea B, et al. Bisphosphonates for steroid induced osteoporosis. CDSR1999;issue 1.

Are the results of this systematic review (systematic review) of therapyvalid?Is it a systematic review ofrandomised trials of the treatmentyou’re interested in?

All trials included were ControlledTrials, randomisation was not aspecific criterion for inclusion.However a sensitivity analysis wasperformed comparing the resultsof randomised and nonrandomizedcontrolled trials and littledifference was detected(nonrandomized studiesunderestimated the effect).

Does it include a methods sectionthat describes:

finding and including all therelevant trials?

Yes

assessing their individualvalidity?

Yes

Were the results consistent fromstudy to study?

Broadly consistent results werefound. Several sensitivity analyseswere performed, formethodological differences as wellas primary vs. secondaryprevention, but no majordifferences could be detected.



Are the valid results of this systematic review important?

Translating odds ratios to NNTs. The numbers in the body of the table are the NNTs for the correspondingodds ratios at that particular patient’s expected event rate (PEER).

Odds Ratios (OR)0.9 0.85 0.8 0.75 0.7 0.65 0.6 0.55 0.5

.05 209 139 104 83 69 59 52 46 41

.10 110 73 54 43 36 31 27 24 21Control .20 61 40 30 24 20 17 14 13 11Event .30 46 30 22 18 14 12 10 9 8Rate .40 40 26 19 15 12 10 9 8 7

(CER) .50 38 25 18 14 11 9 8 7 6.70 44 28 20 16 13 10 9 7 6.90 101 64 46 34 27 22 18 15 12



SYSTEMATIC REVIEW (OF THERAPY) WORKSHEET: page 2 of 2

Can you apply this valid, important evidence from a systematic review in caring for yourpatient?Do these results apply to your patient?

Is your patient so different from those in thesystematic review that its results can’t helpyou?

no

How great would the potential benefit of therapy actually be for yourindividual patient?Method I: In the table on page 1, find theintersection of the closest odds ratio from theoverview and the CER that is closest to yourpatient’s expected event rate if they receivedthe control treatment (PEER):

In the SR the authors presentweighted mean differences in bonemineral density between treatmentand placebo groups. This is theAbsolute Risk Reduction = 4.3%NNT= 1/0.043 = 23

Method II: To calculate the NNT for any ORand PEER:

___1 - {PEER x (1 - OR)}____ NNT = (1 - PEER) x PEER x (1 - OR)Are your patient’s values and preferences satisfied by the regimen and itsconsequences?

Do your patient and you have a clearassessment of their values and preferences?

Needs to be assessed in each patientbut this patient has specifically askedwhat can be done to reduce his pain.

Are they met by this regimen and itsconsequences?

Needs to be assessed in eachpatient. It must be recognised thatthis study used bone mineral densityas a surrogate for pain and fractures.Although there is a correlation, andother studies have confirmed theefficacy of bisphosphonates inreducing fracture rates, this evidenceis not directly applicable to pain andfracture rates.



Should you believe apparent qualitative differences in the efficacy oftherapy in some subgroups of patients? Only if you can say “yes” to allof the following:1. Do they really make biologic and clinical sense?2. Is the qualitative difference both clinically (beneficial for some but useless

or harmful for others) and statistically significant?3. 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?

4. Was this one of just a few subgroup analyses carried out in this study?

Additional Notes:

This systematic review is directly applicable to the patient. The outcome measure (bone mineral density) isof very little interest to the patient who is concerned with pain and fracture rate. Although there is arelationship between BMD and pain and fractures this has been addressed in other studies that have notconcentrated on steroid induced osteoporosis. However it seems likely that if there is concordance betweenthe BMD changes in steroid and non steroid groups, then the impact of bisphosphonates on fractures andpain in the steroid group will also be the same as that seen in the non steroid induced osteoporotic patients.



STEROID INDUCED - OSTEOPOROSIS: BISPHOSPHONATES IMPROVE BONE MINERAL DENSITY

Citation: Homik J, Cranney A, Shea B, et al. Bisphosphonates for steroid induced osteoporosis. CDSR1999;issue 1.

Clinical Question: In a patient with steroid induced osteoporosis, does treatment with bisphosphonatesreduce bone pain, fracture rate and improve bone mineral density?

Search terms: “osteoporosis” and “steroids” in Cochrane Library

The Study

Systematic review of controlled trials that studied the effect of bisphosphonates on steroid inducedosteoporosis. Bone mineral density was taken as the only outcome measure.

Clinical Bottom Line:Bisphosphonates improve bone mineral density in patients with steroidinduced osteoporosis.

á CD Contents ã Contents å


The Evidence

13 trials including 842 patients

Outcomes ARR(weighted)

NNT(95% CI)

Bone mineraldensityincrease

.043 23 (17to37)

Comments

The authors state that there is a relationship between BMD, and pain and fracture rates, but emphasise thatthe results do not permit us to draw conclusions about the efficacy of bisphosphonates in preventingfractures in steroid induced osteoporosis.

Appraised by W. Rosenberg, 1999; Expiry date 2000.

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Gastroenterology and Hepatology