LMWHs have been evaluated in two large, placebo-controlled clinical trials for the prevention of VTE in medical inpatients.
In the first trial, MEDENOX, almost half the patients were older than 75 (mean age approximately 73). Inclusion criteria were NYHA class 3 or 4 heart failure, acute respiratory failure without mechanical ventilation, acute infection without septic shock, acute rheumatic disease, or inflammatory bowel disease. The primary outcome was assessed in 866 patients. Enoxaparin 40 mg SC once daily decreased the rate of VTE by two-thirds, from 15% to 5% (p=0.0002), without increased bleeding or thrombocytopenia compared with placebo.12 Enoxaparin 40 mg SC once daily is approved by the Food and Drug Administration (FDA) for VTE prophylaxis in medically ill patients.
PREVENT was an international, multicenter, randomized, double-blind, placebo-controlled trial evaluating dalteparin’s efficacy and safety. The inclusion criteria in this trial were acute congestive heart failure, non-ventilator-requiring acute respiratory failure, infection without septic shock, acute rheumatologic disorders, or inflammatory bowel disease. It studied 2,991 patients, and the primary outcome was VTE incidence and sudden death at day 21.
Dalteparin at 5,000 units decreased the rate of VTE, as detected by compression ultrasound, from 5% in the placebo group to 2.8%, a relative risk reduction of 45% (p=0.0015). The authors concluded the use of dalteparin reduced the incidence of VTE without increased risk of bleeding.13 Dalteparin is FDA approved for VTE prophylaxis in medical inpatients.
At least two meta-analyses have evaluated LMWHs compared with UFH. In the first, nine trials comparing LMWH to UFH (4,669 patients) were included. No significant effect was observed on DVT, clinical PE, or mortality. However, LMWH reduced the risk of major hemorrhage by 52% (p=0.049).14
In a more recent meta-analysis, 36 studies were included comparing placebos with UFH and LMWH. Both agents were associated with a reduced risk of VTE. A UFH dosage of 5,000 units three times daily was more effective in preventing DVT than a dosage of 5,000 units twice daily when compared with the control (risk ratio [RR], 0.27; 95% confidence interval [CI], 0.20-0.36; vs. RR, 0.52; 95% CI, 0.28-0.96). Neither UFH nor LMWH reduced mortality. When directly compared with UFH, LMWH was associated with a lower risk of DVT (RR, 0.68; 95% CI, 0.52-0.88) and injection-site hematoma (RR, 0.47; 95% CI, 0.36-0.62), but no difference was seen between the two agents in the risk of bleeding or thrombocytopenia.
This contemporary meta-analysis clearly illustrates that UFH and LMWH reduce VTE risk in hospitalized medical patients, but neither agent alters mortality. When directly compared, LMWH is more effective in preventing DVT.15
Despite the higher drug acquisition costs, LMWHs are more cost-effective than UFH for prophylaxis in medical patients because of their lower complication rates of HIT. LMWH reduces incremental costs by $13.88 per day compared with UFH.16, 17
Synthetic pentasaccharide: Fondaparinux is a synthetic analogue of the unique pentasaccharide sequence that mediates the interaction of heparin with antithrombin. It inhibits both free and platelet-bound factor Xa. It binds antithrombin with high affinity, has close to 100% bioavailability, and has a plasma half-life of 17 hours that permits once-daily administration.
The drug is excreted unchanged in the urine and therefore contraindicated in patients with severe renal impairment (e.g., creatinine clearance less than 30 mL/min). It does not bind PF4 in vitro and thus should not cause HIT.
Fondaparinux has been evaluated in medical inpatients in a randomized placebo controlled trial, ARTEMIS. Fondaparinux 2.5 mg SC once daily decreased the rate of venographically-confirmed DVT from 10.5% to 5.6% (p=0.029); there was also a decrease in fatal PE from 1.7% to 0.7% (p=0.029). A reduction in overall mortality from 6% to 3.3% (P=NS) was observed. Major bleeding occurred in 0.2% of patients in both groups. The drug is not FDA approved to prevent VTE in medical inpatients.18