Addendum B

James R. Miller DDS, MSD, PhD

State Oral Health Director, Indiana State Department of Health, Indianapolis, Indiana

Visiting Scholar, Indiana University School of Dentistry, Indianapolis, Indiana

Clinical Assistant Professor, Marian University College of Osteopathic Medicine, Indianapolis, Indiana

October 2015

Analyzing the Risk of Adverse Events associated with NSAIDs

1

Introduction

The previous presentation and hypothetical cases provided

practical information for clinicians concerning important

issues related to prescribing NSAIDs for pain

This addendum is for those who might want extra

information on the methods used to understand risk as it

pertains to adverse effects associated with NSAIDs

2

Objectives

The objectives of this presentation are:

• Present basic concepts of risk useful for understanding adverse

events associated with NSAIDs

• Present data from a meta-analysis of adverse events

associated with NSAIDs which illustrates these concepts of risk

• Present a set of guidelines that illustrates a strategy for

preventing adverse events associated with NSAIDs

3

Source MaterialTwo articles about NSAIDs and Risk

o Meta-analysis of risks associated with NSAIDs

• Coxib and traditional NSAID Trialists’ Collaboration. Vascular

and upper gastrointestinal effects of non-steroidal anti-

inflammatory drugs: meta-analyses of individual participant

data from randomised trials. www.thelancet.com.

2013;382:769-779

o Guidelines for reducing risks associated with NSAIDs

• Lanza FL, et al. Guidelines for prevention of NSAID-related

ulcer complications. Am J Gastoenterol 2009;104:728-238

4

Adverse Events with NSAIDs

A recent Lancet article presents a meta-analysis

of the adverse events associated with the use of

NSAIDs, specifically with Coxibs and various

traditional NSAIDs

5

Adverse Events with NSAIDsmentioned in the Lancet Article

Major Vascular Events

Heart:

Myocardial Infarction

Coronary Death

CNS:

Stroke

Stroke Death

Gastrointestinal Complications

Upper GI:

Bleed

Perforation

Obstruction

Lower GI:

none measured

6

Understanding Risk

In order to make a clinical decision about whether to

prescribe an NSAID, it would be beneficial to have an

understanding of the benefits and risks associated with a

particular medication for a particular patient

This presentation will present some basic concepts of

understanding risk and then use the Lancet article to

provide examples of these concepts

7

Measurement of Risk

• The risk of an adverse event can be measured in different ways

• In general, a measurement of risk includes:

The number of individuals with a first time adverse event within a

group of individuals, at risk for that event, over a certain period of

time

8

Types of Risk in the Lancet Article

• Risk while taking an NSAID (“exposed”)

• Risk while not taking an NSAID (“non-exposed”)

9

Risk while taking an NSAID

In the Lancet article, the risk while taking an NSAID is determined by measuring the risk of an adverse

event in a group of individuals in a medication group

10

Risk while not taking an NSAID

In the Lancet article, the risk while not taking an

NSAID is determined by measuring the risk of an

adverse event in a group of individuals in a placebo

group

11

Comparisons of these Risks

• Relative Risk

• Excess Risk (Absolute Risk)

12

Relative Risk

• In the Lancet article, relative risk is a relative comparison of the risk of having an adverse event when taking a medication (“exposed”) to the risk of having an adverse event when not taking a medication (“non-exposed”)

• Relative risk is the risk among the “exposed” divided by the risk among the “non-exposed”, producing a ratio without a unit of measurement

• Thus, relative risk provides a relative likelihood of an individual having an adverse event

Note: In the Lancet article, direct comparisons of NSAIDs to a placebo group were not possible for all NSAIDs; however, the authors were able to statistically use the available placebo group for indirect comparisons of various NSAIDs to the available placebo group (see article for details)

13

Excess Risk

• In the Lancet article, excess risk (absolute risk) is an absolute

comparison of the risk of having an adverse event when taking a

medication (“exposed”) to the risk of having an adverse event when not

taking a medication (“non-exposed”)

• Absolute risk is the risk among the “exposed” minus the risk among the

“non-exposed”, producing a probability of an adverse events with units

of measurement

• Thus, absolute risk provides an estimate of the absolute likelihood of an

individual having an adverse event

Note: In the Lancet article, direct comparisons of NSAIDs to a placebo group were not possible for all

