Cardiovascular Risk with Non-steroidal Anti-inflammatory Drugs: Clinical ImplicationsIn Februarythe US Cardiovasculwr and Drug Administration FDA convened an advisory committee meeting to discuss the accumulated data relating to the cardiovascular risk of non-steroidal anti-inflammatory drugs NSAIDs and the potential implications on the class prescription labeling. The committee recommended, though not unanimously, that 1 the current data does not support the conclusion that naproxen has a lower risk of thrombotic events than other NSAIDs; 2 there is no latency period for the low t test kit of cardiovascular thrombotic events; 3 there are some patient populations at increased risk for events; and 4 equipoise remains in the major ongoing trial designed to address these issues further. The clinical implications of the FDA deliberations as well as the recently published meta-analyses and observational studies are discussed. With the information available today, there is insufficient evidence to conclude that there are significant differences between the approved NSAIDs with regard to the potential for cardiovascular events. Prescription non-steroidal anti-inflammatory drug NSAID use is prevalent in the USA, reflecting the aging of the population nkn the concomitant rise in musculoskeletal diseases, particularly osteoarthritis OA and rheumatoid arthritis RA. From October to Septemberthe top assessment report for non steroidal anti inflammatory drugs nsaids and cardiovascular risk NSAIDs accounted for nearly 86 million dispensed prescriptions for 44 million unique patients [ 1 ].
Cardiovascular Risk with Non-steroidal Anti-inflammatory Drugs: Clinical Implications
Observational studies and meta-analyses have shown that the administration of nonsteroidal anti-inflammatory drugs NSAIDs , especially when prescribed at high doses for long periods of time, can potentially increase the risk of cardiovascular diseases. The increased thrombotic risk related to the use of NSAIDs is mainly due to their cyclooxygenase 2 selectivity. The dosage use, the formulation selected and the duration of the therapy are other factors that can significantly impact on the cardiovascular risk.
Despite the baseline cardiovascular and gastrointestinal risk of each patient, monitoring of patients is suggested for increases in blood pressure, development of edema, deterioration of renal function, or gastrointestinal bleeding during long-term treatment with NSAIDs.
The use of nonsteroidal anti-inflammatory drugs NSAIDs can be associated with a wide spectrum of adverse events AEs affecting the cardiovascular CV , cerebrovascular and gastrointestinal GI systems, the kidney, the liver and the skin.
In fact, COX-2 inhibition can damage the endothelium, leading to a prothrombotic state which increases the CV risk. Although the absolute CV NSAID-related risk may be relatively low, the widespread diffusion of these molecules make their impact on CV disease a considerable issue in clinical practice worldwide.
Unfortunately, NSAID-related AEs are mainly due to their mechanism of action, therefore the absence of risk associated with their use is a utopian target in daily practice. Prioritization was given to information arising from data collected in randomized controlled trials and meta-analyses.
The lower the value of IC80, the higher the potency. As suggested in previous literature, the extent of inhibition of COXdependent prostacyclin may represent an independent key determinant of the increased risk of myocardial infarction MI among NSAIDs with nonfunctional suppression of platelet COX Therefore, the assessment of whole blood COX-2 may represent a surrogate end point to predict the CV risk of these drugs.
In fact, as shown by Warner and colleagues, 16 nimesulide is a preferential COX-2 inhibitor but in contrast to coxibs, it seems to exhibit no significant CV toxicity. Moreover, Lapi and colleagues 19 recently showed that nimesulide does not show a statistically significant increase in the number of cerebrovascular events. The extent of patient exposure in terms of dose and duration might represent another important determinant of CV risk. Since a linear relationship exists between the degree of inhibition of COX-2 and the degree of inhibition of PGI2 in vivo , reduction of the dose could translate into a reduction of the CV risk.
In fact, it has been shown that even a dose of diclofenac as small as 25 mg, administered orally, is effective in the treatment of postoperative acute pain. A similar result was achieved in same clinical context by a recent study by Dietrich and colleagues 23 in which the subcutaneous administration of 25 and 50 mg of diclofenac proved to be equally effective as a higher dose of 75 mg. Finally, an important determinant of the differences among NSAIDs in terms of therapeutic and toxic effects might be represented by the pharmacokinetic features such as half life and type of formulation, which can influence the extent and duration of patient exposure.
Much of the data are therefore derived from observational studies and meta-analyses rather than randomized controlled trials. In a study by Lapi and colleagues, 19 a cohort of 29, patients with a diagnosis of osteoarthritis OA treated with NSAIDs were evaluated to determine whether the use of NSAIDs is associated with an increased risk of cerebrovascular events.
In a study period of 10 years, the authors identified cases of cerebrovascular events without any correlation between current use of NSAIDs compared with past use. Among individual NSAIDs, diclofenac and ketoprofen were significantly associated with an increased rate of cerebrovascular events. The most frequent event was hemorrhagic stroke following the use of ketoprofen. Another study assessed the risk of nonfatal ischemic stroke related to NSAIDs in patients, considering also the effects of dose, exposure and independent CV risk: The concomitant use of aspirin did not show a significant effect modification.
High dosages of naproxen exert a near complete COX-1 inhibition, which suggests a possible protective effect for MI compared with rofecoxib. Few systematic reviews have analyzed the possible correlation between NSAIDs and cerebrovascular events. In , a large meta-analysis including 85, patients from 40 trials comparing COX-2 inhibitors with either placebo or nonselective NSAIDs demonstrated no increase in stroke risk.
Rofecoxib and celecoxib showed the smallest risk estimates for stroke, while ibuprofen and diclofenac showed the highest risk. Another meta-analysis in compared coxibs with placebo, diclofenac, ibuprofen or naproxen. The authors found no association between any NSAID and stroke events, although they again highlighted the small incidence of events.
Caution suggests considering alternative analgesics in specific high-risk patient populations, such as older people, and to limit the duration of therapy whenever possible. As reported by Lapi and colleagues, 19 a possible explanation for the increased risk of cerebrovascular events related to the use of NSAIDs could be their effect on blood pressure.
The blockage of the COX enzyme and the relative inhibition of prostaglandin PG synthesis, 37 which induces vasoconstriction, as well as volume expansion, due to impaired sodium excretion, all seem to play an important role.
Hypertension is commonly reported by patients older than 65 years with a diagnosis of osteoarthritis. The frequent coadministration of antihypertensive agents and NSAIDs in this population has led Kalafutova and colleagues 28 to review their potential interaction.
The impact of NSAIDs on the effectiveness of antihypertensive therapy is mainly related to the role of PGs in the mechanism of action of each class of antihypertensives. NSAIDs decrease their effect leading to an increased retention of water and salts. In fact, their antihypertensive effect is not dependent on the action of PGs. In contrast to the evidence for an NSAID hypertensive effect, in a study among patients with hypertension and coronary disease, it was found that chronic NSAID use for nearly 3 years was actually associated with slightly lower blood pressure levels compared with nonuse.
The review related to the safety profile of NSAIDs and coxib, conducted by the Committee for Medicinal Products for Human Use CHMP and started in , concluded that, if properly prescribed, the benefits of nonselective NSAIDs outweigh their risks, even though a small increased incidence of thrombotic events associated with their use could not be excluded.
In , the EMA also concluded that a small increased risk of thrombotic events could not be excluded with nonselective NSAIDs, including diclofenac, particularly when they are used at high doses for long-term treatment. Based on the epidemiological data and the SOS findings, CHMP concluded its revision in with the opinion that current treatment advice adequately reflects the knowledge regarding the safety and efficacy of naproxen and ibuprofen, but they decided to modify advice related to diclofenac.
This edition also highlighted updated prescribing advice for aceclofenac, which is now contraindicated in people with certain CV disease, in line with diclofenac and COX-2 inhibitors. Diclofenac is among the most prescribed NSAIDs due to its favorable GI safety profile and efficacy for pain relief, but showed a dose-related CV effect, which increases for the higher doses and becomes comparable to the coxibs.
The panel stated the following: However, the risk of GI events was significantly lower with celecoxib than with naproxen or ibuprofen, while the risk of renal events was significantly lower with celecoxib than with ibuprofen and comparable to naproxen.
Despite some previous data suggesting a possible association of paracetamol with CV risk 46 due to its effect on blood pressure, 47 a retrospective analysis by Fulton and colleagues 48 confirmed the safety of acetaminophen after collecting data from the UK Clinical Research Practice Datalink. No relationship could be found between verified acetaminophen prescription data and risk of MI or stroke in patients with hypertension over a year period.
Among the 10, acetaminophen-exposed individuals aged at least 65 years, there was no relationship between risk of MI, stroke or any CV event and acetaminophen exposure compared with the 13, individuals not exposed.
The safety of paracetamol was also confirmed in another cohort study of 36, patients diagnosed with OA and with a first-time prescription of NSAIDs between and These findings support the choice of acetaminophen therapy for OA-related pain, especially in those patients presenting with cerebrovascular and CV morbidities or related risk factors.
The efficacy of paracetamol and selective NSAIDs has been compared, postulating celecoxib to be superior to acetaminophen in acute postoperative pain relief. Data were confirmed in a Cochrane review comparing the safety and efficacy of acetaminophen with placebo and NSAIDs: The review also found that acetaminophen was superior to placebo on several pain measures while no significant WOMAC score differences were demonstrated between treatments.
