In China, NSAIDs are the second most prescribed drugs after antibiotics and are widely used for antipyretic, anti-inflammatory and analgesic purposes. Cardiovascular disease patients or patients with high risk factors for cardiovascular disease in combination with chronic bone and joint disease, various pain, trauma and acute and chronic inflammatory conditions doctors in various departments often give NSAIDs, because some NSAIDs are over-the-counter drugs, easy to buy in pharmacies, making many people wrongly believe that NSAIDs are harmless, and patients often buy and take them themselves without doctor’s guidance.
In fact, since 1998, NSAIDs have been found to cause elevated blood pressure, swelling, increased heart failure (heart failure), increased myocardial ischemic events, increased stroke, and increased mortality, and in recent years the evidence related to increased cardiovascular risk with NSAIDs has been enriched and more detailed. We should further enhance our understanding of this issue and fully assess the cardiovascular risk before using these drugs and choose them appropriately.
I. Review of events
The VIGOR trial in 2000 compared the gastrointestinal adverse effects of rofecoxib, a new NSAID cyclo-oxygenase 2 (COX-2) inhibitor, with those of naproxen, a traditional NSAID, in patients with rheumatoid arthritis, and concluded that rofecoxib caused fewer gastrointestinal adverse effects, but patients had an exponential increase in sudden heart attacks or strokes. Since then the curtain has been raised on the NSAID cardiovascular risk debate and concerns, and in September 2004 Merck withdrew rofecoxib from the market.
In early December 2004 the US Food and Drug Administration (FDA) announced a “black box” warning against vadixib in patients undergoing coronary artery bypass grafting (CABG), and 2 weeks later the National Institutes of Health (NIH) stopped a study of celecoxib for the prevention of colonic adenomas because of its increased cardiovascular risk. Only 3 d later the NIH prematurely terminated a study of naproxen and celecoxib for Alzheimer’s disease for the same reason.
Based on increased reports of increased thrombotic events with rofecoxib, celecoxib, and vadicoxib, the same month the FDA issued recommendations for all celecoxibs in the NSAID, and in February 2005 the FDA convened a committee to analyze the available evidence and keep celecoxib and vadicoxib on the market under the “black box” warning of cardiovascular disease risk. In February 2005, the FDA convened a committee to analyze the available evidence and kept celecoxib and vadixib on the market under the premise of using “black boxes” to warn of cardiovascular risks, and suggested that all NSAIDs have potential cardiovascular risks, and that patients with cardiovascular disease should avoid these drugs and require the manufacturers of these drugs to warn of this in their instructions, but two months later recommended that Pfizer withdraw vadixib from the market.
In February 2007, the American Heart Association (AHA) issued a statement that NSAIDs that pose a risk of cardiovascular disease should be avoided, COX-2 inhibitors should be avoided in patients with existing cardiovascular disease or at high risk of cardiovascular disease, and other types of painkillers should be used as much as possible. include: contraindicated in the treatment of perioperative pain in CABG, contraindicated in patients with severe heart failure, and used with caution in patients with a history of hypertension and/or heart failure (e.g., fluid retention and edema).
Also noted: can cause new onset of hypertension or exacerbate existing hypertension, may cause an increased risk of fatal serious cardiovascular thrombotic adverse events, myocardial infarction and stroke, all NSAIDs have similar risks; patients with cardiovascular disease or risk factors for cardiovascular disease are at greater risk, and physicians and patients should be alert to the occurrence of such events even in the absence of prior cardiovascular symptoms .
New evidence in recent years
Danish scholars analyzed 107092 heart failure discharges from 1995 to 2004 for rehospitalization and death. 33.9% of patients rehospitalized for heart failure had taken NSAIDs for 14-197 d (mean 60 d), including rofecoxib (5.7%), celecoxib (5.4%), isobufenacin (15.8%), diclofenac (8.8 %), naproxen (2.0%) and other NSAIDs (10.7%), a total of 60,974 (56.9%) patients died during the study period, with an increased risk of death associated with NSAID use, 8970 (8.4%) hospitalizations for myocardial infarction, and 39,984 (37.5%) readmissions for heart failure. The results found that high-dose diclofenac (>100 mg/d) increased the risk of death and myocardial infarction the most, followed by the risk of high-dose rofecoxib (>25 mg/d); high-dose rofecoxib increased the risk of heart failure the most, followed by the risk of high-dose diclofenac, and the risks were all dose-dependent. Low-dose isobutyric acid and naproxen did not increase the risk of death, with naproxen having the lowest risk.
Patricia et al. continued to focus on this topic, and in 2000 they published a study of a 2-fold increase in heart failure hospitalizations with NSAIDs, supporting 3 studies of new or traditional NSAIDs worsening heart failure, and in 2008 published new findings on the relationship between new-onset and re-onset heart failure and NSAIDs, finding interesting changes, with patients with re-onset heart failure after 2003 The rate of NSAID use was 15.4% in patients with recurrent heart failure and 28.4% in patients with new heart failure, and the rate of NSAID use in patients with recurrent heart failure was about half that of patients with new heart failure, and hospitalization for recurrent heart failure was not associated with this, but with low rates of beta-blocker use. This suggests that after 2003 Australian physicians have been significantly more cautious in using NSAIDs in patients with heart failure than before.
They published new findings in 2011, an analytical review of a large body of data, systematically analyzing 30 observational studies, 21 cohort studies, including a total of 2.7 million study subjects, in which a total of 184,946 cardiovascular events (myocardial infarction and myocardial infarction-related deaths) occurred. The studies covered more than a dozen NSAIDs: naproxen, isobutylpropionic acid, celecoxib, rofecoxib, diclofenac, indomethacin, and others. Among the most studied drugs (≥10 studies), those with the highest cardiovascular risk remained rofecoxib and diclofenac, with increased risk at low doses of rofecoxib, celecoxib, and diclofenac, and even higher at high doses; the lowest risk was with isobutymic acid and naproxen, with isobutymic acid also showing increased risk at high doses and naproxen with neutral results at all doses.
Among the less studied drugs etoricoxib, etodolac, and indomethacin had the highest risk: in comparative studies between single drugs, etoricoxib had a higher risk than isobutylpropionic acid and naproxen: etodolac had no difference in risk compared with naproxen and isobutylpropionic acid, naproxen had a significantly lower risk compared with isobutylpropionic acid, and the risk arose 7-14 d after rofecoxib, 14-30 d after celecoxib, isobutylpropionic acid, and butylpropionic acid 7d, and the highest risk emerged immediately after diclofenac use. It was concluded that naproxen and low-dose isobutyric acid, among the widely used DISAID substances, had the lowest potential to increase cardiovascular risk.
A network meta-analysis study of patients with osteoarthritis disease from Switzerland published in 2011, with information from literature databases, conference materials, FDA website materials, drug registry systems, and SCI retrievals of references and reports of relevant articles as of July 2009, looked primarily at myocardial infarction and secondarily at stroke, death due to cardiovascular disease, and death due to any cause. 2 The data were collected independently by the investigators. Data were analyzed for a total of 116,429 patients from 31 trials (115,000 patient-years of follow-up). It was concluded that taking all 7 NSAIDs significantly increased the risk of myocardial infarction, stroke, or death from cardiovascular disease. 7 common analgesics included naproxen, isobufenacic acid, diclofenac, celecoxib, etoricoxib, rofecoxib, and romexib.
The majority of patients surveyed were elderly and were themselves at risk for multiple cardiovascular diseases. Compared with placebo, the highest risk of myocardial infarction occurred with rofecoxib, followed by lumecoxib; the highest risk of stroke occurred with isobutyric acid, followed by diclofenac; the highest risk of cardiovascular death was with etoricoxib, followed by diclofenac, and naproxen had the fewest cardiovascular events. Experts in epidemiological research point out that network meta-analysis can provide a unified, coherent analysis of all randomized studies and can conduct comparative analyses between NSAIDs alone or with placebo, providing more convincing findings for the controversies raised by previous, smaller studies.
The results of a case-crossover analysis through the Taiwan Health Insurance Database published by Taiwanese scholars in 2012, which analyzed the risk of new myocardial infarction due to recent oral or intravenous NSAID use, controlled a total of 13.7 million NSAID users, of whom 8354 new myocardial infarctions met the inclusion criteria, with the use of 14 oral 1-30 d and 91-120 d prior to hospitalization NSAIDs and 3 intravenous NSAIDs (ketorolac, ketoprofen, and diclofenac), the study suggested that, as with celecoxib, both nonselective NSAID and intravenous use resulted in an elevated risk of myocardial infarction, with higher risk with intravenous use than with oral use (P<0.01).
Long-term heavy NSAID use increases the risk of cardiovascular disease, and short-term use is not promising. the SchjemingOlSen et al. study suggests that patients with a history of myocardial infarction are at increased risk even with short-term NSAID use. a total of 83,675 patients with a first myocardial infarction, mean age 68 years, were included in the study, 42% of whom were treated with NSAID. The risk of death and/or recurrence of myocardial infarction within week 1 of combined NSAID therapy was increased by 45%. Diclofenac had the highest risk, and isobufenac, rofecoxib, and celecoxib were associated with a significantly increased risk of death and/or recurrence of myocardial infarction within week 1, after 1 week of treatment, and after 14-30 d of treatment, respectively.
Studies have found an increased risk of paroxysmal or persistent AF with conventional NSAID use, with an increased risk beginning with use >30d and a higher risk in patients who have used it for more than 1 year. Another study reported an increased risk of AF with either conventional or novel NSAIDs in 32,602 patients with inpatient or outpatient AF versus 325,918 controls during 1999-2008 and found that NSAIDs significantly increased the incidence of AF and atrial flutter, with a 40%-70% increase in relative risk compared with controls (40% for non-selective NSAIDs 40% and 70% for COX-2 inhibitors).
III. Mechanisms of increased cardiovascular disease risk
It is believed that NSAID causes cardiovascular disease risk by a variety of mechanisms, the first is to inhibit the production of prostacyclin 2 (PGI2), a cardioprotective substance with anti-atherosclerotic, anti-thrombotic, anti-angiotensin II, vasodilatory and blood pressure-lowering effects, and can inhibit oxygen free radicals, inhibit platelet activation, increase renal blood flow, which is important for maintaining kidney function.
When PCI2 decreases, renal medullary blood flow decreases, urinary sodium excretion decreases, water and sodium retention increases, congestive heart failure and hypertension increase, thrombosis increases, and patients are prone to cardiovascular and cerebrovascular adverse effects, even leading to stroke, myocardial infarction and heart failure exacerbation; other mechanisms include impaired endothelial function, reduced nitric oxide. Another aspect is the enhanced production of leukotriene pathway by lipoxygenase pathway and enhanced inflammatory response.
NSAID works by inhibiting the synthesis of prostacyclin through cyclo-oxygenase (COX), of which there are two main subtypes, COX-1 and COX-2. COX-1, also known as the structural type, produces PGI2, which exists in normal tissues to stabilize and protect cells, and produces adverse effects such as gastrointestinal symptoms when inhibited; COX-2, also known as the inducible type, exists in damaged tissues and has strong inflammatory and pain-causing effects, and produces analgesic and anti-inflammatory therapeutic effects when inhibited.
Different selectivity of COX-1 and COX-2 produce different adverse effects, among which inhibition of COX-1 mainly produces gastrointestinal adverse effects. To reduce gastrointestinal adverse reactions, cyclooxygenase inhibitors that primarily inhibit COX-2 have been studied, but cardiovascular adverse reactions increase as gastrointestinal adverse reactions decrease.
According to the different types of cOx subtypes inhibition, NSAIDs can be divided into the following four categories: (1) COX-1 specific: only inhibit COX-1, no significant effect on COX-2. Currently only small doses of aspirin (<0.3g/d) are included in this category. (2) COX non-specific: i.e. inhibits both COX-1 and COX-2 such as isobutylpropionic acid, naproxen, diclofenac sodium, high-dose aspirin, indomethacin, piroxicam, etc. (3) COX-2 selective: i.e. inhibition of COX-2 does not significantly inhibit COX-1 (20/1 ratio of both), but also inhibits COX-1 at higher doses. e.g. meloxicam, clonoxicam, nimesulide, nabumetone, etodolac, etc. (4) COX-2 specificity (100/1 ratio of both): i.e. almost exclusively inhibits COX-2 and has no activity on COX-1. Such as rofecoxib and celecoxib.
