Course Basics Flashcards
What are the percentages for Side Effects descriptions according to EU?
Very common means >10%
Common means 1-10%
Uncommon means 0.1-1%
Rare means 0.01-0.1%
Very rare means <0.01%
What are the percentages for Side Effects descriptions according to patients?
Very common means 65%
Common means 45%
Uncommon means 18%
Rare means 8%
Very rare means 2%
What’s the perception of high risk to patients?
Most think it’s between 41-50% risk (not true).
Top 5 trial design features of prospective controlled trials
- Randomized
- Double blind
- Allocation concealment
- > 80% of patients at study completion
- Valid clinic outcomes selected (important for patients and clinician)
Why is important to randomize trials?
- Because to assess the effectiveness of a treatment requires a comparison. By doing it random, it gives a more equivalent comparison between groups.
- in non-randomized comparisons, other factors may explain any differences observed (confounding)
- randomization controls for both known and unknown confounders
What is evidence-based practice?
The integration of best research evidence with clinical expertise and patient values.
Barriers to evidence-based practice
- Limited awareness/knowledge
- Limited time
- Limited amount of well designed trials in your practice area
- Lack of motivation (lack of skills/financial incentives)
- Inadequate literature searching skills
- Abundance of information
Clinical Questions (PICO)
Patient: what’s the population age, gender, condition hx..description of the most important characteristics of the patient or target disorder.
Intervention: What do you want to do for the patient? could include exposure, diagnostic test, prognostic factor, surgery, therapy or patient’s perception.
Comparator(s): Relevant alternative(s) most often considered for this type of patient. Could be the gold standards or anything else.
Outcome: clinical outcome of interest to you and your patient. Like increasing mortality (live longer) and quality of life. Goes beyond lab values.
What is the importance of good clinical questions?
- With limited amount of time, is important to ask questions that by design focus on evidence that is directly relevant to the patient’s clinical needs and our knowledge needs.
- Good questions can suggest high yield search strategies.
- Questions suggest forms that useful answers might take.
What is the best evidence for a Therapeutic Intervention?
RCT or systemic review/meta-analysis
What is the best evidence for a Rare Side Effect?
Case control study
What is the best evidence for an Exposure to a potential toxin?
Cohort study
What is the best evidence for an evaluation of a new drug by Medicare?
Pharmacoeconomic analysis
Trial Designs for Therapy Questions
- Randomized controlled trials (RCTs)
- Systemic review (SR)
- Studies
- Meta-analysis (MA)
What is a systemic review?
Process to identify, synthesize, and evaluate the available literature.
What studies are good to answer therapy questions?
Those:
1. identified according to an explicit search strategy
2. selected by defined inclusion & exclusion criteria
3. evaluated against consistent methodological standards
What are meta-analysis?
A statistical process for quantitatively estimating the net benefit/risk from the results of the included studies.
Where to find the best evidence?
- textbooks
- journals
- phone a friend
- medine
- the cochrane library
- evidence based journals (ACP journal Club, EBM)
- internet websites (drug information websites, evidence-based practice websites, therapeutic specialty websites, healthcare websites)
Hierarchy of Evidence for Therapy Studies
(From top of triangle to bottom)
Meta-analysis of RCTs
Single RCTs
Non-randomized comparative studies
Cohort studies
Case-control studies
Non-comparative studies
Case Series (open trial)
Case reports
Expert opinion
What are synopses?
- Evidence-based journal abstracts and commentaries
- Summary of reviews or individual studies
- Easy to interpret & digest
- highly efficient
- detailed information readily available
Where to find Synopses?
- infopoems
- clinical evidence online
- bandolier
- evidence-based medicine
- therapeutics initiative
- ACP journal club
How to efficiently appraise ‘usable evidence’?
- right patient population (external validity)
- study design (right for the question)
- internal validity
- results (are they meaningful and useful? outcome measure? can they be applied to my clinical question?)
What is allocation concealment?
Happens before and during randomization.
Shields those who admit patients into a trial from knowing future assignments. The equal division for gender and age groups and other similarities are distributed equally by a computer - not by a person.