The clinical decision-making process, leading to the prescription of NSAIDs, involves the selection of a significant number of molecules, types of preparations and dosages. In particular, a review of the medical history including advanced age, history of GI ulcer, hypertension, ischemic heart disease, kidney diseases and concomitant treatment with corticosteroids, aspirin, anticoagulants and antihypertensive drugs is essential Table 2. In the last few years, the literature has shown that NSAIDs are nonhomogeneous as a drug class and there are vast differences between individual molecules, not only in terms of AEs but also in their efficacy.
Recently, da Costa and colleagues 57 published a network meta-analysis assessing the effectiveness of different preparations and doses of NSAIDs used to treat OA-related pain. The authors considered trials published between and , with at least patients per group, comparing any of the following interventions: The study included 74 randomized trials with a total of 58, patients.
The treatment effect was evaluated in terms of improving function and pain relief. In fact, the approved maximum daily dose of diclofenac showed an effect size of 1. Compared with the other NSAIDs, celecoxib, diclofenac and naproxen showed a linear correlation between analgesic effect and dose.
The difference in terms of CV and GI risks among the NSAIDs and the availability of different formulations and dosages allow therapies to be customized according to the characteristics of every single patient Table 3. If the patient presents a considerable CV risk, COX-2 selective inhibitors, as well as high doses of diclofenac and ibuprofen, are contraindicated.
If the patient already takes low doses of acetil salicilic acid for secondary CV prophylaxis, naproxen is considered the best choice for coadministration for short periods of time; it should be administered 2 h after the aspirin in order not to interfere with its mechanism of action.
Potentially, this increase can be very serious because even a relatively slight elevation in blood pressure less than 5 mmHg can contribute to increased occurrence of ischemic events or heart failure. In the face of recent and growing concerns associated with the efficacy and safety profile of the most commonly used medications in the chronic treatment of pain, the importance of to depriving patients of their legitimate need for pain relief must be underlined.
Despite the baseline CV and GI risk of each patient, it is suggested that patients are monitored for increases in blood pressure, development of edema, deterioration of renal function or development of GI bleeding during long-term NSAID therapy.
The take-home message of current guidelines is therefore to use NSAIDs at the lowest effective dose and for the shortest period of time. Conflict of interest statement: Lapi provided consultations in protocol preparation for epidemiological studies and data analyses for IBSA and Angelini. Ghisi has no conflicts of interest to disclose. National Center for Biotechnology Information , U. Ther Adv Drug Saf. Published online Feb Received May 16; Accepted Jan 4.
This article has been cited by other articles in PMC. Abstract Observational studies and meta-analyses have shown that the administration of nonsteroidal anti-inflammatory drugs NSAIDs , especially when prescribed at high doses for long periods of time, can potentially increase the risk of cardiovascular diseases.
Background The use of nonsteroidal anti-inflammatory drugs NSAIDs can be associated with a wide spectrum of adverse events AEs affecting the cardiovascular CV , cerebrovascular and gastrointestinal GI systems, the kidney, the liver and the skin.
Open in a separate window. Beyond the ischemic cardiopathy: NSAIDs and their effect on blood pressure As reported by Lapi and colleagues, 19 a possible explanation for the increased risk of cerebrovascular events related to the use of NSAIDs could be their effect on blood pressure.
NSAIDs in clinical practice The clinical decision-making process, leading to the prescription of NSAIDs, involves the selection of a significant number of molecules, types of preparations and dosages. Use the lowest effective dose for a shorter period of time If prescribed as an analgesic drug, stop administration after 7 days if no benefit is reported If prescribed as an anti-inflammatory drug, stop administration after 3 weeks if no benefit is reported If it is possible avoid concomitant therapy with corticosteroids, anticoagulants, low-dose aspirin or antiplatelet agents.
NSAID, nonsteroidal anti-inflammatory drug. Conclusion In the face of recent and growing concerns associated with the efficacy and safety profile of the most commonly used medications in the chronic treatment of pain, the importance of to depriving patients of their legitimate need for pain relief must be underlined. Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population. J Am Coll Cardiol ; Drug Saf ; Risk of upper gastrointestinal complications in a cohort of users of nimesulide and other nonsteroidal anti-inflammatory drugs in Friuli Venezia Giulia, Italy.
Pharmacoepidemiol Drug Saf ; Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Acta Biomedica ; Assessment report for diclofenac containing medicinal products systemic formulations. Do selective cyclo-oxygenase inhibitors eliminate the adverse events associated with nonsteroidal anti-inflammatory drug therapy? Eur J Gastroenterol Hepatol ; 14 Suppl.