CLINICAL DECISION USINGAN ARTICLE ABOUT

HARMFUL EFFECT

The main issue is making choices:

• Diagnosis– Should I request for a laboratory examination or treat right

away?– Between two diagnostic alternatives, which one should I

request?

• Treatment– Should I start treatment or observe first?– Between two or more drugs, which one should I prescribe?

Decision Making in Medicine

Another issue is should I stop the treatment you havechosen?Should you remove the exposure?

• Treatment– Should I stop the treatment because it is causing

harm?

• Exposure– Should I modify the risk factor?– Even if it impairs with the patient’s quality of life?

Decision Making in Medicine HARM

• Harmful or adverse effects are associatedwith treatment

• Clinicians may encounter patients with anadverse outcome who had harmful exposure

RCT

• It can be studied in RCT’s by measuring sideeffects or adverse events

• Rarely done to study harmful exposuresbecause of ethical issues

• Not powered to look for side effects– Sample size computation is based on the

beneficial effect.

Cohort Study

• An alternative to RCT when it is not feasible torandomly assign patients to be exposed or notexposed to a harmful agent

• Selection of subjects starts with identifyingindividuals with or without the exposure

• Observed forward in time and determine whoamong them develop the outcome or effect

Cohort• Subjects in a cohort study select themselves (or

are selected by the investigator) for exposure tothe harmful agent, thus may not be similar to thenon-exposed persons with respect to otherimportant determinants of outcome

• “Must” - to document the characteristics of theexposed and non exposed subjects anddemonstrate their comparability or use statisticaltechniques to adjust for differences

• Susceptible to unmeasured confounders; strengthof the inference may be limited

Case-Control Study• Alternative design if the outcome is rare or takes too long to

develop such that cohort studies may not be feasible

• Inclusion of subjects starts with defining or selecting thosewho have the outcome or effect (cases)

• Compare with subjects who don’t have the outcome oreffect (control) but similar to the cases with respect toimportant determinants of outcome such as age,sex andconcurrent medical conditions

Case-Control Study• The two groups are investigated retrospectively as

to the presence or absence of hypothesizedexposure

• The investigator must ensure balance or adjust forimbalances, in important risk factors in both casesand controls

• Susceptible to unmeasured confounders; strengthof inference drawn from results may be limited

Methodologic strengths and weaknesses fordifferent study designs

Design Starting Point Assessment Strengths WeaknessesRCT Exposure status Adverse event

statusInternal validity Feasibility,

generalizability;Ethical issues

Cohort Exposure status Adverse eventstatus

Feasible whenrandomizationof exposure isnot possible

Susceptible tothreats tointernal validity

Case-control Adverse eventstatus

Exposure status Overcomestemporal delays;may only requiresmall samplesize

Susceptible tothreats tointernal validity

Design Issues for Studies on Harmfuleffects - Summary

• RCT’s would be rare• Weaker designs – Cohort or Case control• Whatever the design, there should be an appropriate control

population before making a strong inference:– For cohort, control group should be similar in baseline risk

of outcome– For case control,the derived exposed and non exposed

groups should be similar with respect to determinants ofoutcome

A 35 year old male came to your cliniccomplaining of dizziness and headache. His BPwas 150/100 and is currently taking Nifedipine 10mg three times a day. Despite this dose his BPremained uncontrolled.

What will you do, increase the dose, addanother drug or shift to another drug?

The Patient

• Pathophysiology– Hypertension is a risk factor for MI and stroke

• Common sense– Lowering BP lowers the risk of MI and stroke

• Experience– Increasing the dose of drug or combining anti-hypertensive drugs

decreases BP more effectively• Experts

– JNC Guideline gives the following alternatives:• Increase the dose or add another drug• Shift to another drug

Decision Making in the Old Paradigm

• Formulate the problem into an answerablequestion

• Conduct a systematic medical literature search• Critically appraise the medical literature• Apply the results• Evaluate the application

Decision Making in the New Paradigm

EBM practitioner–Among hypertensive patients will an

increase in the dose of Nifedipinebeyond 30 mg per day be beneficial?

The search–MEDLINE

The Clinical Question

JAMA 1995;274: 620-625

• Was there clearly defined comparisongroups?

Are the Results Valid

• Population based cases and controls• Controls met the same eligibility criteria as

the cases except for the myocardialinfarction

• Comparable ascertainment of potentialconfounding factors

Was there clearly defined comparisongroups?

YESThis was a case control study and Table

1 compared the characteristics of the twopopulation. There are some differencesin some characteristics but these wereminimal.

• Were the outcomes and exposuresmeasured in the same way in thegroups being compared?

Are the Results Valid

Key points:

• Ascertainment of theexposure is an importantelement

• Those who had the outcome morelikely to recall exposure than thecontrol group(recall bias) or bygreater probing by the interviewer(interviewer bias)

• Exposure opportunity should alsobe similar among cases andcontrols

COHORT• Ascertainment of

outcome is the keyissue

• Susceptible tosurveillance bias-physicians aware of apossible risk tend tosearch more diligentlyand therefore detectdisease that mightotherwise go unnoticed

CASE CONTROL

Were the outcomes and exposures measured inthe same way in the groups being compared?

