COX enzymes play a range of roles in the body, including influencing the process of pain perception, protecting of the lining of the stomach and digestive tract, and maintaining the function of blood vessels.
In the perception of pain, two main COX enzymes are involved: COX-1 and COX-2. Non-selective NSAIDs, such as ibuprofen, affect both enzymes. However, the COX-1 enzyme also plays a role in protecting the lining of the stomach and digestive tract, which has a direct correlation between COX-1 inhibition and increased risk of gastrointestinal complications.1 This situation led to the development of selective COX-2 inhibitors, which could block pain signals, but would not affect the digestive tract.
However, both COX-1 and COX-2 also play roles in maintaining the function of blood vessels and in other processes important for the function of the heart, such as effects on the kidney that ultimately increase blood pressure.1 It is the consequences of blocking the effects of COX enzymes on these important biological pathways that leads to the increase in the risk of CVD events.
What types of CVD events are more likely if NSAIDs are taken?
NSAIDs have been associated with an increased risk of CVD events or with the worsening of the CVD risk profile. NSAIDs are reported to increase the risk of congestive heart failure, especially in people with pre-existing heart disease.2-5 NSAIDs also increase the risk of heart attacks,6,7 stroke8 and death from cardiovascular events.8,9 Furthermore, NSAIDs can increase blood pressure both through actions on the kidney that lead to the release of hormones that narrow the blood vessels, and through reducing the efficacy of some antihypertensive agents.10-13
Do NSAIDs affect the efficacy of CVD medicines?
There are at least two situations where evidence suggests NSAIDs may reduce the efficacy of CVD medicines. The first is that NSAIDs, in particular ibuprofen, may reduce the protective effect of low-dose aspirin. In an analysis of a subset of individuals involved in the large Physicians Health Study, the long-term use of NSAIDs (>60 consecutive days) negated the protective effects of low-dose aspirin.14 A further study monitored the effects of taking or not taking NSAIDs in combination with low-dose aspirin in 7,107 patients with known CVD. After 3.3 years of monitoring, those taking ibuprofen were 73% more likely to die from CVD events than those not taking ibuprofen.15
NSAIDs can also interfere with the efficacy of some widely-used antihypertensive agents. The effects are greatest when NSAIDs are given in combination with angiotensin-converting enzyme (ACE) inhibitors and b-blockers. This is because these agents rely on increasing the production of prostaglandins to decrease blood pressure and NSAIDs act in the opposite way to block production of prostaglandins.11
Does paracetamol increase the risk of CVD events?
Paracetamol has a different mode of action to NSAIDs and is unlikely to influence heart function by the same mechanisms as NSAIDs. Therefore, paracetamol may be considered first choice for patients with, or at risk of, cardiovascular disease.
- Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 2004;56(3):387-437.
- Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Arch Intern Med 2000;160(6):777-84.
- Huerta C, Varas-Lorenzo C, Castellsague J, Garcia Rodriguez LA. Nonsteroidal anti-inflammatory drugs and risk of first hospital admission for heart failure in the general population. Heart 2006.
- Merlo J, Broms K, Lindblad U, Bjorck-Linne A, Liedholm H, Ostergren PO, et al. Association of outpatient utilisation of non-steroidal anti-inflammatory drugs and hospitalised heart failure in the entire Swedish population. Eur J Clin Pharmacol 2001;57(1):71-5.
- Heerdink ER, Leufkens HG, Herings RM, Ottervanger JP, Stricker BH, Bakker A. NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med 1998;158(10):1108-12.
- Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004;364(9450):2021-9.
- 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.
- Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352(11):1071-80.
- Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006;332:1302-1308.
- Gaziano JM, Gibson CM. Potential for drug-drug interactions in patients taking analgesics for mild-to-moderate pain and low-dose aspirin for cardioprotection. Am J Cardiol 2006;97(9A):23-9.
- Whelton A. Clinical implications of nonopioid analgesia for relief of mild-to-moderate pain in patients with or at risk for cardiovascular disease. Am J Cardiol 2006;97(9A):3-9.
- Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med 1993;153(4):477-84.
- Johnson AG, Simons LA, Simons J, Friedlander Y, McCallum J. Non-steroidal anti-inflammatory drugs and hypertension in the elderly: a community-based cross-sectional study. Br J Clin Pharmacol 1993;35(5):455-9.
- Kurth T, Glynn RJ, Walker AM, Chan KA, Buring JE, Hennekens CH, et al. Inhibition of clinical benefits of aspirin on first myocardial infarction by nonsteroidal antiinflammatory drugs. Circulation 2003;108(10):1191-5.
- MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet 2003;361(9357):573-4.