What is blinding?
Not always possible.
Happens after randomization.
Three groups to consider: patient, treatment team, treatment evaluator.
Could be double blinded or triple blinded.
Why is blinding important?
For subjective outcomes.
So patient don’t do other things to improve the outcome other than the one in the study.
What is p-value?
Probability of the data, or more extreme data, occurring in the long run when there is no treatment effect.
How often this result, or one more extreme, will occur by chance alone.
What does p=0.013 mean?
1.3% chance the difference was due to just chance
What can account for the difference for the p-value in the trial?
- a true difference
- bias
- confounding factors
- random error (chance)
- all of the above
What the p-value does not tell us?
- if the difference is valid
- if the difference is clinically meaningful
- if the difference is real
- if the drug/therapy works
What is considered a statistically significant p=value?
p=0.05 (it’s arbitrary and by convention)
What is Confidence Interval?
-quantifies the uncertainty in measurement: a measure of the precession of the “effect estimate” from the study.
How is Confidence Interval usually reported as?
95% CI
In a very large number of repetitions of the study, 95% of all CIs obtained will contain the “true” value of the treatment effect in the population studied (assuming random sampling).
What studies need p-value and CI?
Those who are not studying the whole population.
What does the CI tell us?
the +/- of where the results might lay. we have a range but not an exact result.
The wider the range, the less we know for sure.
How do you decide if its clinically significant?
The magnitude of the difference - agreed before hand, and if you think it is.
Relative Risk Reduction (Relative numbers) (RRR)
Estimate of the percentage of baseline risk that is removed as a result of the new therapy. The problem with using RRR is that we cannot assess the actual effect size if the event rate in the control group is not known.
Useless unless you know the starting point. (a % of what?)
RRR Formula
(rate A - rate B) / rate A
or
ARR/rate A
ARR Formula
rate A - rate B
NNT
1/ARR
Absolute Risk Reduction (Absolute numbers) (ARR)
Risk difference.
The proportion of patients who are spared the adverse outcome as a result of having received the experimental rather than the control therapy.
Number Needed to be Treated (NNT)
The number of patients you need to treat to prevent one additional bad outcome (death, stroke, etc.)
Numbers Needed to be Harmed (NNH)
How many patients must receive a particular treatment for 1 additional patient to experience a particular adverse outcome.
When is ARR/NNT/NNH calculated?
Only when the result is statistically significant.
What is an effect size (ES)?
The magnitude of effect of a treatment.
When effect size is important?
When looking at several options for treatment on a disease.
ES Formula
(mean 1 - mean 2) / SD
SD=Standard Deviation
When it’s Odds Ratio used?
In Systematic reviews and epidemiological studies.
What is an Odds Ratio (OR)?
The likelihood of harm an exposure may cause.
OR Formula
number of events / by the number of non-events
Components of the Best Possible Medication History (BPMH)
- All current and relevant past medications (rx and non-rx), & complimentary/alternative medications (CAMs)
- List, for each item, the dose, dosage form, frequency, route, indication, level of patient adherence & info source
- Information sources: the patient, patient’s family, rx vials/packages, pharmacist/pharmacy, PharmaNet (in BC) primary care provider, & specialists.
- Assess appropriateness of therapies
- Identify and reconcile DISCREPANCIES (what
the patient is doing vs. what the care provider
believes)
How to get the best possible medication history?
