Pharmacology Watch

Does Aspirin Prevent Cancer?

In this issue: Aspirin and cancer prevention; rivaroxaban for pulmonary embolism; new rhinosinusitis practice guidelines; and FDA actions.

Is recommending aspirin next?

Should aspirin be recommended to prevent cancer? Many lines of evidence have suggested that regular low-dose aspirin reduces the risk of colorectal cancer. Can the inexpensive wonder drug reduce the risk of other cancers as well? Researchers in England led by Dr. Peter Rothwell recently published three meta-analyses that looked at aspirin use and long-term cancer incidence and metastasis, as well as the short-term effect on cancer incidence and mortality, and the effect of aspirin on cancer metastasis. More than 200 studies were included in the meta-analyses, which were initially done to assess aspirin's benefit on vascular disease. The three new studies used a combination of case-control, cohort, and randomized clinical trials.

In the long-term study, the 20-year risk of cancer death and metastases was evaluated whereas the short-term study looked at a 3-5 year time frame. The trial for prevention of metastatic disease included five large, randomized trials of daily aspirin vs control in patients who had new solid cancer diagnosed during the trial. In the long-term study, the odds ratio for colon cancer incidence was 0.62 in favor of aspirin, and the odds ratio was 0.58 for death from colon cancer in favor of aspirin. There were similar reductions in the rates of esophageal, gastric, biliary, and breast cancer. The rate of distant metastases was also reduced. The other two studies also showed reduced rates of cancer and reduced rates of metastatic disease.

In the short-term study, cancer rates were 24% lower with aspirin use at 3 years. Curiously, aspirin did not reduce the risk of vascular events but there was no increased risk of major bleeding, including intracranial hemorrhage.

In the meta-analysis of five trials looking at the rate of metastatic disease, a 36% reduction in cancer metastasis was noted, including a 46% reduction in metastatic adenocarcinoma (all three studies published online in Lancet and Lancet Oncology March 21, 2012.) An accompanying editorial points out that these studies show that aspirin at any dose reduces nonvascular deaths by 12% and cancer death by 15% with benefits seen within 3 years for higher doses (> 300 mg/day) and at 5 years for lower doses (< 300 mg/day). The major critique of the studies comes from the United States where the Women's Health Initiative Study and the Physicians' Health Study both failed to show benefit from aspirin on cancer mortality. Both of these studies used low-dose aspirin every other day, a dose that may be too low to show biological effect on cancer. Another critique suggests that aspirin may lead to earlier diagnosis of colorectal cancer since it may cause earlier gastrointestinal bleeding, explaining the lower mortality rate. Despite these concerns, the editorialists suggest that this "impressive collection of data moves us another step closer to broadening recommendations for aspirin use. Moreover, future evidence-based guidelines for aspirin prophylaxis can no longer consider the use of aspirin for the prevention of vascular disease in isolation from cancer prevention." (Lancet published online March 21, 2012).

Rivaroxaban for pulmonary embolism

Rivaroxaban, Janssen's oral factor Xa inhibitor, may be an effective alternative to heparin/warfarin for treatment of symptomatic pulmonary embolism, according to a new study. The drug is currently approved for the prevention of stroke in patients with nonvalvular atrial fibrillation and for deep vein thrombosis (DVT) prophylaxis following hip replacement. It has also been shown to be an effective treatment for DVT, although it is not approved for this indication. The new study was a randomized, open-label, event-driven, noninferiority trial comparing rivaroxaban to standard therapy with enoxaparin followed by adjusted-dose vitamin K antagonist for 3, 6, or 12 months for the treatment of pulmonary embolism. The primary outcome was symptomatic recurrent venous thromboembolism with a secondary safety outcome of clinically relevant nonmajor bleeding. In more than 4800 patients who were randomized, rivaroxaban was noninferior to standard therapy with 50 events in the rivaroxaban group (2.1%) vs 44 events in the standard therapy group (1.8%) (hazard ratio [HR], 1.12; confidence interval [CI] 0.75 to 1.68, noninferiority margin 2.0; P = 0.003). The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard therapy group, while major bleeding occurred in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard therapy group (HR 0.49; 95% CI, 0.31 to 0.79; P = 0.003). The authors conclude that a fixed-dose regimen of rivaroxaban was noninferior to standard therapy with enoxaparin and warfarin for the initial and long-term treatment of pulmonary embolism, and potentially showed an improved benefit-risk profile (N Engl J Med published online March 26, 2012). The doses of rivaroxaban used in the study were 15 mg twice a day for 3 weeks followed by 20 mg once daily for the duration. Rivaroxaban offers the advantage of oral therapy compared to enoxaparin and the lack of need for blood test monitoring compared to warfarin.

New practice guideline for rhinosinusitis

The Infectious Diseases Society of America has published its first Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults. The guideline points out the difficulty in distinguishing bacterial vs viral sinus infections. The following are suggestive of bacterial infection: persistent symptoms of sinusitis lasting more than 10 days without evidence of improvement; onset of severe symptoms or signs with high fever, purulent discharge, or facial pain lasting at least 3-4 consecutive days; or onset with worsening symptoms or signs characterized by new onset of fever, headache, or increased nasal discharge following a viral URI. The guideline recommends empiric antibiotic therapy with amoxicillin-clavulanate rather than amoxicillin alone in both children and adults. Children should be treated for 10-14 days while adults should be treated for 5-7 days. The guideline further recommends beta-lactam agents for treatment of sinusitis rather than respiratory floroquinolones, macrolides, trimethoprim-sulfamethoxazole, or second- or third-generation oral cephalosporins due to emerging resistance patterns. Doxycycline may be used as an alternative. (Clin Inf Dis 2012;54:e72-e112. DOI: 10.1093/cid/cis370).

FDA actions

The FDA has approved the first new erythropoiesis-stimulating agent in more than 10 years. Peginesatide is approved to treat anemia associated with end-stage renal disease in patients on dialysis. The approval was based on two randomized, active-controlled, open-label trials which showed that the drug was as effective as epoetin in maintaining hemoglobin levels. The drug is not approved for chronic kidney disease patients who are not on dialysis or for cancer-related anemia. Peginesatide is marketed by Affymax Inc. as Omontys.

The FDA has approved the first generic ibandronate (Boniva), the popular once-monthly bisphosphonate to treat or prevent osteoporosis in postmenopausal women. Three companies have received approval to manufacture the drug including Apotex Inc., Orchid Healthcare, and Mylan Pharmaceuticals. The generic as well as the brand is dispensed with a medication guide regarding the possible risk of esophagitis, hypocalcemia, bone or muscle pain, osteonecrosis of the jaw, and atypical femoral fractures.

The FDA has also recently approved generic escitalopram (Lexapro), a selective serotonin reuptake inhibitor (SSRI) to treat adults with depression and generalized anxiety disorder. Teva Pharmaceuticals will be the first to market the generic in 5-, 10-, and 20-mg strengths. Like other SSRIs, escitalopram carries a box warning regarding increased risk of suicidal thinking and behavior in children, adolescents, and young adults.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5404. E-mail: