Diana Girnita, MD PhD

UC Rheumatology Fellow

Nonsteroidal anti-inflammatory drugs (NSAIDs)

• Effects– anti-inflammatory

– analgesic– antipyretic

• CDC reported: 52.5 million US people with arthritis

• NSAIDs Indications:– Gout– Spondylarthropathies

(Ankylosing Spondylitis)

– Rheumatoid Arthritis

– Osteoarthritis

– Acute or Chronic Musculoskeletal Pain

NSAIDs Usage

• $5 billion/year - drug costs in prescribed NSAIDs

• $3 billion additional spending/yearly for OTC analgesics including acetaminophen.

Irena Melnikova Nature Reviews Drug Discovery 9, 589-590;2010

CDC data on NSAIDs prescriptions

Percent of NSAID visits

1999-20002000-200118 - 44 years

45 – 64 years

65 -74 years

> 75 years

Centers for Disease Control and Prevention, National Center for Health Statistics. Health, US,2004

Pain assessment scale

McKenna F, Borenstein D, Wendt H et al. Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scand J Rheumatol 2001;30:118.

P<0.001

1899, Bayer Archives

History of Aspirin

NSAIDs

Traditional (starting 1960’s) Salicylic acids Aspirin

Acetic acids DiclofenacEtodolac IndometacinSulindac Ketorolac

Propionic acids KetoprofenIbuprofenNaproxen

Pyrazolones Phenilbutazone

Oxicams PyroxicamMeloxicam

Nonacidic Relafen

Coxibs –COX2 selective(approved 1998)

Sulfonamide Celecoxib (celebrex)

Sulfonylurea Etoricoxib (arcoxia)

Nonacid Lumaricoxib

Mechanism of action

STIMULUS

Phospholipids –cellular membrane

Arachidonic acidLeukotrienes

Phospholipase A2

Lipoxygenase COX

COX = cyclo-oxygenaseTX2 =thromboxanePG =Prostaglandines

TX2

PG

Prostacyclin

COX-1 versus COX-2

COX-1 COX-2

Expression

Tissuelocalization

Role “Housekeeping” and maintenance

Ubiquitous Inflammatory and neoplastic sites (small amounts in kidney, uterus, ovary, CNS [neocortex, hippocampus])Pro-inflammatory and mitogenic functions (? neuronal plasticity)

Constitutive (activated by physiologic stimuli)

Inducible by pro-inflammatory stimuli (LPS, TNFα , IL-2, IFNγ etc)

Mechanism of action

VasoconstrictionPlatelet aggregation

VasodilatationHyperalgesia

FeverDiuresis

Immunomodulation

Smooth muscle contraction

Bronchoconstriction

VasodilatationInhibits platelet

aggregation

Smooth muscle contraction

Inhibits platelet aggregation

Hydrolysis

Oxygenation

NSAIDs

Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed., Copyright © 2006 Saunders

NSAIDs Classification by COX selectivity

In vitro assessmentof COX-1/ COX-2 activity

Non-specific inhibition of COX-1 - gastrointestinal and platelet- adverse effects

Are they safe medication?

Wolfe MM et al. N Engl J Med 1999;340:1888-1899.

Common Side Effects• Gastrointestinal

– Dyspepsia– Esophagitis– Ulcers– Perforations– Small bowel erosions/ strictures– Colitis

• Renal

– sodium retention – Edema– HTN– RTA, AKI, AIN– Hyperkalemia

– Papillary necrosis

• Hepatic – Elevated AST, ALT

• Asthma

-Aspirin induced, rash• Hematologic -cytopenia• Nervous -dizziness,

confusion, seizures, aseptic meningitis

• Cardiac –will discuss later….

Since the reported risk of GI bleed was high with the

traditional NSAIDs (tNSAIDs), the COXIBS - approved 1998

RA- RHEUMATOID ARTHRITISOA-OSTEOARTHRITIS

STUDY Participants RESULT

VIGOR, 2000 8076 COX-2 -Increased CV risk, no difference in mortality

CLASS, 2000 8095 COX-2 -No increase in CV risk

Metaanalysis, 2001 18000 COX-2 Increased CV risk

TARGET, 2004 18325 COX-2 No difference in CV risk, increase in blood pressure

APPROVE, 2005 2586 COX-2 Increased CV risk (thrombotic events, CHF, HTN )

APC+PreSAP 3800 COX-2 Increased CV risk

Metaanalysis, 2006 145343 Increased CV risk for both COX-2 and tNSAIDs, not naproxen

MEDAL, 2009 34701 COX-2 No difference in CV risk

Metaanalysis, 2013 124513 Increased CV risk for both COX-2 and tNSAIDs, not naproxen