NSAIDs; however, the authors were able to statistically use the available placebo group for indirect

comparisons of various NSAIDs to the available placebo group (see article for details)

14

Risk due to taking an NSAID

In the Lancet article,

Excess Risk was used to measure the risk due to taking a NSAID

Excess Risk is provided for coxibs, diclofenac, ibuprofen, and naproxen

Note: Excess Risk can also be referred to as Absolute Risk or Attributable Risk

15

Summary

Excess Risk = Medication Group Risk – Placebo Group Risk

16

Relative Risk = Medication Group Risk / Placebo Group Risk

Note: Medication Group Risk = Risk due to Medication + Inherent Risk

Placebo Group Risk = Inherent Risk

Excess Risk = (Risk due to Medication + Inherent Risk) – (Inherent Risk)

Thus, Excess Risk = Risk due to Medication

Examples

• The Lancet Article presents a meta-analysis of the

adverse events associated with the use of NSAIDS

• This article uses both relative risk (or odds ratio) and

excess risk (absolute risk) to explain the risk for

adverse events associated with the use of NSAIDs

• Examples from this article will be used to illustrate

the utility of using knowledge of excess risk to make

clinical decisions when prescribing NSAIDs

17

Adverse Events with NSAIDsmentioned in the Lancet Article

Major Vascular Events

Heart:

Myocardial Infarction

Coronary Death

CNS:

Stroke

Stroke Death

Gastrointestinal Complications

Upper GI:

Bleed

Perforation

Obstruction

Lower GI:

none measured

18

Relative RisksMajor Vascular Events

• The relative risks for having a major vascular event were elevated for coxibs and diclofenac.

• Although, the RR for ibuprofen was not statistically elevated, there were some fatal adverse events among those taking this medication

• Naproxen does not appear to be associated with major cardiovascular adverse events

* coxibs (RR=1.37) (p=0.0009)

* diclofenac (RR=1.41) (p=0.0036)

* ibuprofen (RR=1.44) (p=0.14)

naproxen (RR=0.93) (p=0.66)

* There were fatal adverse events among those taking coxibs, diclofenac, and ibuprofen

19

Relative RisksGastrointestinal Complications

• The relative risks for having a GI complication were statistically elevated for all of the following NSAIDs:

coxibs (RR=1.81) (p=0.0070)

diclofenac (RR=1.89) (p=0.0106)

ibuprofen (RR=3.97) (p=0.0001)

naproxen (RR=4.22) (p=0.0001)

• Almost all of the gastrointestinal complications were non-fatal

20

Excess Risks

• In the Lancet article, the authors present a interesting summary

(Fig. 5) of the excess risks associated with major vascular events

and gastrointestinal complications, stratified according to

categories of baseline risks for these respective adverse events

• The following table is adapted from this figure and offers

information about excess risk that can be helpful when deciding

what NSAIDs, if any, to prescribe for pain management in a

particular patient

21

Excess Risks for Major Vascular Events and Upper GI Complications

22

The Excess Risks are the number of individuals with adverse events out of 1000 individuals taking the medication for a year of treatment

High Low Moderate Low

2% pa 0.5% pa 0.5% pa 0.2% pa

Non-fatal 7.0 1.5 4.0 2.0Fatal 2.0 0.5 0.0 0.0

Total 9.0 2.0 4.0 2.0

Non-fatal 8.0 1.5 4.0 2.0Fatal 2.0 0.5 0.0 0.0

Total 10.0 2.0 4.0 2.0

Non-fatal 9.0 1.5 15.0 6.0Fatal 3.0 0.5 negligible 0.0

Total 12.0 2.0 15.0 6.0

Non-fatal -0.5 0.0 16.0 6.0Fatal -0.5 0.0 negligible 0.0

Total -1.0 0.0 16.0 6.0

Notes :

a . The va lues presented are approximations

b. Diclofenac 75 mg BID, Ibuprofen 800 mg TID, Naproxen 500 mg BID

Diclofenac vs.

placebo

Ibuprofen vs.

placebo

Naproxen vs.

placebo

Coxib vs. placebo

Baseline Baseline

Major vascular events Upper GI complications

Excess Risk Excess Risk

Fatalities

• Note that the total excess risk in each combination of medication, type of adverse

event, and category of baseline risk is composed of non-fatal and fatal excess risk

• Fortunately, most adverse events are non-fatal

• However, some adverse events are fatal

Most fatal adverse events were associated with a high baseline risk of a major vascular

event, although there were some fatalities even with a low baseline risk of a major vascular

event.