- Use both open-ended questions (what, how, why, when) and yes/no questions
- Use a systematic approach to best get complete information (e.g., meds over last 24 hrs or head to toe)
- Non-judgmental approach
- Keep it simple: e.g., avoid medical jargon
- Avoid leading questions
- Explore vague responses (non-compliance)
- Prompt for specific types of medications (e.g., pain, sleep, GI, eye/ear drops, patches, creams/ ointments, inhalers)
Dosing principles
1.For the majority of conditions there is rarely a need to get an immediate result
2.For many marketed drugs, the recommended starting doses are too high
3.the placebo group response (not the placebo effect) for numerous conditions is approximately 20-40%
4.There is no reliable way to predict how a patient will respond to a drug (pharmacodynamics) or how they will eliminate a drug (pharmacokinetics)
5.Approximately 3⁄4 of side effects of drugs are dose related
Discussion with Patient about prescriptions
- there is no urgency to getting a response - find the lowest effective dose for you over the next few months
- no way to know ahead of time what dose is the “best” one for you
- the typical recommend starting doses for many medications are too high
- Starting with a 1/4 to an 1/8 of the dose - decrease the chance of side effects
5.Many conditions get better over time - “You” will determine the correct dose
- you may get better because of the drug, or tincture of time effect
Practical Suggestions to Prescribe
- Not all drugs come in dosage forms that allow small doses to be used
- The majority of tablets can be split - use a pill cutter
- Some capsules can be opened 4.Increase the interval
5.liquid form - pediatric dosage forms may be useful to start
How to dose?
If Dying (severe pain) - Give lots all at the same time - you don’t want to under-prescribe
If No hurry - start with at most a 1/2, and maybe even 1/4 to 1/8 of recommended dose.
When stopping a medication
IN THE BEGINNING when patients comes to you - until proven otherwise
Assume the drug is wrong
Assume the dose is wrong
Come up with a monitoring plan in conjunction with the patient
Cut dose in 1/2 for a week or two
Cut dose in 1/2 again for a week or two
Then stop
How to avoid drug interactions?
Using low doses. When there is an interaction, you lower the dose.
Most important Drug-Drug Interactions
From duplicate action drugs
Sedation, lower blood pressure, lower potassium
Off Label Prescribing
- Use of a prescription medication to treat a
condition Health Canada has not granted an
“indication” - A medication that is “not indicated” for a
particular use, is NOT necessarily
contraindicated for that condition - Must consider each patient’s circumstances when off label prescribing. Document your rationale and monitoring plan
Prescription Requirements
- Date
- Name and address of patient
- Name, strength, quantity and form of
drug or ingredient(s) - Directions for use (include frequency or
interval or maximum daily use) - Refill authorization (# and interval
between refills) - 0 if left blank - Name and College ID of practitioner
- Signature
Prescriber Information Pharmacy wants
- Name
- Address
- Telephone number
- College of Naturopathic Physicians
Identity Number - Imprinted on blank prescription or
personalized self-inking stamp - SIGNATURE
According to the Ontario College of Pharmacists legislation, Prescriptions need to be either:
- Written & signed
- Dictated to a pharmacist by telephone
(except straight narcotics) - Sent electronically (Faxed)
How long are prescriptions for medications active for?
Prescriptions for medications are active for 1 year from the date on the prescription (except oral contraceptives, which are 2 years)
For how long Pharmacists keep prescriptions?
for at least 2 years
Common Issues that may result in Medication Errors
*Illegible handwriting
*Use of abbreviations
*Incomplete directions
*Lack of patient information (allergies) *Lack of appropriate dosing information (decimals & trailing zeros)
Prescription Checklist
- Patient Name*
- Address*
- Age/weight (for children)
- Purpose
- Date*
- Drug Name* (Rx) (generic drug name)
- Manufacturer (if don’t want substitution or no substitution written)
- Strength* (Dosage) (mg/kg for children)
- Mitte(Send)/Quantity* (total quantity) not needed if sig says tid x 7 days
- Dosage form (for children)
- Sig(Take)/Directions* (Include frequency &
daily maximum if PRN) (bid, tid, qd….) - Prescriber Signature* (any font)
- ND ID Number*
- Prescriber address and phone #*
- Refills (can include time between refills)
Prescribing Tips
- Consider including diagnosis or purpose (if appropriate)
* helps confirm medication and provide context for consistent education - For children or those < 40 kg
* Include age or weight
* List mg/kg dose you used (pharmacist to double check and confirm dose)
* List dosage form (e.g., liquid preferred) - Use generic drug name
- If you don’t want substitution of your prescription, write the manufacturer’s name OR “Do Not Substitute”
- Specify: # of Refills and time interval between refills e.g. Repeat 3 x q 30 days
Types of Signa (Directions)
- Usually uses a standard Latin abbreviation
- Useful shorthand for physicians
- Aids pharmacists detect forged prescriptions
- Common Signa: qd, bid, tid, qid, q8h,hs,PRN, pc
- Note: PRN (alone) is not acceptable when used alone…must include specific frequency, interval or MAX DAILY DOSE and preferentially indication for use
- e.g. qHS PRN sleep
Protecting Prescription Guidelines
- Minimize number of pads in use
- Do not leave visible in office
- Store in secure place (to avoid theft)
- Consider writing amounts of desired medications numerically + alphabetically
- Never sign Rx blanks in advance
- Write Rx in ink
- Do not use Rx blanks for notes or memos which can be erased and used for forgery
When recommending a treatment for a patient, what information do you document?