Danish, 2014 83677 Increased CV risk for COX2 and Diclofenac

VIGOR STUDYNEJM 2000; 343:1520-8

VIGOR study

• 8076 patients > 50 yo / 40 yo on long term steroids with Rheumatoid arthritis

• Double blinded, RTC

• vs

• Primary endpoint: upper GI events (perforation, bleeding, obstruction, ulcers)

Rofecoxib (Vioxx) 50 mg QD(n=4047)

Naproxen 500mg BID(n=4029)

Patients with Events (Rates per 100 Patient-Years)

Event CategoryRofecoxibN=4047

NaproxenN=4029

Relative Risk(95% CI)

Confirmed CV events

45 (1.7) 19 (0.7) 0.42(0.25, 0.72)

Cardiac events

28 (1.0) 10 (0.4) 0.36(0.17, 0.74)

Cerebrovascular events

11 (0.4) 8 (0.3) 0.73(0.29, 1.80)

Peripheral vascular events

6 (0.2) 1 (0.04) 0.17(0.00, 1.37)

VIGOR - Confirmed Thrombotic Cardiovascular Events

Source: Data on file, MSD

No difference in the mortality rate

• 0.5 % for rofecoxib vs 0.4% in naproxen –seven patients died from CV event in each group

• MI less common in the naproxen vs rofecoxib group (0.1% vs 0.4% -95%CI 0.1-0.6; RR =0.2)

• MERK allow patients to use LOW –DOSE aspirin (history of myocardial infarction, angina, stroke, CABG/PCI)

JAMA 2000; 284: 1247-1255

CLASS =Celecoxib long term arthritis safety study

• Prospective, double-blind, RTC (1998-2000)

• 8095 patients ≥ 18yo with OA or RA (27%);

• Aspirin use was permitted ≤325 mg/day (20% of patients)

• vsCelecoxib 400 mg BID (n=3987)

tNSAIDsIbuprofen 800 mg TID (n=1985)Diclofenac 75 mg BID (n=1996)

NO increase risk in CV thromboembolic events

No report about the CV events in patients that WERE TAKING aspirin

ARE COX-2 INHIBITORS ASSOCIATED WITH INCREASED CARDIOVASCULAR (CV) RISK?

Increased CV risk with COX-2

Mukherjee D , Topol E. Risk of CV events associated with selective COX2 inhibitors JAMA 2001, 286 954-959

Increased Risk of Myocardial Infarction

• MI= myocardial infarction

TARGET STUDY

Lancet 2004; 364: 675–84

TARGET study

• 18325 patients ≥ 50 yo with OA for 52 weeks

• Double blinded, RTC

• 24% of patients (n=4326) on low dose ASA

• Primary endpoints• Nonfatal and silent MI, stroke and CV death

Lumiracoxib 400mg QD (n=9158)

Naproxen 500mg BID (n=4754) Ibuprofen 800 mg TID (n=4415)

Farkouh M et al; TARGET study, The Lancet, Volume 364, Issue 9435, 2004, 675 - 684

No Difference in The Composite Primary Endpoint

•Primary endpoints• Nonfatal and

silent MI, stroke and CV death

•No difference between tNSAIDs and Cox-2

No Difference in Confirmed and Probable MI

• Overall, no significant difference

• Ibuprofen sub-study:

rates did not differ irrespective of Aspirin use

• Naproxen sub-study: 4 events, 0.11% vs Coxib group -10 events; 0.28% in patients NOT taking Aspirin

Change in baseline blood pressure

(BP)

• Systolic BP (Least square means change) was +0.4 mmHg for Coxib vs +2.1mmHg for NSAIDS (p<0.001)

• Diastolic BP (least square means) was -0.1 mmHg for Coxib vs +0.5 mmHg for NSAIDS (p<0.001)

APPROVE STUDY

N Engl J Med 2005;352:1092-102.

APPROVE STUDY

• 2586 patients-history of colorectal adenoma

• Double blinded RTC, 3 years (2000-2003)

• vs

• Primary endpoint: Thrombotic CV events

• 20% were on low dose aspirin

Rofecoxib 25 mg QD (n=1287) Placebo (n=1299)

Increased incidence of thrombotic events

Increased incidence of CV events after 18 months

Increased incidence for CHF

Increased Risk for CHF and HTN

2004 FDA Warning for all NSAIDs

Public Health Advisory concerning the use NSAIDs, including COX-2 selective agents: -COX-2 selective agents (Vioxx, Celebrex, and Bextra) may be associated with an increased risk of serious CV events (heart attack and stroke) -Long-term use of a non-selective NSAID, naproxen (sold as Aleve, Naprosyn) may be associated with an increased cardiovascular risk compared to placebo.December 23, 2004

http://www.fda.gov/cder/drug/infopage/cox2/default.htm

2005- Worldwide withdrawal of Rofecoxib

Questions

• Is it a dose related risk?

