American Heart Association warns NSAIDs cause MI

ASPIRIN prevents MI, Cancer, and Alzheimer's disease
Celebrex and COX-2 inhibitors--American Heart Association Warnings
American Heart Association warns NSAIDs cause MI
COX-2 Inhibitors, their deadly mechanism
AHA on COX inhibitors
NSAIDs & Myocardial Infraction Risk--only ASPIRIN is safe
How VIOXX kills--jk
COX-2 INHIBITORS not as good as Ibuprofen
Continued Risk after taking VIOXX
HYDROCODONE--Opiates work for pain management
Acetaminophen, causes asthma, liver failure, & male infertility,
Acetaminophen causes male infertility
Liver failure Acetaminophen
Acetaminophen leading drug cause of liver damage
Acetaminophen increase ASTHMA risk 63%
Asthma risk and acetaminophen
Warfarin Number 1 Causes of Hospital Emergencies--WP


Accumulated evidence that nonsteroidal anti-inflammatory drugs (NSAIDs), with the exception of aspirin, increase risk for heart attack and stroke—American Heart Association release


New York Times  http://www.nytimes.com/2008/11/12/health/12attack.html


Painkiller Risk Found for Heart Patients

By BLOOMBERG NEWS, Published: November 11, 2008

Heart attack and heart failure patients have a higher risk of a second heart attack or death if they take painkillers, including the generic drug ibuprofen and Celebrex, made by Pfizer, a Danish study has found.   Patients who had suffered a heart attack and were taking Vioxx, a painkiller that has been withdrawn from the market, had 2.7 times the risk of having another heart attack or dying compared with patients not taking painkillers, according to research presented Tuesday at the American Heart Association meeting in New Orleans. Patients taking Celebrex had double the risk; patients taking the generic diclofenac had 1.9 times the risk, and those taking ibuprofen had 1.3 times the risk, the study found.

Based on the findings, doctors should avoid prescribing nonsteroidal anti-inflammatory drugs for these patients, or give them at low doses, a researcher said.

Also Tuesday, researchers said that the risk of heart attacks and strokes for heart-stent patients taking the anti-clotting drug Plavix increased if they also took anti-ulcer medicines like Nexium.

Doctors implant about two million stents a year and often prescribe blood thinners like Plavix, made by Bristol-Myers Squibb and Sanofi-Aventis, to avoid clots. But the drugs raise the risk of stomach bleeding, so they also prescribe Nexium, made by AstraZeneca, or a rival drug in a group known as proton pump inhibitors. About a third of these patients suffered complications within a year, the study said.  So What’s wrong with aspirin—stomach bleeding is under 4%--jk. 

American Heart Association


AHA Statement

AHA statement recommends doctors change approach to prescribing pain relievers for patients with or at risk for heart disease

American Heart Association Scientific Statement

DALLAS, Feb. 27 — Many doctors should change the way they prescribe pain relievers for chronic pain in patients with or at risk for heart disease based on accumulated evidence that nonsteroidal anti-inflammatory drugs (NSAIDs), with the exception of aspirin, increase risk for heart attack and stroke, according to an American Heart Association statement published today in Circulation: Journal of the American Heart Association.

“We believe that some physicians have been prescribing the new COX-2 inhibitors as the first line of treatment.  We are turning that around and saying that, for chronic pain in patients with known heart disease or who are at risk for heart disease, these drugs should be the last line of treatment,” said Elliott M. Antman, M.D., FAHA, lead author of the American Heart Association scientific statement and professor of medicine at Harvard Medical School and Brigham and Women’s Hospital.

“We advise physicians to start with non-pharmacologic treatments such as physical therapy and exercise, weight loss to reduce stress on joints, and heat or cold therapy.  If the non-pharmacologic approach does not provide enough pain relief or control of symptoms, we recommend a stepped-care approach when it comes to prescribing drugs.  Take into account the patient’s health history and consider acetaminophen, aspirin and even short-term use of narcotic analgesics as the first step.  If further relief is needed, physicians should suggest the least selective COX-2 inhibitors first, moving progressively toward more selective COX-2 inhibitors, which are at the bottom of the list, only if needed. All drugs should be used at the lowest dose necessary to control symptoms and prescribed for the shortest time possible.”

Drugs in the NSAIDs class inhibit cyclooxygenase (COX), an enzyme system that comes in two major forms: COX-1, which the body produces constantly in most tissues, and COX-2, produced during the body’s inflammatory response. Because COX-1 is also protective of the gastrointestinal (GI) tract, long-term use of drugs that suppress COX-1, such as aspirin, have been associated with gastrointestinal complications, including ulcers[1].  “Selective” COX-2 inhibitors were developed to avoid the GI complications of traditional NSAIDs, not because they had advantages in terms of pain relief, Antman said.

However, multiple studies have indicated an increased risk of cardiovascular disease (CVD) complications from COX-2 selective NSAIDS, particularly in patients with prior CVD or risk factors for CVD.[2]  

“Recent studies indicate that the cells lining the blood vessels have more of the COX-2 enzyme than initially thought. So it’s possible that inhibiting the COX-2 pathway can make a person’s blood more likely to clot.  There is also an increase in sodium and water retention, which in turn could worsen heart failure and produce high blood pressure,” Antman said.  “The more you inhibit COX-1, the greater the increase in GI risk; the more you inhibit COX-2 the greater the cardiovascular risk.”

The scientific statement comes two years after the association released the last one on the issue.  It was prompted, in part, by new analyses indicating that the increased cardiovascular risk associated with COX-2 selective NSAIDs may also extend to less selective traditional NSAIDs.

The statement includes details from a meta-analysis indicating that, compared with placebo, COX-2 selective drugs seem to increase the risk of a heart attack by about 86 percent.   The statement also points out that two common NSAIDs traditionally thought of as non-selective – diclofenac and ibuprofen – appear to increase the relative risk of cardiovascular disease. In the last two years, the U.S. Food and Drug Administration (FDA) added warning statements to NSAIDs, other than aspirin, pointing out the increased risk for cardiovascular events.

One non-selective NSAID, naproxen, did not seem to increase CVD risk in these analyses. However, Antman pointed out that although naproxen appeared safer than the other NSAIDs, relatively few studies have been done with naproxen and doctors should continue to be cautious about prescribing it as well, pending more information.

“This is a fast-moving field with new information available from multiple sources," Antman said. "We feel the most important thing the American Heart Association can do is to give practical advice to clinicians who treat cardiac patients with pain every day.”

Because there are so many drugs in the NSAID class and because they can affect either COX-1 or COX-2 or both, it is very important to know where a given drug falls in the range of selectivity, particularly when evaluating the results of head-to-head comparisons of different drugs, Antman said.  The statement contains guidance that helps doctors see where individual drugs lie on the continuum of COX-1 versus COX-2 selectivity.

Selective COX-2 inhibitors have been in the news since the FDA removed the selective COX-2 inhibitor, rofecoxib, from the market in 2004.   Since then, other COX-2 selective drugs have been removed from the market in the United States and other countries.  One selective COX-2 inhibitor, celecoxib, remains on the market, but warnings on it were strengthened and the FDA advised that patients with a history of CVD or risk factors for CVD should be informed of the possibility of increased risks from long-term use, Antman said. 

Co-authors include: Joel S. Bennett, M.D.; Alan Daugherty, Ph.D., D.Sc.; Curt Furberg, M.D., Ph.D.; Harold Roberts, M.D.; and Kathryn A. Taubert, Ph.D.









Painkiller risk goes beyond Vioxx

November 12, 2008 — 2:08am ET

Taking painkillers could place patients at risk for more cardiac problems or even death if they've already suffered a heart attack or have heart failure, according to a study by Danish researchers.

The researchers presented data at the American Heart Association meeting in New Orleans showing that patients taking any of several non-steroidal anti-inflammatory medications were at increased risk of heart attack or death. Patients taking generic ibuprofen had 1.3 times the risk; patients taking the generic diclofenac had 1.9 times the risk; patients taking Pfizer's Celebrex had twice the risk; and patients who had taken the now-withdrawn Vioxx had 2.7 times the risk of death or another heart attack.

At least one of the researchers recommended that physicians now avoid these types of painkillers, or use low doses, in patients with a history of heart attack or heart failure. 


[1]   This is inaccurate.  It is a deception sold by big PhARMA for promotion of their COX-2 inhibitors such as VIOXX.  It is not what goes on below the mucus lining of the stomach, but rather what goes on its surface.  The NSAIDs are caustic.  Secondly, given the low percentage who have bleeding I suspect that it only effect those who have Pylori bacteria which causes ulcers.  Goodman & Gilman, p. 690, pointed out that “many clinicians favor the use of other NSAIDs perceived to have a better gastrointestinal tolerability, even though this perception remains unproven by convincing clinical trials.”   

[2]   As pointed out elsewhere, the reason that those not at risk don’t show up, is because it causes atherosclerosis, a condition which becomes significant by middle age or later.  It is comparable to smoking cigarettes in effect upon the arteries;  it harms all users. 

Published online before print March 21, 2005, doi:10.1161/01.CIR.0000160005.90598.41

(Circulation. 2005;111:1713-1716.)
2005 American Heart Association, Inc.


AHA Science Advisory (American Heart Association)

The Use of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

A Science Advisory From the American Heart Association

Joel S. Bennett, MD; Alan Daugherty, PhD; David Herrington, MD, MHS; Philip Greenland, MD; Harold Roberts, MD; Kathryn A. Taubert, PhD


Recent clinical trial data have raised questions about the degree to which patients and their physicians should consider an increased risk of cardiovascular or cerebrovascular events when selecting medications for pain relief. In September 2004, Merck announced a voluntary worldwide withdrawal of Vioxx (rofecoxib) because of an increased risk of heart attack and stroke. In early December 2004, the US Food and Drug Administration (FDA)  announced a "black box" warning for Bextra (valdecoxib), stating that its use in patients undergoing coronary artery bypass grafting is contraindicated. A week later, the National Institutes of Health suspended the use of Celebrex (celecoxib) in the APC (Adenoma Prevention with Celecoxib) clinical trial because of increased cardiovascular events. The drug was not removed from the market, but the FDA advised physicians to consider alternate therapy or to use the smallest effective dose of Celebrex. Three days later, the National Institutes of Health announced that the ADAPT (Alzheimer’s Disease Anti-inflammatory Prevention Trial) showed an increase in the risk of cardiovascular events in patients given naproxen but not in those given celecoxib; the trial was halted. At the end of 2004, the FDA issued a Public Health Advisory summarizing the agency’s recent recommendations concerning the use of the nonsteroidal anti-inflammatory drug products (NSAIDs) Vioxx, Bextra, Celebrex, and naproxen.1 Quoting from the Public Health Advisory:

  • "Physicians prescribing Celebrex (celecoxib) or Bextra (valdecoxib) should consider this emerging information when weighing the benefits against risks for individual patients. Patients who are at a high risk of gastrointestinal (GI) bleeding, have a history of intolerance to non-selective NSAIDs, or are not doing well on non-selective NSAIDs may be appropriate candidates for COX-2 selective agents.
  • Individual patient risk for cardiovascular events and other risks commonly associated with NSAIDs should be taken into account for each prescribing situation.
  • Consumers are advised that all over-the-counter (OTC) pain medications, including NSAIDs, should be used in strict accordance with the label directions. If use of an OTC NSAID is needed for longer than ten days, a physician should be consulted."

We support these recommendations and here provide a brief scientific background for them. We also expand on the relevance of these recommendations to patients with or at risk for cardiovascular disease.

MECHANISM OF ACTION:  [T]he primary property of this class of drugs is the inhibition of cyclooxygenase (COX). COX enzymes have 2 major classes. COX-1 is broadly considered to be expressed constitutively (constantly) in most tissues, whereas COX-2 is induced in inflammation. Both COX-1 and -2 enzymes use arachidonic acid to generate the same product, prostaglandin H2 (PGH2). A number of enzymes further modify this product to generate bioactive lipids (prostanoids), including prostacyclin, thromboxane A2, and prostaglandins D2, E2, and F2, which influence immune, cardiovascular, GI, renovascular, pulmonary, central nervous system, and reproductive function. The COX-2 inhibitors vary in their selectivity for the COX-2 versus the COX-1 enzyme (for medications currently or formerly on the market in the US, rofecoxib > valdecoxib > parecoxib > celecoxib). Other COX-2 inhibitors are under development and may be introduced onto the US market in the future. The differences in the biological effects of COX inhibitors are a consequence of the degree of selectivity for COX-2 versus COX-1 and tissue-specific variations in the distribution of COX and related enzymes that convert prostaglandin H2 into specific prostanoids. For example, several prostanoids, including prostaglandin E2 and prostacyclin, are both hyperalgesic (ie, elicit an increased sense of pain) and gastroprotective. Thus, nonselective COX inhibition with agents such as aspirin, ibuprofen, indomethacin, and naproxen, which inhibit both COX-1 and COX-2 enzymes, provides effective pain relief for inflammatory conditions but carries with it a risk for erosive gastritis and GI bleeding. Selective COX-2 inhibitors (valdecoxib, rofecoxib, celecoxib, and others yet in development) were developed to minimize GI toxicity because of the relative paucity of COX-2 expression in the GI tract and the relative abundance of COX-2 expression in inflamed and painful tissues.  [The comparison is between a coated medication which dissolves in the intestines and that of uncoated—usually aspirin--which with prolonged usage in high doses produces a statistically significant upper GI issues—heartburn and bleeding.  Coated aspirin is not used in these comparisons—jk]   

