nsaid

1. 2019 | 03
Optimizing Pain
Management
The Role of Proxen®

2. “Initiation of diclofenac poses
a cardiovascular health risk,
both compared with no use,
paracetamol use, and use of
other traditional NSAIDs”
Schmidt et al., BMJ 2018; 362:k3426
Conclusion

3. Peripheral and Central Analgesic Effect
1. Cashman JN. The mechanisms of Action of NSAIDs in Analgesia . Drugs 1996:52 Suppl. 5: 13-23
Proxen
®
has an inhibitory effect on central prostaglandin synthesis1

4. COX Selectivity of COX-2 Selective
and Traditional NSAIDs

5. GI Tolerability

6. Naproxen + PPI showed lower relative risk
of all NSAIDS and Coxibs
Hippisley-Cox et al., BMJ 2005; 331:1310-1316

7. 8
 The use of ulcer healing drugs reduces the
increased risk of adverse GI outcomes with all
groups except diclofenac, for which the
increased risk remained significant.
Study conclusion
Hippisley-Cox et al., BMJ 2005; 331:1310-1316

8. Cardiac Safety

9. Cardio or cerebro vascular
Complications of Cox 2 inhibition
 Stroke
 Increased thrombosis
 Increase in Na and water retention
 Heart failure and hypertension
 Larger infarct size
 Increased tendency to myocardial rupture
11

10. COX-2 and atherosclerosis
FitzGerald GA Nat Rev Drug Discov 2003;2:879-90
Proxen®
inhibits cox1 & cox2 with the optimal ratio that does not affect
the PGI2 and TXA2 balance compared with other NSAIDs

11. “Naproxen was risk-neutral
at all doses”
McGettigan P, Henry D, PLoS Med, Sept 2011; 8(9):e1001098
Cardiovascular Risk with NSAIDs: Systemic Review of population-
Based Controlled Observational Studies

12. Objective
Study of the extent to which evidence on cardiovascular risk with NSAIDs is
reflected in Essential Medicines Lists (EMLs) and in data on sales across several
countries.
Use of NSAIDs that Elevate CV Risk
McGettigan P, Henry D, PLoS Med, Feb 2013; 10(2):e1001388

13. All NSAIDs were found to have a higher RR than Naproxen in pairwise
analyses in the most recent published meta-analysis.
The NSAIDs that had consistently higher CV risks were rofecoxib, etoricoxib
and diclofenac.
Given the availability of safer alternatives, diclofenac should be de-listed
from national EMLs.
We judged naproxen to have the lowest risk.
McGettigan P, Henry D, PLoS Med, Feb 2013; 10(2):e1001388
Use of NSAIDs that Elevate CV Risk

14. Cardiovascular risk
Naproxen
By contrast with other tNSAIDs,
high-dose naproxen was not associated
with any significant excess risk of
major vascular events (0.93),
and nor was there an increase in
major coronary events (0.84)
N. Bhala et al., Coxib and traditional NSAID Trialists’ (CNT) collaboration (N. Bhala et al.), May 30, 2013

15. Publication
2017

16. Clinical Pharmacology and Cardiovascular
Safety of Naproxen
Angiolillo D. J, Weisman S. M. , Am J Cardiovasc Drugs 2017; 17:197-107
 To discuss the cardiovascular safety profile of naproxen in the
context of the NSAIDs class
Objective
Study design
 Review of the totality of evidence regarding naproxen and CV safety in
the context of NSAIDs as a class

17. Cardiovascular events

18.  The use of coxibs or diclofenac significantly increased
major vascular events, major coronary events, and risk of
vascular death
 Ibuprofen use significantly increased major coronary
events but did not significantly increase risk of vascular
death or major vascular events
 Naproxen use did not significantly increase the risk of
major vascular events and did not result in an increased
risk of vascular death
Thromboembollic events
Angiolillo D. J, Weisman S. M. , Am J Cardiovasc Drugs 2017; 17:197-107

19.  RCTs published after 2005 reported that any NSAID
use does increase the risk of CHF-related hospital
admissions but COX-2-selective inhibitors and ibuprofen
use are associated with the highest risk, whereas naproxen
was associated with a lower, albeit nonsignificant, risk in
comparison
Congestive heart failure (CHF)
Angiolillo D. J, Weisman S. M. , Am J Cardiovasc Drugs 2017; 17:197-107

20. “Naproxen, which has low COX-2
selectivity, has been consistently
observed to possess a low,
or possibly even neutral,
Cardiovascular risk
compared with other NSAIDs”
Conclusion
Angiolillo D. J, Weisman S. M. , Am J Cardiovasc Drugs 2017; 17:197-107

21. Recommendations
AHA & American college of Gastroenterology
“The AHA and American College of
Gastroenterology have issued the
recommendations that naproxen should be
the NSAID of choice for patients
with high cardiovascular risk”
Angiolillo D. J, Weisman S. M. , Am J Cardiovasc Drugs 2017; 17:197-107

22. Publication
BMJ
2018

23. Diclofenac use and cardiovascular risks: series
of nationwide cohort studies
 To examine the cardiovascular risks of diclofenac initiation
compared with initiation of the other traditional NSAIDs,
initiation of paracetamol and no initiation.
Objective
Study design
 Series of 252 nationwide cohort studies, each mimicking the strict
design criteria of a clinical trial ( emulated trial design).
Schmidt et al., BMJ 2018; 362:k3426

24. Results

25.  The adverse event rate among diclofenac initiators
increased by 50% compared with non-initiators , 20% compared
with paracetamol or ibuprofen initiators and 30% compared with
naproxen initiators.
 The event rate of diclofenac initiators increased for each
component of the combined endpoint 1.2 for atrial fibrillation/Flutter,
1.6 for ischemic stroke, 1.7 for heart failure, 1.9 for MI and 1.7 for
cardiac death as well as for low doses of diclofenac compared with
non initiators.
Thromboembollic events
Schmidt et al., BMJ 2018; 362:k3426

26.  It is time to acknowledge the potential health risk of diclofenac
and to reduce its use.
 Diclofenac should not be available over the counter, and when
prescribed, should be accompanied by an appropriate front package
warning about its potential risks.
 Future trials should instead use low dose ibuprofen
(≤1200 mg/day) or naproxen (≤500 mg/day) as comparators
Conclusions & recommendations
Schmidt et al., BMJ 2018; 362:k3426

27. Publication
AAOS
2018

28. Mixed Treatment Comparisons
for
Nonsurgical Treatment of Knee
Osteoarthritis: A Network
Meta-analysis
(AAOS)
Jesevar S. et al., J Am Acad Orthop Surg 2018; 26:325-336

29. Objective
 To provide evidence-based method that determines the relative effectiveness of
NSAIDs, acetaminophen, IA corticosteroid injections, IAPRP injections, and IA HA
injections compared with oral placebo and IA placebo.

30. Study design
 Network Meta Analysis through Systematic search of all databases
 PubMed, EMBASE & Cochrane Central register of Controlled Trials (CENTRAL).
 53 references containing 56 included studies.
 No date limits were used. The most recent search for all databases was conducted on
October 7, 2015.
Data sources

31. Results
 When evaluating both pain reduction and functional improvement, the top 1 to 5 ranking
treatments are naproxen, IA corticosteroids, IA PRP, ibuprofen, and celecoxib.

32. Results

33. Conclusion
 Naproxen is the most effective sole treatment for improving pain and function compared
with other conservative KOA treatments. The combined greatest effect based on this NMA
would be a combination of an IA corticosteroid and naproxen.
 This NMA probability ranking, along with patient pain, function, and comorbidities, should be
used to optimize treatment for patients with symptomatic KOA.
 Future KOA research should use naproxen and IA corticosteroids as active comparators to
evaluate new or existing treatments.

34. Recommendations

35. FDA recommendations:
NSAIDS trials and the Choice of the Comparators
Psaty BM, Weiss NS. N Engl J Med. 2007; 356:328-330
The Arthritis and Drug safety and Risk Management
Advisory committees of the FDA recommended Naproxen
and not diclofenac as the “preferred comparator”
for large trials of Cox2 inhibitors.

36. EMA recommendations
EMEA/CHMP/410051/006
 Taking all available clinical trial and epidemiological data
into account, diclofenac, particularly at high dose
(150 mg/d) may be associated with an increased risk
of arterial thrombotic events.
 Clinical trial data suggest that ibuprofen at a high dose
(2400 mg/d) may be associated with an increased risk
of thrombotic events.

37. EMA recommendations
Clinical trial and epidemiological data suggest that
Naproxen(1000 mg/d) may be associated with a lower
risk of arterial thrombotic events than cox2 inhibitors,
but a small risk cannot be excluded.
EMEA/CHMP/410051/006

38. AHA recommendations
“Naproxen appears to be
the preferred choice”
Antmann et al. Circulation 2007;115:1634-1642

39. Reference Nonusers Reference Naproxen
IRR 95% CI
P
IRR 95% CI P
Serious coronary heart disease
Nonuser 69966 2231 1 Reference
Former 15604 489 0.95 0.86–1.05 0.3242
Naproxen 1908 49 0.88 0.66–1.17 0.3940 1 Reference
Ibuprofen 1613 60 1.18 0.92–1.53 0.1978 1.34 0.92–1.96 0.1280
Diclofenac 1311 47 1.27 0.95–1.70 0.1037 1.44 0.96–2.15 0.0761
Celecoxib 3140 108 1.03 0.85–1.25 0.7795 1.16 0.83–1.63 0.3798
Rofecoxib 2482 94 1.19 0.97–1.47 0.0948 1.35 0.96–1.91 0.0886
Serious cardiovascular
disease/death
Nonuser 69297 4061 1 Reference
Former 15424 887 0.96 0.89–1.03 0.2423
Naproxen 3404 163 0.91 0.78–1.06 0.2346 1 Reference
Ibuprofen 3322 214 1.14 0.99–1.30 0.0726 1.25 1.02–1.53 0.0322
Diclofenac 2436 170 1.38 1.18–1.61 <0.0001 1.52 1.22–1.89 0.0002
Celecoxib 4245 274 0.99 0.87–1.12 0.8341 1.09 0.89–1.32 0.4047
Rofecoxib 3641 238 1.07 0.94–1.22 0.2996 1.18 0.97–1.44 0.1046
Person-years
Wayne A. Ray et al. Journal of the American Heart Association, May 2009; 2:155-163
Occurrence of serious coronary
heart disease
In patients recently hospitalized for serious
coronary heart disease,
“Naproxen
had better cardiovascular safety”
than did diclofenac,
ibuprofen, and higher doses of celecoxib and rofecoxib

40. Major Vascular Events
AHA 2014
Carlo patrono & Colin Baigentet, Journal of the American Heart Association, Feb 2014; 129:907-916
Naproxen,
without any specification of dose,
is indicated as
“the preferred choice”
on the basis of meta-analyses
of randomized Trials
and observational studies