• Is it a time relation between Coxibs and increase the CV risk?

• Is the association with Aspirin of any benefit?

Aspirin- the only Cardio-protective NSAID

287 trials200,000 patients

Lancet. May 30, 2009; 373(9678): 1849–1860. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis - participant data from Antithrombotic Trialists' (ATT) Collaboration

How does Aspirin work?

•Irreversibly inhibits COX1 (selectivity COX1150-200 x >COX2), change catalitycal site of COX2•COX1 enzyme is inhibited for the lifetime of the platelet (~8 -11 days). •Effect achieved at very low dose.

•Thromboxane A2 synthesis is inhibited in platelets no Platelet aggregation

Lipoxins –antiinflammatory

HOW ARE NSAIDS AFFECTING ASPIRIN EFFECT?

Ibuprofen before aspirin limits cardioprotective effect of aspirin

• Ibuprofen (COX-1) inhibits thromboxane B2 and platelet aggregation

Lawson FC et al “Cyclooxigenase inhibitors and the antiplatelet effect of aspirin; NEJM 2001;345:1809-17

Rofecoxib and diclofenac (>COX2)- do not limit aspirin effect

Lawson FC et al “Cyclooxygenase inhibitors and the antiplatelet effect of aspirin; NEJM 2001;345:1809-17

WHAT DO THE CLINICAL TRIALS REPORT?

• Independent committee of both studies evaluated CV events

APC(adenoma

prevention with Celecoxib)

Celecoxib -200mg and 400mg BID vs placebo

PreSAP(prevention of spontaneous adenomatous

polyps)-to reduce colorectal adenoma recurrence

after polypectomy

Celecoxib 400mg QD vs placebo

Solomon S et al. Circulation. 2006;114:1028-1035

Doubled risk for CV events

• 83 patients with CV death, nonfatal MI, nonfatal stroke, heart failure

• Prespecified composite endpoint – overall HR =1.9 (95%CI 1.1-3.1)

• Significant increase in systolic BP at 1 and 3 years in the APC study (2-3mmHg for 200mg BID and 3-6mmHg for 400mg BID)

Higher the dose…higher the CV risk

Solomon S et al. Circulation. 2006;114:1028-1035

Time to the composite end point

Solomon S et al. Circulation. 2006;114:1028-1035

HR for CV death, nonfatal MI, stroke, heart failure

Meta-analysis of randomized trials

Kearney PM et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-

steroidal anti-inflammatory drugs increase the risk of atherothrombosis? BMJ. 2006;332:1302.

Metaanalysis, 2006

• 145 373 participants

• 138 randomised trials involving a comparison of a selective COX 2 inhibitor versus placebo or versus a traditional NSAID (or both)

tNSAIDs vs Placebo

Kearney PM et al. BMJ. 2006;332;1302.

NSAID RR 95% CI

Diclofenac 1.63 1.12 - 2.37

Ibuprofen 1.51 0.96 - 2.37

Naproxen 0.92 0.67 - 1.26

Kearney et al. BMJ. 2006;332:1302.

COX-2 inhibitors vs Placebo

COX-2 inhibitors

vs NSAIDs

Kearney et al. BMJ. 2006;332:1302.

Antman EM et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association.Circulation. 2007 Mar 27;115(12):1634-42.

American College Rheumatology- Drug Safety Committee members

“While we appreciate the documented CV toxicity associated with selective and non-selective NSAIDs, the current AHA

statement does not reflect the proven benefits of these agents in patients with arthritis and other chronic inflammatory

conditions. Sufficient treatment options are critical for patients with arthritis. Just as collaborative treatment plans for a given

patient result in improved care, we urge the cardiology community to engage their rheumatology colleagues in

formulating optimal recommendations for the use of NSAIDs”

Neal S. Birnbaum, MD, ACR President Daniel J. Lovell, MD, MPH, and Daniel H. Solomon, MD, MPH-

RA and Cardiovascular disease (CVD)

• The absolute CV risk in RA patients has been estimated to be similar to that in non-RA patients that are 10 years older.

• The risk of CV events and death in RA is similar to that seen in patients with type 2 diabetes

Kremers HM et al. High ten-year risk of CV disease in newly diagnosed rheumatoid arthritis patients: a population-based cohort study. Arthritis Rheum 2008; 58:2268–2274.Peters MJ et al. Does rheumatoid arthritis equal diabetes mellitus as an independent risk factor for cardiovascular disease? A prospective study. Arthritis Rheum 2009; 61:1571–1579.

RA and cardiovascular disease (CVD)

• People with RA are at excess risk for CVD.

• Systemic inflammation and its interplay with traditional and nontraditional CV risk factors appear to have a major role.

• Cardiovascular risk scores (e.g. Framingham) developed for the general population are unlikely to accurately estimate cardiovascular risk in RA.

Sherine G et al. Risk factors for cardiovascular disease in rheumatoid arthritis. Curr Opin Rheumatol 2012, 24:171–176

MEDAL STUDY -2009

3 Trials 46 countries 1380 sites EDGE (OA): N=7,111 EDGE II (RA): N=4,086 34,701 patients MEDAL (OA/RA): N=23,504

MEDAL Program Trials

n=17,412RANDOMIZE

Etoricoxib60 or 90 mg/d (OA)

90 mg/d (RA)

Diclofenac150 mg/d

(50 mg tid or 75 mg bid)

n=17,289

≥ 50 years of age OA of knee, hip, hand,

or spine; or RA Require long-term therapy

with traditional NSAID orCOX-2 inhibitor

Broad CV risk Allowed aspirin and PPI

use in appropriate patients

Mean duration of therapy=18 months

Patient CharacteristicsNo. of Patients (%)

Etoricoxib (n=17,412)

Diclofenac(n=17,289)

Mean age, years (SD) 63.2 (8.5) 63.2 (8.5)

Female 12,925 (74.2) 12,823 (74.2)

Osteoarthritis 12,533 (72.0) 12,380 (71.6)

Rheumatoid arthritis 4878 (28.0) 4909 (28.4)

Diabetes 1810 (10.4) 1855 (10.7)

Hypertension 8109 (46.6) 8221 (47.6)

Dyslipidemia 5097 (29.3) 5034 (29.1)

Current smoker 2034 (11.7) 2037 (11.8)

Established atherosclerotic CV disease 2014 (11.6) 2010 (11.6)

≥2 CV risk factors* or established atherosclerotic CV disease

6586 (37.8) 6639 (38.4)

*Included hypertension, diabetes mellitus, dyslipidemia, family history of CV disease, or smoking.

Etoricoxib (320 events)

Diclofenac (323 events)

Primary Endpoint: Cumulative Incidence of Thrombotic CV Events

MonthsNo. of patients at risk*

EtoricoxibDiclofenac

16,81916,483

13,359 10,733 8277 6427 4024 80581538326213790110,14212,800

7.0

6.0

5.0

4.0

3.0

2.0

1.0

06 12 18 24 30 36 420

Cu

mu

lati

ve in

cid

ence

(%

) w

ith

95%

CI

Etoricoxib vs diclofenacHR = 0.95 95% CI = (0.81-1.11)

*Per protocol population.

Etoricoxib (216 events)

Diclofenac (216 events)

Etoricoxib (272 events)

Diclofenac (272 events)

Cumulative Incidence of ArterialThrombotic CV and APTC Events

16,819

16,483

13,362

12,801

10,735

10,144

8277

7903

6427

6214

4024

3832

805

815

No. of patients at risk

Etoricoxib

Diclofenac

Months

Etoricoxib vs diclofenacHR = 0.96 95% CI = (0.79-1.16)

06 12 18 24 30 36 420

7.0

6.0

5.0

4.0

3.0

2.0

1.0

Cu

mu

lati

ve in

cid

ence

(%

) w

ith

95%

CI

06 12 18 24 30 36 420

7.0

6.0

5.0

4.0

3.0

2.0

1.0C

um

ula

tive

inci

den

ce (

%)

wit

h 9

5% C

I

Etoricoxib vs diclofenacHR = 0.96 95% CI = (0.81-1.13)

Months

16,819

16,483

13,366

12,814

10,745

10,155

8282

7906

6429

6218

4026

3832

805

816

No. of patients at risk

Etoricoxib

Diclofenac

Arterial Thrombotic CV Events CVD/MI/Stroke

2013 Meta-analysis

• 280 trials of NSAIDs vs placebo (124513 patients, 68342 person years)

• 474 trials one NSAID vs another NSAID (229296 patients, 165456 person-years)

• Main outcomes– Major vascular events (nonfatal MI/ stroke or vascular death)– Major coronary events (nonfatal MI or coronary death)– Upper GI complications (perforation, obstruction, bleed)

