CLIN EP 2 • CLINICAL EPIDEMIOLOGY II

APPLYING RESULTS OF STUDIES OF SHIFT

THERAPY 1
Ida Marie Tabangay-Lim, MD September 6, 2021

● What advice will you give?

LECTURE OUTLINE
○ Problem of the patient: Hypertensive and elevated
I. Clinical Decision Making E. Cohort Study cholesterol
A. Overview F. Crossover Design ○ These problems can put her at risk of cardiac events
B. Decision Making in IV. Clinical Appraisal such as MI and Acute Coronary syndrome
Medicine Parameters
II. Search and Select A. Relevance
III. Study Design B. Validity Guides 1. MAIN ISSUE: MAKING CHOICES
A. Non-Inferiority C. Importance ● Diagnosis
B. Randomized Control D. Applicability ○ Should I request for a laboratory examination or treat
Trial V. References
C. Case-control Study VI.
D. Cross-sectional Survey VII.
Review Questions
Freedom Wall
■ 📑
right away?
Determined in the diagnostic diagnosis
bar/spectrum
VIII. Appendix – Has a lot to do with the lower or low diagnostic

👉 📕 📑
threshold and the upper or treatment threshold
➝ Have you reached the upper threshold and
important/must know book previous trans thus do you treat right away?
➝ Have you reached your lower threshold
and thus no test needs to be done?
I. CLINICAL DECISION MAKING
○ Between two diagnostic alternatives, which one should I

📑 AN OVERVIEW
request?
A. ● Treatment
● Formulate the clinical question ○ Should I start treatment or observe first?
● Search the available literature ○ Between two or more interventions, which one should I
○ Select one based on the guidelines and knowledge
previously learned in making treatment decisions 👉 prescribe?
IMPORTANT: Right now in the COVID pandemic, patients ask
which vaccine is better, some wait for literature to know the more
● Analyze the chosen article on its validity, relevance,
importance and applicability effective vaccine rather than getting what is available.
● Find a resolution to the patient’s problem
2. DECISION-MAKING IN THE OLD PARADIGM
B. DECISION-MAKING IN MEDICINE ● Experts
● 📑 Knowing the patient’s true state is often unnecessary and
maybe impossible
○
○
Have a lot of experience in managing a disease
Established a certain clinical parameter that they can
effectively treat a disease
○ Because of many variables regarding the health of your
● Pathophysiology
patient and there are so many things to consider
● Experience
○ Most of the time, it is very difficult to make decisions
● Common sense
especially when you base your decision on the patient’s
● Medical evidence
● 📑 true health
In making a diagnosis, there is a probability that our
diagnosis may be uncertain
○ Aim for the most recent and valid literature that could
answer the clinical question

● 📑
○ Because of this, treatment error is always a possibility
The need for diagnostic certainty depends in the penalty 3. 📑 DECISION-MAKING IN THE NEW PARADIGM
for being wrong ● Medical evidence
○ Example: What kind of treatment will you be proposing? ● Pathophysiology
■ The treatment could simply be a prescription for a ● Common sense
certain vitamin or, ● Experience
● Experts
👉
■ Can possibly entail an amputation or a major
surgery - the penalty for misdiagnosis in this group Sample Case (OLD PARADIGM): A 72-year-old female consults
would be greater you for hypertension and elevated cholesterol. During your discussion
○ The more severe the penalty for being wrong should be on cardiac risks, she inquires about the need to take an
the basis for more diagnostic certainty anti-cholesterol drug.
○ The less morbid, complicated and complex the treatment ● Experts
is, the less certainty of the diagnosis ○ National Cholesterol Education Program
■ Screen then intervene when necessary
Sample Case: A 72-year-old female consults you for hypertension
● Pathophysiology
and elevated cholesterol. During your discussion on cardiac risks,
○ Hypercholesterolemia promotes CAD thus cholesterol is
she inquires about the need to take an anti-cholesterol drug.
a risk factor

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 ● Experience
○ If cholesterol is elevated by laboratory examination, it
II. 📑 SEARCH AND SELECT
● With the use of MEDLINE
can be lowered by drugs ● Clinical dilemma should be translated into an answerable
● Common sense question
○ Lowering cholesterol lowers the risk of CAD ● The searched article must employ randomization and must
●
○ 📑
Medical Evidence
Journals are indexed in a very big book known as
the “Index Medicus”
report clinically important outcomes such as overall survival,
disease-free survival, and recurrence rates

■
■
This is published every so often
Have to manually look for the page and check if the
📑 Case: Your 45-year-old bank executive uncle previously diagnosed
to have peptic ulcer disease has been on omeprazole therapy for the
abstract would be useful
past 2 years. Recently he had one episode of melena accompanied
■ One can go to the library and ask to borrow a copy
by dizziness. His concern is whether his bleeding peptic ulcer can be
for a journal which may be helpful
managed by omeprazole therapy alone or would an endoscopic
● If not available, a different journal may be
treatment be more effective.
used
● Question: Among patients diagnosed with peptic ulcer
👉 Sample Case (NEW PARADIGM): A 72-year-old female consults
you for hypertension and elevated cholesterol. During your discussion
disease with upper GI bleeding (population), will the
combination of endoscopic therapy and omeprazole therapy
(intervention) be better at preventing recurrent bleeding
on cardiac risks, she inquires about the need to take an
(outcome) compared to omeprazole therapy alone?
●
○
📑
anti-cholesterol drug.
Medical Evidence
Most important criteria/basis
○ Chosen journal article: “The Effects of Endoscopic
Therapy in Patients Receiving Omeprazole for Bleeding
Ulcers with Non Bleeding Visible Vessels or Adherent
○ The follow “evidence-based medicine”
Clots”
○ What do we do in this scenario?
● Question: Among elderly patients who have elevated
■ Formulate the dilemma into an answerable
cholesterol (population), will anti-cholesterol drugs
question
(intervention) be beneficial (outcome)?
■ Conduct a systematic medical literature search
○ Chosen journal article: “Randomized trial of cholesterol
→ In a database system
lowering in 4444 patients with coronary heart disease:
■ Critically appraise the article
the Scandinavian Simvastatin Survival Study”
→ To see if there are actual clinical benefits
Batch 2023 Trans
■ Apply the results to the patient
→ If it can be applied to individual patients
→ Results may be good for an entire population III. STUDY DESIGN
but, not necessarily for your patient due to a lot
of variables A. NON-INFERIORITY
■ Evaluate the application
→ Researchers should be very careful in ● Whether a new experimental treatment is not unacceptably
accepting volunteers less efficacious than an active control treatment already in
→ Some volunteers who are sick may seek to use
join group with intervention/treatment ○ Only marginal benefit over existing treatments
→ Ethical issues ■ Will the new drug have a better effect?
→ Find out whether the patient(s) benefited ○ Assigning patients to a placebo is unethical
● Experts ○ Difficult to compute for the sample size
○ National Cholesterol Education Program ○ More complex to design, conduct, and interpret than
■ Screen then intervene when necessary typical superiority trials
● Pathophysiology ● Refer to Figure 1
○ Hypercholesterolemia promotes CAD thus cholesterol is ○ Margins for equivalence/non-inferiority
a risk factor ■ RR=1
● Experience ■ Control and treatment are the same
○ If cholesterol is elevated by laboratory examination, it ○ Superiority demonstrated
can be lowered by drugs ■ Treatment effect
● Common sense ○ Non-inferiority demonstrated
○ Lowering cholesterol also lowers the risk of CAD ■ There is a struggle in the point of equivalence
Dr. Ida’s Powerpoint Presentation ○ Equivalence demonstrated
○ Inferior

👉 Sample Case: A 72-year-old female consults you for hypertension

and elevated cholesterol. During your discussion on cardiac risks, she
■
■
The control is better
There is no improvement when the new drug is
given
inquires about the need to take an anti-cholesterol drug.
● P: 72-year-old female with hypertension and elevated
cholesterol
● I: Anti-cholesterol drug
● Outcome of Interest: Overall survival
○ The outcome of interest is usually overall survival, but
from epidemiologic studies the outcome of interest in
this case would be: lowering the risk of death
● Study design: Randomized Controlled Trial (RCT)
Dr. Ida’s Powerpoint Presentation
Figure 1. Non-inferiority Trial
Dr. Ida’s Powerpoint Presentation
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 B. RANDOMIZED CONTROL TRIAL Table 3. Cross-sectional survey
●
● 📑
The ideal and most appropriate study design
Standard design to prove effectiveness of drugs or other
forms of intervention.
ADVANTAGES DISADVANTAGES