- Date
- Subjective and observed symptoms
- Assessment of the patient’s problem (if known)
- Purpose and/or Goal(s) of Medication(s)/ Treatment
- Name, dose, dosage form and quantity of medication prescribed
- Monitoring plan (efficacy and safety)
- Discussion you had with patient about treatment and monitoring plan
- Did you have ‘informed consent’?
- Signature
Evidence hierarchy (best to least valuable)
- MA of RCTs (MA = Meta-analysis), Single RCT
- Non-randomized comparative studies (cohort studies, case-control studies)
- Non-comparative studies (case series- open trial)
- Case reports
- Expert opinion
Top 5 trial design features of prospective controlled trials
- RANDOMIZED
- DOUBLE BLIND
- ALLOCATION CONCEALMENT
- > 80% of pts at study completion
- Important, valid clinical outcomes selected
RANDOMIZED
Assessing the effectiveness of a treatment requires a comparison; In non-randomized comparisons, other factors may explain any differences observed (confounding); Randomization controls for both known and unknown confounders; “you want both groups to be equal/similar in terms of chance”
DOUBLE BLIND
aka masked or dummy, most important for SUBJECTIVE outcomes, Unlike allocation concealment, may not always be possible, Happens after randomization; Three main groups to consider: patient, treatment team, treatment evaluators
ALLOCATION CONCEALMENT
allocation concealment means those admitting people into trial can’t know future assignments. Triple blind means tx evaluator also doesn’t know which group person was in, Shields those who allows patients into a trial from knowing future assignments, Happens before and during randomization process
The Questions Defines the type of Research you need:
How to determine the best Therapeutic Intervention?
● RCT
● systematic review (using specific search question)
● meta-analysis (quantifies, uses smaller studies if no large available, more refined)
The Questions Defines the type of Research you need:
Rare side-effects?
● Case control study
The Questions Defines the type of Research you need:
Exposure to potential toxin?
● cohort study
T/F Statistically significant NOT the same as clinically relevant (eg. changes in HbA1c levels).
True
T/F Statistically significant NOT the same as clinically relevant (eg. changes in HbA1c levels).
True
RISK
PROBABILITY SOMETHING WILL OCCUR, commonly expressed as a decimal between 0-1
ODDS
the ration of the probability that an outcome will occur to the probability that it will not occur; commonly expressed as a ratio of two integers (ex- 0.01 = 1:100); AKA the likelihood of something happening
Odd Ratios
OR= OE/OC
OR<1 suggests that the exposure reduces the outcome
OR= 1 suggest the exposure has no effect
OR>1 suggests the exposure increases the outcome
How are the odds calculated?
