EBM

evidence based medicine

Practical info
• course lasts 13 classes
• various tutors
• ends the test

• Credit requirements:
• attendance of sessions
• passing test
Plan

• what is EBM?

• do we need EBM?

• a little bit of history…

• clinical questions and decision making

• evidence
EBM is the conscientious, explicit and judicious use of current best evidence in making
decisions about the care of individual patients
EBM
Clinical situation

Effective treatment

Patient’s
values and preferences
Evidence

5
Evidence
• what is the evidence?
• how to use it in my practice?
Evidence based medicine

the way to practice medicine …

and not ’the art of reading medical papers’

EBM
Clinical situation

Effective treatment

Patient’s
values and preferences
Evidence

8
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 WHO 03.2020

Lombardy Section of the Italian Society

of Infectious and Tropical Diseases 03.2020

PTEiLChZ
03.2020
Hydroxychloroquine or chloroquine with or without a ŻWx W ©rossMark

macrolide for treatment of COVID-19: a multinational

registry analysis
Mandeep R Mehra, Sapan S Desai, Frank Ruschitzka, Amit N Patel

Summary
Background Hydroxychloroquine or chloroquine, often in combination with a second-generation macrolide, are being Published Online

widely used for treatment of COVID-19, despite no conclusive evidence of their benefit. Although generally safe when May 22, 2020
https://doi.org/f10.1016/
used for approved indications such as autoimmune disease or malaria, the safety and benefit of these treatment $0140-6736(20)31180-6
regimens are poorly evaluated in COVID-19.
See Onlinef/Comment
https://doi.org/10.1016/
Methods We did a multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a $0140-6736(20)31174-0
macrolide for treatment of COVID-19. The registry comprised data from 671 hospitals in six continents. We included Brigham and Women's Hospital
patients hospitalised between Dec 20, 2019, and April 14, 2020, with a positive laboratory finding for SARS-CoV-2. Heart and Vascular Center and
Harvard Medical School,
Patients who received one of the treatments of interest within 48 h of diagnosis were included in one of four treatment
Boston, MA, USA
groups (chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a (Prof M R Mehra MD);
macrolide), and patients who received none of these treatments formed the control group. Patients for whom one of Surgisphere Corporation,
the treatments of interest was initiated more than 48 h after diagnosis or while they were on mechanical ventilation, Chicago, IL, USA (5 5 Desai MD);
University Heart Center,
as well as patients who received remdesivir, were excluded. The main outcomes of interest were in-hospital mortality
University Hospital Zurich,
and the occurrence of de-novo ventricular arrhythmias (non-sustained or sustained ventricular tachycardia or Zurich, $witzerland
ventricular fibrillation). (Prof F Ruschitzka MD);
Department of Biomedical
Engineering, University
Findings 96032 patients (mean age 53-8 years, 46-3% women) with COVID-19 were hospitalised during the study
of Utah, Salt Lake City, UT, USA
period and met the inclusion criteria. Of these, 14888 patients were in the treatment groups (1868 received (A N Patel MD); and HCA
chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received Research Institute, Nashville,

hydroxychloroquine with a macrolide) and 81144 patients were in the control group. 10698 (11-1%) patients died in TN, USA (A N Patel)
hospital. After controlling for multiple confounding factors (age, sex, race or ethnicity, body-mass index, underlying Correspondence to:
Prof Mandeep R Mehra, Brigham
cardiovascular disease and its risk factors, diabetes, underlying lung disease, smoking, immunosuppressed condition,
and Women's Hospital Heart and
and baseline disease severity), when compared with mortality in the control group (9-3%), hydroxychloroquine Vascular Center and Harvard
(18 -0%; hazard ratio 1-335, 95% CI 1-223—1-457), hydroxychloroquine with a macrolide (23 - 8%; 1-447, 1-368—1-531), Medical 5chool, Boston,
chloroquine (16 -4%; 1-365, 1-218—1-531), and chloroquine with a macrolide (22. 2%; 1-368, 1-273-1-469) were each MA 02115, USA
mmehrafóbwh.harvard.edu
independently associated with an increased risk of in-hospital mortality. Compared with the control group (0-3%),
hydroxychloroquine (6- 1%; 2-369, 1-935-2-900), hydroxychloroquine with a macrolide (8 - 1%; 5-106, 4. 106—5.-983),
chloroquine (4-3%; 3-561, 2-760-4-596), and chloroquine with a macrolide (6-5%; 4-011, 3-344—4-812) were
independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation.
 Homeopathy
• using „the spirit-like medicinal powers of the crude substances"
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MY NECBI FILTERS [47 5,980 results

RESULTS BY YEAR LC] Effectiveness and cost-effectiveness of treatment with additional enrollment to a
1 homeopathic integrated care contract in Germany.
e” ! Cite Kass B, lcke K, Witt CM, Reinhold T.
| | BMC Health Serv Res. 2020 Sep 15;20(1):872. doi: 10.1186/s12913-020-05706-4.
| Share pyID:32933511 _ Free article.
| | , BACKGROUND: A number of German statutory health insurance companies are offering integrated care
O EEE O contracts for homeopathy (ICCHs) that cover the reimbursement of homeopathic treatment. ...The
primary effectiveness outcomes after six months were statistically significant in ...

TEXT AWAILABILITY

[| Mercurius solubilis as Genus Epidemicus for the COVID-19 Pandemic.

[] Abstract 2 Vaishampayan 5, Mutreja K, Lambe $, Shah J, Shaikh G.
[J Free full text Cite _ Homeopathy. 2020 Sep 15. doi: 10.1055/5-0040-1716336. Online ahead of print.
PMID: 32932537 No abstract available.
[1] Full text Share

ARTICLE ATTRIBUTE
[| Whole Medical Systems the Rehabilitation Setting (Traditional Chinese Medicine,
['] Associated data 3 - Ayurvedic Medicine, Homeopathy, Naturopathy).
Drake DF, Norman DK.
ARTICLE TYPE Cite
Phys Med Rehabil Clin N Am. 2020 Nov:31(4):553-561. doi: 10.1016/].pmr.2020.07.009. Epub 2020 Sep 9.
[|] Books and Documents Share pyID: 32981578 _ Review.
o. , Many of these re-emerging modalities had their origins in traditional Chinese medicine, ayurvedic
[J Clinical Trial e
medicine, homeopathy, or naturopathy. ...
[| Meta-Analysis

[] Randomized Controlled [] The Need for Multidisciplinary Research within the History and Theory of
Trial 4 Homeopathy.
FP] mo ELkhroc-a4 JIRA EEE
Mercurius solubilis as Genus Epidemicus for the COVID-19
Pandemic
Shailendra Vaishampayan, Kirti Mutreja, Sunil Lambe, Jawahar Shah, Gulnaaz Shaikh

» Author Affiliations

» Further Information

Abstract Full Text References

> Buy Article » Permissions and Reprints

we are writing this letter to propose Mercurius solubilis as genus epidemicus for
the current coronavirus disease 2019 (COVID-19) pandemic.

From mid-June to mid-July 2020, our team of homeopathic doctors treated 104
patients in two COVID treatment centers—Pandit Bhimsen Joshi Hospital and
Sheth P.V. Doshi Hospital—on the outskirts of Mumbai, India, with adjuwant
homeopathy. It was observed by the patients, hospital staff, and the management
that those patients an adjuvant homeopathy were discharged 3 to 7 days earlier
than other comparable patients in the same wards, allowing us gradually to
accommodate more severely ill patients who required oxygen, continuous positive
airway pressure, or a wentilator. 1Q|

Twenty-five different homeopathic medicines in total were prescribed to the

patients, each receiving individualized treatment according to his or her
symptoms. After collecting 143 clinical and individualizing (homeopathic) symptoms of 104 patients and
converting those symptoms into rubrics, we repertorized the combined data with the help of the software
Hompath, with an aim to arrive at a genus epidemicus. We observed that the medicine Merc Sol was at the top
of the combined repertarization chart. After reviewing repertory sheets of all 104 patients, we discowered that
Merc Sol was at the fourth or fifth place of all individual repertorization charts as well.