● Cheap and simple ● Recall bias susceptibility

● Provide the best evidence of effectiveness. ● Ethically safe ● Confounders may be
● Individuals are randomly assigned (randomization) to either ● Establishes association unequally distributed
of the two or more groups at most, not causality ● Neyman bias
○ One group with intervention being tested ● Group sizes may be
○ The other group without intervention or another unequal
intervention
○ Tries to make the two groups similar for both known and
unknown factors that may affect the outcome other than E. 📑 COHORT STUDY
the intervention being tested. ● Exposure is already present at the start of the study which is
● The groups are observed forward in time and their outcomes followed by the outcome
are compared. (Prospective study) ● Prospective
● The outcome can be: ○ One group of Exposed (E) and Non-Exposed (NE) will
○ Cure of a disease, relief of symptoms, improvement of equally be followed up to determine who develops the
quality of life outcome

● 📑
○ Death or recurrence
Most appropriate study design for research which aim to
evaluate one or a combination
● Retrospective
○ Done after the development of the outcome of interest
○ Establish the exposure status

Table 1. RCT Table 4. Cohort Study

ADVANTAGES DISADVANTAGES ADVANTAGES DISADVANTAGES

● Unbiased distribution of ● Expensive: time and cost ● Ethically safe ● Controls may be difficult
confounders ● Volunteer bias ● Subjects can be to identify
● Blinding more likely ● Ethically problematic at matched ● Exposure may be linked
● Randomization times ● Can establish timing to hidden confounders
facilitates statistical ○ Surgical procedures and directionality of ● Blinding is difficult
analysis ○ Diagnostic tests events ● Randomization not
● Eligibility criteria and present

C. 📑 CASE CONTROL STUDIES outcome assessments

can be standardized
● For rare diseases, large
sample sizes or long
● Outcome first before grouping into exposure (Retrospective) ● Administratively easier ● Follow-ups are necessary
● Both exposure and risk factor are already present at the time and cheaper than RCT
of determination
● Compares patients who have a disease or outcome of
interest (cases) with patients who do not have the disease or F. 📑 CROSSOVER DESIGN
outcome (controls), and looks back to compare how ● Same comparator or control group
frequently the exposure to a risk factor is present in each ● Retrospective
group to determine the relationship between risk factor and ○ Specific study population and outcome measured at the
the disease. same time

Table 2. Case-Control Studies Table 5. Crossover Design

ADVANTAGES DISADVANTAGES ADVANTAGES DISADVANTAGES

● Quick and Cheap
● Only feasible method for
very rare disorders or
those with long lag
between exposure and
outcome
● Fewer subjects needed
than cross-sectional
studies
● Reliance on recall or
records to determine
exposure status
● Confounders
● Selection of control
groups is difficult
● Potential bias: recall,
selection ( validity
questionable)
● All subjects serve as
own controls; error
variance is reduced thus
reducing sample size is
needed
● All subjects receive
treatment (at least some
of the time)
● Statistical tests
assuming randomization
● All subjects receive
placebo or alternative
treatment at some point
● Washout period
lengthy/unknown
● Cannot be used for
treatments with
permanent effects

D. 📑 CROSS SECTIONAL SURVEY ●

can be used
Blinding can be
● Collects data to make inferences about a population of maintained
interest (universe) at one point in time
● Retrospective
Specific study population and outcome is measured at the
same time

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 1. TREATMENT DILEMMA ○ Randomization balances groups for prognostic factors
■ Eliminates over-representation of any one
● Among elderly patients who have elevated cholesterol, will
characteristic within the study groups
anti-cholesterol drugs be beneficial?
○ Rarity of disease and small sample size limits
○ Answerable with “Yes” or “No”
randomization
○ P: Elderly with elevated cholesterol
■ Clinician must rely on weaker studies but should be
○ I: Anti-cholesterol Drug
aware of its potential for errors
○ O: Overall survival or decreased cardiac risk
○ Blinding helps eliminate conscious or unconscious bias
● Pubmed search
○ Example:
○ Randomized trial of cholesterol lowering in 4444 patients
■ Case: Yes, the title, abstract, and methodology
with coronary heart disease: the Scandinavian
section stated that the study was a double-blind
Simvastatin Survival Study
randomized controlled trial
● Randomized Clinical Trial is recommended
✓ NOTE: Blinding is usually done if the outcome of interest is
○ If none, use Cohort study, if that’s the best available
subjective.
evidence that can be found
● Were all the patients who entered the trial properly accounted
for and attributed at its conclusion? Was the follow up
complete?
○ Every patient who entered trial must accounted for at its
conclusion
■ Substantial numbers “lost to follow-up” leads to
questions in validity
■ Dropout rate of >20% is declared substantial
- Assume “worst case” scenario if <20% to
determine if it affects conclusion
- Numbers lost in treatment group are bad
outcomes
- Numbers lost in control are assumed to be
cured

Figure 3. Example of Drop Out and Death Rate

Dr. Ida’s Powerpoint Presentation

■ Dropout rates may be used to challenged death rate

Figure 2. Abstract of the Clinical Scenario (Assume worst case scenario)
Dr. Ida’s Powerpoint Presentation ■ Article A:
- Control death rate becomes 19% (20%-1%)
- Treatment death rate becomes 11% (10%+1%)
IV. CLINICAL APPRAISAL
- Treatment remains beneficial (19%>11%)
■ Article B:
A. RELEVANCE - Control death rate becomes 1%
● Question: Is the objective of the article comparing - Treatment death rate becomes 2%
interventions similar to your clinical dilemma? - Treatment is no longer beneficial
○ In sample case: YES ■ Article C:
■ The objective of the study is to compare - Control death rate becomes 40%
Simvastatin, an anti-cholesterol drug with placebo. - Treatment death rate becomes 20%
○ Population of the Study (P) - Treatment remains beneficial
■ Should be similar to the characteristic of your patient ■ Article D:
○ Intervention/ Comparative Intervention/ Exposure (I) - Control death rate becomes 0%
■ Should include the therapeutic intervention you want - Treatment death rate becomes 15%
to test - Treatment is no longer beneficial
○ Outcome (O) ■ Article E:
■ One of the outcomes measure should be the goal - Control death rate becomes 4%
you and your patient wish to work for - Treatment death rate becomes 15%
- Treatment is no longer beneficial
○ When to doubt results:
B. VALIDITY GUIDES
■ When drop-out rates are greater than or equal to
● Was the assignment of patients to treatment randomized? event rates
○ Randomization and blinding ensure the study results are ■ Gross imbalance in drop-out rates between groups
not overly influenced by the investigator or patients. ■ Worst assumptions lead to opposite conclusions
○ Sufficiently large sample size assure both known and ○ Determine whether an intention to treat analysis was
unknown determinants of outcome are evenly distributed done
between treatment and control groups

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Figure 4. Example of Intention-To-Treat Analysis
Dr. Ida’s Powerpoint Presentation

● 📑 Were patients analyzed in the groups to which they

were randomized?
○ All those belonging to the control or treatment group are Figure 5. Formulas for determining results
analyzed from beginning to end in the same grouping
○
○
No crossing over treatment modalities were done
Results in an “intention-to-treat” analysis
👉 Dr. Ida’s Powerpoint Presentation
IMPORTANT: Memorize formulas in figure 5.

● When comparing the 2 groups, the outcomes are expressed

● Were patients, their clinicians, and study personnel based on the the risk in the treatment group and the risk in the

○
○
📑
“blind” to treatment?
Blinding: process by which intervention being given is
concealed from the patient, the clinicians, and the one
control group
○ Identify the risk in the treatment group before the
control group
who analyzes the data ○ If the article gives you survival rate, you may convert it to
■ Done to avoid “reporter and observer” bias the risk of death
■ Not always possible (i.e. surgical trials) ● It’s not always the death rate, it may include those who did not
- Outcomes should be checked by investigators recover, the number of complications, etc.
or adjudication committees not involved in trial ● Relative Risk (RR)
○ Example Case: Yes, the study was a double-blind ○ Always be interested in the risk in the treatment
controlled trial ○ The risk of the outcome among the treatment group
✓ NOTE: Remember to check the abstract or methodology to identify compared to the risk of the outcome in the control group
easier ● What would tell us that the treatment is better?
○ You want the risks in the treatment group to be lower
●
○ 📑
Were the groups similar at the start of the treatment?
The greater similarity between known prognostic
factors means results are more likely attributed to
✓ NOTE: If it is lower than what it used to be, the number should be <1
for the relative risk
● Relative Risk Reduction (RRR)

👉 intervention
IMPORTANT: Look for a report of the comparison of baseline. It is
often labeled as table 1.
○
○ 📑Risk in the control group is supposedly higher
Most useful measure to use in explaining the benefit

○ Example Case: Yes, table 1 of the results section showed

no major difference in the baseline characteristics
● 📑
○
of treatment to patients
Absolute Risk Reduction (ARR)
Absolute difference between the proportion who had
between the two groups deaths in the control group compared to the experimental
group
● Aside from the experimental intervention, were the ✓ NOTE: If the ARR is negative → there is an increased risk than
groups treated equally? reduction of the risk
○ Example Case: Yes, there were no planned ● How precise was the estimate of the treatment effect?
co-interventions for the two groups ○ RR of death in the Simvastatin group (control group) =

