1. Aschenbrenner, Diane S. MS, RN, CS

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May be inappropriate for primary prevention of cardiovascular events.

Findings of the clinical drug trial Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) were presented on March 12 at the Annual Scientific Session of the American College of Cardiology (ACC) and simultaneously published electronically in the New England Journal of Medicine. News media reporting of the findings stated that clopidogrel (Plavix) plus aspirin was not shown to be more effective than low-dose aspirin alone in the prevention of myocardial infarction (MI), stroke, or death from cardiovascular causes.



The reporting elicited concern in the ACC that some patients may misinterpret the reports and inappropriately discontinue taking clopidrogrel, prompting it to release a Public Health Alert on March 16 warning patients not to stop taking the drug if they have a vascular stent in place or have recently had an MI or stroke. Discontinuing the drug in these cases could put patients in danger of a serious clot formation.



Clopidogrel is an antiplatelet drug with a mechanism of action that is different from that of aspirin and has approved indications for use after recent MI or stroke, in the presence of established arterial disease, and in acute coronary syndrome. Treatment in acute coronary syndrome encompasses patients who are treated medically as well as those who undergo procedural interventions such as percutaneous coronary intervention (PCI), with or without stenting, or coronary artery bypass grafting (CABG). The drug is not approved for use in the prevention of cardiovascular events in other patients (primary prevention), such as those in whom there are risk factors for such an event. Clinical trials have shown that the combination of clopidogrel and aspirin is more effective than either agent alone in reducing ischemic events in patients with unstable angina or MI, with or without ST-segment elevation, and in patients undergoing angioplasty and stenting. Aspirin has been found to lessen the risk of cardiovascular events in patients at risk for them and is therefore often prescribed for prophylactic use.


Study design

Recognizing that practitioners often prescribe drug therapy for off-label uses, the CHARISMA trial, a large multisite, international, randomized, double-blind, placebo-controlled trial, was designed to determine whether the prophylactic use of clopidogrel and low-dose aspirin in combination would be more effective than the use of aspirin alone. The majority of the 15,603 patients enrolled in it met the criteria for having established cardiovascular disease, about one fourth met the criteria for having two or three atherothrombotic risk factors, and the primary efficacy end point was the first occurrence of MI, stroke (by any cause), or death from cardiovascular causes, including hemorrhage.



The trial findings were surprising to the researchers. Instead of the combination of clopidogrel and aspirin decreasing the incidence of cardiovascular events in patients deemed to be at high risk (and without a history of established cardiovascular disease), there were more fatalities attributable to both cardiovascular and all causes among them, as well as a greater risk of moderate-to-severe bleeding as an adverse effect, compared with those who took aspirin alone. There was a slight benefit noted among study patients with established cardiovascular disease who received the combination antiplatelet therapy, although the authors of the study state that the barely statistically significant finding should be interpreted cautiously and suggest that further research be conducted before a conclusion concerning clopidogrel's effectiveness is accepted as primary prevention in patients with atherothrombotic risk factors. Overall, the present study revealed that the combination of clopidogrel and aspirin is not significantly more effective than aspirin alone when used as primary prevention in patients with stable cardiovascular disease or several cardiovascular risk factors. Clopidogrel and aspirin should be used as combination therapy only in patients with established cardiovascular disease, which is the current approved indication; off-label use in patients without it should be avoided.


Nursing implications.

The results of the study have several implications in nursing. First, it should be noted that clopidogrel plays an important role in decreasing thrombotic events that might lead to ischemia in patients who recently have suffered MI or stroke or who have undergone PCI or CABG. Combining clopidogrel with aspirin in either circumstance improves outcomes and patients should be informed of this benefit. Second, patients who take clopidogrel for those approved indications should not stop drug therapy because that would increase the risk of a possibly life-threatening clot. Third, clopidogrel and aspirin are not appropriate when used off-label to prevent initial cardiovascular events.


The interpretation of clinical trial data is a complex matter, and the version publicized in the news media may or may not completely or accurately represent the research findings. The findings of one trial should also be considered in respect to the entire body of research data concerning a drug. Patients commonly have only news media reporting to which to respond-in this case, the failure of the reporting to clearly indicate that the findings of greater risk of death pertain only to the use of clopidogrel as primary prevention, not to its approved use as secondary prevention, may have induced patients who were prescribed the drug after stent insertion or after MI or stroke to stop taking it. Nurses should be aware of the actual findings of major clinical trials, not only of news media reports, and assist patients in considering all findings in proper perspective according to particular health status.


American College of Cardiology. Dangers of stopping clopidogrel (Plavix) for patients with stents and certain other conditions. 2006 Mar 16.; Bhatt DL, et al. N Engl J Med 2006;354(16):1706-17.



