Warfarin Effectively Prevents Venous Thromboembolism

Pharmacology Watch

Low intensity warfarin therapy effectively prevents recurrent venous thromboembolism, according to a recent study in the New England Journal of Medicine. After a median of 6.5 months of full-dose anticoagulation therapy, 508 patients with idiopathic venous thromboembolism were randomized to placebo or low intensity warfarin therapy with target INRs of 1.5 to 2.0. The study was terminated early after 4.3 years of follow-up due to a marked reduction in recurrent thromboembolism in the low intensity warfarin therapy group. Of 253 patients assigned to placebo, 37 had recurrent venous thromboembolism compared with 14 of 255 patients assigned to low intensity warfarin, a risk reduction of 64% (hazard ratio 0.36; [95% CI, 0.19-0.67]; P < 0.001). Major hemorrhage occurred in 2 patients assigned to placebo and in 5 assigned to low intensity warfarin (P = 0.25). Death occurred in 8 patients in the placebo group and 4 in the low intensity warfarin group (P = 0.26). The composite end point was recurrent venous thromboembolism, major hemorrhage, or death. There was a 48% reduction in the composite end point with low intensity warfarin therapy. Because of the importance of these findings, the journal published the study online more than a month prior to its publication date of April 10, 2003.

Vitamin D Reduces Osteoporotic Fractures

British researchers have reduced the rate of osteoporotic fractures in older adults by mailing low-cost vitamin D3 supplements to study subjects every 4 months. Researchers from Cambridge and Oxford universities randomized 2686 adults age 65-85 (2037 men and 649 women) to 100,000 IU vitamin D3 or placebo every 4 months for 5 years. The active medication and placebo were sent to patients by mail and compliance was tracked by completion of a form. At the end of the study period, 149 fractures were noted in the control group and 119 were noted in the vitamin D3 group (RR = 0.78). Fractures of the hip, wrist, forearm, or spine were considered osteoporotic fractures, of which 87 were noted in the control group and 60 in the vitamin D3 group (RR = 0.67). The vitamin D treatment was well tolerated and cost less than 1 pound per year. The authors suggest that vitamin D may be a good, inexpensive primary prevention strategy for the prevention of osteoporotic fractures (BMJ. 2003;326:469-472).

Adefovir Effective for Hepatitis B Treatment

Adefovir is an effective treatment for chronic hepatitis B, according to 2 studies published in February. The first study from Greece randomly assigned 185 patients (in a 2:1 fashion) with e antigen-negative chronic hepatitis B, to 10 mg of adefovir or placebo daily for 48 weeks. Patients in the adefovir group were significantly more likely to have improvement in histologic abnormalities as shown by liver biopsy compared to placebo (64% improvement [77 of 121] adefovir group, 33% [19 of 57] placebo group; P < 0.001). Patients in the treatment group also had reduced hepatitis B virus DNA levels and improved alanine aminotransferase levels compared to placebo. Resistant hepatitis B virus was not noted, and the drug was well tolerated (N Engl J Med. 2003;348:800-807). In a second multinational study of e antigen-positive chronic hepatitis B, 515 patients were randomized to adefovir 10 mg/d, adefovir 30 mg/d, or placebo for 48 weeks. The primary end point was histologic improvement, which was noted in 53% of the 10 mg group, 59% of the 30 mg group, and 25% of the placebo group (P < 0.001 for both dose schedules). Once again, evidence of hepatitis B virus was markedly reduced, and there was significant normalization of alanine aminotransferase levels in both treatment groups. The safety profile of 10 mg/d adefovir was similar to placebo; however, there was a higher frequency of adverse events and renal laboratory abnormalities in the 30 mg/d group. Again no hepatitis B virus mutations were noted in the treatment groups. The authors conclude that 10 mg/d adefovir is a favorable risk benefit profile for long-term treatment of e antigen-positive chronic hepatitis B (N Engl J Med. 2003;348:808-816). An accompanying editorial states "we appear to be at the dawn of the new era" in the treatment of hepatitis B (N Engl J Med. 2003;348:848-850).