1. 📑 OVERALL VALIDITY ○
0.71
95% Confidence Interval 0.58 - .85, p = 0.0003
● If the study fails any of the above criteria, we need to decide if
the flaw is significant and threatens the validity of the study. If
this is the case, we’ll need to look for another study.
● Summary of all the validity guide questions

C. IMPORTANCE
● The results of a study on treatment is expressed in terms of
risk, relative risk, absolute risk, and relative risk
reduction
● Example: If you weighed 80 kg after the Christmas holidays,
and 60 kg after a summer diet, what would be the ways of
expressing the weight loss?
○ Relative weight (current): I am now 75% of what I used to
weigh Figure 6. Confidence Interval
○ Relative weight reduction (how much was lost): I lost Dr. Ida’s Powerpoint Presentation
25% of my weight
○ Absolute weight reduction (difference): I lost 20 kg

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 D. APPLICABILITY 4. Which part of the article should one look at to check whether
the control and experimental groups in a RCT are similar in
● Can the results be applied to my patient care?
other characteristics except for the intervention?
○ Yes. Subjects included in this study were patients with
a. Abstract
angina or MI and elevated cholesterol
b. Table 1 showing demographics and characteristics
● Were all clinically important outcomes considered?
c. Conclusion
○ Yes. The main outcomes considered were new onset MI,
d. Statistical significance of results
coronary death, and overall cause of death
● Are the likely treatment benefits worth the potential harm
5. The most important characteristic of a randomized control
and cost?
trial that makes it superior when comparing therapeutic
○ EXAMPLE:
interventions is:
○ NNT: 33 patients to prevent 1 death/save 1 life
a. All variables are expected to be distributed equally
○ 40 mg tab @ 25 PHP
b. Interventions can be standardized in both groups
■ 365 days = 18, 250 PHP
c. Blinding of research and subjects can be done
■ For 33 patients = 602, 250 PHP
d. Characteristics of either group are similar
■ For 5 years = 3 million PHP
● Are your patient’s values and preferences satisfied by the
1C, 2D, 3C, 4B, 5A
regimen and its consequences?
○ Do your patient and you have a clear assessment of your VII. FREEDOM WALL
values and preferences?
○ Are they met by this regimen and its consequences?

1. RESOLUTION
● What advice will you give to this patient?
○ A 72 year old female consults you for hypertension and
elevated cholesterol. During your discussion on cardiac
risks, she inquires about the need to take an
anti-cholesterol drug.
■ “I would rather not prescribe an anti-cholesterol drug
because the benefit is too small for the cost it will
take.”
■ OR “I will prescribe an anti-cholesterol drug because
my patient can afford the cost even if the benefit is
small.”

✓ NOTE: The patient’s social class should also be taken into

consideration when giving out medical advice.

V. REFERENCES
● Lecture and presentation slides from Dr. Ida Lim (2021)
● Critical Appraisal of an Article about Therapy or Prevention VIII. APPENDIX
Handout, UST-FMS Department of Clinical Epidemiology
● 2023 Trans
MEASURE FORMULA UNIT INTERPRETATION
VI. 📑 REVIEW QUESTIONS Risk in DeathT / NumberT % Death even when
1. What is the best study design to choose if you are looking for
Treatment (RT) taking drug
an article concerning therapeutic options?
a. Case control
Risk in Control DeathC / NumberC Death without drug
b. Cohort
(RC)
c. Randomized controlled trial
d. Cross sectional study
Relative Risk RT / RC Risk of death is now
X of what it should
2. Why is randomization important in a study comparing
be
treatment?
a. To eliminate/ minimize bias
b. To ensure that the groups would have equal chances of Relative Risk 1 - RR X reduction in death
falling under the experimental or control arm Reduction when taking drug
c. To ensure that the result/outcome is due to the (RRR)
intervention being tested and not to any confounder
d. All of the above Absolute Risk RC - RT Death is prevented
Reduction in X of patients
3. To determine if you would believe the outcome of an RCT for (ARR) taking the drug
therapy in spite of incomplete follow up, which process
should it be done? Number 1 / ARR You will have to treat
a. Intention to treat analysis Needed to X patients to prevent
b. Worse case scenario analysis Treat (NNT) 1 death
c. Both
d. Neither 👉 IMPORTANT: Memorize formulas
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