YES The methods section stated that review of the

Group Health Cooperative (GHC) ambulatoryhmedical records was done for all patients.

Antihypertensive therapy was assessed using theGHC’s computerized pharmacy database

Although it was not practical to blind the researchersto case-control status, they were not told about thehypotheses related to specific antihypertensivetherapies to minimize bias

• Was the follow-up sufficiently longand complete?

Are the Results Valid Key points:

• Losing patients to follow up threatens validityof the results because those who are lostmay have very different outcomes from thoseavailable for assessment

• The longer the follow up, the greater thepossibility that follow up will be incomplete

Was the follow-up sufficiently long andcomplete?

YESFollow-up was done at least 30 days

onward from start of Nifedipine use

• Is the temporal relationship correct?

Are the Results Valid

Key point:

• Exposure to the harmful agent shouldprecede the outcome

Is the temporal relationship correct?

YES Nifedipine use was defined as use at least 30

days before the index date (date when outcomewas observed).

• Is there a dose response gradient?Key:• Generally, we would be more confident in

attributing an adverse outcome to anexposure if, as the quantity or duration ofexposure increase, the risk of adverseoutcome also increases

Are the Results Valid

Is there a dose response gradient?

YES Figure 2 showed increasing incidence of MI

with increasing dose of Nifedipine• The risk increased with the dose of

calcium channel blocker(even afteradjustment for potential confoundingfactors)

• How strong is the association betweenexposure and outcome?

• How precise was the estimate of therisk?

What are the Results

Key points

• Relative risk- most common way of expressing anassociation between exposure and outcome (for acohort study)

• RR = incidence of adverse effect in exposedgroup/incidence of adverse effect in unexposed

• RR > 1 represents increased risk ; RR < 1 signifiesdecreased risk

• RR is not applicable to case control studiesin which the number of cases and controlsand therefore the proportion of individualswith the outcome, is chosen by theinvestigator

• Odds ratio is used instead:odds of a case being exposed_____odds of a control patient being exposed

Estimates of Relative Risks and OddsRatios for Exposed and Unexposedpatients

ADVERSEEVENT(Case)

NO ADVERSEEVENT (Control)

EXPOSED a bNOT EXPOSED c d

Key points:

• When the study design is strong, a smallincrease in risk may be interpreted asrepresenting a true harmful effect

• In weaker designs, a much higher increase inrisk might be required as subtle findings maybe due to flaws in design

How strong is the association betweenexposure and outcome?

Dose RRLow 1.13 (0.75-1.71)Medium 1.42 (0.97-2.07)High 1.81 (1.20-2.75)

How precise was the estimate of therisk?

• Looking at the 95% confidenceinterval–It is precise with the high dose

Key points

• In a study showing association betweenexposure and adverse outcome, the lowerlimit of the estimate of relative risk associatedwith the adverse exposure provides aminimal strength of association

• In a study which fails to demonstrate anassociation,the upper boundary of theconfidence interval around the relative risktells the clinician just how big an adverseevent may still be present despite the failureto show a statistically significant association

• Are the results applicable to my patient?• YES• The characteristic of our patient fits the inclusion

criteria of the study.

Will the Results Help Me in Caring for MyPatient

Key points:Are your patients similar to those described in the study with regards tomorbidity, age , race or other potentially important factors

Are there clinically important differences in the treatments or exposuresbetween your patients and the patients studied?

• What is the magnitude of the risk?

Will the Results Help Mein Caring for My Patient

Key points

• The relative risk and odds ratio do not tell howfrequently the problem occurs- only that theobserved effect occurs more or less often in theexposed group compare d to the unexposed group.

• When the issue is harm, we may compute for thenumber of people that may be exposed to theharmful agent to cause an adverse outcome

Example:

• CAST study, 3% mortality for placebo and7.7% for encainide/flecainide

• AR = 7.7% - 3% = 4.7% increase in risk

1/AR = 1/4.7 = 21 (for every 21 patient treated withencainide/flecainide, we will cause one excessdeath)

What is the magnitude of the risk?

–2x–To develop MI when taking Nifedipine at

high dose

• Should I attempt to stop the exposure?Key points:

Three things to consider in making a clinicaldecision:

oStrength of inference - How strong was the studythat demonstrated the harm?

oWhat is the magnitude of risk to patient ifexposure to the harmful agent continues?

oWhat are the adverse consequences of reducingor eliminating exposure to the harmful agent?

Will the Results Help Me in Caring for MyPatient

Summary• In this population based Case control study, the

use of Ca channel blockers as antihypertensive Txwas consistently associated with about 60%increase in the risk ratio for MI

• The association persisted after controlling for manyrisk factors for MI -– It was consistent across multiple subgroups and was

more pronounced with higher doses

Should I attempt to stop the exposure?

• YES–Shift to another drug

A 35 year old male came to your cliniccomplaining of dizziness and headache. His BP was150/100 and is currently taking Nifedipine 10 mgthree times a day. Despite this dose his BP remaineduncontrolled.

I would rather shift the patient to another drugand investigate other factors that might lead touncontrolled BP like compliance, stress etc.

The EBM Practitioner Keep on Asking

Keep on Searching

Keep on Learning