New warnings and indications.


In response to post-marketing case reports of rare hepatotoxicity, the warning on the labeling of bosentan (Tracleer) has been strengthened. Bosentan, used in the treatment of pulmonary arterial hypertension, is a neurohormone that binds to endothelin receptors, producing an antagonistic effect that reduces pulmonary arterial blood pressure. The label now includes data derived from case reports indicating that there have been rare occurrences of liver toxicity in closely monitored patients taking the drug, one of whom was a woman with several comorbidities taking several drug therapies who had been treated for pulmonary arterial hypertension since childhood and who took bosentan for 21 months at the recommended dosage. The label revision emphasizes the necessity of monthly monitoring of liver enzymes as well as of strict adherence to the recommended dosage and adjustment-monitoring guidelines. The drug is accompanied by a medication guide to provide the patient additional information.


Long-acting bronchodilators.

In response to the request made in November 2005 by the Food and Drug Administration (FDA) to manufacturers for updated warnings pertaining to asthma treatment products containing long-acting[low single comma quotation mark] [beta]-2-adrenergic agonist (LABA) bronchodilators, new medication guides for patients have been created and revisions to the drug labeling made for Serevent (salmeterol) and Advair (salmeterol and fluticasone) (but not yet for Foradil [formoterol], despite the FDA request). The findings of a large study had shown that more asthma patients died from asthma-related complications while using LABAs, compared with those using a placebo. The agonists, while decreasing the frequency of episodes of asthma, can heighten their severity when they do occur, possibly fatally. The FDA's recommendations for the use of LABAs indicate that they should be used only supplementally, when other drugs do not control asthma; should not be discontinued without the prescriber's approval; should not be used to treat worsening wheezing, for which medical attention should be sought immediately; and should not be used to treat sudden wheezing, for which a short-acting bronchodilator medication should be kept close at hand. The medication guides will be dispensed with every prescription of Serevent and Advair filled and should be reviewed each time, as new information may have been added.



A new warning has been added to the labeling of denileukin diftitox (Ontak) (a pharmacologic therapy used in the treatment of persistent or recurrent cutaneous T-cell lymphoma in which malignant cells express the CD25 component of the IL-2 receptor), indicating that there have been reports of loss of visual acuity, usually with loss of color perception with or without retinal pigment mottling, after administration of the drug. While some patients have recovered acuity of sight after discontinuation of the drug, most have reported persistent visual impairment.



A new approved indication has been added to the labeling of tacrolimus (Prograf), an immunosuppressant used to prevent rejection after liver or kidney transplantation. The drug is now approved for use in a combination regimen in the prevention of rejection after heart transplantation, having been found to be as effective as cyclosporine, another immuno-suppressant used for that purpose. The use of tacrolimus has been associated with a greater risk of neurotoxicity, impairment of renal function, infection, and posttransplantation diabetes mellitus and-like most combination immunosuppressive regimens used in solid-organ transplantation-the tacrolimus-based regimen is associated with a greater risk of malignancies, particularly nonmelanoma skin cancers.



A new indication for zanamivir (Relenza), an antiviral medication, is the prevention of influenza A and B in adults and children five years of age and older. The drug formerly had been approved only for the treatment of influenza A and B viruses, but in recent studies it reduced their incidence in people ages 12 to 94 years. In preparation for a possible flu pandemic, the FDA has identified zanamivir, as well as oseltamivir (Tamiflu), another prophylactic antiviral, as a drug that should be stockpiled and is working with the pharmaceutical industry to ensure that an adequate supply of each is made available. Zanamivir is not recommended for treatment of seasonal influenza or prophylaxis for it in patients with underlying airway disease such as asthma or cardiopulmonary obstructive disease, in whom death has occurred after use; nor should the medication be used prophylactically in place of the annual influenza vaccination, according to the Centers for Disease Control and Prevention immunization practices guidelines.


Actelion Pharmaceuticals US. Dear health-care professional [letter: bosentan (Tracleer)]. 2006 Mar 1.; U.S. Food and Drug Administration. FDA public health advisory: Serevent Diskus (salmeterol xinafoate inhalation powder), Advair Diskus (fluticasone propionate and salmeterol inhalation powder), Foradil Aerolizer (for-moterol fumarate inhalation powder). 2005 Nov 18.; Ligand Pharmaceuticals.Dear health care professional [letter: denileukin difititox (Ontak)]. 2006 Mar 3.; U.S. Food and Drug Administration. FDA news: FDA approves Prograf to prevent rejection of heart transplant. 2006 Mar 30.; U.S. Food and Drug Administration. FDA news: FDA approves a second drug for the prevention of influenza A and B in adults and children. 2006 Mar 29.