In the cardiovascular system, the products of COX regulate complex interactions between platelets and the vessel wall. Prostacyclin is the dominant prostanoid produced by endothelial cells.2,3 In addition to producing local smooth muscle cell relaxation and vasodilation, prostacyclin can also interact with platelet IP receptors, thereby antagonizing aggregation. Platelets contain only COX-1, which converts arachidonic acid to the potent proaggregatory, vasoconstrictive eicosanoid thromboxane A2 (TXA2), the major COX product formed by platelets. Nonselective COX inhibition with aspirin is effective for arterial thrombosis because of its ability to reduce COX-1–dependent production of platelet TXA2; however, selective inhibition of COX-2 could produce a relative reduction in endothelial production of prostacyclin, but leave the platelet production of TXA2 intact. It has been speculated that this imbalance of hemostatic prostanoids may increase the risk for cardiovascular events.4,5 COX-2 inhibitors, like NSAIDs, also raise blood pressure slightly, and in one study the incidence of heart failure was significantly increased compared with placebo.6 Prostacyclin may also retard the pathogenesis of atherosclerosis,4 and inhibition of prostacyclin with a COX-2 inhibitor has been predicted to promote lesion formation4; however, results in different mouse models of atherosclerosis have been contradictory.7–13  The extent to which these effects may contribute to adverse cardiovascular effects of COX-2 is unclear. However, renal function and blood pressure should be monitored in subjects taking COX-2 inhibitors and extra caution should be taken when giving these drugs to subjects with preexisting hypertension, renal disease, and heart failure.

In mid-February 2005, the FDA conducted an extensive review of all of the data concerning the cardiovascular risks of selective and nonselective COX inhibitors. It is anticipated that more information and guidance are forthcoming as a result of this meeting. In the meantime, practical guidance is needed by patients (and their physicians) who are making decisions about the use of these drugs for pain relief, especially if the patients are also at high risk for cardiovascular events. The importance of these issues for patients with or at risk for cardiovascular or cerebrovascular disease cannot be overstated because it is in these patients that the absolute risks are likely the greatest.

From the patient’s—and the physician’s—perspective, the decision turns on balancing the risks and benefits of medications for pain relief. Of course, risks and benefits are not unique to these medications, but their use highlights the issues to be considered. The following lists several issues that should be considered when treatment decisions are made concerning pain medications in patients with or at high risk for cardiovascular disease.

RISK RATIOS:  Recently published results of three randomized, placebo-controlled clinical trials, although not primarily designed to evaluate the effects of COX-2 inhibitors on cardiovascular outcomes, provide some estimates of absolute risk associated with COX-2 inhibitor use in various populations. The APC trial included patients with a history of colorectal neoplasia who were given two different doses of celecoxib or placebo. There was a 1% composite cardiovascular end point of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or nonfatal heart failure in the placebo group, compared with a 2.3% composite cardiovascular end point in patients receiving a total dose of 400 mg per day celecoxib and a 3.4% composite cardiovascular end point in those taking 800 mg celecoxib per day.14 The APPROVe trial included patients with a history of colorectal adenomas who received long-term rofecoxib or placebo. An increased risk of thrombotic events was observed in the treatment group after 18 months of treatment (0.78 events/100 patient-years versus 1.5 events/100 patient-years in the rofecoxib group).6 Finally, a study in post-CABG patients compared valdecoxib/parecoxib with placebo and found that cardiovascular events were more frequent in the treatment group (2.0% versus 0.5% for the placebo group).15 [1% VS 2,3% and 3.4% for the higher dosage of celecoxib, and similar numbers for other studies when comparing to placebo; viz., a three fold increase—jk]



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