Ibuprofen/Aspirin Study Revisited

Another study suggests that ibuprofen blocks the cardioprotective effects of aspirin. In 2001, researchers showed that ibuprofen may block the COX-1 receptor on platelets, keeping aspirin from binding to the receptor (N Engl J Med. 2001;345:1807-1817). Now a new study suggests that ibuprofen may reduce the cardioprotective effect of aspirin. Researchers in the United Kingdom reviewed the records of more than 7000 patients who were admitted for MI, angina, stroke, TIA, or peripheral vascular disease and were given aspirin at discharge.

All survived at least 1 month post discharge. In addition to aspirin, 187 patients were also prescribed ibuprofen and 206 were prescribed diclofenac. The patients who took the aspirin/ibuprofen combination were associated with significantly higher all-cause mortality (hazard ratio, 1.93 [P = 0.011]) and higher cardiovascular mortality (hazard ratio, 1.73 [P = 0.0305]) compared to patients who took aspirin alone. There was no adverse effect noted with aspirin/diclofenac (Lancet. 2003;361:573-574). An accompanying editorial suggests that the lack of effect of diclofenac may be due to its relative COX-2 selectivity. The author also suggests that because of the wide availability of over-the-counter ibuprofen, physicians need to be vigilant and explain this potential drug-drug interaction to patients on aspirin cardioprotection (Lancet. 2003;361:542-544).

ACE Inhibitors Favored in Cardiovascular Care

A head-to-head study of ACE inhibitors vs diuretics for the treatment of hypertension suggests that ACE inhibitors are better at reducing cardiovascular events. The Second Australian National Blood Pressure Study (ANBP2) compared ACE inhibitors to diuretics and a perspective, randomized, open-label study with blinded assessment of end points. More than 6000 hypertensive men and women age 65-84 were followed for a median of 4.1 years. The drug treatment was titrated to a similar level of blood pressure lowering (a decrease of 26/12 mm Hg). The end point was the total number of cardiovascular events in the 2 treatment groups. There were 695 events in the ACE inhibitor group (56.1/1000 patient years) and 736 events in the diuretic group (59.8/1000 patient years). The hazard ratio for the ACE inhibitor group was 0.89 (95% CI, 0.79-1.00 [P = 0.05]). The hazard ratio for male patients was 0.83 and for female patients was 1.00. The authors conclude that treatment of hypertension with ACE inhibitors leads to better cardiovascular outcomes than treatment with diuretics, particularly in older men (N Engl J Med. 2003;348:583-592). The results of this study seem to contradict the recently published ALLHAT study which showed better outcomes with diuretics (JAMA. 2002;288:2981-2997).

Digoxin Dosing and Heart Failure

If digoxin is to be used in men with heart failure, serum digoxin concentrations (SDC) are optimal between 0.5 to 0.8 ng/dL, according to further analysis of the Digitalis Investigation Group (DIG) trial. The initial reports of DIG reported that digoxin provided no overall mortality benefit and only modest reduction in hospitalizations among patients with heart failure and depressed left ventricular function. This new study looked at outcomes in 1171 men based on SDC of 0.5-0.8 ng/mL, 0.9-1.1 ng/mL, and greater than or equal to 1.2 ng/mL, compared to 2611 men randomly assigned to receive placebo. The main outcome was all-cause mortality of follow-up of 37 months. The highest SDC were associated with higher all-cause mortality. Patients in the lowest SDC range( 0.5-0.8ng/mL) had a 6.3% lower mortality rate compared with patients receiving placebo (95% CI, 2.1-10.5). Patients in the midrange SDC (0.9-1.1 ng/mL) had no reduction mortality, while patients with the SDCs above 1.2 ng/mL had 11.8% higher mortality rate than those receiving placebo (95% CI, 5.7-18%). The authors conclude that higher serum digoxin concentrations were associated with increased mortality and that the optimal SDC for men with heart failure is 0.5-0.8 ng/mL, and the authors suggest this for the new optimal therapeutic range (JAMA. 2003;289:871-878).

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. Telephone: (404) 262-5517. E-mail: robin.mason@ahcpub.com. 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.