Calculated by event occurring/event not occurring- usually expressed in decimals (ex 5/9995-= 0.0005)
RELATIVE RISK (AKA RISK RATIO)
the ratio of the probability of the vent occurring in the experimental group to the probability of the event occurring in the comparator group
RR> 1- outcome more like to occur in experimental group than control group
RR= 1- there is no difference in outcome between the two groups
RR <1- the outcome is less likely to occur in the experimental group than the control
Relative Risk Reduction/Increase
RRR/RRI- the percentage change in risk
RRR (Relative Risk Reduction)
the difference in risk of developing an outcome between the control and experimental group expressed as a proportion of the risk in the control group- RRR= (CR-ER)/CR
RRI (relative risk increase)
the difference in risk of developing an outcome between the control and experimental group expressed as a proportion of the risk in the experimental group- RRI= (ER-CR)/ER
NNT/NNH (Numbers needed to treat/numbers needed to harm)
1/ARR (keep the ARR in its decimal form not % if using this); otherwise its 100/the percentage
Confidence Intervals
An estimate of the range within which the true treatment lies
CI of 95%- is the range of values that we are 95% certain the true value lies, if it includes 1- it is not statistically significant
P Value- anything over >0.05…
…is not significant
Effect size
difference between two outcomes divided by the variability that exists
Tx A- Tx B/ std deviation (larger means more confidence)
magnitude of an effect of a treatment
P-value
- If the difference could be BY CHANCE ALONE and if the assumption of no difference is true. eg: p=0.2 (20% chance due to chance), vs p=0.05 (5% chance…)
● Quantifies the probability of the study findings (e.g. the differences between the 2 groups) when we assume that (in truth) there is no difference at all
● Tells us if the difference is due to chance (“a difference greater than chance”, i.e. if both groups are equal, the number that may be due to chance)
The p-value does NOT tell us …
If the difference is valid
If the difference is clinically meaningful
If the difference is real
If the drug works
p=0.013 … what does that mean?
1.3% chance the difference was due to just chance?
TRUE
p=0.013 … what does that mean?
98.7% chance the difference was due to the intervention?
FALSE because P value is only assuming that chance is the reason for the difference and doesn’t measure anything else.(the other reasons could be bias, poor design etc)
Confidence interval
- Quantifies uncertainty in measurement (s/a +-5%), usually reported as 95%CI. True result somewhere between boundaries. Not-significant if includes 1.
- Quantifies the uncertainty in measurement
- A measure of the precision of the “effect estimate” from the study
- Usually reported as “95% Cl”
- Range of values within which we are 95% sure that the true value for the whole population lies (95% of studies done will include true results, i.e. reflect what is really going on in a population
- the lower N (sample size is) the lower the CI (i.e. if you study 100% of the population, your CI = 100%) (.. N / total population under study)
- E.g. for an odds ratio of 3 (95% Cl 2 to 4) we would have 95% confidence that the true odds
- CI should not include 1.0 or more (i.e. ration of 1:1 would have meant “no difference:)
- Example: A risk estimate of 0.88 (0.81 - 0.96) = a 12% reduction of risk… but with CI of (0.81 - 0.96) the reduction could be as big as 19% or as small as 4%.
What happens if the prescription is missing the refills?
Refills won’t be the problem because missing = 0 refills
What happens if Patient address is missing from prescription?
Patient address won’t be the problem – pharmacist will just call patient for it
When prescriptions expired?
All prescriptions Expired = 1 year
except for OCP = 2yrs
Double drug interactions (DDIs) for warfarin
- Thyroid meds
- NSAIDS
- Cimetidine
- Fibric acid
- Barbiturates
- Sulfinpyrazones
Double drug interactions (DDIs) for benzodiazepines
Azoles
Double drug interactions (DDIs) for carbamazepine
- Propoxyphene
- Macrolides
Double drug interactions (DDIs) for cyclosporine
Rifampin
Double drug interactions (DDIs) for dextromethorphan
MAOIs
Double drug interactions (DDIs) for digoxin
Clarithromycin
Double drug interactions (DDIs) for ergots
Macrolides
Double drug interactions (DDIs) for ganciclovir
Zidovudine
Double drug interactions (DDIs) for MAOIs
Sympathomimetics
Double drug interactions (DDIs) for meperidine
MAOIs
Double drug interactions (DDIs) for methotrexate
Trimethoprim
Double drug interactions (DDIs) for nitrates
Sildenafil
Double drug interactions (DDIs) for pimozide
- Macrolides
- Azoles
Double drug interactions (DDIs) for SSRIs
MAOIs
Double drug interactions (DDIs) for theophylline
- Quinolones
- Fluvoxamine