Few fatal adverse events were associated with a high or low baseline risk for upper GI

complications, although those that did occur were mostly in the high risk group

• By examining this table carefully, the clinician can obtain valuable information about

the excess risk associated with prescribing particular NSAIDs for particular patients

23

Different Perspectives

• Relative risk and excess risk provide different perspectives on the risk of adverse events associated with NSAIDs

• As the name implies, relative risk provides a relative comparison of the risk of an adverse event among those taking an NSAID to those not taking an NSAID

• Relative risk is a ratio and is without units of measurement, so one may not be able to calculate the actual amount of risk a patient assumes by taking an NSAID

• Excess risk is a difference between risks, and does have units of measurement and provides information about the actual amount of risk associated with taking a NSAID

24

Relative Risk and Excess Risk

The following information is available in the Lancet article:

o Relative risks for coxibs, diclofenac, ibuprofen, and naproxen versus a

placebo group

o Baseline risk categories for vascular events and GI complications

o Relative risk does not vary across categories of baseline risk for each of

the above mentioned drugs (there may be some variation, but it is not

statistically significant), while excess risk does vary

o Excess risk for each of these medications, categorized by type of adverse

event and the categories of baseline risk associated with each of these

types of adverse events

25

Constructed Tables:Relative Risk and Excess Risk

• Using this information, one can calculateo Theoretical values for the risk associated with each medication

(Medication Risk) for each combination of risk type and category of

baseline risk

• The following two tables, constructed with this

information, allows one to better visualize how

relative risk and excess risk provide different

perspectives on risk

26

Risk of Major Vascular Event

27

Medication Risk Excess Risk

("exposed") (absolute risk)

risk while taking risk due to

(Fatal + Non-fatal)

29/1000/yr High 20/1000/yr (2.0% pa) 9/1000/yr 29/20 = 1.45

7/1000/yr Low 5/1000/yr (0.5% pa) 2/1000/yr 7/5 = 1.40

30/1000/yr High 20/1000/yr (2.0% pa) 10/1000/yr 30/20 = 1.50

7/1000/yr Low 5/1000/yr (0.5% pa) 2/1000/yr 7/5 = 1.40

32/1000/yr High 20/1000/yr (2.0% pa) 12/1000/yr 32/20 = 1.60

7/1000/yr Low 5/1000/yr (0.5% pa) 2/1000/yr 7/5 = 1.40

19/1000/yr High 20/1000/yr (2.0% pa) neg. 1/1000/yr 19/20 = 0.95

5/1000/yr Low 5/1000/yr (0.5% pa) 0/1000/yr 5/5 = 1.00

Ibuprofen vs. placebo

Naproxen vs. placebo

("non-exposed")

Placebo Risk (Basel ine Risk)

risk while not taking

Relative Risk

Coxib vs. placebo

Diclofenac vs. placebo

Risk of Major Vascular

Adverse Event For each of the NSAIDs, the Relative Risks do not vary (statistically) across baseline risk categories, while the Excess Risks do vary

Risk of GI Complication

28

Medication Risk Excess Risk

("exposed") (absolute risk)

risk while taking risk due to

(Fatal + Non-fatal)

9/1000/yr Moderate 5/1000/yr (0.5% pa) 4/1000/yr 9/5 = 1.80

4/1000/yr Low 2/1000/yr (0.2% pa) 2/1000/yr 4/2 = 2.00

9/1000/yr Moderate 5/1000/yr (0.5% pa) 4/1000/yr 9/5 = 1.80

4/1000/yr Low 2/1000/yr (0.2% pa) 2/1000/yr 4/2 = 2.00

20/1000/yr Moderate 5/1000/yr (0.5% pa) 15/1000/yr 20/5 = 4.00

8/1000/yr Low 2/1000/yr (0.2% pa) 6/1000/yr 8/2 = 4.00

21/1000/yr Moderate 5/1000/yr (0.5% pa) 16/1000/yr 21/5 = 4.20

8/1000/yr Low 2/1000/yr (0.2% pa) 6/1000/yr 8/2 = 4.00Naproxen vs. placebo

Risk of GI Complication Placebo Risk (Basel ine Risk) Relative Risk

("non-exposed")

risk while not taking

Coxib vs. placebo

Diclofenac vs. placebo

Ibuprofen vs. placebo

For each of the NSAIDs, the Relative Risks do not vary (statistically) across baseline risk categories, while the Excess Risks do vary