To substantiate our deduction, we studied the Materia Medica of Merc Sol fram the original prowings of
Hahnemann[1] and other sourcebooks.[2] [2] [4] We also searched research articles and case studies about
toxicological effects of mercury.[5] [6] [7] [8] These showed that acute exposure to mercury produces an acute
respiratory distress syndrome-like presentation, a picture similar to the COVID symptomatology. Moreover,
anosmia, aphthae, gastrointestinal and ocular manifestations that are seen in patients with COVID-19 were
produced also by mercury the toxin and mercury the homeopathy-proved medicine. This finding is in
accordance with the homeopathic Law of Similars: a substance producing a symptom in a healthy person is able
to cure a similar symptom in a sick person.

To confirm our hypothesis, we identified 13 common symptoms of Merc 50l, such as indented tongue,
saliwation, perspiration, and night aggrawation, which were present in variaus intensities in the previously
treated 104 patients. We created a 13-point questionnaire and, after obtaining suitable Ethics Committee
approwal and individual informed consent from the patients, we evaluated 68 further patients in the above-
mentioned COVID hospitals. People with at least eight confirmed symptoms from the questionnaire were
prescribed Merc Sol 200c thrice a day for a week. In our 2-week study at both the locations, we observed a
speedy recovery and a hospital stay reduction by 5 to 7 days in all the 68 patients when Merc Sol was used
along with the standard Indian Council of Medical Research clinical protocol. Many of them were not newly
admitted patients but were those who exceeded the mandatory minimum hospital stay. We are now using Merc
Sal as a preventive medicine for over 1,000 people in a COVID hot-spot area in Powai, Mumbai, with the
expressed permission of local authorities.

Following the Hahnemannian method of arriving at a genus epidemicus [9] (5 99-103), and deducing it from
the combined data of symptoms of more than 100 patients, we arrived at the conclusion that Merc Sol, "the
deceitful malefic mercury” known for various symptomatic presentations and tissue destruction, is genus
epidemicus of this pandemic. Qur efforts are in accordance with the logic of homeopathy proffered by Dr. Stuart
Close[10]: exact observation, correct interpretation, rational explanation, and scientific construction.

'We now appeal to the global homeopathy community to test our findings in their respective areas, designing
specific research projects to explore the utility of Mercurius sofubilis in the COVID-19 pandemic as genus
epidemicus.
Mercurius solubilis as Genus Epidemicus for the COVID-19
Pandemic
Shailendra Vaishampayan, Kirti Mutreja, Sunil Lambe, Jawahar Shah, Gulnaaz Shaikh

» Author Affiliations

» Further Information

Abstract Full Text References

> Buy Article » Permissions and Reprints

we are writing this letter to propose Mercurius solubilis as genus epidemicus for
the current coronavirus disease 2019 (COVID-19) pandemic.

From mid-June to mid-July 2020, our team of homeopathic doctors treated 104
patients in two COVID treatment centers—Pandit Bhimsen Joshi Hospital and
Sheth P.V. Doshi Hospital—on the outskirts of Mumbai, India, with adjuwant
homeopathy. It was observed by the patients, hospital staff, and the management
that those patients an adjuvant homeopathy were discharged 3 to 7 days earlier
than other comparable patients in the same wards, allowing us gradually to
accommodate more severely ill patients who required oxygen, continuous positive
airway pressure, or a wentilator. 1Q|

rwenty-five different homeopathic medicines in total were prescribed to the

patients, each receiving individualized treatment according to his or her
symptoms. After collecting 143 clinical and individualizing (homeopathic) symptoms of 104 patients and
converting those symptoms into rubrics, we repertorized the combined data with the help of the software
Hompath, with an aim to arrive at a genus epidemicus. We observed that the medicine Merc Sol was at the top
of the combined repertarization chart. After reviewing repertory sheets of all 104 patients, we discowered that
Merc Sol was at the fourth or fifth place of all individual repertorization charts as well.

