Identifying and Treating Patients at Risk: Epidemiology of Cardiovascular Disease and the Mechanism of COX-2 NSAID-Associated Events

In: Main

30 Jun 2010

Each year in the U.S., cardiovascular disease claims more lives than the next seven leading causes of mortality combined. During 1999, it was estimated that more than 59 million Americans had one or more types of cardiovascular disease; in 1996 (the most recent year for which statistics are available), cardiovascular disease had been at least a contributing factor in the deaths of 1.4 million individuals. Myocardial infarction is the primary cause of cardiovascular event-related death, with a substantial proportion of these events occurring in middle-aged adults. The risk for women is similar to that for men.

Recent data suggest that the use of COX-2 selective inhibitors has the potential to increase a patient’s risk for cardiovascular events. Mukherjee and colleagues analyzed the data obtained in the VIGOR and CLASS studies and in two smaller trials involving approximately 1,000 patients each, to determine whether COX-2 inhibitors were associated with a protective or a hazardous effect on the risk of cardiovascular events.

Despite some methodological limitations to this study, the investigators found that, compared with the placebo group, in the large primary prevention aspirin trials (with more than 23,400 patients), COX-2 inhibitors posed a significantly greater risk of myocardial infarction when the data were pooled. The annualized rates of myocardial infarction for patients taking COX-2 inhibitors in both the VIGOR and the CLASS trials were significantly higher than in patients taking placebo (0.52%): 0.74% with rofecoxib (P = .04, compared with placebo) and 0.80% with  (P = .02, compared with placebo). Patients enrolled in the VIGOR trial who received rofecoxib had a significantly increased risk for thrombotic cardiovascular events than patients receiving naproxen (RR = 2.38, P= .002). The investigators noted no differences in the incidence of cardiovascular events in their analysis of the CLASS trial between subjects given celecoxib.

The differences in cardiovascular events observed in this analysis of the VIGOR study might be explained either by a significant prothrombotic effect from rofecoxib or by an the index date and acute myocardial infarction (OR 1.04, P = .55). However, analysis of specific NSAID use found a 16% reduction in the odds of myocardial infarction among patients who were given. Etodolac (Lodine®, Wyeth-Ayerst) and fenoprofen (Nalfon®, Eli Lilly) were associated with an increased risk of acute myocardial infarction (OR = 1.28 and 1.95, respectively; P < .05); in contrast, ibupro-fen use was not associated with acute myocardial infarction risk (OR = 1.02).

Rahme and colleagues also found that the incidence of acute myocardial infarction in individuals who were concurrent, chronic users of naproxen was lower than in patients using other NSAIDs (OR = 0.64).

Watson and colleagues found a 35% reduction in the risk of thromboembolic cardiovascular events (myocardial infarction, sudden death, and stroke) and a 60% reduction in the risk of myocardial infarction among patients with rheumatoid arthritis who received naproxen canadian compared with other non-naproxen NSAIDs.

Identifying Patients at Risk for NSAID-Associated Complications

Numerous studies have defined the factors that increase the risk for NSAID-associated gastrointestinal injury (Table 1). The American College of Gastroenterology has published guidelines for identifying factors that place patients at increased risk for NSAID-induced gastrointestinal injury. Some of these patient factors include (1) age older than 60 years; (2) a history of ulcer disease or a gastrointestinal event; (3) the need for high-dose NSAID therapy or chronic use of NSAIDs, or both; and (4) the need for concurrent corticosteroids or therapy, or both. In addition, some recent studies suggest that the use of aspirin therapy, even at low doses, places patients at increased risk for gastrointestinal injury and at an even greater risk if another NSAID, regardless of its cyclooxygenase selectivity, is added to the mix.

Because H. pylori infection is an independent risk factor for gastrointestinal injury, patients with a history of ulcer disease who require NSAID therapy should be tested for the presence of the bacterium; if the results are positive, cure of the bacterial infection is essential. Similarly, if H. pylori infection and an ulcer have developed during NSAID therapy, it is clinically prudent to cure the bacterial infection.

Whether the choice between a traditional NSAID and a COX-2 selective NSAID changes a patient’s risk for cardiovascular events remains controversial. However, it is known that patients at risk for cardiovascular events, as defined by recently released guidelines , often require low-dose aspirin therapy, which increases their risk for gastrointestinal injury.

Recommendations for Patients at Risk

The patient’s current use of aspirin and past gastrointestinal history dictate the NSAID-selection process. The decision-making process is also influenced by the fact that many patients are receiving maintenance therapy with PPIs for gastroesophageal reflux disease.

Among patients not receiving aspirin, those with no history of gastrointestinal injury may be treated with a traditional NSAID. Selection of NSAID therapy among patients not taking aspirin but who have a history of gastrointestinal injury should be based on their concurrent use of a PPI. For example, patients who are not receiving PPI therapy should be given a COX-2-selective NSAID; adding an antisecretory agent can be considered if gastric symptoms develop. Patients receiving a PPI may be given a traditional NSAID.

Among patients receiving aspirin therapy, the concurrent use of an antisecretory agent (e.g., a PPI or a histamine H2 receptor antagonist) or a gastroprotective agent should be considered, especially in those with a history of gastrointestinal complications. However, a trial comparing misoprostol (Cytotec tablet, Pharmacia) with histamine H2 receptor antagonists found that only misopros-tol produced a significant and consistent reduction in the risk of NSAID-induced gastrointestinal lesions or ulceration.

A more recent study found PPI therapy to be superior to misoprostol canadian, offering greater symptom relief and a more favorable tolerability profile with a positive effect on patient compli-ance. The choice between a traditional NSAID and a COX-2 NSAID in patients receiving concurrent aspirin should thus be based on the patient’s history of gastrointestinal injury. A traditional NSAID may be considered the first choice among patients without a history of gastrointestinal injury, whereas a COX-2 selective NSAID might be considered the first choice among those with a history of gastrointestinal injury, although many would argue that the concurrent use of aspirin negates or minimizes the gastrointestinal protection advantage

Table 1 Factors That Might Place Patients at Increased Risk for NSAID-Induced Gastrointestinal Injury

  • Age greater than 60 (risk increases with increasing age)
  • History of ulcer disease
  • Patient’s need for high-dose, chronic NSAID administration
  • Patient’s need for concurrent use of corticosteroids and/or warfarin canadian
  • Concurrent use of aspirin
  • Helicobacter pylori infection

of the latter (COX-2) regimen. In addition, if a patient is receiving a PPI, these two classes of NSAIDs may be interchangeable.

In all cases, it is prudent to prescribe the lowest therapeuti-cally effective dose of the selected NSAID needed to reduce the risk of adverse events. If an ulcer develops during NSAID therapy, treatment with the offending agent should be discontinued, if possible, and the patient should receive an effective ulcer-healing regimen. In subsequent assessments of pain management, such individuals should be considered at risk for gastrointestinal injury and should be managed accordingly. For patients who are unable to discontinue their pain management regimens, several randomized, controlled, clinical trials have documented significantly higher ulcer healing rates with PPI therapy than with H2 receptor antagonist therapy and higher tolerability.


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