We have no randomized controlled trials (RCT) comparing twice-daily (bid) with three-times-daily (tid) dosing of unfractionated heparin (UFH) for the prevention of VTE in medically ill patient populations. It is unlikely that such a study, involving an adequate number of patients, will ever be conducted. Though low molecular weight heparins (LMWH) are used more frequently for VTE prevention, many hospitalists still use UFH to prevent VTE in patients who are morbidly obese or who have profound renal insufficiency. King and colleagues have done a meta-analysis to find out whether or not tid dosing is superior to bid dosing for VTE prevention. Twelve studies, including almost 8,000 patients from 1966 to 2004, were reviewed. All patients were hospitalized for medical rather than surgical conditions.
Tid heparin significantly decreased the incidence of the combined outcome of pulmonary embolism (PE) and proximal deep vein thrombosis (DVT). There was a trend toward significance in decreasing the incidence of PE. There was a significant increase in the number of major bleeds with tid dosing compared with bid dosing. There are many limitations to this study: It is retrospective, the population is extremely heterogeneous, and varying methods have been employed to diagnosis VTE across the many studies from which data were pooled. This is likely the best data we will have for UFH in VTE prevention, however. In summary, tid dosing is preferred for high-risk patients, but bid dosing should be considered for those at risk for bleeding complications.
Data are limited for the clinical course of PE. Outpatient treatment of PE with LMWH is not uncommon in select patients, but choosing who is safe to treat in this arena is uncertain. Nijkeuter and colleagues assessed the incidence of recurrent VTE, hemorrhagic complications from therapy, mortality, risk factors for recurrence, and the course of these events from the time of diagnosis through a three-month follow-up period.
Six hundred and seventy-three patients completed the three-month follow-up. Twenty of them (3%) had recurrent VTE; 14 of these had recurrent PE. Recurrence predominantly transpired in the first three weeks of therapy. Of those with recurrent PE, 11 (79%) were fatal, and most of these occurred within the first week of diagnosis. Major bleeding occurred in 1.5% of the patients. Immobilization for more than three days was a significant risk factor for recurrence. Inpatient status, a diagnosis of COPD, and malignancy were independent risk factors for bleeding complications. Fifty-five patients (8.2%) died over the three-month period. Twenty percent died of fatal recurrent PE, while 4% suffered fatal hemorrhage.
Multivariate analysis revealed four characteristics as independent risk factors for mortality in patients with PE. These include age, inpatient status, immobilization for more than three days, and malignancy. It appears that the majority of recurrent and fatal PE occurs during the first week of therapy. Physicians should not discharge patients to home with LMWH for PE without considering these risk factors for hemorrhage, recurrence, and mortality.
Annals of Internal Medicine has published a systematic review of management issues in VTE to provide the framework for the American College of Physicians practice guidelines. These guidelines pool data from more than 100 randomized controlled trials and comment on six areas in VTE management. The following are quotes from this document.
Recommendation #1: Use low molecular-weight heparin (LMWH) rather than unfractionated heparin whenever possible for the initial inpatient treatment of deep vein thrombosis (DVT). Either unfractionated heparin or LMWH is appropriate for the initial treatment of pulmonary embolism.
Recommendation #2: Outpatient treatment of DVT, and possibly pulmonary embolism, with LMWH is safe and cost-effective for carefully selected patients and should be considered if the required support services are in place.