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doi:10.1378/chest.06-1861
(Chest. 2007; 131:507-516)
© 2007 American College of Chest Physicians
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Twice vs Three Times Daily Heparin Dosing for Thromboembolism Prophylaxis in the General Medical Population*

A Metaanalysis

Christopher S. King, MD; Aaron B. Holley, MD; Jeffrey L. Jackson, MD; Andrew F. Shorr, MD, FCCP and Lisa K. Moores, MD, FCCP

* From the Department of Medicine (Dr. King), the Pulmonary and Critical Care Medicine Service (Dr. Holley), Walter Reed Army Medical Center, Washington, DC; Pulmonary and Critical Care Medicine Service, Washington Hospital Center (Dr. Shorr), Washington, DC; and the Department of Medicine (Drs. Jackson and Moores), Uniformed Services University of the Health Sciences, Bethesda, MD.

Correspondence to: Lisa K. Moores, MD, FCCP, PCCMS, Bldg 2, WD 77, Walter Reed Army Medical Center, 6900 Georgia Ave NW, Washington, DC 20307; e-mail: Lisa.Moores{at}na.amedd.army.mil

Abstract

Objectives: Prophylaxis with unfractionated heparin (UFH) has been proven to reduce rates of venous thromboembolism (VTE) in hospitalized medical patients. While twice-daily (BID) and three-times-daily (TID) dosing regimens have been studied, the two have never been directly compared. We performed a metaanalysis to assess whether TID is superior to BID dosing in the prevention of VTE.

Methods: Medline, EMBASE, and Cochrane Controlled Trials Register from 1966 through December 2004 were searched for randomized trials comparing subcutaneously dosed UHF (either BID or TID) with placebo or control for VTE prophylaxis in medical patient populations. Two reviewers independently rated study quality on the basis of predetermined criteria. Data were extracted on patient age, hospital setting, comorbidities, VTE rates, and bleeding complications.

Results: Twelve studies were identified; 7,978 patients (1,664 patients in the TID arm, and 6,314 patients in the BID arm) were included. After adjustment for baseline risk, there was no difference in the overall rate (per 1,000 patient-days) of VTE (BID, 5.4; vs TID, 3.5; p = 0.87). TID heparin showed a trend toward a decrease in pulmonary embolism (PE) [BID, 1.5; vs TID, 0.5; p = 0.09] and in proximal DVT and PE (BID, 2.3; vs TID, 0.9; p = 0.05). The risk for major bleeding was significantly increased with TID heparin (BID, 0.35; vs TID, 0.96; p < 0.001).

Conclusions: BID heparin dosing causes fewer major bleeding episodes, while TID dosing appears to offer somewhat better efficacy in preventing clinically relevant VTE events. Practitioners should use underlying risk for VTE and bleeding to individualize pharmacologic prevention.

Key Words: heparin • primary prevention • thrombosis

Venous thromboembolism (VTE) is a major cause of mortality in the United States, causing an estimated 200,000 deaths every year. Hospitalized patients are at particularly high risk for VTE. A review1 of patients in Olmstead County from 1980 to 1990 showed a 130-times higher incidence of VTE in hospitalized patients (960 per 10,000 person-years) vs nonhospitalized community dwellers (7.1 per 10,000 person-years) after adjustment for age and sex. Prophylaxis of hospitalized patients with subcutaneous unfractionated heparin (UFH) has been proven to reduce VTE incidence and mortality.123 The most recent American College of Chest Physicians (ACCP) guidelines4 recommend low-dose UFH or low-molecular-weight heparin (LMWH) be administered to acutely ill medical patients admitted with congestive heart failure or severe respiratory disease, and to those who are confined to bed and have one or more additional risk factors. ACCP guidelines4 do not specify UFH frequency or dose.