Drug Major vascular events

Major coronary events

Coxibs RR -1.3795% CI -1.14-1.66P=0.009

RR – 1.7695% CI 1.31–2.37 P=0·0001

Diclofenac RR-1.4195% CI - 1.12- 1.78P =0.036

RR - 1·7095% CI – 1.19–2·41 P=0·0032

Ibuprofen RR- 1·44, 95% CI -0.89–2.33P>0.05

RR - 2.22, 95% CI 1.10–4.48 P=0·0253

Naproxen RR- 0.9395% CI -0.69-1.27P-0.66

RR- 0.8495% CI -0.52-1.35P= 0.48

RR-rate ratio!!!ALL NSAIDS doubled the risk of heart failure

Coxibs and traditional NSAID Trialist’s collaboration. Vascular and upper GI effects of NSAIs: meta-analyses from randomized trails. Lancet 2013; 382 769-79

The Impact of NSAID Treatment on Cardiovascular Risk –

Insight from Danish Observational Data (1997-2006)

Anne-Marie Schjerning Olsen et al. Basic & Clinical Pharmacology & Toxicology, 2014, 115, 179–184

Increased CV risk with NSAID use in healthy people

• the risk might be the same in healthy people

• most NSAIDs were associated with increased CV risk (worse for diclofenac and rofecoxib)

Diclofenac and Rofecoxib increased risk of MI/ re-MI

The RR ofNSAID use was associated with persistently increased CVrisk throughout all 5 years after discharge from hospitalafter the first MI.

NSAIDs and Platelets/Endothelial Cells

CONCLUSION

2014 – FDA recommendations

NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases:

•with increasing doses of NSAID medicines

•with longer use of NSAID medicines

•in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG)."

http://www.fda.gov/downloads/drugs/drugsafety/ucm387559.pdf

2014-FDA recomendations

NSAID medicines should only be used:

• exactly as prescribed

• at the lowest dose possible

• for the shortest time needed

http://www.fda.gov/downloads/drugs/drugsafety/ucm387559.pdf

Some practical advises

• NSAIDs (Coxibs) - viable and effective options to treat pain, fever and inflammation

• They are associated with increased CV risk (varying degrees)

• Consider co-morbidities• Elderly patients are at increased risk of

adverse events

Practical advises for patients with high CV risk

• Counsel patients about NSAIDs cardiovascular risks.

• Low dose coxibs and Naproxen seem to be safer than Diclofenac, rofecoxib, and ibuprofen that seem to have increased risk

• Regularly review for the need of continuing this medication

Association with Aspirin does not confer cardioprotection

• The use of low dose aspirin does not consistently abrogate the potential CV risk of a NSAID or COX-2 inhibitor.

• Patients who require the cardioprotective effects of aspirin may not be ideal candidates for NSAID therapy.

The Future….

• Await results of trials such as PRECISION (Prospective Randomised Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen)-

phase IV

Celecoxib 100 to 200 mg BID vs Ibuprofen 600 mg to 800 mg TID or Naproxen 375mg to 500 mg BID

• http://clinicaltrials.gov/ct2/show/results/NCT00346216

THANK YOU!

VIGOR - GI Endpoints

†p < 0.001. * p = 0.005.

0

1

2

3

4

5

Confirmed Clinical Upper GI Events

ConfirmedComplicated

Upper GI Events

All ClinicalGI Bleeding

RR: 0.46†

(0.33, 0.64)

RR: 0.43*(0.24, 0.78)

RR: 0.38†

(0.25, 0.57)

Ra

tes

pe

r 1

00 P

atie

nt-

Ye

ars

RofecoxibNaproxen

( ) = 95% CI.

Source: Bombardier, et al. N Engl J Med. 2000.

CLASS -Incidence of upper GI events

Numbers above bars indicated events per patient-years exposureNSAIDS- nonsteroidal anti-inflammatory drugs

Aspirin- dose dependent effects

Low: < 300mg blocks platelet aggregation

Intermediate: 300-2400mg/day antipyretic and analgesic effect

High: 2400-4000mg/day anti-inflammatory +/- uricosuric effect

Effect of NSAID’s on Platelet-Endothelial Interactions

Inhibiting COX-2

• COX-2 derived PGI2 can antagonize catecholamine- and angiotensin II-induced vasoconstriction that will elevate blood pressure

• Destabilize atherosclerotic plaques (due to its anti-inflammatory actions)

• COX-1 and COX-2 – generated PGs (TxA2, PGF2 , PGI2 (glom), PGE2 (medulla), powerful vasodilators) affect Na+ retention at kidney level

Role of Lipoxins in Anti-inflammatory effects of Aspirin