To substantiate our deduction, we studied the Materia Medica of Merc Sol fram the original prowings of
Hańnemann[1T and other sourcebOOK=:|2] 141 [4] WE also searched TesearCh articles and case studies about
toxicological effects of mercury.[5] [6] [7] [8] These showed that acute exposure to mercury produces an acute
respiratory distress syndrome-like presentation, a picture similar to the COVID symptomatology. Moreover,
anosmia, aphthae, gastrointestinal and ocular manifestations that are seen in patients with COVID-19 were
produced also by mercury the toxin and mercury the homeopathy-proved medicine. This finding is in
accordance with the homeopathic Law of Similars: a substance producing a symptom in a healthy person is able
to cure a similar symptom in a sick person.

To confirm our hypothesis, we identified 13 common symptoms of Merc 50l, such as indented tongue,
saliwation, perspiration, and night aggrawation, which were present in variaus intensities in the previously
treated 104 patients. We created a 13-point questionnaire and, after obtaining suitable Ethics Committee
approwal and individual informed consent from the patients, we evaluated 68 further patients in the above-
mentioned COVID hospitals. People with at least eight confirmed symptoms from the questionnaire were
prescribed Merc Sol 200c thrice a day for a week. In our 2-week study at both the locations, we observed a
speedy recovery and a hospital stay reduction by 5 to 7 days in all the 68 patients when Merc Sol was used
along with the standard Indian Council of Medical Research clinical protocol. Many of them were not newly
admitted patients but were those who exceeded the mandatory minimum hospital stay. We are now using Merc
Sal as a preventive medicine for over 1,000 people in a COVID hot-spot area in Powai, Mumbai, with the
expressed permission of local authorities.

Following the Hahnemannian method of arriving at a genus epidemicus [9] (5 99-103), and deducing it from
the combined data of symptoms of more than 100 patients, we arrived at the conclusion that Merc Sol, "the
deceitful malefic mercury” known for various symptomatic presentations and tissue destruction, is genus
epidemicus of this pandemic. Qur efforts are in accordance with the logic of homeopathy proffered by Dr. Stuart
Close[10]: exact observation, correct interpretation, rational explanation, and scientific construction.

'We now appeal to the global homeopathy community to test our findings in their respective areas, designing
specific research projects to explore the utility of Mercurius sofubilis in the COVID-19 pandemic as genus
epidemicus.
What % of France population use
homeopathic drugs?
Piolot M. et al. Homeopathy in France in 2011-2012 according to
reimbursements in the French national health insurance database
(SNIIRAM). Fam Pract. 2015; 32: 442-8
• „A total of 6,705,420 patients received at least one reimbursement
for a homeopathic preparation during the 12-month period, i.e.
10.2% of the overall population…”

• „A total of 120,110 healthcare professionals (HCPs) prescribed at least

one homeopathic drug or preparation. They represented 43.5% of the
overall population of HCPs, nearly 95% of general practitioners…”

