Abstract
Deep venous thrombosis (DVT) is a common clinical problem associated with substantial morbidity and mortality. Knowledge of the global burden of DVT recurrence is deficient in Africa, including Ethiopia. The objective of the study was to assess deep venous thrombosis recurrence and its predictors at selected tertiary hospitals in Ethiopia. Prospective cohort study was conducted among hospitalized DVT patients. Data were analyzed using SPSS version 21.0. To identify the independent predictors of DVT-recurrence, multiple stepwise-backward Cox-regression analysis was done. Statistical significance was considered at P value < .05. A total of 129 participants were included (65.1% females) with mean ± SD age of 38.63 ± 17.67 years. About 26.4% of patients developed recurrent venous thromboembolism. Pulmonary embolism accounted for 17.60% of recurrent event. The overall incidence density of DVT recurrence was 2.99 per 1000 person-days. The mean ± SD survival time to DVT recurrence was 42.03 ± 22.371 days. Age ≥ 50 years (adjusted hazard ratio [AHR]: 5.566; 95% CI: 1.587-19.518; P = .007), occasional alcohol consumption (AHR: 2.011; 95% CI: 1.307-6.314; P = .019), surgical history (AHR: 6.218; 95% CI: 1.540-25.104; P = .010), pregnancy (AHR: 2.0911; 95% CI: 1.046-4.179; P = .037), diabetes mellitus (AHR: 8.048; 95% CI: 2.494-25.966; P < .001), unmet activated partial thromboplastin time target after 24 hours of heparin (AHR: 1.129; 95% CI: 0.120-10.600; P = .011), proximal site involvement (AHR: 5.937; 95% CI: 1.300-27.110; P = .022), and previous history of DVT (AHR: 2.48; 95% CI: 1.085-11.20; P = .0002) were independent predictors of DVT recurrence. The DVT recurrence rate was high in the study area, which is even complicated with pulmonary embolism as well as death. Efforts are needed to prevent and reduce the development of DVT recurrence.
Keywords: deep vein thrombosis, recurrence, pulmonary embolism, bleeding
Introduction
Venous thromboembolism (VTE) is the formation of a blood clot in a deep vein that can lead to complications including deep vein thrombus (DVT), a pulmonary embolism (PE), or postthrombotic syndrome (PTS). Venous thromboembolism is a serious condition with an incidence of 10% to 30% of people dying within 1 month of diagnosis and half of those diagnosed with a DVT have long-term complications. Deep venous thrombosis is considered the third most common cardiovascular condition after myocardial infarction and stroke, and it is a growing public health problem due to an increase in the aging population.1 The development of single or multiple blood clots within the deep veins of the extremities or pelvis, usually accompanied by inflammation of the vessel wall and which is commonly affects the leg veins (such as the femoral vein or the popliteal vein) or the deep veins of the pelvis which made them common sources of serious complications.2,3
Deep venous thrombosis is a major and common preventable cause of death worldwide; it affects approximately 0.1% of persons per year. Both sexes are equally afflicted by a first DVT, men having a higher risk of recurrent thrombosis. Deep venous thrombosis is predominantly a disease of the elderly with an incidence that rises markedly with age.3 Data from the United States show that DVT and PE are a major disease burden, it affects an estimated population of approximately 1 million each year and results in several hundred thousand hospitalizations that can be contributing an about 33% of death from the disease. The estimated 66% nonfatal cases of DVT result in several hundred thousand primary hospitalizations or extended hospital stays in patients who develop both DVT and PE while hospitalized.4
In Western countries, population studies have reported incidence rates of VTE was estimated to be between 80 and 180 per 100 000 person-years. Autopsy studies have suggested that the incidence of the most serious complication of VTE, fatal PE, could be underestimated in population studies. For almost a quarter of PE patients, the initial clinical presentation is sudden death.5,6 The outlook after an episode of symptomatic VTE can be blighted by long-term sequelae including recurrence of VTE. A mortality rate of 6% has been reported in the first 6 months after the disease onset. Recent studies found a high incidence of recurrent DVT with half of DVT incidences in the United States. A relapse after a 5-year disease-free interval is observed in 20% to 30% of the patients.7 While some studies reported the annual incidence rate of the first recurrent attack to be 3% to 5%, which is generally most probable to happen during the first 2 years after the discontinuation of anticoagulation treatment, others claimed a higher rate of 5% to 10%.8
The incidence of disease recurrence, as a condition with multifactorial pathogenesis, is related to the number and severity of the risk factors.9,10 Patients with an initial episode of symptomatic DVT are at high risk of recurrent DVT. Recurrence rates are higher if there is residual thrombus in the vessel.11,12 A recent report found that 60% of higher recurrence risk among men compared to women. A study suggested that this increase in risk could be explained by a lower recurrence risk among women who were using exogenous hormones at the time of their first event. The risk appears to be highest in the 6 to 12 months following cessation of anticoagulation, regardless of the initial duration of anticoagulation.13
One prospective cohort study from Ethiopia conducted in 1998 G.C among admitted DVT patients revealed a relatively common disease associated with severe complications and mortality.14 A similar recent study at a tertiary hospital showed malignancy, prolonged immobilization, pregnancy-related problems, and major trauma were the most common risk factors noted for DVT occurrence.15 Due to a lack of evidence on the DVT recurrence in Ethiopian hospitals, we focused to assess the recurrence rate of DVT over 3-months period among patients on anticoagulation at 2 selected tertiary care setting in Ethiopia.
Methods and Materials
Study Setting and Period
This study was conducted among hospitalized DVT patients at 2 tertiary hospitals available in the country; Jimma University Medical Center (JUMC) and St. Paul’s Hospital Millennium Medical College (SPHMMC). Jimma University Medical Centre found in Southwest Ethiopia about 352 km far away from the capital, Finfinnee (Addis Ababa) and St. Paul’s Hospital Millennium Medical College is located in Finfinnee (Addis Ababa) city. We enrolled participants at these 2 selected tertiary teaching hospitals concurrently from March 2018 to August 2018.
Study Design and Population
Three-months prospective open cohort study was conducted among adult patients diagnosed with DVT, who was admitted to inpatients wards of JUMC and SPHMMC.
Participants Enrollment and Inclusion
We included adults with age ≥18 years old patients with proven DVT by Doppler ultrasonography and patient willing to give consent. Participation in study was offered to all consecutive patients with DVT. Each patient included for the final analysis was followed within the cohort at least for 90 days for the outcome. Patients who were unable to follow their monthly follow-up and who started anticoagulants for the prophylaxis purpose were excluded from the study. A total of 146 patients, who initially had confirmed DVT by Doppler ultrasound at JUMC and SPHMMC were recruited to participate in the study. Eight patients dropped out/lost to follow-up during the study period. All loss to follow-ups were from SPHMMC. Nine patients also self-discharged (left against medical advice) by themselves. Finally, a total of 129 patients, whose outcome within 90 days was known, were included in the final analysis (Figure 1).
Figure 1.
Study participant recruitment flow diagram.
Data Collection Procedure and Quality Assurance
A structured data collection questionnaire was developed by researchers from relevant kinds of literature. Patient chart review and self-report were used to determine the various variables. Patient information, sociodemographic and clinical characteristics, and diagnostic test results were collected from patient medical charts, medication order sheets, and laboratory orders at the time of clinical diagnosis during the patient’s hospital stay. Patients were enrolled in the cohort starting from the anticoagulation initiation date. Then, those patients were followed for the outcome using laboratory investigations, periodic reviews of medical charts of the patients, and face-to-face and/or a telephone interview by using a structured questionnaire at first, second, and the third month of anticoagulant initiation. The training was given for data collectors on the data collection procedure, objectives and collection of follow-up data. Four pharmacists and 2 medical residents were involved in the data collection and patient evaluation. The investigators were involved in a supervision role, data daily quality management, and following each patient at follow-up clinic and/or by telephone.
Data Processing and Analysis
All collected patient’s data were entered into EpiData version 4.2 for data cleaning and then exported to Statistical Package for Social Science (SPSS) version 21.0 for analysis. Categorical and continuous data were expressed as percentages and mean ± SD, respectively. Descriptive statistics were applied for the analysis of patient characteristics, including means, SD, medians, and percentiles and categorical variables were analyzed by using the χ2 test. Using Cox proportional hazards (PHs) modeling, we tested relevant variables as potential associated factors for DVT recurrence from anticoagulation date to 90 days. All variables were initially tested for an association with the rate of DVT recurrence in bivariate Cox PH models. Those variables demonstrating a univariate association with at least marginal significance (P < .25) were included in a multivariable model. Multivariable Cox-regression analyses were used to assess the crude and adjusted effect of seemingly significant predictors of DVT recurrence. The adjusted hazard ratio was used as a measured strength of association. A P value of < .05 was considered to be statistically significant.
Outcome and Validating Methods
Deep venous thrombosis management in Ethiopia depends on the national Standard Treatment Guidelines for General Hospital16 and international clinical practice guideline such as American college chest physicians DVT treatment guideline.17 The protocol for management and case definition is similar. In Ethiopian hospital, acute DVT is treated in inpatient setting for 5 to 7 days. Initially, a weight-based parenteral anticoagulant is initiated. Usually, unfractionated heparin (UFH) is preferable to low-molecular-weight heparin–like enoxaparin (except in selected patients) due to cost and availability. After 24 to 48 hours, warfarin, the only routinely available oral anticoagulant, will be added to the parenteral regimen. The parenteral regimen will be continued until 5 to 7 days and then after, it will be discontinued when international normalization ratio (INR) is between the recommended ranges of 2 to 3. Based on the risk factor(s), the patient is prescribed with warfarin for the recommended duration of anticoagulation. In case of pregnancy and oncology, enoxaparin is drug of choice in the setting. In our setting, there is not test of hereditary thrombophilia. The available medications in the setting were UFH and enoxaparin and warfarin. In this study, patients were enrolled and followed starting from patient hospital arrival and date of anticoagulant initiation until 90 days. Recurrence ascertainment was made based on the following criteria; if the patient is readmitted to the hospital:
With a new case of DVT or its complication during 90 days of anticoagulant therapy and/or
Exacerbation of the current DVT, which was diagnosed on the preceding hospital admission.
Ethical Consideration
A letter of ethical clearance was obtained from the Ethical Review Board of the institute of health, Jimma University. A formal request letter was presented to JUMC and SPHMMC to get access permission to patient data. After relevant information was given on the research purpose and process, written informed consent was obtained from participants, and the patient’s confidentiality was secured. The raw data were not made available to anyone and not used as the determinant of the participant. All steps in data collection and compilation were conducted and supervised by the investigators. Strict confidentiality was assured through anonymous recording and coding of questionnaires and placed in a safe place.
Definitions of Terms
Bleeding is defined as clinical status, laboratory, and/or imaging evidence of bleeding from the internal or external body as a result of anticoagulant therapy.18
Comorbidity is the presence of one or more additional diseases or disorders co-occurring with (ie, concomitant or concurrent with) a primary disease DVT.
Recurrence is an objectively verified hospital discharge diagnosis of DVT or as a fatal complication of DVT confirmed at ultrasonography, or occurrence of thrombosis on previously uninvolved site or had interval documentation of incident DVT (it is a worsened DVT) after anticoagulation initiation.
Results
Sociodemographic Characteristics of Study Participants
From a total of 129 study participants included in the final analysis, about 84 (65.1%) were females, with male to female ratio of 1:1.86. The mean ± SD age of participants was 38.63 ± 17.67 years. The majority of the patients 76 (58.9%) were within the age-group between 18 and 35 years. About 57.4% of participants were residing in a rural area. A large number (111 [86.0%]) of study participants were living with their immediate family. About three-fourth of patients were married. Nearly, 5% of study participants had a smoking history (Table 1 ).
Table 1.
Baseline Socio-Demographic and Behavioral Characteristics of Study Participants.
| Variables | Settings | Total (n [%]) | P value | ||
|---|---|---|---|---|---|
| JUMC (n [%]) | St. Paul (n [%]) | ||||
| Gender | Male | 29 (40.8) | 16 (27.6) | 45 (34.9) | .116 |
| Female | 42 (59.2) | 42 (72.4) | 84 (65.1) | ||
| Age (years) | 18-35 | 40 (56.3) | 36 (62.1) | 76 (58.9) | .384 |
| 35-50 | 12 (16.9) | 5 (8.6) | 17 (13.2) | ||
| >50 | 19 (26.8) | 17 (29.3) | 36 (27.9) | ||
| Marital status | Single | 17 (23.9) | 9 (15.5) | 26 (20.1) | .237 |
| Married | 49 (69.0) | 47 (81.0) | 96 (74.4) | ||
| Divorced | 2 (2.8) | 2 (3.4) | 4 (3.1) | ||
| Widowed | 3 (4.2) | 0 | 3 (2.3) | ||
| Occupation | Office worker | 3 (4.2) | 12 (20.7) | 15 (11.6) | <.001 |
| Farmer | 33 (46.5) | 4 (6.9) | 37 (28.7) | ||
| Merchant | 9 (12.7) | 13 (22.4) | 22 (17.1) | ||
| Student | 5 (7.0) | 5 (8.6) | 10 (7.8) | ||
| Daily labourer | 6 (8.4) | 4 (6.9) | 10 (7.8) | ||
| Othersa | 15 (21.1) | 20 (34.5) | 35 (27.1) | ||
| Residence location | Rural | 48 (67.6) | 26 (44.8) | 74 (57.4) | .009 |
| Urban | 23 (32.4) | 32 (55.2) | 55 (42.6) | ||
| Educational status | Cannot read and write | 36 (50.7) | 16 (27.6) | 52 (40.3) | .001 |
| Primary school | 25 (35.2) | 16 (27.6) | 41 (31.8) | ||
| Secondary school | 7 (9.9) | 20 (34.5) | 27 (20.9) | ||
| College and above | 3 (4.2) | 6 (10.3) | 9 (7.0) | ||
| Living condition | With immediate family | 54 (76.1) | 57 (98.3) | 111 (86.0) | .004 |
| With extended family | 6 (8.5) | 1 (1.7) | 7 (5.4) | ||
| Living alone | 5 (7.0) | 0 | 5 (3.9) | ||
| Othersb | 6 (8.5) | 0 | 6 (4.6) | ||
| Alcohol consumption | Never | 50 (70.4) | 37 (63.8) | 87 (67.4) | .491 |
| Occasionally | 11 (15.5) | 15 (25.9) | 26 (20.2) | ||
| Regularly | 9 (12.7) | 5 (8.6) | 14 (10.8) | ||
| Ex-consumer | 1 (1.4) | 1 (1.7) | 2 (1.5) | ||
| Smoking behavior | Current Smoker | 8 (12.3) | 0 | 8 (6.2) | .018 |
| Nonsmoker | 63 (88.7) | 57 (98.3) | 120 (95.2) | ||
| Ex-smoker | 0 | 1 (1.7) | 1 (0.8) | ||
| Khat chewing behavior | Yes | 11 (15.5) | 0 | 11 (8.5) | .002 |
| No | 60 (84.5) | 58 (100) | 118 (91.5) | ||
| Herbal medicine use | Yes | 10 (14.1) | 0 | 10 (7.8) | .003 |
| No | 61 (85.9) | 58 (100) | 119 (92.2) | ||
Abbreviation: JUMC, Jimma University Medical Center.
a House wife.
b Live in prison.
Clinical Characteristics and Laboratory Test Data of Study Participants
As to the anatomic site of DVT, the majority of patients (124/96.1%) had the thrombosis of the lower extremities extending from the common iliac vein to the popliteal veins. About 115 (89.1%) of participants were found to have unilateral and only 14 (10.1%) patients have combined involvement of bilateral DVT, whereas approximately two-third of participants had left lower extremity involvement. On the Doppler ultrasonography examination, the majority of 103 (79.8%) of DVT cases were proximal and only 21 (16.3%) cases were located distal area for the lower extremity. The mean ± SD length of hospital stay (LOS) was 22.03 ± 16.719 days and 21.33 ± 14.104 days at JUMC and SPHMMC, respectively, with an overall range of 2 to 90 days. From a total of 129 DVT patients, 127 (98.4%) of participants had received UFH, with a mean ± SD duration of UFH-warfarin overlap of 15.792 ± 9.2454 days (range of 1-44 days). The mean ± SD result of aPTT was 34.164 ± 12.024 seconds within 24 hours and 38.81 ± 18.07 seconds in the fifth days; it was 45.628 ± 21.06 seconds immediately before discontinuing heparin. The mean ± SD of INR was 1.822 ± 1.061 and 2.136 ± 1.455 on fifth day and immediately before stopping heparin, respectively. About 34 (26.4%) had a higher risk of major bleeding, with a Hypertension, Abnormal renal and liver function, Stroke Bleeding, Labile INR, Elderly, Drugs or alcohol (HAS-BLED) score of ≥3 points (Table 2).
Table 2.
Baseline Clinical Characteristics and Laboratory Test Data of Study Participants.
| Variables | Settings | Total (n [%]) | P value | |||
|---|---|---|---|---|---|---|
| JUMC (n [%]) | St. Paul (n [%]) | |||||
| Baseline clinical data | ||||||
| Types of DVT | Unilateral | 61 (85.9) | 54 (93.1) | 115 (89.1) | .192 | |
| Bilateral | 10 (14.1) | 4 (6.9) | 14 (10.9) | |||
| Sites of DVT | Upper extremitya | 1 (1.4) | 4 (6.9) | 5 (3.9) | .108 | |
| Lower extremity | 70 (98.6) | 54 (93.1) | 124 (96.1) | |||
| Lower extremity DVT | Right leg | 15 (21.1) | 18 (31.0) | 33 (25.6) | .234 | |
| Left leg | 52 (73.2) | 33 (56.9) | 85 (65.9) | |||
| Both legs | 3 (4.2) | 3 (5.2) | 6 (4.7) | |||
| Anatomic location of DVTb | Proximal DVT | 61 (85.9) | 42 (72.4) | 103 (79.8) | .168 | |
| Distal DVT | 9 (12.7) | 12 (20.7) | 21 (16.3) | |||
| Pain | Yes | 70 (98.6) | 58 (100) | 128 (99.2) | .550 | |
| No | 1 (1.4) | 0 | 1 (0.8) | |||
| Swelling | Yes | 68 (95.8) | 58 (100) | 126 (97.7) | .164 | |
| No | 3 (4.2) | 0 | 3 (2.3) | |||
| Local tenderness | Yes | 49 (69.0) | 26 (44.8) | 75 (58.1) | .006 | |
| No | 22 (31.0) | 32 (77.6) | 54 (51.9) | |||
| Pitting edema | Yes | 41 (57.7) | 27 (46.6) | 68 (52.7) | .138 | |
| No | 30 (42.3) | 31 (53.4) | 61 (47.3) | |||
| Skin discoloration | Yes | 20 (28.2) | 12 (20.7) | 32 (24.8) | .328 | |
| No | 51 (71.8) | 46 (79.3) | 97 (75.2) | |||
| Baseline laboratory tests and others data during hospital stay (mean ± SD) | ||||||
| Hemoglobin (g/L) | 10.685 ± 3.0484 | 12.656 ± 3.0517 | 11.604 ± 3.1917 | .001 | ||
| Hematocrit (percentage) | 31.494 ± 8.4922 | 38.951 ± 8.4922 | 34.951 ± 9.3860 | <.001 | ||
| Platelet, × 109/L | 317.2 ± 146.53 | 340.3 ± 165.5 | 327.3 ± 154.84 | .440 | ||
| aPTT (seconds) at 24 hours | 33.34 ± 5.713 | 35.973 ± 19.90 | 34.164 ± 12.024 | .358 | ||
| aPTT (seconds) at 48 hours | 34.3 ± 16.76 | 38.030 ± 17.657 | 36.41 ± 17.156 | .500 | ||
| aPTT (seconds) at fifth days | 32.059 ± 8.46 | 43.587 ± 21.47 | 38.81 ± 18.07 | .043 | ||
| aPTT (seconds) at immediately before DC heparin | 35.625 ± 4.95 | 48.591 ± 23.093 | 45.628 ± 21.06 | .128 | ||
| INR at 24 hours | 1.441 ± 0.603 | 1.747 ± 1.268 | 1.5612 ± 0.93 | .101 | ||
| INR at 48 hours | 1.521 ± 0.783 | 1.854 ± 1.3235 | 1.7242 ± 1.147 | .260 | ||
| INR at fifth days | 1.666 ± 0.6891 | 1.9411 ± 1.269 | 1.822 ± 1.061 | .244 | ||
| INR on discharge days | 2.046 ± 1.1658 | 2.204 ± 1.649 | 2.136 ± 1.455 | .661 | ||
| Serum creatinine (mmol/L) | 0.0851 ± 0.0815 | 0.0845 ± 0.0781 | 0.0848 ± 0.0795 | .969 | ||
| Duration of heparin–warfarin overlap (days) | 16.394 ± 9.276 | 14.918 ± 9.2259 | 15.792 ± 9.2454 | .392 | ||
| Length of hospital stay (days) | 22.03 ± 16.719 | 21.33 ± 14.104 | 21.71 ± 15.542 | .800 | ||
| Antithrombotic use prior to admission | 9 (12.9) | 16 (27.6) | 25 (19.4) | .033 | ||
| Base line HAS-BLED score | ≥3 points (high risk) | 11 (15.5) | 23 (39.7) | 34 (26.4) | .02 | |
| <3 points (low risk) | 60 (84.5) | 35 (60.3) | 95 (73.6) | |||
Abbreviations: aPTT, activated partial thromboplastin time; DC, discontinue; DVT, deep venous thrombosis; HAS-BLED, Hypertension, Abnormal renal and liver function, Stroke Bleeding, Labile INR, Elderly, Drugs or alcohol; INR, international normalization ratio; US, ultrasonography.
a Two were right hand and 3 were on the left hand, all occurred at proximal sites.
b For lower extremity only.
Deep Venous Thrombosis Risk Factors Among Study Participants
The major risk factors related to DVT occurrence among the study participant at the 2 clinical care settings were prolonged immobilization 113 (87.6%), prior surgical history 35 (27.1%), and pregnancy 32 (24.8%). Left side DVT 23 (71.9%) was the predominant location in pregnant women. It was found that 74 (57.4%) of the patients were presented with a combined significant medical condition (ie, metabolic, endocrine or respiratory pathologies, acute infectious disease, inflammatory conditions [arthritis]). Other risk factors included chronic lung disease (17.8%), active cancer (10.9%), oral contraceptive pills use (18.6%), and congestive heart failure (15.5%; Table 3).
Table 3.
Distribution of Risk Factors of Deep Venous Thrombosis Among Study Participants.
| S.no | Risk factors | Settings | Total [n (%)] | P value | |
|---|---|---|---|---|---|
| JUMC (n [%]) | SPHMMC (n [%]) | ||||
| 1. | Pregnancy | 10 (14.1) | 22 (37.9) | 32 (24.8) | .002 |
| 2. | Active cancer | 8 (11.3) | 6 (10.3) | 14 (10.9) | .549 |
| 3. | Prior history of surgery | 13 (18.3) | 22 (37.9) | 35 (27.1) | .013 |
| 4. | Obesity | 3 (4.2) | 2 (3.4) | 5 (3.9) | .603 |
| 5. | Chronic lung disease | 8 (11.3) | 15 (25.9) | 23 (17.8) | .027 |
| 6. | Prolonged immobilization | 69 (97.2) | 44 (75.9) | 113 (87.6) | <.001 |
| 7. | Heart failure | 6 (8.4) | 14 (24.1) | 20 (15.5) | .014 |
| 8. | Prior history of Trauma | 9 (12.7) | 6 (10.3) | 15 (11.6) | .681 |
| 9. | Neurologic disease | 3 (4.2) | 6 (10.3) | 9 (7.0) | .175 |
| 10. | History of major bleeding | 19 (26.8) | 13 (22.4) | 32 (24.8) | .059 |
| 11. | OCP use | 16 (22.5) | 8 (13.8) | 24 (18.6) | .204 |
| 12. | HRT | 2 (2.8) | 0 | 2 (1.6) | .198 |
| 13. | Previous VTE history | 8 (11.3) | 10 (17.2) | 18 (14.0) | .330 |
| 14. | More significant medical conditionsa | 48 (67.6) | 26 (44.8) | 74 (57.4) | .561 |
Abbreviation: HRT, hormone replacement therapy, JUMC, Jimma University Medical Centre; OCP, Oral contraceptive pills; SPHMMC, St, Paul’s Hospital Millennium Medical College; VTE, venous thromboembolism.
a Metabolic, endocrine, or respiratory pathologies, acute infectious disease, inflammatory conditions (arthritis).
The prevalence of comorbidity among study participants showed that about 77.5% of them had current comorbid conditions. Thus, 15 (11.6%) of them had active cancer. Renal failure and heart failure accounted for 19 (14.7%) and 20 (15.5%), respectively (Table 4).
Table 4.
Distribution of Comorbidity Presenting With DVT in Study Participants.
| S.no | Types of comorbidities | Settings | Total (n [%]) | P value | ||
|---|---|---|---|---|---|---|
| JUMC (n [%]) | SPHMMC (n [%]) | |||||
| 1. | Presence of comorbidity | Yes | 53 (74.60) | 47 (81) | 100 (77.5) | .387 |
| No | 18 (25.40) | 11 (19) | 29 (24.5) | |||
| 2. | Types of comorbidity | |||||
| a. Atrial fibrillation | 0 | 2 (3.4) | 2 (1.5) | .115 | ||
| b. Diabetes mellitus | 1 (1.4) | 6 (10.3) | 7 (5.4) | .026 | ||
| c. Hypertension | 5 (7.0) | 7 (12.1) | 12 (8.6) | .328 | ||
| d. Previous stroke | 1 (1.4) | 1 (1.7) | 2 (1.5) | .885 | ||
| e. Heart failure | 6 (8.4) | 14 (24.1) | 20 (15.5) | .014 | ||
| f. Chronic liver disease | 3 (4.2) | 4 (6.9) | 7 (5.4) | .505 | ||
| g. Renal failure | 5 (7.0) | 14 (24.1) | 19 (14.7) | .006 | ||
| h. Coronary artery disease | 2 (2.8) | 3 (5.2) | 5 (3.9) | .491 | ||
| i. HIV/AIDS | 2 (2.8) | 4 (6.9) | 6 (4.6) | .274 | ||
| j. Othersa | 41 (57.7) | 20 (34.5) | 61 (47.3) | .904 | ||
| k. Cancer | 8 (11.3) | 7 (12.1) | 15 (11.6) | .888 | ||
| l. Type of cancer | CRC | 0 | 1 (1.7) | 1 (0.8) | .461 | |
| Rectal | 0 | 1 (1.7) | 1 (0.8) | |||
| Brain | 0 | 1 (1.7) | 1 (0.8) | |||
| Lung | 0 | 1 (1.7) | 1 (0.8) | |||
| Otherb | 5 (7.0) | 4 (6.9) | 9 (7.0) | |||
Abbreviations: CRC, colorectal cancer, DVT, deep venous thrombosis; MDD, major depressive disorder.
a combined comorbidity (anemia, TB, epilepsy, MDD).
b Ovarian cancer, non-Hodgkin lymphoma.
The majority of study participants, 127 (98.4%) received UFH on their admission. About 89.1% of patients’ warfarin was prescribed with parenteral anticoagulant therapy. Majority of the participant was on ancillary medication, of which one-third of participants were on antibiotics, 16 (12.4%) were on cardiovascular drugs, and 26 (20.2%) of participants were on vitamin and minerals (Figure 2).
Figure 2.
In-hospital medications used by study participants from March to August, 2018. CV indicates cardiovascular; GI, gastrointestinal; JUMC, Jimma University Medical Center, SPHMMMC, St Paul Hospital Millennium Medical College; LMWH, low molecular weight heparin; UFH, unfractionated heparin.
Deep Venous Thrombosis Follow-Up Outcome of Participants
A cohort of 129 patients was followed up for a total of 11 348 person-days. More than three-fourth of study participants developed DVT for the first time. During the 90-day follow-up period of each participant from a cohort of DVT, 34 (26.4%) recurrent VTE was observed. The type of event was DVT in 28 (82.40%) patients and the rest were admitted with PE, which was confirmed by computed tomography scan. During the study period, none of the patients with recurrent VTE event were within the therapeutic range. Their INR was below 2. The overall incidence rate was 2.99 per 1000 patient-days. A few numbers of patients, 6 (4.7%), had confirmed complete DVT resolution within 3 months of treatment. The overall mean ± SD duration of DVT recurrence was 42.03 ± 22.371 with a range of 26 to 90 days (Table 5).
Table 5.
Distribution of DVT Outcome Measures Among Study Participants.
| Variables | Setting | Total (n [%]) | P value | ||
|---|---|---|---|---|---|
| JUMC (n [%]) | SPHMMC (n [%]) | ||||
| DVT admission status | First episode | 60 (84.5) | 38 (65.5) | 98 (76.0) | .035 |
| Second times | 9 (12.7) | 18 (31.0) | 27 (20.9) | ||
| > 2 times | 2 (2.8) | 2 (3.6) | 4 (3.1) | ||
| 90 days follow-up DVT status | Recurrence | 12 (16.9) | 22 (37.9) | 34 (26.4) | .007 |
| No recurrence | 59 (83.1) | 36 (62.1) | 95 (73.6) | ||
| Recurrence diagnosis | DVT + PE | 0 | 6 (27.3) | 6 (17.6) | .046 |
| DVT only | 12 (100.0) | 16 (72.7) | 28 (82.4) | ||
| 90 days of DVT status | Worsened | 12 (16.9) | 22 (37.9) | 34 (26.3) | .147 |
| No change | 19 (26.8) | 11 (19.0) | 30 (23.3) | ||
| Improved | 36 (50.7) | 23 (39.7) | 59 (45.7) | ||
| Complete resolution | 4 (5.6) | 2 (3.4) | 6 (4.7) | ||
| All-cause mortality | Yes | 0 | 4 (6.9) | 4 (3.1) | .025 |
| No | 71 (100) | 54 (93.1) | 125 (96.9) | ||
| Platelet less than 150 000 cells/mm3 | Yes | 3 (4.2) | 8 (13.8) | 11 (8.5) | .053 |
| No | 68 (95.8) | 50 (86.2) | 118 (91.5) | ||
| Drop in platelet count >50% from baseline | Yes | 4 (5.6) | 7 (12.1) | 11 (8.5) | .193 |
| No | 67 (94.4) | 51 (87.9) | 118 (91.5) | ||
| Time to DVT recurrence in days (mean ± SD) | 41.42 ± 18.595 | 42.03 ± 22.37 | 42.03 ± 22.371 | .908 | |
| INR (2-3) achievement in days (mean ± SD) | 10.73 ± 17.232 | 15.70 ± 21.086 | 13.22 ± 19.286 | .270 | |
| aPTT ≥ 2 to 2.5 above baseline in days (mean ± SD) | 7.50 ± 6.364 | 7.74 ± 8.812 | 7.71 ± 8.480 | .971 | |
Abbreviations: aPTT, activated partial thromboplastin time; DVT, deep venous thrombosis; INR, international normalization ratio; JUMC, Jimma University Medical Centre; PE, pulmonary embolism; SPHMMC, St, Paul’s Hospital Millennium Medical College.
Kaplan Meier Survival Outcome Analysis
The mean ± SD survival time to DVT recurrence was 42.03 ± 22.371 days. On the Kaplan Meier survival outcome analysis, variables such as LOS, anatomical location of DVT, HAS-BLED score, age of the patients, diabetes mellitus (DM) comorbidity, gender, early initiation of warfarin, achieving target aPTT within 24 hours of heparin were done. From the result, the survival time to DVT recurrence were not statistically significant between gender (log-rank P = .120), early initiation of warfarin (log-rank P = .174), and LOS (log-rank P = .303). However, there were differences in survival time to DVT recurrence concerning HAS-BLED score (Log rank P = .05; Figure 3).
Figure 3.
Survival function estimates of cumulative incidence of DVT recurrence event derived from Log rank Kaplan Meier; early warfarin therapy (A), length of hospital stay (B), HAS BLED score (C), and gender of patients (D).
Factors Associated With DVT Recurrence Among Study Participants
The association of independent variables with the dependent variable was investigated using both univariate and multivariate Cox regression techniques. On univariate Cox regression analysis, female gender (crude hazard ratio [CHR]: 1.799; 95% CI: 0.828-3.905; P = .038), age ≥ 50 years (CHR: 3.438; 95% CI: 1.091-10.838; P = .035), occasional alcohol consumption (CHR: 2.460; 95% CI: 0.694-8.723; P = .031), regular alcohol consumption (CHR: 1.110; 95% CI: 0.494-2.656; P = .054), pregnancy (CHR: 1.091; 95% CI: 1.46-11.179; P = .057), hypertension (CHR: 0.077; 95% CI: 0.017-0.358; P = .001), DM (CHR: 3.869; 95% CI: 1.295-11.558; P = .015), uninitiated warfarin within 24 hours of heparin initiation (CHR: 2.797; 95% CI: 1.087-7.213; P = .051), not achieving aPTT target within 24 hours (CHR: 1.108; 95% CI: 0.020-0.600; P = .032), and (CHR: 2.130; 95% CI: 1.201-11.472; P ≤ .001) showed statistically significant association with DVT recurrence. The result of the multivariate Cox regression analysis showed that, age between 30 and 50 years, age ≥ 50 years, alcohol consumption, prior history of surgery, pregnancy, DM comorbidity, inability to achieve target aPTT within 24 hours of heparin and proximal site involvement were statistically associated with DVT recurrence. On adjusted model, there was statistically significant hazard (more than twice) of DVT recurrence for patients with previous history of DVT (adjusted hazard ratio [AHR]: 2.48; 95% CI: 1.085-11.20; P = .0002).
The likelihood of DVT recurrence was about 8 times among diabetic comorbid patients (AHR: 8.048; 95% CI: 2.494-25.966; P < .001) when compared with nondiabetics. And also the relative risk of DVT recurrence was about 6 times among patients with prior history of surgery (AHR: 6.218; 95% CI: 1.540-25.104; P = .010). The relative risk of DVT recurrence was also higher among patients who didn’t achieve target aPTT within 24 hours (AHR: 1.129; 95% CI: 0.120-10.600; P = .011) of in-hospital heparin administration. The relative risk of DVT recurrence was also seen among alcoholics. For example, regular consuming of alcohol (AHR: 1.947, 95% CI: 0.448-8.468; P = .074) and occasional users (AHR: 2.011; 95% CI: 0.701-5.768; P = .019) doubled the risk of DVT recurrence. The relative risk of DVT recurrence among pregnant women was about 2 times (AHR: 2.0911; 95% CI: 1.046-4.179; P = .037). The likelihood of DVT recurrence was also associated with the age of the patients. For example, age ≥50 years carries a risk of DVT recurrence more than 5 times for patients (AHR: 5.566; 95% CI: 1.587-19.518; P = .007). Proximal site involvement (AHR: 5.937; 95% CI: 1.300-27.110; P = .022) showed higher hazards of DVT recurrence (Tables 6 and 7).
Table 6.
Socio-Demographic and Behavioral Factors Associated With DVT Recurrence Among Study Participants.
| Variables | Recurrent event | CHR (95% CI) | P value | AHR (95% CI) | P value | ||
|---|---|---|---|---|---|---|---|
| Yes (n [%]) | No (n [%]) | ||||||
| Gender | Male | 10 (7.8) | 35 (27.1) | 1 | 1 | ||
| Female | 24 (18.6) | 60 (46.5) | 1.799 (0.828-3.905) | .038 | 1.116 (0.516-2.411) | .138 | |
| Age (years) | 18-35 | 22 (17.1) | 54 (41.8) | 1 | 1 | ||
| 35-50 | 7 (5.4) | 10 (7.8) | 2.287 (0866-6.041) | .095 | 3.545 (1.216-10.338) | .056 | |
| ≥50 | 5 (3.9) | 31 (24) | 3.438 (1.091-10.838) | .035 | 5.566 (1.587-19.518) | .007 | |
| Marital status | Single | 7 (5.4) | 19 (14.7) | 1 | |||
| Married | 27 (20.9) | 69 (53.5) | 0.591 (0.249-1.439) | .903 | |||
| Divorced | 0 | 4 (3.2) | 0.947 (0.118-11.468) | .999 | |||
| Widowed | 0 | 3 (2.3) | 0.471 (0.713-6.408) | .731 | |||
| Educational status | Cannot read and write | 9 (7) | 43 (33.3) | 1.776 (0.658-4.790) | .257 | ||
| Primary school | 10 (7.8) | 31 (24) | 1.477 (0.559-3.905) | .431 | |||
| Secondary school | 11 (8.4) | 16 (12.4) | 1.842 (0.536-6.330) | .332 | |||
| College and above | 4 (3.2) | 5 (3.9) | 1 | ||||
| Residence location | Rural | 13 (10.7) | 61 (47.3) | 1 | |||
| Urban | 21 (16.3) | 34 (26.4) | 0.759 (0.373-1.547) | .448 | |||
| Occupational status | Office worker | 7 (5.4) | 8 (6.2) | 1 | 1 | ||
| Farmer | 6 (4.7) | 31 (24) | 1.516 (0.486-4.735) | .474 | 1.376 (0.354-5.348) | .645 | |
| Merchant | 8 (6.2) | 14 (10.8) | 1.858 (0.659-5.240) | .241 | 3.249 (0.900-11.730) | .072 | |
| Student | 2 (1.6) | 8 (6.2) | 2.654 (0.508-13.858) | .247 | 1.651 (0.214-12.715) | .630 | |
| Daily laborer | 4 (3.2) | 6 (4.6) | 0.492 (0.137-1.767) | .277 | 0.236 (0.054-1.044) | .057 | |
| Othersa | 7 (5.4) | 28 (21.7) | 0.660 (0.244-1.944) | .451 | 0.500 (0.155-1.619) | .245 | |
| Living condition | With immediate family | 30 (23.3) | 81 (62.8) | 1 | |||
| With extended family | 2 (1.6) | 5 (3.9) | 1.594 (0.368-6.916) | .533 | |||
| Living alone | 1 (0.8) | 4 (3.2) | 1.922 (0.250-14.769) | .530 | |||
| Others | 1 (0.8) | 5 (3.9) | 1.361 (0.180-10.310) | .766 | |||
| Alcohol consumption | Never | 22 (17.1) | 65 (50.4) | 1 | 1 | ||
| Occasionally | 7 (5.4) | 19 (14.7) | 2.460 (0.694-8.723) | .031 | 2.011 (0.701-5.768) | .019 | |
| Regularly | 3 (2.3) | 11 (8.4) | 1.110 (0.494-2.656) | .054 | 1.947 (0.448-8.468) | .074 | |
| Ex-alcohol consumer | 2 (1.6) | 0 | 0.723 (0.168-3.121) | .664 | 0.098 (0.11-0.870) | .037 | |
| Smoking behavior | Current smoker | 1 (0.8) | 6 (4.6) | 1.392 (0.185-10.485) | .748 | ||
| Nonsmoker | 33 (25.6) | 89 (69) | 1 | ||||
| Khat chewing behavior | Yes | 3 (2.3) | 8 (6.2) | 1.517 (0.445, 5.164) | .505 | ||
| Herbal medicine use | No | 31 (24) | 87 (67.4) | 1 | |||
| Herbal medicine use | Yes | 2 (1.6) | 8 (6.2) | 1.877 (0.436-8.034) | .398 | ||
| No | 32 (24.8) | 87 (67.4) | 1 | ||||
Abbreviations: AHR, adjusted hazard ratio; CHR, crude hazard ratio; DVT, deep venous thrombosis.
a House wife.
Table 7.
Clinical and Laboratory Data Related Factors Associated With DVT Recurrence Among Study Participants.
| Variables | Recurrent event | CHR (95% CI) | P value | AHR (95% CI) | P value | ||
|---|---|---|---|---|---|---|---|
| Yes (n [%]) | No (n [%]) | ||||||
| Pregnancy | Yes | 13 (10.7) | 19 (14.7) | 1.091 (1.46-11.179) | .057 | 2.091 (1.046-4.179) | .037 |
| No | 21 (16.3) | 76 (58.9) | 1 | 1 | |||
| Prior history of surgery | Yes | 11 (8.5) | 24 (18.6) | 1.242 (0.275-1.185) | .132 | 6.218 (1.540-25.104) | .010 |
| No | 23 (18.3) | 71 (55) | 1 | 1 | |||
| Chronic lung disease | Yes | 5 (3.9) | 18 (13.9) | 2.000 (0.758-5.278) | .162 | 0.922 (0.341-2.495) | .874 |
| No | 29 (22.5) | 77 (59.7) | |||||
| Prolonged immobilization | yes | 27 (20.9) | 86 (66.7) | 1.834 (0.771-4.360) | .170 | 2.392 (0.818-7.00) | .111 |
| No | 7 (5.4) | 9 (7) | 1 | 1 | |||
| Heart failure | Yes | 5 (3.9) | 15 (11.6) | 2.162 (0.808-5.786) | .125 | 0.440 (0.081-2.379) | .340 |
| No | 29 (22.5) | 80 (62) | 1 | 1 | |||
| Prior history of Trauma | Yes | 3 (2.3) | 12 (9.3) | 1.109 (0.328-3.746) | .868 | ||
| No | 31 (24) | 83 (64.3) | 1 | ||||
| Neurologic disease | Yes | 3 (2.3) | 6 (4.6) | 0.432 (0.127-1.465) | .178 | 2.504 (0.515-48.504) | .255 |
| No | 31 (24) | 89 (69) | 1 | 1 | |||
| History of major bleeding | Yes | 13 (10.7) | 19 (14.7) | 1.884 (0.440-1.776) | .729 | ||
| No | 21 (16.3) | 76 (58.9) | 1 | 1 | |||
| OCP use | Yes | 8 (6.2) | 16 (12.4) | 1.965 (0.874-4.416) | .102 | 0.493 (0.177-1.375) | .176 |
| No | 26 (20.2) | 79 (61.2) | 1 | ||||
| HRTa | Yes | 1 (0.8) | 1 (0.8) | 3.152 (0.399-24.899) | .276 | ||
| No | 33 (25.6) | 94 (72.9) | 1 | ||||
| Previous DVT history | Yes | 18 (13.9) | 0 | 2.130 (1.201-11.472) | <.001 | 2.48 (1.085-11.20) | .0002 |
| No | 16 (12.4) | 95 (73.6) | 1 | 1 | |||
| Other comorbidityb | Yes | 16 (12.4) | 58 (45) | 1.054 (0.534-2.079) | .880 | ||
| No | 18 (13.9) | 37 (28.7) | 1 | ||||
| Antithrombotic drug prior to admission | Yes | 14 (11.1) | 11 (8.5) | 1.374 (0.684-2.758) | .372 | ||
| No | 20 (15.5) | 84 (65.1) | 1 | ||||
| Diabetes mellitus | Yes | 4 (3.1) | 3 (2.3) | 3.869 (1.295-11.558) | .015 | 8.048 (2.494-25.966) | <.001 |
| No | 30 (23.3) | 92 (71.3) | 1 | 1 | |||
| Hypertension | Yes | 3 (2.3) | 9 (7) | 0.077 (0.017-0.358) | .001 | 0.518 (0.046-5.782) | .593 |
| No | 31 (24) | 86 (66.7) | 1 | 1 | |||
| Chronic liver disease | Yes | 2 (1.6) | 5 (3.9) | 3.236 (0.733-14.294) | .121 | 3.33 (0.371-29.930) | .283 |
| No | 32 (24.8) | 90 (69.8) | 1 | 1 | |||
| Lower extremity DVT | Proximal DVT | 31 (25) | 73 (58.9) | 2.258 (0.670-7.614) | .189 | 5.937 (1.300-27.110) | .022 |
| Distal DVT | 3 (2.4) | 18 (14.5) | 1 | 1 | |||
| Patient received UFH | Yes | 32 (24.8) | 95 (73.6) | 1 | 1 | ||
| No | 2 (1.6) | 0 | 2.207 (0.720-14.281) | .106 | 0.521 (0.096-2.833) | .451 | |
| Don’t received warfarin within 24 hours of heparin | Yes | 28 (21.7) | 87 (64.4) | 2.797 (1.087-7.213) | .051 | 1.453 (0.187-1.100) | .080 |
| No | 6 (4.6) | 8 (6.2) | |||||
| Risk factors for DVT | Single risk factor | 2 (1.6) | 15 (11.6) | 1 | .312 | 1 | |
| Two risk factors | 8 (6.2) | 38 (29.5) | 2.188 (0.488. 10.680) | .130 | 1.658 (0.322-8.543) | .546 | |
| Multiple risk factors | 24 (18.6) | 42 (32.6) | 1.169 (0.272-5.020) | .312 | 1.026 (0.230-4.582) | .973 | |
| Parenteral anticoagulant for ≥5 days | Yes | 29 (22.5) | 86 (66.6) | 1 | |||
| No | 5 (3.9) | 9 (7) | 0.895 (0.334-2.398) | .824 | |||
| INR ≥2.0 for ≥24 hours before | Yes | 2 (1.6) | 16 (12.4) | 1 | |||
| No | 32 (24.8) | 79 (61.2) | 0.852 (0.201-3.618) | .832 | |||
| Early start of VKA (within 24 hours) | Yes | 23 (17.8) | 75 (58.2) | 1 | |||
| No | 11 (8.5) | 20 (15.5) | 1.167 (0.558-2.441) | .682 | |||
| Initial with SC heparin | Yes | 32 (24.8) | 95 (73.6) | 1 | 1 | ||
| No | 2 (1.6) | 0 | 3.207 (0.720-14.281) | .184 | 1.918 (0.353-10.424) | .451 | |
| Reach aPTT target within 24 hours | Yes | 2 (1.6) | 7 (5.4) | 1 | 1 | ||
| No | 32 (24.8) | 88 (68.2) | 1.108 (0.020-0.600) | .032 | 1.129 (0.120-10.600) | .011 | |
Abbreviations: AHR, adjusted hazard ratio; aPTT, activated partial thromboplastin time; CHR, crude hazard ratio; DVT, deep venous thrombosis; HRT, hormonal replacement therapy; INR, international normalization ratio; OCP, oral contraceptive pills; VKA, vitamin K dependent anticoagulant; SC, subcutaneous; UFH, unfractionated heparin.
a Denominator female gender.
b Active infection, metabolic, endocrine or respiratory pathologies, inflammatory conditions, and varicose veins with phlebitis.
Discussions
The risk of recurrence following an episode of VTE is highest during the first 3 months and declines rapidly to about 5% per year. We conducted this current study at 2 tertiary teaching hospitals setting using a prospective open cohort study design to determine the burden of DVT recurrence and associated factors. Hospitalized confirmed DVT patients were carefully assessed for valuable information, and the study participants were strictly followed for about 3 months for the outcome.
During the study period, about 713 medical cases at JUMC and 893 at SPHMMC were admitted; with a total of 1606 patients. It was found that the incidence of DVT was 9.96% and 6.5% at JUMC and SPHMMC, respectively, with the overall incidence of 8.1%. This DVT incidence burden was comparable with the study done in Thailand,19 which was 10.5%, and in Uganda,20 which was 9.1%. The recurrence rate of DVT was 16.9% and 32.3% from JUMC and SPHMMC, respectively, with an overall recurrence rate of 26.4%. The result was comparable with the study done in the United States,21 which showed a DVT recurrence rate of 22%. But, the study done in France22 showed a lower recurrence rate (5.5%). This variation may be related to a larger sample size (n = 1804) and the retrospective study design in the settings.
In our study, the highest DVT incidents were found in the age greater than 35 years. A similar result was found in Addis Ababa.15,23,24 The highest incidence of DVT was varied from different studies. In most of the studies, DVT occurrence was high at a mean ± SD age of 63 ± 19.4 and 66 ± 17.21,25 And also on the Cox regression analysis, older age increased the risk of DVT recurrence. Patients aged between 35 and 50 years old had greater than 3 times relative risk of DVT recurrence and older than 50 years had significantly higher hazards (more than 5 times) of DVT recurrence. This report is incomparable with 2 studies from Spain,21,26 which showed increased risk per additional decade. In addition to increased exposure to DVT risk factors, older age linked with a sedentary lifestyle, restricted movement, and biology of aging on vascular patency.
About two-thirds of participants had left lower extremity involvement. On multivariate Cox regression analysis, a proximal extension of DVT had strong risk predictors of DVT recurrence. This is strongly supported by different studies.25,27–29 This is maybe explained by the anatomy of DVT of the lower extremity, showing highly involved site for DVT cases. And also multiple studies showed as if a resolution of proximal DVT is slow and less than half have complete lysis after 6 months of anticoagulation.
In our study, we found that previous history of thromboembolism to be independent risk factors for the DVT recurrence. The risk of DVT recurrence doubled among patient with previous history of DVT. This study was similar to a report from Iran,28 United States,30 Canada,31 and Sweden.32 May be this is related to the presence of a residual thrombus which is associated with an increased risk of thrombotic recurrence. In our setting, there is a poor monitoring for anticoagulation adequacy during the course of treatment. Therefore, residual vein thrombosis (RVT) assessment, which is not available in our setting, is useful for evaluating the features of a DVT of the affected limb. In fact, RVT assessment not only identifies a subset of patients at lower risk of recurrence but also allows us to gauge the individual risk of recurrence after a first DVT episode.
Among the study participants, pregnancy accounted for 32 (47.8%) of associated risk factors with DVT from a female of childbearing age. Pregnancy was significantly associated with the development of DVT recurrence, which is similar to reports from Arizona hospital,21,33 where pregnancy is a common risk of DVT occurrence and rate of DVT recurrence. This is related to venous stasis (due to pregnancy-associated changes in venous capacitance and compression of large veins by the gravid uterus), endothelial injury (due to changes at the uteroplacental surface and vascular injury during delivery), and a hypercoagulable state (pregnancy is associated with progressive increases in several coagulation factors, a decrease in protein S, and a progressive increase in resistance to activated protein C).34
Regarding gender, our study finding showed that being female was statistically associated with DVT recurrence (CHR, 1.799; 95% CI: 0.828-3.905; P = .038). This finding was in line with the study from Minnesota.21 But, other prospective studies failed to support this observation,26,35 and male sex increased the risk of DVT recurrence. This difference might be related to long-term follow-up (up to 2 years) observational cohort with a large sample, and also a few numbers of male participants were included in our study. Besides, in this current study, more female within childbearing age was included, as females at a productive age are more susceptible, due to the hormonal influences.
In this study, we found that prior history of surgery as an independent predictor of increased risk of DVT recurrence. This finding was in line with the data from Minnesota.26,35 This probably due to poor thromboprophylaxis practice in our set up and also endothelial damage exposes blood to collagen and tissue factor, which will then activate the coagulation cascade leading to DVT and as well general anesthesia has been documented to induce hypoxic endothelial activation and a prothrombotic state through reduction of blood flow to the lower limbs.36
Diabetes mellitus comorbidity was an independent predictor of DVT recurrence. Hazards on developing recurrent DVT was 8 times more among patients living with DM (AHR, 8.048; 95% CI: 2.494-25.966; P < .001). This finding was supported by a study from Canada37 and also similar data from the previous study found that DM was associated with a 3-fold increase in the likelihood of developing DVT recurrence.1 Theoretically, hyperglycemia contributes to elevated coagulation factors, impaired fibrinolysis, and increased likelihood of thrombosis. And also high plasma glucose level increase oxidative stress, which in turn increases gene transcription of coagulation factors; degrade the glycocalyx layer of the endothelial wall, which releases coagulation factors and stimulates the coagulation cascade; and increase glycation of proteins involved in coagulation and fibrinolysis, shifting their activity toward a procoagulant state.38 Besides due to vascular complications from diabetes, decreased peripheral circulation will result in distal ischemia, which affects DVT occurrence and recurrence.
Another remarkable finding in this present study was the inability to achieve target aPTT within 24 hours of parenteral anticoagulant medications was 93%. In this study, it was an independent predictor for the development of recurrent DVT. Failure to rapidly achieve a target APTT appears to reflect heparin dosing, which will affect the inpatient anticoagulation adequacy.
Furthermore, we found that the unspecified amount of regular alcohol consumption was linked with increases in the development of DVT recurrence. Similar results were found from San Diego, California, United States,39 where high maximum alcohol use is the behavior most linked to increasing the risk of DVT recurrence. This may be related to oxidative stress and mitochondrial toxicity from alcohol, which will cause tissue injury and cell death. This lead to triggers coagulation activation, via exposure at the cell surface of phosphatidylserine.40
Strengths and Limitations of the Study
The present study was the first original research reporting the recurrence of DVT in Ethiopia. The study also uses a more robust study design, prospective cohort study, which will control some of the confounders. However, the study has several limitations; small sample size due to short enrollment period, only 2 studies set in the country so cannot represent all of the countries. It will be better to research with long-term follow-up and large sample sizes across the country.
Conclusions
In general, the DVT recurrence rate was higher than most previously reported results. The recurrent DVT also complicated with PE as well as death during the follow-up period. The overall incidence recurrence rate was 2.99 in 1000 patient-days. Complete resolution of DVT was seen for a small number of patients within the currently recommended duration of anticoagulation, indicating poor inpatient treatment adequacy. Older age, prior history of surgery, pregnancy, DM, comorbidity, inability to achieve target aPTT within 24 hours of heparin initiation, proximal site involvement, previous history of DVT, and unquantified alcohol consumption were independent predictors of DVT recurrence. It is a high time that patient with these risk factors should be evaluated and followed to prevent the occurrence of DVT recurrence.
Acknowledgments
The authors would like to express our heartfelt gratitude to the Jimma University, Institute of Health, for giving us the chance to conduct this research. The authors have also unreserved thanks to St. Paul Millennium Medical College and Jimma University Medical Center for cooperation and permission during patient enrollment and data collection. Our acknowledgment extends to all data collectors and health care professionals at the 2 tertiary hospitals for their friendly work.
Authors’ Note: The analysis was conceptualized by AM & TM. Data collection was managed by AM and data analysis was conducted by AM, TM, and LC. TM drafted the manuscript. All authors (AM, TM, and LC) participated in editing, feedback, and revisions. The data sets generated during and/or analyzed during the current study are available from the corresponding authors on reasonable request. Ethical clearance approval was obtained from the institution review board (IRB) of Jimma University. Before the start of the survey, informed consent was requested and received from the patient.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by Jimma University, Ethiopia.
ORCID iD: Tsegaye Melaku 
https://orcid.org/0000-0001-8373-5309
References
- 1. Goldhaber SZ, Bounameaux H. Pulmonary embolism and deep vein thrombosis. Lancet. 2012;379(9828):1835–1846. [DOI] [PubMed] [Google Scholar]
- 2. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2008;133(6):381S–453S. [DOI] [PubMed] [Google Scholar]
- 3. Yamaki T, Nozaki M, Sakurai H, Takeuchi M, Soejima K, Kono T. Presence of lower limb deep vein thrombosis and prognosis in patients with symptomatic pulmonary embolism: preliminary report. Eur J Vasc Endovasc Surg. 2009;37(2):225–231. [DOI] [PubMed] [Google Scholar]
- 4. Flordal PA, Bergqvist D, Ljungström KG, Törngren S. Clinical relevance of the fibrinogen uptake test in patients undergoing elective general abdominal surgery—relation to major thromboembolism and mortality. Thromb Res. 1995;80(6):491–497. [DOI] [PubMed] [Google Scholar]
- 5. Spencer FA, Emery C, Joffe SW, et al. Incidence rates, clinical profile, and outcomes of patients with venous thromboembolism. The Worcester VTE study. J Thromb Thrombolysis. 2009;28(4):401–409. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Hirsh J, Hoak J. Management of deep vein thrombosis and pulmonary embolism: a statement for healthcare professionals from the council on thrombosis (in consultation with the council on cardiovascular radiology), American Heart Association. Circulation. 1996;93(12):2212–2245. [DOI] [PubMed] [Google Scholar]
- 7. Palareti G. Recurrent venous thromboembolism: what is the risk and how to prevent it. Scientifica. 2012;2012:391734. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Khan F, Rahman A, Carrier M, et al. Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis. BMJ. 2019;366:l4363. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100(10):3484–3488. [DOI] [PubMed] [Google Scholar]
- 10. Gader AA, Haggaz AED, Adam I. Epidemiology of deep venous thrombosis during pregnancy and puerperium in Sudanese women. Vasc Health Risk Manag. 2009;5(1):85–87. [PMC free article] [PubMed] [Google Scholar]
- 11. Zöller B, Ohlsson H, Sundquist J, Sundquist K. Family history of venous thromboembolism is a risk factor for venous thromboembolism in combined oral contraceptive users: a nationwide case-control study. Thromb J. 2015;13(1):34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Conklin P, Soares GM, Dubel GJ, Ahn SH, Murphy TP. Acute deep vein thrombosis (DVT): evolving treatment strategies and endovascular therapy. R I Med J. 2009;92(12):394–397. [PubMed] [Google Scholar]
- 13. Khalil L, Wong HS, Keeling DM, Desborough MJ. Venous thromboembolism: risk of recurrence and long-term anticoagulation. Br J Hosp Med (Lond). 2015;76(2):72–77. MA Healthcare London. [DOI] [PubMed] [Google Scholar]
- 14. Gebremedhin A, Shamebo M. Deep venous thrombosis in a university teaching hospital, Addis Ababa, Ethiopia. East Afr Med J. 1998;75(7):432–435. [PubMed] [Google Scholar]
- 15. Haile L, Hawaz Y, Assefa G. Risk Factors of Deep Venous Thrombosis in Duplex and Colour Doppler Ultrasound at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia. East Central African J Surg. 2013;18(2):61–69. [Google Scholar]
- 16. Food M, Administration HC, Ethiopia CAo. Standard Treatment Guidelines for General Hospitals. 2014.
- 17. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2):e419S–e496S. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123(23):2736–2747. [DOI] [PubMed] [Google Scholar]
- 19. Wilasrusmee C, Kiranantawat K, Horsirimanont S, et al. Deep venous thrombosis in surgical intensive care unit: prevalence and risk factors. Asian J Surg. 2009;32(2):85–88. [DOI] [PubMed] [Google Scholar]
- 20. Vululi ST, Bugeza S, Zeridah M, et al. Prevalence of lower limb deep venous thrombosis among adult HIV positive patients attending an outpatient clinic at Mulago Hospital. AIDS Res Ther. 2018;15(1):3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Heit JA, Lahr BD, Petterson TM, Bailey KR, Ashrani AA, Melton LJ. Heparin and warfarin anticoagulation intensity as predictors of recurrence after deep vein thrombosis or pulmonary embolism: a population-based cohort study. Blood. 2011;118(118):4992–4999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Bouée S, Emery C, Samson A, Gourmelen J, Bailly C, Cotté FE. Incidence of venous thromboembolism in France: a retrospective analysis of a national insurance claims database. Thromb J. 2016;14(1):4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Daba FB, Tadesse F, Engidawork E. Drug-related problems and potential contributing factors in the management of deep vein thrombosis. BMC Hematol. 2016;16(1):2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Goran A. Deep vein thrombosis of the lower limbs in Duhok: a descriptive study using Doppler ultrasound. Duhok Med J. 2009;3:64–72. [Google Scholar]
- 25. Arcelus JI, Caprini JA, Monreal M, Suárez C, González-Fajardo J. The management and outcome of acute venous thromboembolism: a prospective registry including 4011 patients. J Vasc Surg. 2003;38(5):916–922. [DOI] [PubMed] [Google Scholar]
- 26. Nagler M, Ten Cate H, Prins MH, Ten Cate-Hoek AJ. Risk factors for recurrence in deep vein thrombosis patients following a tailored anticoagulant treatment incorporating residual vein obstruction. Res Pract Thromb Haemost. 2018;2(2):299–309. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Ouriel K, Green RM, Greenberg RK, Clair DG. The anatomy of deep venous thrombosis of the lower extremity. J Vasc Surg. 2000;31(5):895–900. [DOI] [PubMed] [Google Scholar]
- 28. Farzamnia H, Rabiei K, Sadeghi M, Roghani F. The predictive factors of recurrent deep vein thrombosis. ARYA Atheroscler. 2011;7(3):123–128. [PMC free article] [PubMed] [Google Scholar]
- 29. Kyrle PA, Kammer M, Eischer L, et al. The long-term recurrence risk of patients with unprovoked venous thromboembolism: an observational cohort study. J Thromb Haemost. 2016;14(12):2402–2409. [DOI] [PubMed] [Google Scholar]
- 30. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158(6):585–593. [DOI] [PubMed] [Google Scholar]
- 31. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med. 1999;340(12):901–907. [DOI] [PubMed] [Google Scholar]
- 32. Hansson P-O, Sörbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med. 2000;160(6):769–774. [DOI] [PubMed] [Google Scholar]
- 33. Devis P, Knuttinen MG. Deep venous thrombosis in pregnancy: incidence, pathogenesis and endovascular management. Cardiovasc Diagn Ther. 2017;7(suppl 3):S309–S319. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Kujovich JL. Hormones and pregnancy: thromboembolic risks for women. Br J Haematol. 2004;126(4):443–454. [DOI] [PubMed] [Google Scholar]
- 35. Moreno AF, Navarro MG, Sánchez JO, et al. A risk score for prediction of recurrence in patients with unprovoked venous thromboembolism (DAMOVES). Eur J Intern Med. 2016;29:59–64. [DOI] [PubMed] [Google Scholar]
- 36. Cohen AT. Prevention of postoperative venous thromboembolism. BMJ. 2009;339:b4477. [DOI] [PubMed] [Google Scholar]
- 37. Piazza G, Goldhaber SZ, Kroll A, Goldberg RJ, Emery C, Spencer FA. Venous thromboembolism in patients with diabetes mellitus. Am J Med. 2012;125(7):709–716. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Lemkes BA, Hermanides J, DeVries JH, Holleman F, Meijers JC, Hoekstra JB. Hyperglycemia: a prothrombotic factor? J Thromb Haemost. 2010;8(8):1663–1669. [DOI] [PubMed] [Google Scholar]
- 39. Golomb BA, Chan VT, Denenberg JO, Koperski S, Criqui MH. Risk marker associations with venous thrombotic events: a cross-sectional analysis. BMJ Open. 2014;4(3):e003208. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Hansen-Krone IJ, Brækkan SK, Enga KF, Wilsgaard T, Hansen JB. Alcohol consumption, types of alcoholic beverages and risk of venous thromboembolism: the Tromsø Study. Thromb Haemost. 2011;106(2):272–278. Universitetet i Tromsø. [DOI] [PubMed] [Google Scholar]