Baseline Risk and Choice of NSAIDs

• The information in the Lancet article indicate that:

• In patients with a high baseline risk for major vascular events,

o naproxen might be acceptable for pain, while

o coxib(s), diclofenac, and possibly ibuprofen likely should be avoided

• In patients with a high baseline risk of gastrointestinal complications,

o coxib(s) and diclofenac might be acceptable for pain, while

o ibuprofen and naproxen likely should be avoided

29

There are other risks associated with taking NSAIDs, such as those pertaining to pre-existing medical conditions and current medications, that are not addressed in this article

Guidelines

Lanza FL, et al. Guidelines for prevention of NSAID

related ulcer complications. Am J Gastoenterol

2009;104:728-238

30

Guidelines

• Lanza et al. published an article in 2009 that offered

guidelines for prescribing pain medication based on baseline

risk categories for gastrointestinal (GI) and cardiovascular

(CV) adverse events

• These guidelines were designed to reduce the risk of having

an ulcer (upper GI adverse event), subsequent to prescribing

an NSAID to a patient for pain

Reference: Lanza FL, et al. Guidelines for prevention of NSAID-related ulcer complications. Am J

Gastoenterol 2009;104:728-238

31

Guidelines

• These guidelines were written by Lanza et al., based on the

analysis of the data available in 2009

• As the authors stated, guidelines may change as more data become available

• Although the Lancet article was not available at the time of

the publication of these guidelines, epidemiological data

from case-control and cohort studies, and available RCTs,

were used to develop these guidelines

32

Baseline Risk Categories

Adapted from: Lanza FL, et al. Guidelines for prevention of NSAID-related ulcer complications. Am J

Gastoenterol 2009;104:728-238

33

GI Risk Factors

Significant Risk Factor

* HX: Complicated ulcer (especially recent)

Less Significant Risk Factors

* AGE: > 65

* HX: Uncomplicated ulcer

* MEDS: Aspirin, Corticosteroids, Anticoagulants

* TX: Proposed High Dose NSAIDS

Note

GI Risk Categories

* LOW

* MODERATE

* HIGH

CV Risk Factors

* MEDS: Aspirin (required use of low-dose ASA to prevent CVD)

GI Risk Categories

* LOW

* HIGH

HX of complicated ulcer (Significant Risk Factor)

OR

3 or more Less Significant Risk Factors

Not using low-dose ASA to prevent CVD

Using low-dose ASA to prevent CVD

Patients with HX of ulcer (compl icated or uncompl icated) should be tested for H.

pylori and, i f present, treated

None of the above risk factors

1 or 2 Less Significant Risk Factors

Guidelines for reducing risk of ulcer when prescribing NSAIDs

Adapted from: Lanza FL, et al. Guidelines for prevention of NSAID-related ulcer complications. Am J

Gastoenterol 2009;104:728-238

34

LOW MODERATE HIGH

LOW*NSAID alone

> least ulcerogenic

> lowest dose

*NSAID + PPI/misoprostol

Alternative therapy

OR

Coxib + PPI/misoprostol

HIGH Naproxen + PPI/misoprostol Naproxen + PPI/misoprostolAlternative therapy only

(AVOID NSAIDS or Coxibs)

* In this table when the authors refer to an *NSAID, they are probably referring to a traditional NSAID (tNSAID)

Strategies to Prevent NSAID related complications

CV RISK

GI RISK

There are other risks associated with taking NSAIDs, such as those pertaining to pre-existing medical conditions and

current medications, that are not addressed by these guidelines

Conclusions

• Although NSAIDs are effective pain medications, and are widely

used, they are not without risk

• An evaluation of a patient’s baseline risk for major vascular events

and baseline risk for GI complications would be prudent prior to

prescribing NSAIDs

• It would also be prudent to carefully consider all of a patient’s

current medical conditions and medications before prescribing

NSAIDs

• Patients with certain medical conditions and medications can

complicate the decision about prescribing NSAIDs. In these cases,

consultation with the patient’s physician would be prudent

35