• ???!!!!!!!!!!
 Steinsbekk A et al. Patients’ assessments of the effectiveness of
homeopathic care in Norway: A prospective observational multicentre
outcome study. Homeopathy 2005; 94: 10–16
Objective: To evaluate the patient reported effects of homeopathic care 6 months after
first consultations.
Methods: Prospective uncontrolled observational multicentre outcome study. All patients visiting 80 homeopaths
all over Norway for the first time in eight different time periods from 1996 to 1998 were approached. Patients
wrote down their main complaint and scored its impact on daily living on a 100 mm Visual Analogue Scale
(VAS) at the first consultation. Six months later they were asked to score again. The homeopaths recorded
treatments given for up to two follow-up consultations.
Main outcome measure: Predefined as a reduction of at least 10 mm in the VAS score between the first
consultation and follow-up.
Result: Patients 1097 were recruited, 654 completed the follow-up questionnaire. The main complaint improved
by at least 10 mm on the VAS for 71% (95% confidence interval 67–74%) of patients. The average reduction was
32 mm (95% CI 30–35 mm). Fifty-one per cent (95% CI 48–55%) of the patients had an improvement in their
general well being of more than 10 mm. The mean reduction in the whole group was 14 mm (95% CI 12–16
mm). The proportion of patients using conventional medication reduced from 39% to 16%. Regression
analysis showed that lower age and higher baseline score were predictors of better outcome.
Conclusion: In this study, seven out of ten patients visiting a Norwegian homeopath reported a meaningful
improvement in their main complaint 6 months after the initial consultation.
Clinical questions
Everydays phycisian’s practice

= knowledge of asking clinical questions

.......and answering them

21
67 years old male with severe COPD

• with pronounced resting dyspnoe

• using home oxygen therapy due to chronić respiratory
insufficiency
• with CO2 retention (pCO2 ca. 70-75 mmHg)

Real life question: does this patient needs chronic non-

invasive ventilation?

22
What you are going to do?

23
→ clinical question
Does patient with COPD needs mechanical ventilation? →

Does patient with stable COPD and respiratory failure with hypercapnia needs
mechanical ventilation? →

Does patient with stable COPD and respiratory failure with hypercapnia needs prolonged
non-invasive mechanical ventilation?

In patient with stable COPD and respiratory failure with hypercapnia ------is prolonged non-
invasive mechanical ventilation effective ------compared with usual care?

In patients with stable COPD and respiratory failure with hypercapnia ----does prolonged
non-invasive mechanical ventilation ----improves survival ----compared with usual care?
Asking a clinical question.
• Every clinical question should include description of population,
intervention (comparison), and outcome measures.

•Population
•Intervention
•Comparison
•Outcome
25
What you are going to do?

search the textbook→ no information

26
What you are going to do?

Look at the guidelines (GOLD)→ method mentioned,

no clear recomendations

27
What you are going to do?

search for relevant studies…

28
29
Lancet Respir Med. 2014; 2: 698 –705

30
Evidence based medicine

the way to practice medicine …

and not ’the art of reading medical papers’

Is the evidence of efficacy enough?

• 40 year old woman, with metastatic cancer of the stomach. Unable to eat. Would you
expect to introduce a feeding tube?

• The same woman. Few weeks later. Feeding tube in the stomach blocked. Only way to put a
feeding tube is through the abdominal wall directly to bowel. Would you expect it / suggest
it?

• Few weeks later. All feeding tubes blocked. Patient in constant discomfort. The only way to
feed is intravenously. Would you expect it / suggest it?

• Few weeks later. Unable to swallow. In severe pain. Aspiration. The way to prolong life is to
use breathing machine Would you expect it/suggest it?

• Few weeks later. On respirator. Sedated due to constant severe discomfort. No urine
output. The only way to prolong life is to use dialysis. Would you expect/suggest it?

• Few weeks later. Unable to maintain blood pressure. About to have cardiac arrest. Would
you expect resuscitation (CPR, electric shocks) if she has cardiac arrest?

32
EBM  statistics

33
 OLD PARADIGM: ASSUMPTIONS

• Clinical experience = Valid way to gain information

• Physiologic principles adequate guide for clinical practice.

• Ability to assess evidence is acquired through usual medical

training and common sense.

• Experts crucial.

• There is always ‘best way’.

34
Lags in knowledge transfer…
• from RCTs to clinic
case 1…in the ambulance…
• 56 male, report burning retrosternal pain + dyspnea + normal SpO2
• you order ECG →features of acute MI

Question
• Should the patient receive oxygen (2-3 l/min) during transport to the
hospital?
Clinical case
AVOID Study
Abstract
Background—0Oxygen is commonly administered to patients with ST-elevation myocardial
infarction (5TEMI) despite previous studies suggesting a possible increase in myocardial
injury due to coronary wasoconstriction and helghtened oxidative stress.

Methods and Resulfts—VVe conducted a muliicenter, prospective, randomized, controlled

trial comparing oxygen (8 L/min) with no supplemental oxygen in patients with STEMI
diagnosed on paramedic 12-lead electrocardiogram. Of 635 patlents randomized, 441 were
confirmed STEMI patients who underwent primary endpolnt analysis. The primary endpolnt
was myocardial infarct size as assessed by cardiac enzymes, troponin (cTnl) and creatine
kinase (CK). secondary endpolnts included recurrent myocardial infarction, cardiac
arrhytnmia and myocardial infarct size assessed by cardiac magnetic resonance (GMR)
imaging at 6 months. Mean peak troponin was similar in the oxygen and no oxygen groups
(57.4 mcegi/L vs. 46.0 mceg/L; ratio, 1.20; 95% confidence interval [CI], 0.92 to 1.56; P=0.18).
There was a significant increase In mean peak CK in the oxygen group compared to the no
oxygen group (1948 U/L vs. 1543 U/L; means ratio, 1.27, 95% GI, 1.04 to 1.52, P= 0.01).
There was an increase in the rate of recurrent myocardial infarction in the oxygen group
compared to the no oxygen group (5.5%ov5.0.9%, P=0.006) and an increase in frequency of
cardiac arrhnythmia (40.4% vs. 31.4%, P=0.05). At 6-months the oxygen group had an
increase In myocardial infarct size on CMR (n=139; 20.3 grams vs. 13.1 grams; P=0.04).

Supplemental oxygen therapy in patients with STEMI but without hypoxia

EJ ALNGNZEEIERSZ A) ZO GZTGJ EIU AEWA CEC CZTEREM GEEIOEMIELEJFA:J
assessed at six months.

Clinical Trial Registration Information—clinicaltrials.gov. Identifier. NCT01272713.

Downloaded from http://thorax.bmj.com/ on July 11, 2017 - Published by group.bmj.com

BTS guideline

BTS guideline for oxygen use in adults in healthcare

and emergency settings
B R O'Driscoll,'* L S Howard,” J Earis," V Mak,” on behalf of the British Thoracic
Society Emergency Oxygen Guideline Group

Additional comments

Myocardial infarction and acute coronary Most patients with acute coronary artery syndromes are not hypoxaemic and the benefits/
syndromes harms of oxygen therapy are unknown in such cases. Unnecessary use of high concentration
oxygen may increase infarct size.
Stroke Most patients with stroke are not hypoxaemic. Oxygen therapy may be harmful for
non-hypoxaemic patients with mild—moderate strokes.
British Thoracic Society Guidelines
 Front Cardiovasc Med. 2018; 5: 114. PMCID: PMC6120988
Published online 2016 Aug 28. doi: 10.3389/fcvm.2018.00114 PMID: 30211171

Supplemental Oxygen Protects Heart Against Acute Myocardial Infarction

Anjali M. Prabhat,! M. Lakshmi Kuppusamy, 1* Shan K. Naidu,* Sarath Meduru.* Praneeth T. Reddy,”

DO|Ą| SEAOIPJEŚ) JUOJĄ

Abishai Dominic.” Mahmood Khan.*-* Brian K. Rivera * and Periannan Kuppusamy! z

+ Author information + Article notes + Copyright and License information Disclaimer

Abstract Go to:

Myvocardial infarction (MI), which occurs often due to acute ischemia followed by reflow. 1s associated
with irreversible loss (death) of cardiomyocytes. If left untreated. MI will lead to progressive loss of viable
cardiomyocytes, deterioration of cardiac function, and congestive heart failure. While supplemental oxygen
therapy has long been in practice to treat acute MI, there has not been a clear scientific basis for the
observed beneficial effects. Further, there 1s no rationale for the amount or duration of administration of
supplemental oxygenation for effective therapy. The goal of the present study was to determine an
optimum oxygenation protocol that can be clinically applicable for treating acute MI. Using EPR oximetry,
we studied the effect of exposure to supplemental oxygen cycling (OxCv) administered by inhalatton of
21—1007% oxygen for brief periods (15—90 min), daily for 5 days, using a rat model of acute MI.
Myocardial oxygen tension (pO7), cardiac function and pro-survival'apoptotic signaling molecules were
used as markers of treatment outcome. OxCyv resulted in a significant reduction of infarct size and
J8|N OSBAOIPIEX) JUOJ4

improvement of cardiac function. An optimal condition of 30-min OxCy with 957% oxygen © 5% CO7
under normobaric conditions was found to be effective for cardioprotection.

Keywords: supplemental oxygen, oxygen cycling, myocardial infarction, ischemia-reperfusion injury.

oximetry
Thrombolytic therapy in MI
Textbooks/Guidelines
Cumulative

Not mentioned
Year RCTs N 0,5 1,0 2,0

experimental
sometimes
1960 1 23

routine
2 65
1965 3 149 21
5
4 316
1970 1 10
7 1793
1 2
10 2544
11 2651 P <.01 2 8
15 3311
17 3929 7
22 5452
8
23 5767 1 12
1980
27 6125 M 1 8 4
30 6346 P <.001
1985 M 1 7 3
33 6571
43 21 059 M 5 2 2 1
54 22 051 P <.00001
65 47 185 M 15 8 1
67 47 531 M 6 1
1990 70 48 154
Odds Ratio (Log Scale)
Drug better Placebo better 43
 DELAY IN IMPLEMENTING STRONG EVIDENCE
Can J Cardiol 1999;11:1259.

• Prophylactic interventions in patients undergoing peripheral vascular surgery

• Antiplatelet treatment - 38%

• Beta-Blockers - 20%

• Cholesterol lowering treatment - 16%

• According to the authors less than 50% of eligible patients were receiving
beneficial treatments

44
history…
46
CAST Study

• enkainid, flekainid vs placebo

47
48
49
Course aims (alternative version :)
• where to find medical information

• how to search

• how to judge its appropriate

• how to assess its quality

• how to use it to decision making

Evidence [data • facts • observations]
Assessment of validity
Laparoscopic resection of esophageal cancer

• One patient operated and dies in the peri-operative period.

Surgeon is upset.
• case-report
• why did this patient die?
• Five patients operated. After six months 80% is dead (4/5).
Surgeon is worried?
• case-series
• why did these patients die?
• Factors influencing the outcome, yet not dependent on the subject of
interest = confounders

51
Case series
• 1981 (33 years ago)
• NEJM
• 11 men with pneumonia caused by Pneumocystis carinii

52
Case-controlled study

53
Evidence [data • facts • observations]
Assessment of validity
• 10 patients operated laparoscopically, after 6 months 30% dead.
• Compared with another similar 10 patients operated by the same surgeon
using open surgery during previous year (40% mortality)
• case-control study with historical control
• Are patients identical? Is their care the same?
• Factors influencing the outcome, yet not dependent on the subject of
interest = confounders
• Imbalance of confounders = results systematically different from the truth
(not valid, biased)
Cross-sectional study

55
Cohort study
• P: 34 439 British physicians
• I: smoking
• C: no smoking
• O: death

choice
chance

time
56
Evidence [data • facts • observations]
Assessment of validity

• Cohort study with concurrent control

• Are patients comparable?

• Is their treatment, except intervention under study, the same?