The magnitude of NSAID cardiovascular adverse effects is currently considered to be in the following order: specific COX02 inhibitors > selective COX-2 inhibitors > non-selective COX inhibitors. Selective COX-1 inhibitors (such as low-dose aspirin) have cardiovascular protective effects, so taking low-dose aspirin has no cardiovascular risk but rather beneficial, because low-dose aspirin is the only selective COX-1 inhibitor, the selectivity of COX-1 is 166 times that of COX-2, and produces irreversible inhibition of platelet COX-1, and low-dose application can be better Inhibition of TXA2 synthesis has the effect of inhibiting TXA-dependent platelet aggregation without affecting prostacyclin (PGI2) synthesis.
Fourth, how to choose pain-relieving and anti-inflammatory drugs in clinical work
A group of 19 experts from 10 European countries, including specialists in rheumatology, cardiology and gastroenterology, published online in September 2010 a guideline article entitled How to use NSAIDs appropriately in patients with rheumatic diseases, which was published in the Annals of Rheumatic Diseases in May 2011. After evaluating the benefits/risks of using five NSAIDs: isobutalbital, diclofenac, naproxen, celecoxib, and etoricoxib alone or in combination with proton pump inhibitors (PPIs) in 144 patients with chronic rheumatic disease, it was noted that a combination of the following conditions were evaluated for patients: age ≥65 years, upper gastrointestinal disease, anticoagulant use such as warfarin or other antiplatelet agents such as clopidogrel use, systemic corticosteroid use, intermittent repeat or continuous treatment patterns, 10-year cardiovascular risk ≥10%, and low-dose aspirin use (in patients with cardiovascular risk).
The panel concluded that for patients with minimal risk of gastrointestinal and cardiovascular disease, the use of a nonselective NSAID (isobutalbital propionic acid, diclofenac, or naproxen) is reasonable; for patients with increased gastrointestinal risk, the use of the COX-2 inhibitors celecoxib and etoricoxib alone or the use of a nonselective NSAID plus a PPI is reasonable; and if the patient has a high gastrointestinal risk but an average cardiovascular risk isobutyric acid, diclofenac plus PPI or COX-2 inhibitor plus PPI is the best choice; if the patient has a high gastrointestinal and cardiovascular risk, it is recommended to avoid all NSAIDs or try to use diclofenac, naproxen, celecoxib or etoricoxib plus PPI for a short period of time and at low doses.
Another better approach is to first try acetaminophen or aspirin, which does not work, and then naproxen. However, it should be noted that acetaminophen has no effect on platelets and coagulation but has a weak analgesic effect, and attention should be paid to its hepatotoxicity.
For severe traumatic pain and pain caused by visceral smooth muscle spasm (except dysmenorrhea), the use of central nervous system analgesics is recommended. For acute pain, a combination of acetaminophen and opioids is recommended because they have a synergistic effect and their combined use can reduce the amount of opioids. Opioids can be used safely in patients with heart failure. Guidelines published by the American Geriatrics Society state that low-dose opioids are less life-threatening than long-term NSAID use for patients with persistent pain.
Colchicine has long been used to treat pain caused by acute gout, but on September 3, 2010 the FDA announced that marketing of colchicine drugs within the U.S. The FDA says the drug has not been validated by FDA review. Severe gout pain can be managed with opioids or a combination of opioids and acetaminophen. For neuropathic pain, it is recommended that a psychoneurological evaluation be performed first and that antidepressants, anxiolytics, or antiepileptics be used as appropriate for the diagnosis. Non-pharmacologic measures such as patient education, exercise, relaxation, meditation, physical therapy, and cognitive-behavioral therapy may also be used. Intensify monitoring when NSAID use is unavoidable and inform all patients of the risks of using NSAID medications.