Prior studies of low-dose UFH have used both twice-daily (BID) and three-times-daily (TID) dosing; however, these dosing regimens have never been compared head-to-head in a randomized controlled trial (RCT). Given that such a trial is unlikely to be undertaken, we performed a metaanalysis of existing trials utilizing low-dose subcutaneous heparin for VTE. Our specific purpose was to determine if TID dosing of UFH (5,000 U subcutaneous) is superior to BID dosing in hospitalized nonsurgical patients.

Materials and Methods

Literature Search
Two investigators and a medical librarian independently searched the published literature (1966 through December 2004) to identify published RCTs of subcutaneous UFH prophylaxis. The search was not limited to the English language. Databases searched were Medline, EMBASE, ClinicalTrials.gov, Computer Retrieval of Information on Scientific Projects, Cochrane Controlled Trials Register, ACP Journal Club, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effectiveness. Search terms included venous thromboembolism, prophylaxis, heparin, and randomized controlled trial. Full articles of all potentially appropriate abstracts were reviewed. Hand searching of cited bibliographies increased completeness.

Study Selection Criteria
Inclusion criteria were as follows: (1) randomized trial comparing subcutaneously dosed UFH with placebo or suitable control; (2) heparin dosing of 5,000 U either BID or TID; (3) objective assessment of deep-venous thrombosis (DVT) [Doppler compression sonography, impedance plethysmography, radiofibrinogen uptake scanning, autopsy, or venography] and pulmonary embolism (PE) [CT angiography, ventilation perfusion scanning, pulmonary angiogram, or autopsy] with reporting of incidence; and (4) nonsurgical patient population. We did not require that included studies report bleeding complications; however, these data were extracted when provided. Studies were excluded if the patient population included trauma, pregnant, or pediatric patients. Two authors (C.A.K. and L.K.M.) independently selected articles for inclusion, with 100% agreement on first review.

Study Quality Assessment
All studies were rated independently for quality by two investigators (C.S.K., L.K.M.) using the index of Jadad et al5 (Table 1 ) for RCTs, with a high degree of agreement ({kappa} = 0.97, p = 0.0004). Disagreements were resolved by consensus.


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  		Table 1.. Elements of the Jadad Instrument for Quality Assessment of Clinical Trials*

 
Data Extraction
We extracted the following data from each article: patient age, sex distribution, hospital setting (ie, ward, ICU, critical care unit [CCU]), comorbidity rates in study population, DVT event rate, PE event rate, location of DVT (proximal vs distal), duration of follow-up, and bleeding complications. Rates of thrombocytopenia were not reported in the majority of studies and were not included in the analysis. Data were extracted independently by three investigators (C.A.K., A.B.H., and L.K.M.); disagreements were settled by consensus. Primary outcome variables were DVT rate, PE rate, and a combined VTE rate. Since calf DVTs do not embolize with the same frequency as those that are more proximal,4 we analyzed two combined outcome groups: (1) combined VTE (any DVT or PE), and (2) only proximal DVT (popliteal and above) or PE. If the studies did not report enough data to separate proximal from distal DVTs, all DVTs were assumed to be proximal. When available, we abstracted data on major and minor bleeding events.

Risk Stratification of Patient Populations
All three investigators determined whether the patients in each trial were at low, medium, or high risk for VTE. Risk was assessed as previously described by Holley et al,6 based on discussion with content experts and review of the literature. For each trial, subjects were collectively considered high risk if they had four or more risk factors. This was taken from a scoring system developed by Arcelus et al7 and a retrospective review by Goldhaber et al8 showing an increase in failure rates for chemical prophylaxis in patients with three or more risk factors. Those with class III/IV congestive heart failure or severe respiratory failure based on data from Harenberg et al9 were considered to be at high risk, along with any study group that was predominantly made up of ICUs patients.41011

Patients were considered to be at moderate risk if they had two to three risk factors or age > 70 years, based on the data from Arcelus et al.7 Those without prior thrombosis but with severe sepsis were also considered moderate risk based on the Thromboembolic Risk Factors Consensus Group guidelines.12

Statistical Analysis
All rates, except minor bleeding, for each study were calculated per 1,000 patient-days using the abstracted numbers. Most minor bleeds were hematomas per patient, so these rates were recorded per patient.

Variance for each study was calculated using exact binomial methods. Heterogeneity was assessed visually with Galbraith plots13 and with Q statistics (Mantel and Haenszel). Data were combined using the random-effects model of DerSimonian and Laird,14 and publication bias was assessed with the Shapiro-Wilks normality test. Heterogeneity was explored using metaregression and stratified analyses. Because we found baseline risk to be an important factor in explaining the variance between studies, metaregression (random effects) was used to adjust for these differences when calculating the subgroup p values. In addition, we performed a sensitivity analysis to assess whether our results were overly sensitive to the inclusion of any one individual study. Given the range in year of study and assessment methods, and the fact that metaregression is neither stable nor sensitive for differences with so few study points, we chose not to perform a sensitivity analysis based on overall study quality or separate components of the Jadad index score.

Results

The initial search yielded 443 studies. An additional four studies were identified through hand searching. Of these, 435 studies were excluded, mainly because they involved surgical populations (Fig 1 ). In all, 12 RCTs involving 7,978 patients (1,664 patients in the TID arm, 6,314 patients in the BID arm) met the inclusion criteria. Of these 12 studies, 5 studies used BID heparin1516171819 and 7 studies used TID heparin2202122232425 regimens (Table 2 ). Comparison groups included identical placebo (two studies1617), LMWH (five studies1521222324), flubiprofen (one study25), and patients receiving no treatment (four studies2181920). Study samples ranged in size from 38 to 5,776 patients, with an average of 665 patients per trial. The study by Gardlund18 was the largest, accounting for 72% of all patients in the metaanalysis. The proportion of studies that included high-risk patients was different between the BID and TID heparin studies. Three of the five studies involving BID heparin included high-risk patients,151718 while only two of the seven TID heparin studies2324 included high-risk patients (Table 2). The remaining studies were considered moderate-risk populations. Different protocols and modalities were used to assess for VTE (outlined in Table 3 ).


Figure 1
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  		Figure 1.. Study selection process. CRISP = Computer Retrieval of Information on Scientific Projects; CCTR = Cochrane Controlled Trials Register; ACP = American College of Physicians; CDSR = Cochrane Database of Systematic Reviews; DARE = Database of Abstracts of Reviews of Effectiveness.

 

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  		Table 2.. Characteristics of Included Studies

 

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  		Table 3.. Primary Outcome Events

 
Overall quality rating ranged from 3 to 8 (Table 2), with only the trial of Bergmann and Neuhart15 receiving a score of 8. Common quality problems included lack of blinding in six studies,21819202325 ineffective randomization in six studies,21819212224 inadequate description of withdrawals and dropouts in five trials,216202425 and inadequate discussion of statistical methods in three trials.161725

VTE Outcomes
DVT: A total of 87 DVTs occurred in the 6,314 patients in the BID study arm, and there were 36 DVTs in the 1,664 patients in the TID arm. The event rate after adjustment for baseline risk for VTE was found to be 5.40 per 1,000 patient-days (95% confidence interval [CI], 1.65 to 9.15) for BID heparin vs 3.01 per 1,000 patient-days (95% CI, 0.68 to 5.25) for TID heparin, a statistically insignificant difference (p = 0.42) [Fig 2 ].


Figure 2
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  		Figure 2.. Peto plot for DVT.

 
PE: There were a total of 62 PEs in the BID arm vs 8 PEs in the TID arm. The event rate for PE was found to be 1.50 per 1,000 patient-days (95% CI, 1.12 to 1.88) for BID heparin, vs 0.53 per 1,000 patient-days (95% CI, 0.04 to 1.01) for TID heparin, a difference approaching statistical significance (p = 0.09) [Fig 3 ].


Figure 3
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  		Figure 3.. Peto plot for PE.

 
Combined VTE: The combined event rates of PE and DVT after adjustment for baseline risk was found to be 5.41 per 1,000 patient-days (95% CI, 2.47 to 8.36) for BID heparin and 3.46 per 1,000 patient-days (95% CI, 0.97 to 5.94) for TID heparin (p = 0.87) [Fig 4 ].


Figure 4
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  		Figure 4.. Peto plot for all VTE.

 
Proximal DVT Plus PE: In five studies, the location of the DVT could not be determined (four studies2202125 used TID, and one study18 used BID heparin dosing). A total of 124 proximal DVTs or PEs occurred in the BID group, vs 23 proximal DVTs or PEs in the TID group. The event rate after adjustment for baseline risk was 2.34 events per 1,000 patient-days (95% CI, 1.34 to 3.34) in the BID arm, vs 0.86 events per 1,000 patient-days (95% CI, 0.30 to 1.4) in the TID arm (p = 0.05) [Fig 5 ]. All VTE events are summarized in Table 3.


Figure 5
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  		Figure 5.. Peto plot for proximal DVT and PE.

 
Bleeding Complications
Major and minor bleeding definitions varied by study (Table 4 ). A total of 52 minor bleeding events and 16 major bleeding events occurred in the BID group, with 175 minor bleeding events and 17 major bleeding events in the TID arm. The event rate of minor bleeding was 0.18 events per patient (95% CI, – 0.16 to 0.52) in the BID heparin group vs 0.14 per patient (95% CI, 0.094 to 0.184) in the TID heparin group (p = 0.83) [Fig 6 ]. The adjusted event rate for major bleeding was 0.33 per 1,000 patient-days (95% CI, 0.14 to 0.52) in the BID arm vs 0.73 per 1,000 patient-days (95% CI, 0.20 to 1.27) in the TID arm (p < 0.001) [Fig 7 ]. All outcome event rates are summarized in Table 5 .


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  		Table 4.. Bleeding Definitions

 

Figure 6
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  		Figure 6.. Peto plot for minor bleeding.

 

Figure 7
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  		Figure 7.. Peto plot for major bleeding.

 

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  		Table 5.. Summary of Outcome Event Rates*

 
Sensitivity Analysis
When assessing for sensitivity to individual studies, we found differences only with the omission of the data from Gardlund18 (BID heparin). This study was the only one to use autopsy findings to assess VTE and bleeding; consequently, the rates for both VTE and major bleeding were significantly lower in this study, yet it accounted for the majority of the weight in this arm (5,776 patients). It was also the only BID study to report PEs (all other studies in this group assessed for PE but none were found).

When our data were reanalyzed without the study by Gardlund18 (Table 6 ), the adjusted DVT rate in the BID group increased from 5.40 to 6.71 per 1,000 patient-days, and this rate was significantly higher than that seen for the TID heparin group (p = 0.004). Similarly, the combined any DVT or PE group rate increased from 5.41 to 6.71 per 1,000 patient-days, also significantly greater than the TID group (p = 0.029). For the proximal DVT or PE group, the rate with BID heparin decreased from 2.3 to 1.7 events per 1,000 patient-days, but this remained significantly greater than with TID heparin (p = 0.05). PE could not be analyzed without the Gardlund study18 patients because no other BID studies reported PE.


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  		Table 6.. Sensitivity Analysis Excluding Data*

 
With the exclusion of the data of Gardlund,18 the major bleeding rate in the BID study arm increased from 0.33 to 0.88 (95% CI, 0.67 to 2.43), no longer statistically different from TID heparin (p = 0.71). There was no change in the minor bleeding rate when the study by Gardlund18 was excluded.

Discussion

The Seventh ACCP Consensus Conference on Antithrombotic Therapy4 recommends the use of either LMWH or LDUH for VTE prophylaxis in acutely ill hospitalized medical patients. Although LWMH may become the preferred agent because of once-daily dosing convenience and lower rates of heparin-induced thrombocytopenia (HIT), many clinicians continue to use LDUH in patients in whom dosing of LMWH is less reliable, such as those with severe renal insufficiency or morbid obesity. Dose frequency of LDUH is not specified, but both BID and TID regimens have been used. Based on a rate of two VTEs for every 1,000 patients treated with BID heparin, it would take an RCT of 150,000 patients to show a 10% decrease in VTE with TID heparin (at an {alpha} of 0.05 and ß of 0.80). This study is unlikely to be conducted. In the absence of such a trial, metaanalytic data are the best guide for clinical decision making.

In our metaanalysis comparing rates of VTE and bleeding for general medical patients receiving BID or TID subcutaneous heparin, we found that TID heparin significantly decreased the incidence of the combined outcome of proximal DVT or PE and showed a trend toward decreasing the incidence of PE. The number of hospital days needed to treat with TID to prevent one PE is 1,031, and the days needed to treat to prevent one proximal DVT or PE is 676. While the incidence of these outcomes is reduced with TID heparin, this comes at a price, a significant increase in major bleeding events, with 1,649 hospital days of TID dosing required to cause one major bleed.

One of the major limitations of our study is the varying methods used to detect DVT and PE, as well as the likely change in practice and standard of care over the 23 years of included studies. This leaves open the possibility that varying sensitivity among the methods of detection could result in varying event rates due to false-negative results. The study by Gardlund18 is the only one to use autopsy data to confirm the presence of VTE and major bleeding. Rates per hospital day were particularly difficult to calculate using data from this study because duration of screening was not easy to quantify. As this study was only designed to find fatal PE, the analysis of the raw numbers after eliminating this study are likely more meaningful to current practicing physicians. Doing so eliminated the difference in bleeding rates, while suggesting that TID heparin is superior for all outcomes evaluated.

Other limitations include the heterogeneity of the study subjects and the limitations in assessing patient population risk. In several studies, detailed information on demographics, comorbidities, and hospitalization location was not available, making risk stratification by our methods difficult. Because UFH was compared to different variables (LMWH, placebo, no treatment, flubiprofen), there was no consistent control group available to establish a baseline VTE rate that could be compared across studies. In addition, we attempted to determine the clinically relevant outcome of combined proximal DVT and PE. In one TID study21 and in two BID studies,218 we were unable to extract isolated calf DVT, and thus all DVT were considered to be proximal. As this involved a much larger number of patients in the BID arm, any significant bias would be in favor of TID dosing. Bleeding definitions varied across studies, and rates were not mentioned in two studies1620; this end point, therefore, may be less reliable.

Lastly, information on thrombocytopenia was not provided in most studies. Among larger trials of thromboprophylaxis with heparin, the highest frequency of HIT occurred in those using TID dosing.2627 If TID UFH causes an increased rate of HIT in comparison to BID, this may negate the small benefit in VTE reduction.

Conclusion

We conclude that TID is likely superior to BID UFH for preventing VTE in hospitalized medical patients. However, bleeding rates may be increased with this approach. An assessment of individual patient risk for VTE and bleeding should be undertaken prior to deciding the preferred dosing regimen. In patients at high risk for bleeding complications, the BID regimen may offer a superior risk/benefit ratio. Conversely, in patients at high risk for VTE, the TID regimen should be used.

Footnotes

Abbreviations: ACCP = American College of Chest Physicians; BID = twice daily; CCU = critical care unit; CI = confidence interval; DVT = deep vein thrombosis; HIT = heparin-induced thrombocytopenia; LMWH = low-molecular-weight heparin; PE = pulmonary embolism; RCT = randomized controlled trial; TID = three times daily; UFH = unfractionated heparin; VTE = venous thromboembolism

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

The authors have no conflicts of interest to disclose.

Received for publication July 26, 2006. Accepted for publication September 26, 2006.

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A. F. Shorr, W. L. Jackson, J. H. Sherner, and L. K. Moores
Differences Between Low-Molecular-Weight and Unfractionated Heparin for Venous Thromboembolism Prevention Following Ischemic Stroke: A Metaanalysis
Chest, January 1, 2008; 133(1): 149 - 155.
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