Association of age, gender, and weight on maintenance dose of intravenous unfractionated heparin

Unfractionated heparin (UFH) therapy is commonly used for the management of acute coronary syndrome (ACS), atrial fibrillation (AF) or atrial flutter (A-Flutter). Weight based heparin nomogram is widely used to determine the dosage of continuous intravenous infusion. Frequent monitoring is required due to the variable responses to its anticoagulant effects. We investigated factors that may influence the dose of UFH. We performed a retrospective cohort study of all patients who received continuous UFH for ACS, AF, or A-Flutter from January 2008 to December 2008 and reached maintenance dose of UFH within 48 hr. A total of 199 patients were included in this study: 42.7% were females and mean age was 66.6 ± 2.0 years. Univariate analysis revealed that age, gender, weight, serum albumin, and serum protein level were significantly associated with maintenance of UFH dose. After adjustment with multivariate analysis, age (R = −0.27, P ≤ 0.001), gender (R = −0.14, P ≤ 0.044), and weight (R = 0.54, P ≤ 0.001) remained to have significant association with maintenance UFH dose. In conclusion, we have identified not only weight but also age and gender as significant factors that may affect the maintenance of heparin dose in clinical setting. Heparin is an indirect thrombin inhibitor that complexes with antithrombin (AT, also known as AT III), converting this circulating cofactor from a slow to a rapid inactivator of particularly thrombin and factor Xa [1, 2]. The binding of heparin to the heparin-binding site on AT greatly accelerates the inactivating function of AT [3]. Its main use in medicine is anticoagulation for conditions such as ACS [4-6], AF/A-Flutter [7], deep venous thrombosis (DVT), and pulmonary embolism (PE) [8]. Heparin's effect on anticoagulation can be monitored by obtaining the activated partial thromboplastin time (aPTT). Maintenance of aPTT is generally set between 1.5 and 2.5 times the mean of the control value [1]. A landmark study by Raschke provided the current widely used weight-based heparin nomogram [9]. The formula for the weight-based nomogram starts with an initial starting dose of 80 U/kg body weight bolus, followed by a continuous 18 U/(kg hr) infusion rate with goal aPTT of 60 to 90 sec if patients are having PE or DVT and for ACS, initial dose would be 60 U/kg body weight bolus followed by a continuous 12 U/(kg hr) with goal aPTT 50–70 sec. Monitoring the anticoagulation effect by checking the aPTT is required and it is recommended to check serum aPTT every 6 hr until two stable therapeutic aPTT are achieved [10]. Despite its clinical benefit, continuous UFH infusion is associated with a small but significant incidence of complications such as bleeding. In addition, regardless of the use of weight-based nomogram, UFH requires frequent monitoring to maintain the therapeutic range of aPTT, which can be challenging to control due to the narrow therapeutic window UFH has [11, 12]. Although the underlying reasons for difficulty controlling heparin infusion rate are not fully understood, there are studies done in the past to explore the factors that may affect the heparin dose. Multiple extensive pharmacokinetic studies in the past, mainly in vitro studies, have indicated heparin nonspecifically binds to plasma proteins that neutralize the effect of heparin by limiting the amount of heparin available to bind to antithrombin [13-17]. Another study showed age-related differences in heparin response between children and adults [18]. There is also an in vitro study that showed that the effect of heparin differs between genders [19]. Currently, there are no dedicated clinical studies examining whether gender, race, various medical conditions, and serum protein level affect the standard heparin based nomogram. We have performed a retrospective cohort study to investigate whether these factors influence the maintenance UFH dose. One hundred ninety-nine patients met the inclusion and exclusion criteria during the 1-year study period. The mean age was 66.2 years, 42.7% (N = 85) were women (Table I), and 84.5% (N = 168) received intravenous UFH for ACS. Univariate regression analysis was used to assess the coefficient of determination (R2) between each confounding factor and maintenance UFH dose. A significant association existed between UFH dose and age and weight (age; R2: 0.24, P ≤ 0.001, weight; R2: 0.43, P ≤ 0.001; Table II). Furthermore, gender, serum albumin, and serum protein are also shown to have an association with UFH dose (gender; R2: 0.08, P ≤ 0.001, serum albumin; R2: 0.024, P = 0.03, serum protein; R2 : 0.03, P = 0.015; Table II). Ethnicity and past medical history were not shown to have correlation with UFH dose (Table II). When these factors were controlled with multivariate regression analysis, statistically significant associations continue to remain in gender, age, and weight. Regression coefficients after multivariate regression analysis in each factor were as follows: age: −4.4 (P ≤ 0.001), female gender: −60 (P = 0.044), and weight: 8.0 (P ≤ 0.001) with a coefficient of determination (R2) of 0.49 (P ≤ 0.001; Table III). The result from multivariate regression analysis generated following nomogram suggests that female and elderly may require less UFH to maintain therapeutic anticoagulation. UFH dose (U/hr) for male = 550 + 8 × (Weight: kg) – 4.4 × (Age), (R2= 0.49). UFH dose (U/hr) for female = 490 + 8 × (Weight: kg) – 4.4 × (Age), (R2= 0.49). UFH is commonly used in the treatment and management of reducing embolic events in patients with ACS, AF, and A- Flutter. While heparin-based nomogram are routinely used to calculate the amount of heparin to administer, effective anticoagulation treatment with UFH remains clinically challenging, mainly due to its narrow therapeutic range and pharmacokinetic characteristics [12]. Limitations of pharmacokinetics in UFH have been studied in the past [20]. An in vitro study by Monte et al. demonstrated the coagulability variations among men and women [19]. However, to our knowledge, no clinical studies exist examining the heparin-based nomogram effects on gender and ethnic. Our study demonstrated a relationship between gender and heparin dosage rate (R2: 0.08, P ≤ 0.001). When controlling other factors using multivariate regression analysis, statistically significant association between UFH dosage and gender remained (Table III). Although Monte et al. demonstrated heparin resistance in gender, their study was in vitro examination of these differences [19]. The underlying explanation for this result is unclear, but it is possible that different sex hormones produce different types of heparin-binding proteins that may affect the activity of UFH. Hormone-binding protein ratios may play a role in the reduced requirements of heparin in females. Further investigations into hormones, binding protein levels, gender, and heparin interactions should provide more information. Current study also demonstrated a negative correlation between age and maintenance dose of UFH (R2: 0.24, P ≤ 0.001). This difference persisted even after adjusted with multivariate analysis (Table III). This may suggest that elderly requires less UFH to maintain therapeutic aPTT. A recent study by Ignjatovic et al. demonstrated age-related differences in heparin response among pediatric and adult population [18]. This study showed that pediatric plasma samples had higher aPTT compared to adult group when same amount of heparin was administered. Although our study was in vitro, it suggests a potential difference in the adult and geriatrics population. As our study demonstrated heparin requirement decreases with age, further studies to modify nomograms within the geriatrics population may not only demonstrate other potential differences but also decrease morbidity and risks association with excessive anticoagulation. We formulated a nomogram to demonstrate that females and elderly require lower doses of UFH to maintain therapeutic anticoagulation. Despite that multiple in vitro studies have showed its nonspecific binding to plasma proteins, which limits the amount of heparin available binding to antithrombin III and decreases anticoagulation effect [13, 15-17], nearly no correlation existed between serum protein/albumin level and UFH dosage under multivariate regression analysis (Table III). This can be due to the complex interactions and temporal changes in underlying nutritional status. Current study has potential limitation. We did not evaluate the effects of renal function on clearance of heparin. Although heparin is cleared mainly by a highly efficient hematological saturation mechanism at low dosages, proper renal functioning may be required, as heparin is cleared predominantly by renal elimination at higher dosages due to over saturation of cellular binding sites [21, 22]. Overall, our study provides a closer investigation and application of UFH. In patients requiring UFH for management of ACS, AF, or A- flutter, factors such as age and gender may affect therapeutic dosage rate, as per the standard nomogram. This was a retrospective cohort study of patients admitted to Beth Israel Medical Center from January 2008 to December 2008. All patients of at least 18 years of age and receiving UFH for management of ACS, AF, or A-Flutter were included. Patients were bolused initially with 60 U/kg of UFH, followed by a continuous infusion of 12 U/(kg hr), as per the standard weight-based heparin nomogram set forth by Raschke [10]. This nomogram has been adopted by and recommended by the American College of Cardiology and American Heart Association [10]. Patients receiving heparin for management of DVT or PE were excluded, as heparin requirements are different. Pharmacy database and laboratory records were used to screen and collect data. Patients were included if they had at least two consecutive therapeutic range of aPTT, defined as aPTT value of 50–70 sec, recorded at least 6-hr apart while on same infusion rate. Laboratory data recorded were weight, serum protein, albumin, baseline international normalized ratio (INR), and aPTT. Inpatient medical records were examined for demographics (age, gender, and ethnicity), past medical history, indication for intravenous UFH, and maintenance dose of UFH. Laboratory and inpatient medical records lacking aforementioned information were excluded from the study. Other exclusion criteria included patients with past medical history of hepatitis, liver cirrhosis, renal insufficiency (defined as serum creatinine 1.3 mg/dl and over), concomitant use of other anticoagulants before reaching two consecutive therapeutic range of aPTT, failure to reach maintenance dose of UFH within 48 hr after starting intravenous UFH, abnormal INR, or aPTT before the administration of UFH. Univariate regression analysis was used to assess univariate relationships between individual variables and maintenance UFH dose. Multivariate regression was used to adjust for the effect of confounders. P-values less than 0.05 were considered statistically significant. The SAS system version 9.1 was used to analyze the data. Siddharth Verma*, Shumei Kato*, Ronald Blum*, Ilan Shapira*, Patricia Friedmann*, Mala Varma , * Beth Israel Medical Center, University Hospital and Manhattan Campus for the Albert Einstein College of Medicine, New York, NY 10003, St. Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY.