Download An update on nonsteroidal anti

Review
An update on nonsteroidal
anti-inflammatory drugs and
cardiovascular risk. Part 1
Jacky van Schoor, MPharm
Amayeza Info Services
Correspondence to: Jacky van Schoor, e-mail: [email protected]
Keywords: update, nonsteroidal anti-inflammatory drugs, NSAIDs, cardiovascular risks, CV risk
Abstract
Guidelines for the prevention of nonsteroidal anti-inflammatory drug (NSAID)-related gastrointestinal ulceration and cardiovascular
(CV) complications have recently been made available through an initiative designed in collaboration with leading specialists in South
Africa. For the purposes of this publication, the prevention of CV complications, and that of NSAID-related gastrointestinal ulceration,
are discussed in two articles. The first article in this two-part series presents an update on NSAID-related CV complications and how to
reduce NSAID-associated CV risk.
© Medpharm
S Afr Pharm J 2014;81(1):19-21
Introduction
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the
most commonly used medicines in the world, used by more
than 30-million people every day.1 However, their long-term use
is associated with a well-recognised spectrum of adverse effects,
and in particular, those involving the cardiovascular (CV) and the
gastrointestinal systems.1
NSAIDs vary in their chemical structure and relative ability to
block cyclo-oxygenase (COX)-1 and COX-2 isoenzymes. Traditional
NSAIDs, such as indomethacin, naproxen, ibuprofen and
diclofenac, are associated with greater COX-1 selectivity and a
higher risk of gastrointestinal events.2 The introduction of the COX2 selective NSAIDs early in the last decade offered prescribers and
patients an alternative to traditional NSAIDs with similar efficacy,
but improved gastrointestinal tolerability.1 COX-2 selective NSAIDs
were associated with a lower risk of gastrointestinal events than
the traditional NSAIDs.2 However, it soon became evident that
increasing degrees of COX-2 selectivity appeared to be associated
with augmented CV risk, and amid concerns about CV safety,
resulted in the withdrawal of the selective COX-2 inhibitors,
rofecoxib and valdecoxib, in the mid-2000s.1,3
Nonsteroidal anti-inflammatory drugs and the
cardiovascular system
NSAIDs are associated with an increased risk of CV events, such as
myocardial infarction (MI), heart failure and hypertension, and this
increase in risk appears to be dependent on the choice of NSAID,
the associated dose, as well as the duration of exposure.1
CV and renal risks associated with NSAIDs are summarised in Table I.
Several factors modify CV risk associated with NSAIDs.
Patient factors
The risk of a CV event in patients without known CV disease can be
calculated using the modified Framingham risk score.9 However,
it is difficult to provide estimates of CV risk in patients with
established CV disease.3
Table I: Cardiovascular and renal risks associated with nonsteroidal anti-inflammatory drug use
Aggravates hypertension
• The observed rise in blood pressure varies widely among individuals4
• Cardiovascular mortality increases 2.6 times in chronic users4
Precipitates acute myocardial
infarction
• Current use has been associated with a 24-55% increase in the risk of myocardial infarction in patients with and
without pre-existing coronary heart disease5
Precipitates heart failure
• Increases the incidence of heart failure by 2-10 times6
• Reduces the efficacy of diuretic therapy7
Precipitates or aggravates
kidney injury
• Nonsteroidal anti-inflammatory drugs are the second most common cause of drug-induced nephrotoxic acute
renal failure8
• Nonsteroidal anti-inflammatory drugs constitute a particular risk in intravascular volume-depleted states, such as
heart failure, cirrhosis with ascites, chronic renal failure and gastrointestinal fluid loss8
S Afr Pharm J
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2014 Vol 81 No 1
Review
Choice of nonsteroidal anti-inflammatory drug
More recently, it has become evident that all NSAIDs are capable of
causing CV complications, but that CV risk increases as treatment
choice progresses from aspirin to the traditional NSAIDs, to the
partially selective COX-2 inhibitors and to the highly selective
COX-2 inhibitors.3
A 2006 meta-analysis that compared the effects of different
COX-2 inhibitors found that there was a significant increase in
the incidence of serious vascular events with COX-2 inhibitors
compared with placebo, and that it was primarily owing to an
increased risk of MI.10 In this study, high-dose diclofenac and highdose ibuprofen, but not high-dose naproxen, were also associated
with an increased risk of vascular events.10
A 2011 systematic review of controlled observational studies that
compared the risks of CV events with individual NSAIDs, found
that of the extensively studied NSAIDs (10 or more published
studies available), the highest overall risk was seen with rofecoxib
and diclofenac, and the lowest overall risk with ibuprofen and
naproxen. In addition, naproxen was found to be risk-neutral at all
doses, and unlike ibuprofen, was not associated with an increased
risk at higher doses.11
A 2011 network analysis of CV safety data on seven NSAIDs
and placebo found that compared with placebo, rofecoxib was
associated with the highest risk of MI, followed by lumiracoxib.12
Ibuprofen was linked to the highest risk of strokes, followed by
diclofenac. Etoricoxib and diclofenac were connected to the
highest risk of CV death.12
The 2013 Coxib and traditional NSAID Trialists’ (CNT) collaboration
meta-analysis of individual participant data from clinical
trials concluded that major vascular events were increased
by approximately one-third by a coxib or diclofenac, mainly
because of an increase in major coronary events.13 Naproxen
did not significantly increase major vascular events.13 The CNT
collaboration concluded that high-dose naproxen is associated
with less vascular risks than other NSAIDs.13
In summary, naproxen appears to be the least harmful in CV terms.
However, this CV advantage needs to be considered in conjunction
with the gastroinstestinal risk profile of naproxen, and the need
for concomitant prescription of a proton-pump inhibitor for many
patients.12
Reducing cardiovascular risk
The American Heart Association (as well as several other guidelines)
recommends that when contemplating long-term NSAID therapy
in patients requiring treatment for musculoskeletal pain:1
• All NSAIDs should be used at their lowest effective dose and for
the shortest possible duration
• All NSAIDs, and particularly COX-2 inhibitors, should be
avoided where possible in patients with CV risk factors, such as
Review
hypertension, hypercholesterolaemia, angina, oedema, recent
bypass surgery and a history of MI or other CV events
3.
Antman EM, Bennet JS, Daugherty A, et al. Use of nonsteroidal anti-inflammatory drugs: an
update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007;115(12):1634-1642.
• The CV risk for all other patients should be estimated using the
modified Framingham risk score9
4.
Bavry AA, Khaliq A, Gong Y, et al. Harmful effects of NSAIDs among patients with hypertension and coronary artery disease. Am J Med. 2011;124(7):614-620.
5.
Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population
based nested case-control analysis. BMJ. 2005;330(7504):1366.
6.
Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure
in elderly patients. Arch Intern Med. 2000;160(6):777-784.
7.
Heerdink ER, Leufkens HG, Herings RMC, et al. NSAIDs associated with increased
risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med.
1998;158(10):1108-1112.
8.
Ejaz P, Bhojani K, Joshi VR. NSAIDs and kidney. J Assoc Physicians India. 2004;52:632-640.
9.
Klug E, South African Heart Association, Lipid and Atherosclerosis Society of Southern Africa. South African dyslipidaemia guideline consensus statement. S Afr Med J 2012;102(3
Pt 2):177-188.
• Naproxen is recommended as the NSAID of choice when NSAID
therapy is required for patients at risk of CV complications.
Conclusion
All NSAIDs are associated with varying degrees of CV, as well as
gastrointestinal, risk. The choice of NSAID and several patient
factors need to be taken into consideration when making
treatment decisions. Many NSAIDs are available over-the-counter
in the pharmacy. Based on findings from the latest research,
pharmacists need to counsel patients on the appropriate use of
NSAIDs, and ensure that patients use these effective medicines to
the greatest benefit with the least possible risk.
References
1.
Conaghan PG. A turbulent decade for NSAIDs. Update on current concepts of classification,
epidemiology, comparative efficacy, and toxicity. Rheumatol Int. 2012;32(6):1491-1502.
2.
Laine L, White WB, Rostom A. COX-2 selective inhibitors in the treatment of osteoarthritis.
Semin Arthritis Rheum. 2008;38(3):165-187.
10. Kearney PM, Baigent C, Godwin J, et al. Do selective cyclo-oxygenase-2 inhibitors and
traditional non-steroidal anti-inflammatories increase the risk of atherothrombosis? Metaanalysis of randomised trials. BMJ. 2006;332(7553):1302-1308.
11. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs.
Systematic review of population-based controlled observational studies. PLoS Med.
2011;8(9):1-18.
12. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086.
13. Coxib and traditional NSAID Trialists’ (CNT) collaboration, Bhala N, Emberson J, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769-779.
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