(co-interventions)

• Imbalance of factors influencing outcome but not related to the factor under study =
imbalance of confounders → results systematically different from the truth (not valid,
biased)

• Different hospitals, different ICUs, different physicians… outcome studies)

• Main source of prognostic data

57
Cohort study
• P: 34 439 British physicians
• I: smoking
• C: no smoking
• O: death

choice
chance

time
58
Doll et al.: Mortality in relation to smoking: 40 years' observations on male British doctors. BMJ 1994;
309: 901-911

survivors
Never smoked
[%] 100 regularly
Currently
80 smoking 80%

60 59%
7.5 years

40
33%

20
12%
0
35 40 55 70 85 100 age [years]
59
Observational studies

Descriptive
- case report
- case series

Analytical (control group)

- cross-sectional
- cohort
- case-control
Evidence [data • facts • observations]
Assessment of validity

• How to get a comparable control group?

• Achieve a situation where comparable groups are, before treatment, similar

(identical) in respect to confounders

• Achieve a situation where getting or not getting treatment depends only on chance

• Achieve a situation where each patient entering the experiment has the same
probability to enter experimental or control group as any other patient entering
study (definition of randomization).

61
Randomized controlled trial (RCT)
Cohort study

Independent of
investigator,
Patient decision,
chance
RCT

randomization

time 62
Methods
• randomized vs quasi-randomized vs non-RCT

• Randomization was performed after obtaining patient consent to enter the

study with the use of central computer…physician do not know allocation
of patients
(concealed randomization)
• Allocation concealment - A technique used to prevent selection bias by
concealing the allocation sequence from those assigning participants to
intervention groups, until the moment of assignment. Allocation
concealment prevents researchers from (unconsciously or otherwise)
influencing which participants are assigned to a given intervention group

63
Methods
randomization

• Goal: comparable groups should be similar in respect to prognostic

factors

• Mechanism: each patient entering the experiment has the same

probability to enter experimental or control group as any other
patient entering study

64
Methodology of RCT – real life …..
randomization
• Patients with cholecystitis. RCT comparing open vs. laparoscopic technique. It is
difficult to organize laparoscopic surgery at night.

• Randomization code in envelopes. Patient admitted at night → checking the

envelopes → if open surgery, patient in, if laparoscopic → patient out or a new
envelop

• In effect, most (all) patient admitted at night got into ‘open’ group.
• Are patients admitted at night similar to those admitted during the day?
• Are surgeons the same?
• How could it influence the results?

65
Methods
• open
• single-blind
• double-blind

• placebo controlled
• controlled with treatment (effective? proven?)

66
Who can be ‘blinded’:

• person entering the patient to the study

• patient
• clinician
• outcome assessor
• person analyzing data
• author of manuscript
 Placebo
• Power of placebo

• Placebo effect – effect associated with the knowledge of getting an ‘effective’

intervention

• Placebo effect is superimposed on the natural history of a disease

• Placebo effect – double blinding

68
RCT methods
Concealed randomization

• Review of 250 RCTs

• Studies with concealed randomization had systematically lower effect

size (1/4 to 1/2)

• Double-blind vs. non-double-blind studies had systematically lower

effect size (1/5)
69
Methods
Bisoprolol In High-risk Surgical Patients NEJM 1999;341:1789
Intent to treat analysis
Treatment 100 20 non-tolerant
patients

80 tolerant

R “per protocol”
comparison

“intention to treat”
comparison
Control 100 patients
70
Methods
completeness of follow-up
20 status
100 unknown
Surgery patients
80 status known,
5% mortality

R
“comparing those
who are followed

mortality?
Medical Tx
100 patients
10% mortality
71
Outcomes
Outcomes
• objective vs subjective

• clinically important vs surrogate

• main vs additional

73
Quality of life
• general vs disease specific instruments

• validity → test measures what it should measure

• reliability → consistent results in similar subjects, and across time in
the same subjects
• sensitivity → to detect a change

• minimal clinically important difference

74
Methodology of clinical trials

Was exposure decided by the clinician?

Yes No

experimental study Observational study

75
Methodology of clinical trials
Experimental study

Was there randomization?

yes no

RCT Quasi-randomized

76
Methodology of clinical trials
Observational study

Was there a control group?

no yes

descriptive analytical

case report Cohort

case series Case-control

Cross-sectional 77
questions, comments?

→ filipmejza@mp.pl